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Sample records for alters colorectal transport

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

    PubMed

    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.

  2. Epigenetic Alterations in Colorectal Cancer: Emerging Biomarkers

    PubMed Central

    Okugawa, Yoshinaga; Grady, William M.; Goel, Ajay

    2015-01-01

    Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide. One of the fundamental processes driving the initiation and progression of CRC is the accumulation of a variety of genetic and epigenetic changes in colon epithelial cells. Over the past decade, major advances have been made in our understanding of cancer epigenetics, particularly regarding aberrant DNA methylation, microRNA (miRNA) and noncoding RNA deregulation, and alterations in histone modification states. Assessment of the colon cancer “epigenome” has revealed that virtually all CRCs have aberrantly methylated genes and altered miRNA expression. The average CRC methylome has hundreds to thousands of abnormally methylated genes and dozens of altered miRNAs. As with gene mutations in the cancer genome, a subset of these epigenetic alterations, called driver events, is presumed to have a functional role in CRC. In addition, the advances in our understanding of epigenetic alterations in CRC have led to these alterations being developed as clinical biomarkers for diagnostic, prognostic and therapeutic applications. Progress in this field suggests that these epigenetic alterations will be commonly used in the near future to direct the prevention and treatment of CRC. PMID:26216839

  3. Epigenetic Alterations in Colorectal Cancer: Emerging Biomarkers.

    PubMed

    Okugawa, Yoshinaga; Grady, William M; Goel, Ajay

    2015-10-01

    Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide. One of the fundamental processes driving the initiation and progression of CRC is the accumulation of a variety of genetic and epigenetic changes in colonic epithelial cells. Over the past decade, major advances have been made in our understanding of cancer epigenetics, particularly regarding aberrant DNA methylation, microRNA (miRNA) and noncoding RNA deregulation, and alterations in histone modification states. Assessment of the colon cancer "epigenome" has revealed that virtually all CRCs have aberrantly methylated genes and altered miRNA expression. The average CRC methylome has hundreds to thousands of abnormally methylated genes and dozens of altered miRNAs. As with gene mutations in the cancer genome, a subset of these epigenetic alterations, called driver events, are presumed to have a functional role in CRC. In addition, the advances in our understanding of epigenetic alterations in CRC have led to these alterations being developed as clinical biomarkers for diagnostic, prognostic, and therapeutic applications. Progress in this field suggests that these epigenetic alterations will be commonly used in the near future to direct the prevention and treatment of CRC.

  4. Serum amino acid profiles and their alterations in colorectal cancer.

    PubMed

    Leichtle, Alexander Benedikt; Nuoffer, Jean-Marc; Ceglarek, Uta; Kase, Julia; Conrad, Tim; Witzigmann, Helmut; Thiery, Joachim; Fiedler, Georg Martin

    2012-08-01

    Mass spectrometry-based serum metabolic profiling is a promising tool to analyse complex cancer associated metabolic alterations, which may broaden our pathophysiological understanding of the disease and may function as a source of new cancer-associated biomarkers. Highly standardized serum samples of patients suffering from colon cancer (n = 59) and controls (n = 58) were collected at the University Hospital Leipzig. We based our investigations on amino acid screening profiles using electrospray tandem-mass spectrometry. Metabolic profiles were evaluated using the Analyst 1.4.2 software. General, comparative and equivalence statistics were performed by R 2.12.2. 11 out of 26 serum amino acid concentrations were significantly different between colorectal cancer patients and healthy controls. We found a model including CEA, glycine, and tyrosine as best discriminating and superior to CEA alone with an AUROC of 0.878 (95% CI 0.815-0.941). Our serum metabolic profiling in colon cancer revealed multiple significant disease-associated alterations in the amino acid profile with promising diagnostic power. Further large-scale studies are necessary to elucidate the potential of our model also to discriminate between cancer and potential differential diagnoses. In conclusion, serum glycine and tyrosine in combination with CEA are superior to CEA for the discrimination between colorectal cancer patients and controls.

  5. Polyamines alter intestinal glucose transport.

    PubMed

    Johnson, L R; Brockway, P D; Madsen, K; Hardin, J A; Gall, D G

    1995-03-01

    Polyamines are required for the growth of all eukaryotic cells. Enterocytes respond to luminal nutrients with large increases in polyamine synthesis, even though they are mature, nonproliferating cells. The role of polyamines in these cells is unknown. The current experiments examined whether polyamines affected intestinal transport of glucose, since absorption is the primary activity of enterocytes and since polyamines are known to affect membrane function and stability. Glucose transport was examined in rabbit brush-border membrane vesicles (BBMV). BBMV from rabbits given 5% alpha-difluoromethylornithine (DFMO) in their drinking water 24 h before they were killed transported significantly less glucose than control vesicles [38% decrease in maximal transport rate (Jmax)]. Orogastric administration of spermine, spermidine, or putrescine to DFMO-treated animals 24 h before they were killed prevented the decrease. In rabbits receiving only orogastric spermine, glucose transport was significantly increased (64% increase in Jmax), whereas in vivo spermidine and putrescine decreased Jmax. This increase in Jmax caused by in vivo administration of spermine was not dependent on protein synthesis. Addition of polyamines whether in vivo or in vitro decreased Michaelis constant in vesicles from control and DFMO-treated animals. The change in glucose transport induced by DFMO or polyamines was not related to altered membrane lipid composition or fluidity.(ABSTRACT TRUNCATED AT 250 WORDS)

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

    PubMed

    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

  7. Alterations of the apical junctional complex and actin cytoskeleton and their role in colorectal cancer progression

    PubMed Central

    Gehren, Adriana Sartorio; Rocha, Murilo Ramos; de Souza, Waldemir Fernandes; Morgado-Díaz, José Andrés

    2015-01-01

    Colorectal cancer represents the fourth highest mortality rate among cancer types worldwide. An understanding of the molecular mechanisms that regulate their progression can prevents or reduces mortality due to this disease. Epithelial cells present an apical junctional complex connected to the actin cytoskeleton, which maintains the dynamic properties of this complex, tissue architecture and cell homeostasis. Several studies have indicated that apical junctional complex alterations and actin cytoskeleton disorganization play a critical role in epithelial cancer progression. However, few studies have examined the existence of an interrelation between these 2 components, particularly in colorectal cancer. This review discusses the recent progress toward elucidating the role of alterations of apical junctional complex constituents and of modifications of actin cytoskeleton organization and discusses how these events are interlinked to modulate cellular responses related to colorectal cancer progression toward successful metastasis. PMID:26451338

  8. Altered Purinergic Signaling in Colorectal Dorsal Root Ganglion Neurons Contributes to Colorectal Hypersensitivity

    PubMed Central

    La, Jun-Ho; Bielefeldt, Klaus; Gebhart, G. F.

    2010-01-01

    Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by pain and hypersensitivity in the relative absence of colon inflammation or structural changes. To assess the role of P2X receptors expressed in colorectal dorsal root ganglion (c-DRG) neurons and colon hypersensitivity, we studied excitability and purinergic signaling of retrogradely labeled mouse thoracolumbar (TL) and lumbosacral (LS) c-DRG neurons after intracolonic treatment with saline or zymosan (which reproduces 2 major features of IBS—persistent colorectal hypersensitivity without inflammation) using patch-clamp, immunohistochemical, and RT-PCR techniques. Although whole cell capacitances did not differ between LS and TL c-DRG neurons and were not changed after zymosan treatment, membrane excitability was increased in LS and TL c-DRG neurons from zymosan-treated mice. Purinergic agonist adenosine-5′-triphosphate (ATP) and α,β-methylene ATP [α,β-meATP] produced inward currents in TL c-DRG neurons were predominantly P2X3-like fast (∼70% of responsive neurons); P2X2/3-like slow currents were more common in LS c-DRG neurons (∼35% of responsive neurons). Transient currents were not produced by either agonist in c-DRG neurons from P2X3−/− mice. Neither total whole cell Kv current density nor the sustained or transient Kv components was changed in c-DRG neurons after zymosan treatment. The number of cells expressing P2X3 protein and its mRNA and the kinetic properties of ATP- and α,β-meATP-evoked currents in c-DRG neurons were not changed by zymosan treatment. However, the EC50 of α,β-meATP for the fast current decreased significantly in TL c-DRG neurons. These findings suggest that colorectal hypersensitivity produced by intracolonic zymosan increases excitability and enhances purinergic signaling in c-DRG neurons. PMID:20861433

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

    PubMed

    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.

  10. Integrated analysis of homozygous deletions, focal amplifications, and sequence alterations in breast and colorectal cancers.

    PubMed

    Leary, Rebecca J; Lin, Jimmy C; Cummins, Jordan; Boca, Simina; Wood, Laura D; Parsons, D Williams; Jones, Siân; Sjöblom, Tobias; Park, Ben-Ho; Parsons, Ramon; Willis, Joseph; Dawson, Dawn; Willson, James K V; Nikolskaya, Tatiana; Nikolsky, Yuri; Kopelovich, Levy; Papadopoulos, Nick; Pennacchio, Len A; Wang, Tian-Li; Markowitz, Sanford D; Parmigiani, Giovanni; Kinzler, Kenneth W; Vogelstein, Bert; Velculescu, Victor E

    2008-10-21

    We have performed a genome-wide analysis of copy number changes in breast and colorectal tumors using approaches that can reliably detect homozygous deletions and amplifications. We found that the number of genes altered by major copy number changes, deletion of all copies or amplification to at least 12 copies per cell, averaged 17 per tumor. We have integrated these data with previous mutation analyses of the Reference Sequence genes in these same tumor types and have identified genes and cellular pathways affected by both copy number changes and point alterations. Pathways enriched for genetic alterations included those controlling cell adhesion, intracellular signaling, DNA topological change, and cell cycle control. These analyses provide an integrated view of copy number and sequencing alterations on a genome-wide scale and identify genes and pathways that could prove useful for cancer diagnosis and therapy.

  11. Foscarnet alters antidiuretic hormone-mediated transport.

    PubMed Central

    Hoch, B S; Shahmehdi, S J; Louis, B M; Lipner, H I

    1995-01-01

    Therapy with foscarnet is associated with acute renal failure. Prior studies have emphasized foscarnet's proximal tubular toxicity, but there have been isolated reports of foscarnet-induced nephrogenic diabetes insipidus. As a phosphate analog, foscarnet is a competitive inhibitor of NaPO4 cotransport. However, foscarnet's effect on antidiuretic hormone (ADH)-induced transport has not been previously investigated. We studied foscarnet's modulation of transport in the toad urinary bladder. Foscarnet at 10 microM to 10 mM did not alter basal water or urea flux. Urea transport induced by a maximal dose of ADH (24 mIU/ml) was inhibited by 0.1 to 5.0 mM foscarnet. In tissues challenged with 0.5 to 1.0 mIU of ADH per ml, 1.0 to 10 mM foscarnet increased water flow but did not alter urea flux. Foscarnet also increased water flow induced by 1.0 to 10 microM forskolin. In tissues pretreated with 10 microM naproxen, foscarnet did not alter water flow induced by 0.5 to 1.0 mIU of ADH per ml or forskolin. These results indicate that foscarnet stimulates water flow induced by 0.5 to 1.0 mIU of ADH per ml at a site proximal to that of the generation of cyclic AMP and inhibits urea flux induced by a maximal dose of ADH at a separate site. In humans, foscarnet nephrotoxicity is likely not limited to the proximal nephron, but extends to the collecting duct. Patients receiving foscarnet should be closely monitored for disorders of urinary concentration. PMID:8540707

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

    PubMed

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

    2016-10-01

    Mutation frequencies of common genetic alterations in colorectal cancer have been in the spotlight for many years. This study highlights few rare somatic mutations, which possess the attributes of a potential CRC biomarker yet are often neglected. Next-generation sequencing was performed over 112 tumor samples to detect genetic alterations in 31 rare genes in colorectal cancer. Mutations were detected in 26/31 (83.9 %) uncommon genes, which together contributed toward 149 gene mutations in 67/112 (59.8 %) colorectal cancer patients. The most frequent mutations include KDR (19.6 %), PTEN (17 %), FBXW7 (10.7 %), SMAD4 (10.7 %), VHL (8 %), KIT (8 %), MET (7.1 %), ATM (6.3 %), CTNNB1 (4.5 %) and CDKN2A (4.5 %). RB1, ERBB4 and ERBB2 mutations were persistent in 3.6 % patients. GNAS, FGFR2 and FGFR3 mutations were persistent in 1.8 % patients. Ten genes (EGFR, NOTCH1, SMARCB1, ABL1, STK11, SMO, RET, GNAQ, CSF1R and FLT3) were found mutated in 0.9 % patients. Lastly, no mutations were observed in AKT, HRAS, MAP2K1, PDGFR and JAK2. Significant associations were observed between VHL with tumor site, ERBB4 and SMARCB1 with tumor invasion, CTNNB1 with lack of lymph node involvement and CTNNB1, FGFR2 and FGFR3 with TNM stage. Significantly coinciding mutation pairs include PTEN and SMAD4, PTEN and KDR, EGFR and RET, EGFR and RB1, FBXW7 and CTNNB1, KDR and FGFR2, FLT3 and CTNNB1, RET and RB1, ATM and SMAD4, ATM and CDKN2A, ERBB4 and SMARCB1. This study elucidates few potential colorectal cancer biomarkers, specifically KDR, PTEN, FBXW7 and SMAD4, which are found mutated in more than 10 % patients. PMID:27568332

  13. Altered colorectal afferent function associated with TNBS-induced visceral hypersensitivity in mice.

    PubMed

    Feng, Bin; La, Jun-Ho; Tanaka, Takahiro; Schwartz, Erica S; McMurray, Timothy P; Gebhart, G F

    2012-10-01

    Inflammation of the distal bowel is often associated with abdominal pain and hypersensitivity, but whether and which colorectal afferents contribute to the hypersensitivity is unknown. Using a mouse model of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis, we investigated colorectal hypersensitivity following intracolonic TNBS and associated changes in colorectum and afferent functions. C57BL/6 mice were treated intracolonically with TNBS or saline. Visceromotor responses to colorectal distension (15-60 mmHg) were recorded over 8 wk in TNBS- and saline-treated (control) mice. In other mice treated with TNBS or saline, colorectal inflammation was assessed by myeloperoxidase assay and immunohistological staining. In vitro single-fiber recordings were conducted on both TNBS and saline-treated mice to assess colorectal afferent function. Mice exhibited significant colorectal hypersensitivity through day 14 after TNBS treatment that resolved by day 28 with no resensitization through day 56. TNBS induced a neutrophil- and macrophage-based colorectal inflammation as well as loss of nerve fibers, all of which resolved by days 14-28. Single-fiber recordings revealed a net increase in afferent drive from stretch-sensitive colorectal afferents at day 14 post-TNBS and reduced proportions of mechanically insensitive afferents (MIAs) at days 14-28. Intracolonic TNBS-induced colorectal inflammation was associated with the development and recovery of hypersensitivity in mice, which correlated with a transient increase and recovery of sensitization of stretch-sensitive colorectal afferents and MIAs. These results indicate that the development and maintenance of colorectal hypersensitivity following inflammation are mediated by peripheral drive from stretch-sensitive colorectal afferents and a potential contribution from MIAs.

  14. Altered colorectal afferent function associated with TNBS-induced visceral hypersensitivity in mice

    PubMed Central

    La, Jun-Ho; Tanaka, Takahiro; Schwartz, Erica S.; McMurray, Timothy P.; Gebhart, G. F.

    2012-01-01

    Inflammation of the distal bowel is often associated with abdominal pain and hypersensitivity, but whether and which colorectal afferents contribute to the hypersensitivity is unknown. Using a mouse model of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis, we investigated colorectal hypersensitivity following intracolonic TNBS and associated changes in colorectum and afferent functions. C57BL/6 mice were treated intracolonically with TNBS or saline. Visceromotor responses to colorectal distension (15–60 mmHg) were recorded over 8 wk in TNBS- and saline-treated (control) mice. In other mice treated with TNBS or saline, colorectal inflammation was assessed by myeloperoxidase assay and immunohistological staining. In vitro single-fiber recordings were conducted on both TNBS and saline-treated mice to assess colorectal afferent function. Mice exhibited significant colorectal hypersensitivity through day 14 after TNBS treatment that resolved by day 28 with no resensitization through day 56. TNBS induced a neutrophil- and macrophage-based colorectal inflammation as well as loss of nerve fibers, all of which resolved by days 14–28. Single-fiber recordings revealed a net increase in afferent drive from stretch-sensitive colorectal afferents at day 14 post-TNBS and reduced proportions of mechanically insensitive afferents (MIAs) at days 14–28. Intracolonic TNBS-induced colorectal inflammation was associated with the development and recovery of hypersensitivity in mice, which correlated with a transient increase and recovery of sensitization of stretch-sensitive colorectal afferents and MIAs. These results indicate that the development and maintenance of colorectal hypersensitivity following inflammation are mediated by peripheral drive from stretch-sensitive colorectal afferents and a potential contribution from MIAs. PMID:22859364

  15. Exome capture sequencing of adenoma reveals genetic alterations in multiple cellular pathways at the early stage of colorectal tumorigenesis.

    PubMed

    Zhou, Donger; Yang, Liu; Zheng, Liangtao; Ge, Weiting; Li, Dan; Zhang, Yong; Hu, Xueda; Gao, Zhibo; Xu, Jinghong; Huang, Yanqin; Hu, Hanguang; Zhang, Hang; Zhang, Hao; Liu, Mingming; Yang, Huanming; Zheng, Lei; Zheng, Shu

    2013-01-01

    Most of colorectal adenocarcinomas are believed to arise from adenomas, which are premalignant lesions. Sequencing the whole exome of the adenoma will help identifying molecular biomarkers that can predict the occurrence of adenocarcinoma more precisely and help understanding the molecular pathways underlying the initial stage of colorectal tumorigenesis. We performed the exome capture sequencing of the normal mucosa, adenoma and adenocarcinoma tissues from the same patient and sequenced the identified mutations in additional 73 adenomas and 288 adenocarcinomas. Somatic single nucleotide variations (SNVs) were identified in both the adenoma and adenocarcinoma by comparing with the normal control from the same patient. We identified 12 nonsynonymous somatic SNVs in the adenoma and 42 nonsynonymous somatic SNVs in the adenocarcinoma. Most of these mutations including OR6X1, SLC15A3, KRTHB4, RBFOX1, LAMA3, CDH20, BIRC6, NMBR, GLCCI1, EFR3A, and FTHL17 were newly reported in colorectal adenomas. Functional annotation of these mutated genes showed that multiple cellular pathways including Wnt, cell adhesion and ubiquitin mediated proteolysis pathways were altered genetically in the adenoma and that the genetic alterations in the same pathways persist in the adenocarcinoma. CDH20 and LAMA3 were mutated in the adenoma while NRXN3 and COL4A6 were mutated in the adenocarcinoma from the same patient, suggesting for the first time that genetic alterations in the cell adhesion pathway occur as early as in the adenoma. Thus, the comparison of genomic mutations between adenoma and adenocarcinoma provides us a new insight into the molecular events governing the early step of colorectal tumorigenesis. PMID:23301059

  16. Laminin gene LAMB4 is somatically mutated and expressionally altered in gastric and colorectal cancers.

    PubMed

    Choi, Mi Ryoung; An, Chang Hyeok; Yoo, Nam Jin; Lee, Sug Hyung

    2015-01-01

    Laminins are important in tumor invasion and metastasis as well as in maintenance of normal epithelial cell structures. However, mutation status of laminin chain-encoding genes remains unknown in cancers. Aim of this study was to explore whether laminin chain genes are mutated and expressionally altered in gastric (GC) and colorectal cancers (CRC). In a public database, we found that laminin chain genes LAMA1, LAMA3, LAMB1 and LAMB4 had mononucleotide repeats in the coding sequences that might be mutation targets in the cancers with microsatellite instability (MSI). We analyzed the genes in 88 GC and 139 CRC [high MSI (MSI-H) or stable MSI/low MSI (MSS/MSI-L)] by single strand conformation polymorphism analysis and DNA sequencing. In the present study, we found LAMB4 (11.8% of GC and 7.6% of CRC with MSI-H), LAMA3 (2.9% of GC and 2.5 of CRC with MSI-H), LAMA1 (5.9% of GC with MSI-H) and LAMB1 frameshift mutations (1.3% of CRC with MSI-H). These mutations were not found in MSS/MSI-L (0/114). We also analyzed LAMB4 expression in GC and CRC by immunohistochemistry. Loss of LAMB4 expression was identified in 17-32% of the GC and CRC. Of note, the loss expression was more common in the cancers with LAMB4 mutation or those with MSI-H. Our data show that frameshift mutations of LAMA1, LAMA3, LAMB1 and LAMB4, and loss of LAMB4 may be features of GC and CRC with MSI-H. PMID:25257191

  17. Norepinephrine transporter heterozygous knockout mice exhibit altered transport and behavior.

    PubMed

    Fentress, H M; Klar, R; Krueger, J J; Sabb, T; Redmon, S N; Wallace, N M; Shirey-Rice, J K; Hahn, M K

    2013-11-01

    The norepinephrine (NE) transporter (NET) regulates synaptic NE availability for noradrenergic signaling in the brain and sympathetic nervous system. Although genetic variation leading to a loss of NET expression has been implicated in psychiatric and cardiovascular disorders, complete NET deficiency has not been found in people, limiting the utility of NET knockout mice as a model for genetically driven NET dysfunction. Here, we investigate NET expression in NET heterozygous knockout male mice (NET(+/-) ), demonstrating that they display an approximately 50% reduction in NET protein levels. Surprisingly, these mice display no significant deficit in NET activity assessed in hippocampal and cortical synaptosomes. We found that this compensation in NET activity was due to enhanced activity of surface-resident transporters, as opposed to surface recruitment of NET protein or compensation through other transport mechanisms, including serotonin, dopamine or organic cation transporters. We hypothesize that loss of NET protein in the NET(+/-) mouse establishes an activated state of existing surface NET proteins. The NET(+/-) mice exhibit increased anxiety in the open field and light-dark box and display deficits in reversal learning in the Morris water maze. These data suggest that recovery of near basal activity in NET(+/-) mice appears to be insufficient to limit anxiety responses or support cognitive performance that might involve noradrenergic neurotransmission. The NET(+/-) mice represent a unique model to study the loss and resultant compensatory changes in NET that may be relevant to behavior and physiology in human NET deficiency disorders.

  18. Norepinephrine Transporter Heterozygous Knockout Mice Exhibit Altered Transport and Behavior

    PubMed Central

    Fentress, HM; Klar, R; Krueger, JK; Sabb, T; Redmon, SN; Wallace, NM; Shirey-Rice, JK; Hahn, MK

    2013-01-01

    The norepinephrine (NE) transporter (NET) regulates synaptic NE availability for noradrenergic signaling in the brain and sympathetic nervous system. Although genetic variation leading to a loss of NET expression has been implicated in psychiatric and cardiovascular disorders, complete NET deficiency has not been found in people, limiting the utility of NET knockout mice as a model for genetically-driven NET dysfunction. Here, we investigate NET expression in NET heterozygous knockout male mice (NET+/−), demonstrating that they display an ~50% reduction in NET protein levels. Surprisingly, these mice display no significant deficit in NET activity, assessed in hippocampal and cortical synaptosomes. We found that this compensation in NET activity was due to enhanced activity of surface-resident transporters, as opposed to surface recruitment of NET protein or compensation through other transport mechanisms, including serotonin, dopamine or organic cation transporters. We hypothesize that loss of NET protein in the NET+/− mouse establishes an activated state of existing, surface NET proteins. NET+/− mice exhibit increased anxiety in the open field and light-dark box and display deficits in reversal learning in the Morris Water Maze. These data suggest recovery of near basal activity in NET+/− mice appears to be insufficient to limit anxiety responses or support cognitive performance that might involve noradrenergic neurotransmission. The NET+/− mice represent a unique model to study the loss and resultant compensatory changes in NET that may be relevant to behavior and physiology in human NET deficiency disorders. PMID:24102798

  19. Radionuclide transport through engineered barrier system alteration products

    SciTech Connect

    Viani, B.E.; Torretto, P.C.; Matzen, S.L.

    1997-12-01

    The primary rationale for studying the transport behavior of radionuclides through the Engineered Barrier system / Near Field Environment (EBS/NFE) is to ascertain whether the material properties of the introduced and altered host rock can significantly affect the transport of radionuclides from the waste container to the far field. The intent of this report is to present data and modeling results that can be used to assess the importance of canister corrosion products and cementitious materials to transport of radionuclides to the far field.

  20. Assessment of epigenetic alterations in early colorectal lesions containing BRAF mutations

    PubMed Central

    Nojima, Masanori; Harada, Taku; Maruyama, Reo; Ashida, Masami; Aoki, Hironori; Matsushita, Hiro-o; Yoshikawa, Kenjiro; Harada, Eiji; Tanaka, Yoshihito; Wakita, Shigenori; Niinuma, Takeshi; Kai, Masahiro; Eizuka, Makoto; Sugai, Tamotsu; Suzuki, Hiromu

    2016-01-01

    To clarify the molecular and clinicopathological characteristics of colorectal serrated lesions, we assessed the DNA methylation of cancer-associated genes in a cohort of BRAF-mutant precancerous lesions from 94 individuals. We then compared those results with the lesions' clinicopathological features, especially colorectal subsites. The lesions included hyperplastic polyps (n = 16), traditional serrated adenomas (TSAs) (n = 15), TSAs with sessile serrated adenomas (SSAs) (n = 6), SSAs (n = 49) and SSAs with dysplasia (n = 16). The prevalence of lesions exhibiting the CpG island methylator phenotype (CIMP) was lower in the sigmoid colon and rectum than in other bowel subsites, including the cecum, ascending, transverse and descending colon. In addition, several cancer-associated genes showed higher methylation levels within lesions in the proximal to sigmoid colon than in the sigmoid colon and rectum. These results indicate that the methylation status of lesions with BRAF mutation is strongly associated with their location, histological findings and neoplastic pathways. By contrast, no difference in aberrant DNA methylation was observed in normal-appearing background colonic mucosa along the bowel subsites, which may indicate the absence of an epigenetic field defect. PMID:27145369

  1. Colorectal cancer cell-derived extracellular vesicles induce phenotypic alteration of T cells into tumor-growth supporting cells with transforming growth factor-β1-mediated suppression

    PubMed Central

    Yamada, Nami; Kuranaga, Yuki; Kumazaki, Minami; Shinohara, Haruka; Taniguchi, Kohei; Akao, Yukihiro

    2016-01-01

    Emerging studies on tumor cell-derived extracellular vesicles (EVs) have shown the biological significance in tumor development and microenvironment through reprogramming immune cells around cancer cells. In this study, we used colorectal cancer cells as EVs donor, and T cells as recipients to examine whether EVs impair the T cell function. As a result, we found that colorectal cancer cell-derived EVs (CRC-EVs) were enriched with TGF-β1. Interestingly, CRC-EVs induced phenotypic alteration of the T cells to Treg-like cells through activating TGF-β/Smad signaling and inactivating SAPK signaling. Furthermore, the CRC-EVs-induced-Treg-like cells had a remarkable tumor-growth promoting activity in vitro and in vivo. These results suggest that colorectal cancer cells utilize EVs to tame immune cells for their prosperity. PMID:27081032

  2. Inhibition of Fried Meat-Induced Colorectal DNA Damage and Altered Systemic Genotoxicity in Humans by Crucifera, Chlorophyllin, and Yogurt

    PubMed Central

    Shaughnessy, Daniel T.; Gangarosa, Lisa M.; Schliebe, Barbara; Umbach, David M.; Xu, Zongli; MacIntosh, Beth; Knize, Mark G.; Matthews, Peggy P.; Swank, Adam E.; Sandler, Robert S.; DeMarini, David M.; Taylor, Jack A.

    2011-01-01

    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. Trial Registration ClinicalTrials.gov NCT00340743. PMID:21541030

  3. Uranium (VI) and Neptunium (V) Transport Fractured, Hydrothermally Altered Concrete

    SciTech Connect

    Matzen, S.L.; Beiriger, J.M.; Torretto, P.C.; Zhao, P.

    1999-11-04

    In a high level waste repository in which temperatures are elevated due to waste decay, concrete structures will be subjected to hydrothermal conditions that will alter their physical and chemical properties. Virtually no studies have examined the interaction of hydrothermally altered concrete with radionuclides. We present the results of experiments in which soluble and colloid-associated actinides, uranium (U) and neptunium (Np), were eluted into a fractured, hydrothermally altered concrete core. Although the fluid residence time in the fracture was estimated to be on the order of 1 minute, U and Np were below detection (10{sup -9}-10{sup -8} M) in the effluent from the core, for both soluble and colloid-associated species. Inorganic colloids and latex microspheres were similarly immobilized within the core. Post-test analysis of the core identified the immobilized U and Np at or near the fracture surface, with a spatial distribution similar to that of the latex microspheres. Because hydrothermal alteration followed fracturing, the growth of crystalline calcium silicate hydrate and clay mineral alteration products on, and possibly across the fracture, resulted in a highly reactive fracture that was effective at capturing both soluble and colloidal radionuclides. Comparison of results from batch experiments [1] with these experiments indicate that partitioning of U and Np to the solid phase, and equilibration of the incoming fluid with the concrete, occurs rapidly in the fractured system. Transport of U through the concrete may be solubility and/or sorption limited; transport of Np appears to be limited primarily by sorption.

  4. Tumor genome wide DNA alterations assessed by array CGH in patients with poor and excellent survival following operation for colorectal cancer.

    PubMed

    Lagerstedt, Kristina K; Staaf, Johan; Jönsson, Göran; Hansson, Elisabeth; Lönnroth, Christina; Kressner, Ulf; Lindström, Lars; Nordgren, Svante; Borg, Ake; Lundholm, Kent

    2007-10-12

    Genome wide DNA alterations were evaluated by array CGH in addition to RNA expression profiling in colorectal cancer from patients with excellent and poor survival following primary operations. DNA was used for CGH in BAC and cDNA arrays. Global RNA expression was determined by 44K arrays. DNA and RNA from tumor and normal colon were used from cancer patients grouped according to death, survival or Dukes A, B, C and D tumor stage. Confirmed DNA alterations in all Dukes A - D were judged relevant for carcinogenesis, while changes in Dukes C and D only were regarded relevant for tumor progression. Copy number gain was more common than loss in tumor tissue (p < 0.01). Major tumor DNA alterations occurred in chromosome 8, 13, 18 and 20, where short survival included gain in 8q and loss in 8p. Copy number gains related to tumor progression were most common on chromosome 7, 8, 19, 20, while corresponding major losses appeared in chromosome 8. Losses at chromosome 18 occurred in all Dukes stages. Normal colon tissue from cancer patients displayed gains in chromosome 19 and 20. Mathematical Vector analysis implied a number of BAC-clones in tumor DNA with genes of potential importance for death or survival. The genomic variation in colorectal cancer cells is tremendous and emphasizes that BAC array CGH is presently more powerful than available statistical models to discriminate DNA sequence information related to outcome. Present results suggest that a majority of DNA alterations observed in colorectal cancer are secondary to tumor progression. Therefore, it would require an immense work to distinguish primary from secondary DNA alterations behind colorectal cancer.

  5. Fish oil supplement alters markers of inflammatory and nutritional status in colorectal cancer patients.

    PubMed

    Silva, Juliana de Aguiar Pastore; Trindade, Erasmo Benício Santos de Moraes; Fabre, Maria Emilia de Souza; Menegotto, Vicente Martorano; Gevaerd, Sheila; Buss, Ziliane da Silva; Frode, Tânia Silvia

    2012-01-01

    Inflammation is a common feature in cancer. The presence and magnitude of the chronic systemic inflammatory responses may produce progressive nutritional decline. This study aims at investigating whether there are changes in inflammation markers and/or in nutritional status of patients with colorectal cancer undergoing chemotherapy who were supplemented with fish oil. The clinical trial was conducted with 23 patients randomly distributed in 2 groups. The supplemented group (SG) consumed 2 g of fish oil containing 600 milligrams of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) for 9 wk. Nutritional and inflammatory markers status was available, both at a baseline (M0), and after 9 wk of chemotherapy (M9) in the SG and in the nonsupplemented group (NSG). Statistical analysis was conducted with STATA 11.0 software. SG and NSG presented the same baseline characteristics (P > 0.05). Nutritional status indicators such as body mass index and body weight were modified only in the NSG when comparing baseline and M9, P = 0.03 and P = 0.01 respectively, whereas in SG these indicators did not vary. Patients supplemented with fish oil (SG) showed a clinically relevant decrease in the C-reactive protein/albumin relation (P = 0.005). Low doses of fish oil supplement can positively modulate the nutritional status and the C-reative protein/albumin ratio.

  6. SNPs in transporter and metabolizing genes as predictive markers for oxaliplatin treatment in colorectal cancer patients.

    PubMed

    Kap, Elisabeth J; Seibold, Petra; Scherer, Dominique; Habermann, Nina; Balavarca, Yesilda; Jansen, Lina; Zucknick, Manuela; Becker, Natalia; Hoffmeister, Michael; Ulrich, Alexis; Benner, Axel; Ulrich, Cornelia M; Burwinkel, Barbara; Brenner, Hermann; Chang-Claude, Jenny

    2016-06-15

    Oxaliplatin is frequently used as part of a chemotherapeutic regimen with 5-fluorouracil in the treatment of colorectal cancer (CRC). The cellular availability of oxaliplatin is dependent on metabolic and transporter enzymes. Variants in genes encoding these enzymes may cause variation in response to oxaliplatin and could be potential predictive markers. Therefore, we used a two-step procedure to comprehensively investigate 1,444 single nucleotide polymorphisms (SNPs) from these pathways for their potential as predictive markers for oxaliplatin treatment, using 623 stage II-IV CRC patients (of whom 201 patients received oxaliplatin) from a German prospective patient cohort treated with adjuvant or palliative chemotherapy. First, all genes were screened using the global test that evaluated SNP*oxaliplatin interaction terms per gene. Second, one model was created by backward elimination on all SNP*oxaliplatin interactions of the selected genes. The statistical procedure was evaluated using bootstrap analyses. Nine genes differentially associated with overall survival according to oxaliplatin treatment (unadjusted p values < 0.05) were selected. Model selection resulted in the inclusion of 14 SNPs from eight genes (six transporter genes, ABCA9, ABCB11, ABCC10, ATP1A1, ATP1B2, ATP8B3, and two metabolism genes GSTM5, GRHPR), which significantly improved model fit. Using bootstrap analysis we show an improvement of the prediction error of 3.7% in patients treated with oxaliplatin. Several variants in genes involved in metabolism and transport could thus be potential predictive markers for oxaliplatin treatment in CRC patients. If confirmed, inclusion of these variants in a predictive test could identify patients who are more likely to benefit from treatment with oxaliplatin. PMID:26835885

  7. SNPs in transporter and metabolizing genes as predictive markers for oxaliplatin treatment in colorectal cancer patients.

    PubMed

    Kap, Elisabeth J; Seibold, Petra; Scherer, Dominique; Habermann, Nina; Balavarca, Yesilda; Jansen, Lina; Zucknick, Manuela; Becker, Natalia; Hoffmeister, Michael; Ulrich, Alexis; Benner, Axel; Ulrich, Cornelia M; Burwinkel, Barbara; Brenner, Hermann; Chang-Claude, Jenny

    2016-06-15

    Oxaliplatin is frequently used as part of a chemotherapeutic regimen with 5-fluorouracil in the treatment of colorectal cancer (CRC). The cellular availability of oxaliplatin is dependent on metabolic and transporter enzymes. Variants in genes encoding these enzymes may cause variation in response to oxaliplatin and could be potential predictive markers. Therefore, we used a two-step procedure to comprehensively investigate 1,444 single nucleotide polymorphisms (SNPs) from these pathways for their potential as predictive markers for oxaliplatin treatment, using 623 stage II-IV CRC patients (of whom 201 patients received oxaliplatin) from a German prospective patient cohort treated with adjuvant or palliative chemotherapy. First, all genes were screened using the global test that evaluated SNP*oxaliplatin interaction terms per gene. Second, one model was created by backward elimination on all SNP*oxaliplatin interactions of the selected genes. The statistical procedure was evaluated using bootstrap analyses. Nine genes differentially associated with overall survival according to oxaliplatin treatment (unadjusted p values < 0.05) were selected. Model selection resulted in the inclusion of 14 SNPs from eight genes (six transporter genes, ABCA9, ABCB11, ABCC10, ATP1A1, ATP1B2, ATP8B3, and two metabolism genes GSTM5, GRHPR), which significantly improved model fit. Using bootstrap analysis we show an improvement of the prediction error of 3.7% in patients treated with oxaliplatin. Several variants in genes involved in metabolism and transport could thus be potential predictive markers for oxaliplatin treatment in CRC patients. If confirmed, inclusion of these variants in a predictive test could identify patients who are more likely to benefit from treatment with oxaliplatin.

  8. Osmotic stress alters chromatin condensation and nucleocytoplasmic transport

    SciTech Connect

    Finan, John D.; Leddy, Holly A.; Guilak, Farshid

    2011-05-06

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

  9. Altered Reward Circuitry in the Norepinephrine Transporter Knockout Mouse

    PubMed Central

    Hall, F. Scott; Uhl, George R.; Bearer, Elaine L.; Jacobs, Russell E.

    2013-01-01

    Synaptic levels of the monoamine neurotransmitters dopamine, serotonin, and norepinephrine are modulated by their respective plasma membrane transporters, albeit with a few exceptions. Monoamine transporters remove monoamines from the synaptic cleft and thus influence the degree and duration of signaling. Abnormal concentrations of these neuronal transmitters are implicated in a number of neurological and psychiatric disorders, including addiction, depression, and attention deficit/hyperactivity disorder. This work concentrates on the norepinephrine transporter (NET), using a battery of in vivo magnetic resonance imaging techniques and histological correlates to probe the effects of genetic deletion of the norepinephrine transporter on brain metabolism, anatomy and functional connectivity. MRS recorded in the striatum of NET knockout mice indicated a lower concentration of NAA that correlates with histological observations of subtle dysmorphisms in the striatum and internal capsule. As with DAT and SERT knockout mice, we detected minimal structural alterations in NET knockout mice by tensor-based morphometric analysis. In contrast, longitudinal imaging after stereotaxic prefrontal cortical injection of manganese, an established neuronal circuitry tracer, revealed that the reward circuit in the NET knockout mouse is biased toward anterior portions of the brain. This is similar to previous results observed for the dopamine transporter (DAT) knockout mouse, but dissimilar from work with serotonin transporter (SERT) knockout mice where Mn2+ tracings extended to more posterior structures than in wildtype animals. These observations correlate with behavioral studies indicating that SERT knockout mice display anxiety-like phenotypes, while NET knockouts and to a lesser extent DAT knockout mice display antidepressant-like phenotypic features. Thus, the mainly anterior activity detected with manganese-enhanced MRI in the DAT and NET knockout mice is likely indicative of

  10. Altered reward circuitry in the norepinephrine transporter knockout mouse.

    PubMed

    Gallagher, Joseph J; Zhang, Xiaowei; Hall, F Scott; Uhl, George R; Bearer, Elaine L; Jacobs, Russell E

    2013-01-01

    Synaptic levels of the monoamine neurotransmitters dopamine, serotonin, and norepinephrine are modulated by their respective plasma membrane transporters, albeit with a few exceptions. Monoamine transporters remove monoamines from the synaptic cleft and thus influence the degree and duration of signaling. Abnormal concentrations of these neuronal transmitters are implicated in a number of neurological and psychiatric disorders, including addiction, depression, and attention deficit/hyperactivity disorder. This work concentrates on the norepinephrine transporter (NET), using a battery of in vivo magnetic resonance imaging techniques and histological correlates to probe the effects of genetic deletion of the norepinephrine transporter on brain metabolism, anatomy and functional connectivity. MRS recorded in the striatum of NET knockout mice indicated a lower concentration of NAA that correlates with histological observations of subtle dysmorphisms in the striatum and internal capsule. As with DAT and SERT knockout mice, we detected minimal structural alterations in NET knockout mice by tensor-based morphometric analysis. In contrast, longitudinal imaging after stereotaxic prefrontal cortical injection of manganese, an established neuronal circuitry tracer, revealed that the reward circuit in the NET knockout mouse is biased toward anterior portions of the brain. This is similar to previous results observed for the dopamine transporter (DAT) knockout mouse, but dissimilar from work with serotonin transporter (SERT) knockout mice where Mn(2+) tracings extended to more posterior structures than in wildtype animals. These observations correlate with behavioral studies indicating that SERT knockout mice display anxiety-like phenotypes, while NET knockouts and to a lesser extent DAT knockout mice display antidepressant-like phenotypic features. Thus, the mainly anterior activity detected with manganese-enhanced MRI in the DAT and NET knockout mice is likely indicative of

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

    PubMed Central

    Andersen, Vibeke; Svenningsen, Katrine; Knudsen, Lina Almind; Hansen, Axel Kornerup; Holmskov, Uffe; Stensballe, Allan; Vogel, Ulla

    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 transporter proteins, inflammatory bowel disease, ulcerative, colitis, Crohns disease, colorectal cancer, colitis, intestinal inflammation, intestinal carcinogenesis, ABCB1/P-glycoprotein (P-gp/CD243/MDR1), ABCC2/multidrug resistance protein 2 (MRP2) and ABCG2/breast cancer resistance protein (BCRP), Abcb1/Mdr1a, abcc2/Mrp2, abcg2/Bcrp, knock-out mice, tight junction, membrane lipid function. RESULTS: Recently, human studies reported that changes in the levels of ABC transporters were early events in the adenoma-carcinoma sequence leading to CRC. A link between ABCB1, high fat diet and gut microbes in relation to colitis was suggested by the animal studies. The finding that colitis was preceded by altered gut bacterial composition suggests that deletion of Abcb1 leads to fundamental changes of host-microbiota interaction. Also, high fat diet increases the frequency and severity of colitis in specific 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 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 and which may additionally affect ABC transporter function through nuclear receptors and transcriptional regulation. Another critical role of ABCB1 was suggested by the finding that

  12. Do high risk patients alter their lifestyle to reduce risk of colorectal cancer?

    PubMed Central

    2014-01-01

    Background Colorectal cancer (CRC) may be reduced by healthy lifestyle behaviours. We determined the extent of self-reported lifestyle changes in people at increased risk of CRC, and the association of these reports with anxiety, risk and knowledge-based variables. Methods We randomly selected 250 participants who had undergone surveillance colonoscopy for family history of CRC. A telephone interview was conducted, recording demographics and family history. Self-reported lifestyle change due to thoughts about CRC across a range of dietary and lifestyle variables was assessed on a four-point scale. Participants’ perceptions of the following were recorded: risk factor knowledge, personal risk, and worry due to family history. General anxiety was assessed using the GAD-7 scale. Ordinal logistic regression was used to calculate adjusted results. Results There were 148 participants (69% response). 79.7% reported at least one healthy change. Change in diet and physical activity were most frequently reported (fiber, 63%; fruit and vegetables, 54%; red meat, 47%; physical activity, 45%), with consumption of tobacco, alcohol, and body weight less likely (tobacco, 25%; alcohol, 26%; weight 31%). People were more likely to report healthy change with lower levels of generalized anxiety, higher worry due to family history, or greater perceived knowledge of CRC risk factors. Risk perception and risk due to family history were not associated with healthy changes. Conclusions Self-reported lifestyle changes due to thoughts about CRC were common. Lower general anxiety levels, worries due to family history, and perceived knowledge of risk factors may stimulate healthy changes. PMID:24507382

  13. Boswellic acid induces epigenetic alterations by modulating DNA methylation in colorectal cancer cells

    PubMed Central

    Shen, Yan; Takahashi, Masanobu; Byun, Hyang-Min; Link, Alexander; Sharma, Nupur; Balaguer, Francesc; Leung, Hon-Chiu; Boland, C. Richard; Goel, Ajay

    2012-01-01

    Accumulating evidence suggests that chemopreventive effects of some dietary polyphenols may in part be mediated by their ability to influence epigenetic mechanisms in cancer cells. Boswellic acids, derived from the plant Boswellia serrata, have long been used for the treatment of various inflammatory diseases due to their potent anti-inflammatory activities. Recent preclinical studies have also suggested that this compound has anti-cancer potential against various malignancies. However, the precise molecular mechanisms underlying their anti-cancer effects remain elusive. Herein, we report that boswellic acids modulate DNA methylation status of several tumor suppressor genes in colorectal cancer (CRC) cells. We treated RKO, SW48 and SW480 CRC cell lines with the active principle present in boswellic acids, acetyl-keto-β-boswellic acid (AKBA). Using genome-wide DNA methylation and gene expression microarray analyses, we discovered that AKBA induced a modest genome-wide demethylation that permitted simultaneous re-activation of the corresponding tumor suppressor genes. The quantitative methylation-specific PCR and RT-PCR validated the gene demethylation and re-expression in several putative tumor suppressor genes including SAMD14 and SMPD3. Furthermore, AKBA inhibited DNMT activity in CRC cells. Taken together, these results lend further support to the growing notion that anti-cancer effect of boswellic acids may in part be due to its ability to demethylate and reactivate methylation-silenced tumor suppressor genes. These results suggest that not only boswellic acid might be a promising epigenetic modulator in the chemoprevention and treatment of CRC, but also provide a rationale for future investigations on the usefulness of such botanicals for epigenetic therapy in other human malignancies. PMID:22415137

  14. Network signatures of nuclear and cytoplasmic density alterations in a model of pre and postmetastatic colorectal cancer

    NASA Astrophysics Data System (ADS)

    Damania, Dhwanil; Subramanian, Hariharan; Backman, Vadim; Anderson, Eric C.; Wong, Melissa H.; McCarty, Owen J. T.; Phillips, Kevin G.

    2014-01-01

    Cells contributing to the pathogenesis of cancer possess cytoplasmic and nuclear structural alterations that accompany their aberrant genetic, epigenetic, and molecular perturbations. Although it is known that architectural changes in primary and metastatic tumor cells can be quantified through variations in cellular density at the nanometer and micrometer spatial scales, the interdependent relationships among nuclear and cytoplasmic density as a function of tumorigenic potential has not been thoroughly investigated. We present a combined optical approach utilizing quantitative phase microscopy and partial wave spectroscopic microscopy to perform parallel structural characterizations of cellular architecture. Using the isogenic SW480 and SW620 cell lines as a model of pre and postmetastatic transition in colorectal cancer, we demonstrate that nuclear and cytoplasmic nanoscale disorder, micron-scale dry mass content, mean dry mass density, and shape metrics of the dry mass density histogram are uniquely correlated within and across different cellular compartments for a given cell type. The correlations of these physical parameters can be interpreted as networks whose nodal importance and level of connection independence differ according to disease stage. This work demonstrates how optically derived biophysical parameters are linked within and across different cellular compartments during the architectural orchestration of the metastatic phenotype.

  15. Polymorphisms in the selenoprotein S and 15-kDa selenoprotein genes are associated with altered susceptibility to colorectal cancer

    PubMed Central

    Sutherland, Alison; Kim, Dong-Hyun; Relton, Caroline; Ahn, Yoon-Ok

    2010-01-01

    Selenium (Se), a dietary trace metal essential for human health, is incorporated into ~25 selenoproteins including selenoprotein S (SelS) and the 15-kDa selenoprotein (Sep15) both of which have functions in the endoplasmic reticulum protein unfolding response. The aim of this study was to investigate whether genetic variants in such selenoprotein genes are associated with altered risk of colorectal cancer (CRC). A Korean population of 827 patients with CRC and 733 healthy controls was genotyped for 7 SNPs in selenoprotein genes and one SNP in the gene encoding manganese superoxide dismutase using Sequenom technology. Multivariate logistic regression analysis showed that after adjustment for lifestyle factors three SNP variants were associated with altered disease risk. There was a mean odds ratio of 2.25 [95% CI 1.13,4.48] in females homozygous TT for rs34713741 in SELS with the T variant being associated with higher risk of rectal cancer, and odds ratios of 2.47 and 2.51, respectively, for rs5845 and rs5859 in SEP15 with the minor A and T alleles being associated with increased risk of male rectal cancer. The data indicate that the minor alleles for rs5845, rs5859 and rs34713741 are associated with increased rectal cancer risk and that the effects of the three SNPs are dependent on gender. The results highlight potential links between Se, the function of two selenoproteins involved in the protein unfolding response and CRC risk. Further studies are required to investigate whether the effects of the variants on CRC risk are also modulated by dietary Se intake. PMID:21052528

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

    PubMed

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

    2016-09-01

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

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

    PubMed Central

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

    2015-01-01

    Background: Active efflux of irinotecan by ATP-binding cassette (ABC)-transporters, in particular ABCB1 and ABCG2, is a well-established drug resistance mechanism in vitro and in pre-clinical mouse models, but its relevance in colorectal cancer (CRC) patients is unknown. Therefore, we assessed the association between ABC-transporter expression and tumour response to irinotecan in patients with metastatic CRC. Methods: Tissue microarrays of a large cohort of metastatic CRC patients treated with irinotecan in a prospective study (CAIRO study; n=566) were analysed for expression of ABCB1 and ABCG2 by immunohistochemistry. Kaplan-Meier and Cox proportional hazard regression analyses were performed to assess the association of ABC transporter expression with irinotecan response. Gene expression profiles of 17 paired tumours were used to assess the concordance of ABCB1/ABCG2 expression in primary CRC and corresponding metastases. Results: The response to irinotecan was not significantly different between primary tumours with positive versus negative expression of ABCB1 (5.8 vs 5.7 months, p=0.696) or ABCG2 (5.7 vs 6.1 months, p=0.811). Multivariate analysis showed neither ABCB1 nor ABCG2 were independent predictors for progression free survival. There was a mediocre to poor concordance between ABC-transporter expression in paired tumours. Conclusion: In metastatic CRC, ABC-transporter expression in the primary tumour does not predict irinotecan response. PMID:26516354

  18. Fluoxetine-induced alterations in human platelet serotonin transporter expression: serotonin transporter polymorphism effects

    PubMed Central

    Little, Karley Y.; Zhang, Lian; Cook, Edwin

    2006-01-01

    Objective Long-term antidepressant drug exposure may regulate its target molecule — the serotonin transporter (SERT). This effect could be related to an individual's genotype for an SERT promoter polymorphism (human serotonin transporter coding [5-HTTLPR]). We aimed to determine the effects of fluoxetine exposure on human platelet SERT levels. Method We harvested platelet samples from 21 healthy control subjects. The platelets were maintained alive ex vivo for 24 hours while being treated with 0.1 μM fluoxetine or vehicle. The effects on SERT immunoreactivity (IR) were then compared. Each individual's SERT promoter genotype was also determined to evaluate whether fluoxetine effects on SERT were related to genotype. Results Fluoxetine exposure replicably altered SERT IR within individuals. Both the magnitude and the direction of effect were related to a person's SERT genotype. People who were homozygous for the short gene (SS) displayed decreased SERT IR, whereas those who were homozygous for the long gene (LL) demonstrated increased SERT IR. A mechanistic experiment suggested that some individuals with the LL genotype might experience increased conversion of complexed SERT to primary SERT during treatment. Conclusions These preliminary results suggest that antidepressant effects after longer-term use may include changes in SERT expression levels and that the type and degree of effect may be related to the 5-HTTLPR polymorphism. PMID:16951736

  19. Prognostic impact and the relevance of PTEN copy number alterations in patients with advanced colorectal cancer (CRC) receiving bevacizumab.

    PubMed

    Price, Timothy J; Hardingham, Jennifer E; Lee, Chee K; Townsend, Amanda R; Wrin, Joseph W; Wilson, Kate; Weickhardt, Andrew; Simes, Robert J; Murone, Carmel; Tebbutt, Niall C

    2013-06-01

    Loss of phosphatase and tensin homologue (PTEN) expression may be prognostic in colorectal cancer (CRC) and may have a correlation with vascular endothelial growth factor (VEGF) expression via hypoxia-inducible factor 1 (HIF-1) alpha, and the PI3K/mTOR pathways. We therefore have explored the prognostic association of PTEN loss and the potential that PTEN loss may be predictive of outcome with bevacizumab. Patients enrolled in the AGITG MAX trial, a randomized Phase III trial of capecitabine (C) +/- bevacizumab (B) (+/- mitomycin C [M]) with available tissues were analyzed for PTEN expression (loss vs. no loss) as assessed using a Taqman® copy number assay (CNA). Of the original 471 patients enrolled, tissues from 302 (64.1%) patients were analyzed. PTEN loss was observed in 38.7% of patients. There was no relationship between PTEN loss and KRAS or BRAF mutation. PTEN status was not prognostic for progression-free survival (PFS) or overall survival (OS) in multivariate analyses adjusting for other baseline factors; loss versus no loss PFS hazard ratio (HR) 0.9 (0.7-1.16), OS HR 1.04 (0.79-1.38). PTEN was not prognostic when assessed by KRAS and BRAF status. By using the comparison of C versus CB+CBM, PTEN status was not significantly predictive of the effectiveness of B for PFS or OS. PTEN status was not prognostic for survival in advanced colorectal cancer, irrespective of KRAS or BRAF status. PTEN status did not significantly predict different benefit with bevacizumb therapy.

  20. Low-sulfur coal usage alters transportation strategies

    SciTech Connect

    Stein, H.

    1995-07-01

    As electricity production has grown, so has the amount of coal burned by US utilities. In order to comply with the 1990 Clean Air Act Amendments (CAAA), many utilities have changed from high-sulfur coal to lower-sulfur coal to reduce sulfur dioxide emissions. The primary mode of transporting coal to utilities remains the railroad, and coal represents the largest freight tonnage shipped - two out of every five tons. Since coal is so important to the railroads, it is logical that as utilities have changed their coal-buying strategies, the railroads` strategies have also changed. The increased demand for Western coal has caused rail lines some capacity problems which they are attempting to meet head-on by buying new railcars and locomotives and expanding track capacities. The new railcars typically have aluminum bodies to reduce empty weight, enabling them to carry larger loads of coal. Train locomotives are also undergoing upgrade changes. Most new locomotives have as motors to drive the wheels which deliver more motive power (traction) to the wheel trucks. In fact the motors are up to 30% more efficient at getting the traction to the trucks. Trackage is also being expanded to alleviate serious congestion on the tracks when moving Western coal.

  1. Colorectal Cancer

    MedlinePlus

    ... 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 ...

  2. Pyrethroid pesticide-induced alterations in dopamine transporter function

    PubMed Central

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

    2016-01-01

    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. PMID:16005927

  3. Pyrethroid pesticide-induced alterations in dopamine transporter function

    SciTech Connect

    Elwan, Mohamed A.; Richardson, Jason R.; Guillot, Thomas S.; Caudle, W. Michael; Miller, Gary W. . E-mail: gary.miller@emory.edu

    2006-03-15

    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 {mu}M) had no effect on DAT-mediated dopamine uptake. Extending exposures to both pesticides for 30 min (10 {mu}M) or 24 h (1, 5, and 10 {mu}M) 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.

  4. Usefulness of analysis of p53 alteration and observation of surface microstructure for diagnosis of ulcerative colitis-associated colorectal neoplasia.

    PubMed

    Fujii, S; Fujimori, T; Chiba, T

    2003-03-01

    Patients with ulcerative colitis (UC) have a higher incidence of colorectal cancer. UC-associated colorectal cancer is thought to develop in patients with preexisting UC-associated dysplasia. It is crucial to diagnose UC-associated dysplasia and early stage of cancer in patients with long-standing UC for the purpose of treatment of UC-associated neoplasia. However, it is difficult to detect UC-associated dysplasia and the early stage of cancer endoscopically, and to discriminate these neoplasias from inflammatory regenerative epithelium pathologically. The aim of this study was to clarify whether observation of the surface microstructure could aid in the detection of UC-associated neopalsia, and whether analysis of genetic alterations could be used to discriminate between UC-associated neoplasia and inflammatory regenerative epithelium. Tissue samples were obtained from colectomy specimens from eight cases of UC-associated neoplasia. We examined the surface microstructure of these tissues using stereomicroscopy. We also investigated mutation of K-ras codon 12 using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and alteration of the p53 gene, using immunohistochemistry and PCR-single stranded conformation polymorphism (PCR-SSCP). The surface microstructure of UC-associated neoplasia revealed a packed distribution of oval and/or, club-shaped and/or, branch-shaped pits and a villous appearance. Nuclear accumulation of p53 protein occurred in 59.5% of UC-associated neoplasia. Mutations of the p53 exon 5-8 were detected in 95.2% of UC-associated neoplasia, and these mutations were detected in 92.9% of UC-associated neoplasia that showed negative p53 immunohistochemical staining. Mutations of the p53 exon 5-8 in regenerative epithelium occurred infrequently. The K-ras mutation rate in UC-associated neoplasia was 7.4%. In conclusion, immunohistochemistry and PCR-SSCP analysis of p53 would be useful tools for pathological discrimination

  5. Alterations in adult behavioral responses to cocaine and dopamine transporters following juvenile exposure to methamphetamine.

    PubMed

    McFadden, Lisa; Yamamoto, Bryan K; Matuszewich, Leslie

    2011-01-20

    The present experiment assessed whether preadolescent exposure to methamphetamine would alter adult behavioral responses to cocaine and dopamine transporter immunoreactivity in the striatum of male and female rats. Juvenile rats were injected once daily with 0 or 2 mg/kg methamphetamine from postnatal days 21 to 35 and tested in adulthood. Male rats, but not female rats, exposed to methamphetamine showed an increase in responsiveness to cocaine in the open field and an increase in dopamine transporter immunoreactivity in the striatum. These findings suggest that early exposure to methamphetamine can lead to sex specific altered responses to psychostimulants in adulthood, which may contribute to later vulnerability to drug use.

  6. Alteration of human hepatic drug transporter activity and expression by cigarette smoke condensate.

    PubMed

    Sayyed, Katia; Vee, Marc Le; Abdel-Razzak, Ziad; Jouan, Elodie; Stieger, Bruno; Denizot, Claire; Parmentier, Yannick; Fardel, Olivier

    2016-07-01

    Smoking is well-known to impair pharmacokinetics, through inducing expression of drug metabolizing enzymes. In the present study, we demonstrated that cigarette smoke condensate (CSC) also alters activity and expression of hepatic drug transporters, which are now recognized as major actors of hepatobiliary elimination of drugs. CSC thus directly inhibited activities of sinusoidal transporters such as OATP1B1, OATP1B3, OCT1 and NTCP as well as those of canalicular transporters like P-glycoprotein, MRP2, BCRP and MATE1, in hepatic transporters-overexpressing cells. CSC similarly counteracted constitutive OATP, NTCP and OCT1 activities in human highly-differentiated hepatic HepaRG cells. In parallel, CSC induced expression of BCRP at both mRNA and protein level in HepaRG cells, whereas it concomitantly repressed mRNA expression of various transporters, including OATP1B1, OATP2B1, OAT2, NTCP, OCT1 and BSEP, and enhanced that of MRP4. Such changes in transporter gene expression were found to be highly correlated to those caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin, a reference activator of the aryl hydrocarbon receptor (AhR) pathway, and were counteracted, for some of them, by siRNA-mediated AhR silencing. This suggests that CSC alters hepatic drug transporter levels via activation of the AhR cascade. Importantly, drug transporter expression regulations as well as some transporter activity inhibitions occurred for a range of CSC concentrations similar to those required for inducing drug metabolizing enzymes and may therefore be hypothesized to be relevant for smokers. Taken together, these data established human hepatic transporters as targets of cigarette smoke, which could contribute to known alteration of pharmacokinetics and some liver adverse effects caused by smoking. PMID:27450509

  7. CHROMATOGRAPHIC ALTERATION OF A NONIONIC SURFACTANT MIXTURE DURING TRANSPORT IN DENSE NONAQUEOUS PHASE LIQUID CONTAMINATED SEDIMENT (R826650)

    EPA Science Inventory

    Chromatographic alteration of a nonionic surfactant mixture during transport through DNAPL-contaminated aquifer sediment may occur due to differential loss of oligomers to sediment and to dense nonaqueous phase liquid (DNAPL). These losses may significantly alter the solubilizing...

  8. Expression and localization of the immunophilin FKBP51 in colorectal carcinomas and primary metastases, and alterations following oxaliplatin-based chemotherapy

    PubMed Central

    Rotoli, Deborah; Morales, Manuel; Del Carmen Maeso, María; Del Pino García, María; Morales, Araceli; Ávila, Julio; Martín-Vasallo, Pablo

    2016-01-01

    The immunophilin FK506-binding protein 5 (FKBP51) is a scaffold protein that serves a pivotal role in the regulation of multiple signaling pathways, integrating external and internal stimuli into distinct signal outputs. In a previous study, we identified several genes that are significantly up- or downregulated in the peripheral white cells (PWCs) of colorectal adenocarcinoma (CRC) patients undergoing oxaliplatin-based chemotherapy. In our screening, FKBP51 gene expression was downregulated following chemotherapy. In order to determine whether this alteration in gene expression observed in PWCs may be detected at the protein level in tumors and metastases following the administration of adjuvant chemotherapy, an immunohistochemical analysis of FKBP51 in CRC and primary metastasis tissues was performed. The present study confirmed the downregulation of FKBP51 gene expression elicited by chemotherapy with folinic acid (leucovorin), fluorouracil and oxaliplatin in metastasized liver tissue that had been resected after the oxaliplatin-based chemotherapy, compared with tissue section samples of CRC from patients (prior to antineoplastic treatment). Furthermore, the results indicated that, in CRC tissue sections, the expression of FKBP51 protein is associated with an immature phenotype of stromal fibroblasts and with the epithelial-to-mesenchymal transition (EMT) phenotype, suggesting a role for this protein in the EMT process in CRC. Finally, the observation that only certain cells of the stroma express FKBP51 protein suggests a potential role for this immunophilin as a stroma cell subtype marker. PMID:27446431

  9. Activity of NA(+)/H(+) exchangers alters aquaporin-mediated water transport in human placenta.

    PubMed

    Dietrich, Valeria; Damiano, Alicia E

    2015-12-01

    The intracellular pH (pHi) of syncytiotrophoblasts is regulated, in part, by Na(+)/H(+) exchanger (NHE)-1, NHE-2, and NHE-3. Failures in pHi homeostasis could alter critical cellular functions such as water transport and cell volume. Here, we evaluated whether alterations in syncytiotrophoblast pHi could modify water uptake mediated by aquaporins (AQPs) and the contribution of NHEs to this mechanism. We showed that changes in syncytiotrophoblast pHi did not affect water uptake in the presence of functional NHEs. However, inhibition of NHEs alters transcellular water transport mediated by AQPs in acidosis. These results suggest an interaction between placental AQPs and NHEs in the regulation of water uptake during acidotic states.

  10. A 2.5D Reactive Transport Model for Fracture Alteration Simulation.

    PubMed

    Deng, Hang; Molins, Sergi; Steefel, Carl; DePaolo, Donald; Voltolini, Marco; Yang, Li; Ajo-Franklin, Jonathan

    2016-07-19

    Understanding fracture alteration resulting from geochemical reactions is critical in predicting fluid migration in the subsurface and is relevant to multiple environmental challenges. Here, we present a novel 2.5D continuum reactive transport model that captures and predicts the spatial pattern of fracture aperture change and the development of an altered layer in the near-fracture region. The model considers permeability heterogeneity in the fracture plane and updates fracture apertures and flow fields based on local reactions. It tracks the reaction front of each mineral phase and calculates the thickness of the altered layer. Given this treatment, the model is able to account for the diffusion limitation on reaction rates associated with the altered layer. The model results are in good agreement with an experimental study in which a CO2-acidified brine was injected into a fracture in the Duperow Dolomite, causing dissolution of calcite and dolomite that result in the formation of a preferential flow channel and an altered layer. With an effective diffusion coefficient consistent with the experimentally observed porosity of the altered layer, the model captures the progressive decrease in the dissolution rate of the fast-reacting mineral in the altered layer. PMID:27357572

  11. Genetic variants of human organic anion transporter 4 demonstrate altered transport of endogenous substrates

    PubMed Central

    Shima, James E.; Komori, Takafumi; Taylor, Travis R.; Stryke, Doug; Kawamoto, Michiko; Johns, Susan J.; Carlson, Elaine J.; Ferrin, Thomas E.

    2010-01-01

    Apical reabsorption from the urine has been shown to be important for such processes as the maintenance of critical metabolites in the blood and the excretion of nephrotoxic compounds. The solute carrier (SLC) transporter OAT4 (SLC22A11) is expressed on the apical membrane of renal proximal tubule cells and is known to mediate the transport of a variety of xenobiotic and endogenous organic anions. Functional characterization of genetic variants of apical transporters thought to mediate reabsorption, such as OAT4, may provide insight into the genetic factors influencing the complex pathways involved in drug elimination and metabolite reclamation occurring in the kidney. Naturally occurring genetic variants of OAT4 were identified in public databases and by resequencing DNA samples from 272 individuals comprising 4 distinct ethnic groups. Nine total nonsynonymous variants were identified and functionally assessed using uptake of three radiolabeled substrates. A nonsense variant, R48Stop, and three other variants (R121C, V155G, and V155M) were found at frequencies of at least 2% in an ethnic group specific fashion. The L29P, R48Stop, and H469R variants displayed a complete loss of function, and kinetic analysis identified a reduced Vmax in the common nonsynonymous variants. Plasma membrane levels of OAT4 protein were absent or reduced in the nonfunctional variants, providing a mechanistic reason for the observed loss of function. Characterization of the genetic variants of reabsorptive transporters such as OAT4 is an important step in understanding variability in tubular reabsorption with important implications in innate homeostatic processes and drug disposition. PMID:20668102

  12. Embryonic Stem Cell Proliferation Stimulated By Altered Anabolic Metabolism From Glucose Transporter 2-Transported Glucosamine

    PubMed Central

    Jung, Jin Hyuk; Iwabuchi, Kumiko; Yang, Zhihong; Loeken, Mary R.

    2016-01-01

    The hexose transporter, GLUT2 (SLC2A2), which is expressed by mouse embryos, is important for survival before embryonic day 10.5, but its function in embryos is unknown. GLUT2 can transport the amino sugar glucosamine (GlcN), which could increase substrate for the hexosamine biosynthetic pathway (HBSP) that produces UDP-N-acetylglucosamine for O-linked N-acetylglucosamine modification (O-GlcNAcylation) of proteins. To understand this, we employed a novel murine embryonic stem cell (ESC) line that, like mouse embryos, expresses functional GLUT2 transporters. GlcN stimulated ESC proliferation in a GLUT2-dependent fashion but did not regulate pluripotency. Stimulation of proliferation was not due to increased O-GlcNAcylation. Instead, GlcN decreased dependence of the HBSP on fructose-6-PO4 and glutamine. Consequently, glycolytic- and glutamine-derived intermediates that are needed for anabolic metabolism were increased. Thus, maternally obtained GlcN may increase substrates for biomass accumulation by embryos, as exogenous GlcN does for GLUT2-expressing ESC, and may explain the need for GLUT2 expression by embryos. PMID:27311888

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

    SciTech Connect

    Hoskins, B.

    1981-10-01

    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.

  14. Altered regulation of hepatic efflux transporters disrupts acetaminophen disposition in pediatric nonalcoholic steatohepatitis.

    PubMed

    Canet, Mark J; Merrell, Matthew D; Hardwick, Rhiannon N; Bataille, Amy M; Campion, Sarah N; Ferreira, Daniel W; Xanthakos, Stavra A; Manautou, Jose E; A-Kader, H Hesham; Erickson, Robert P; Cherrington, Nathan J

    2015-06-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, representing a spectrum of liver pathologies that include simple hepatic steatosis and the more advanced nonalcoholic steatohepatitis (NASH). The current study was conducted to determine whether pediatric NASH also results in altered disposition of acetaminophen (APAP) and its two primary metabolites, APAP-sulfate and APAP-glucuronide. Pediatric patients with hepatic steatosis (n = 9) or NASH (n = 3) and healthy patients (n = 12) were recruited in a small pilot study design. All patients received a single 1000-mg dose of APAP. Blood and urine samples were collected at 1, 2, and 4 hours postdose, and APAP and APAP metabolites were determined by high-performance liquid chromatography. Moreover, human liver tissues from patients diagnosed with various stages of NAFLD were acquired from the Liver Tissue Cell Distribution System to investigate the regulation of the membrane transporters, multidrug resistance-associated protein 2 and 3 (MRP2 and MRP3, respectively). Patients with the more severe disease (i.e., NASH) had increased serum and urinary levels of APAP-glucuronide along with decreased serum levels of APAP-sulfate. Moreover, an induction of hepatic MRP3 and altered canalicular localization of the biliary efflux transporter, MRP2, describes the likely mechanism for the observed increase in plasma retention of APAP-glucuronide, whereas altered regulation of sulfur activation genes may explain decreased sulfonation activity in NASH. APAP-glucuronide and APAP-sulfate disposition is altered in NASH and is likely due to hepatic membrane transporter dysregulation as well as altered intracellular sulfur activation.

  15. Apple Polyphenol Phloretin Inhibits Colorectal Cancer Cell Growth via Inhibition of the Type 2 Glucose Transporter and Activation of p53-Mediated Signaling.

    PubMed

    Lin, Sheng-Tsai; Tu, Shih-Hsin; Yang, Po-Sheng; Hsu, Sung-Po; Lee, Wei-Hwa; Ho, Chi-Tang; Wu, Chih-Hsiung; Lai, Yu-Hsin; Chen, Ming-Yao; Chen, Li-Ching

    2016-09-14

    Glucose transporters (GLUTs) are required for glucose uptake in malignant cells, and they can be used as molecular targets for cancer therapy. An RT-PCR analysis was performed to investigate the mRNA levels of 14 subtypes of GLUTs in human colorectal cancer (COLO 205 and HT-29) and normal (FHC) cells. RT-PCR (n = 27) was used to assess the differences in paired tissue samples (tumor vs normal) isolated from colorectal cancer patients. GLUT2 was detected in all tested cells. The average GLUT2 mRNA level in 12 of 27 (44.4%) cases was 2.4-fold higher in tumor compared to normal tissues (*, p = 0.027). Higher GLUT2 mRNA expression was preferentially detected in advanced-stage tumors (stage 0 vs 3 = 16.38-fold, 95% CI = 9.22-26.54-fold; *, p = 0.029). The apple polyphenol phloretin (Ph) and siRNA methods were used to inhibit GLUT2 protein expression. Ph (0-100 μM, for 24 h) induced COLO 205 cell growth cycle arrest in a p53-dependent manner, which was confirmed by pretreatment of the cells with a p53-specific dominant negative expression vector. Hepatocyte nuclear factor 6 (HNF6), which was previously reported to be a transcription factor that activates GLUT2 and p53, was also induced by Ph (0-100 μM, for 24 h). The antitumor effect of Ph (25 mg/kg or DMSO twice a week for 6 weeks) was demonstrated in vivo using BALB/c nude mice bearing COLO 205 tumor xenografts. In conclusion, targeting GLUT2 could potentially suppress colorectal tumor cell invasiveness. PMID:27538679

  16. Serum 25-hydroxyvitamin D, vitamin D binding protein, and risk of colorectal cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial

    PubMed Central

    Weinstein, Stephanie J.; Purdue, Mark P.; Smith-Warner, Stephanie A.; Mondul, Alison M.; Black, Amanda; Ahn, Jiyoung; Huang, Wen-Yi; Horst, Ronald L.; Kopp, William; Rager, Helen; Ziegler, Regina G.; Albanes, Demetrius

    2014-01-01

    The potential role of vitamin D in cancer prevention has generated substantial interest, and laboratory experiments indicate several anti-cancer properties for vitamin D compounds. Prospective studies of circulating 25-hydroxyvitamin D [25(OH)D], the accepted biomarker of vitamin D status, suggest an inverse association with colorectal cancer risk, but with some inconsistencies. Furthermore, the direct or indirect impact of the key transport protein, vitamin D binding protein (DBP), has not been examined. We conducted a prospective study of serum 25(OH)D and DBP concentrations and colorectal cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, based on 476 colorectal cancer cases and 476 controls, matched on age, sex, race, and date of serum collection. All subjects underwent sigmoidoscopic screening at baseline and once during follow-up. Conditional logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs). Circulating 25(OH)D was inversely associated with colorectal cancer (OR=0.60, 95% CI 0.38-0.94 for highest versus lowest quintile, p-trend 0.01). Adjusting for recognized colorectal cancer risk factors and accounting for seasonal vitamin D variation did not alter the findings. Neither circulating DBP nor the 25(OH)D:DBP molar ratio, a proxy for free circulating 25(OH)D, was associated with risk (OR=0.82, 95% CI 0.54-1.26, and OR=0.79, 95% CI 0.52-1.21, respectively), and DBP did not modify the 25(OH)D association. The current study eliminated confounding by colorectal cancer screening behavior, and supports an association between higher vitamin D status and substantially lower colorectal cancer risk, but does not indicate a direct or modifying role for DBP. PMID:25156182

  17. Morphology Alters Fluid Transport and the Ability of Organisms to Mix Oceanic Waters.

    PubMed

    Katija, Kakani

    2015-10-01

    Mixing in the ocean is opposed by the stratification of fluid, such that density of seawater increases with greater depth. The mechanisms by which mixing occurs have been attributed largely to physical processes that include atmospheric forcing, tides, and internal waves. Biogenic mixing, another potential source of mixing in the ocean, may generate significant transport of fluid during diel vertical migrations of organisms. Biogenic mixing is not limited to the near-surface or to regions of rough bottom topography, as are other physical mixing processes, and may contribute significantly to the energy budget of mixing in mid-ocean. "Fluid drift", a mechanism first described by Charles Galton Darwin, has been identified as a mechanism that allows for long-distance, vertical transport of fluid by the smallest of swimming organisms. However, little is known about how fluid drift varies with morphology and behavior of swimming organisms. We conducted numerical simulations of theoretical and experimentally measured flows of swimming medusae (Phyllorhiza sp.), and compared the volume of the drift induced by these flows. Our numerical simulations of fluid drift showed that morphology coupled with swimming behavior alters the transport of fluid both spatially and temporally. Given empirical velocity field data, the methods presented here allow us to systematically compare fluid transport across taxa, and enable us to deduce the potential of swimming organisms to influence fluid transport.

  18. Morphology Alters Fluid Transport and the Ability of Organisms to Mix Oceanic Waters.

    PubMed

    Katija, Kakani

    2015-10-01

    Mixing in the ocean is opposed by the stratification of fluid, such that density of seawater increases with greater depth. The mechanisms by which mixing occurs have been attributed largely to physical processes that include atmospheric forcing, tides, and internal waves. Biogenic mixing, another potential source of mixing in the ocean, may generate significant transport of fluid during diel vertical migrations of organisms. Biogenic mixing is not limited to the near-surface or to regions of rough bottom topography, as are other physical mixing processes, and may contribute significantly to the energy budget of mixing in mid-ocean. "Fluid drift", a mechanism first described by Charles Galton Darwin, has been identified as a mechanism that allows for long-distance, vertical transport of fluid by the smallest of swimming organisms. However, little is known about how fluid drift varies with morphology and behavior of swimming organisms. We conducted numerical simulations of theoretical and experimentally measured flows of swimming medusae (Phyllorhiza sp.), and compared the volume of the drift induced by these flows. Our numerical simulations of fluid drift showed that morphology coupled with swimming behavior alters the transport of fluid both spatially and temporally. Given empirical velocity field data, the methods presented here allow us to systematically compare fluid transport across taxa, and enable us to deduce the potential of swimming organisms to influence fluid transport. PMID:26117832

  19. Genetical and comparative genomics of Brassica under altered Ca supply identifies Arabidopsis Ca-transporter orthologs.

    PubMed

    Graham, Neil S; Hammond, John P; Lysenko, Artem; Mayes, Sean; O Lochlainn, Seosamh; Blasco, Bego; Bowen, Helen C; Rawlings, Chris J; Rios, Juan J; Welham, Susan; Carion, Pierre W C; Dupuy, Lionel X; King, Graham J; White, Philip J; Broadley, Martin R

    2014-07-01

    Although Ca transport in plants is highly complex, the overexpression of vacuolar Ca(2+) transporters in crops is a promising new technology to improve dietary Ca supplies through biofortification. Here, we sought to identify novel targets for increasing plant Ca accumulation using genetical and comparative genomics. Expression quantitative trait locus (eQTL) mapping to 1895 cis- and 8015 trans-loci were identified in shoots of an inbred mapping population of Brassica rapa (IMB211 × R500); 23 cis- and 948 trans-eQTLs responded specifically to altered Ca supply. eQTLs were screened for functional significance using a large database of shoot Ca concentration phenotypes of Arabidopsis thaliana. From 31 Arabidopsis gene identifiers tagged to robust shoot Ca concentration phenotypes, 21 mapped to 27 B. rapa eQTLs, including orthologs of the Ca(2+) transporters At-CAX1 and At-ACA8. Two of three independent missense mutants of BraA.cax1a, isolated previously by targeting induced local lesions in genomes, have allele-specific shoot Ca concentration phenotypes compared with their segregating wild types. BraA.CAX1a is a promising target for altering the Ca composition of Brassica, consistent with prior knowledge from Arabidopsis. We conclude that multiple-environment eQTL analysis of complex crop genomes combined with comparative genomics is a powerful technique for novel gene identification/prioritization.

  20. Norepinephrine transporter knock-out alters expression of the genes connected with antidepressant drugs action.

    PubMed

    Solich, Joanna; Kolasa, Magdalena; Kusmider, Maciej; Faron-Gorecka, Agata; Pabian, Paulina; Zurawek, Dariusz; Szafran-Pilch, Kinga; Dziedzicka-Wasylewska, Marta

    2015-01-12

    Norepinephrine transporter knock-out mice (NET-KO) exhibit depression-resistant phenotypes. They manifest significantly shorter immobility times in both the forced swim test and the tail suspension test. Moreover, biochemical studies have revealed the up-regulation of other monoamine transporters (dopamine and serotonin) in the brains of NET-KO mice, similar to the phenomenon observed after the chronic pharmacological blockade of norepinephrine transporter by desipramine in wild-type (WT) animals. NET-KO mice are also resistant to stress, as we demonstrated previously by measuring plasma corticosterone concentration. In the present study, we used a microdissection technique to separate target brain regions and the TaqMan Low Density Array approach to test the expression of a group of genes in the NET-KO mice compared with WT animals. A group of genes with altered expression were identified in four brain structures (frontal and cingulate cortices, dentate gyrus of hippocampus and basal-lateral amygdala) of NET-KO mice compared with WT mice. These genes are known to be altered by antidepressant drugs administration. The most interesting gene is Crh-bp, which modulates the activity of corticotrophin--releasing hormone (CRH) and several CRH-family members. Generally, genetic disturbances within noradrenergic neurons result in biological changes, such as in signal transduction and intercellular communication, and may be linked to changes in noradrenaline levels in the brains of NET-KO mice.

  1. BRAF, PIK3CA, and HER2 Oncogenic Alterations According to KRAS Mutation Status in Advanced Colorectal Cancers with Distant Metastasis

    PubMed Central

    Koh, Jiwon; Kwak, Yoonjin; Seo, An Na; Park, Kyoung Un; Kim, Duck-Woo; Kang, Sung-Bum; Kim, Woo Ho; Lee, Hye Seung

    2016-01-01

    Background Anti-EGFR antibody–based treatment is an important therapeutic strategy for advanced colorectal cancer (CRC); despite this, several mutations—including KRAS, BRAF, and PIK3CA mutations, and HER2 amplification—are associated with the mechanisms underlying the development of resistance to anti-EGFR therapy. The aim of our study was to investigate the frequencies and clinical implications of these genetic alterations in advanced CRC. Methods KRAS, BRAF, and PIK3CA mutations were determined by Cobas real-time polymerase chain reaction (PCR) in 191 advanced CRC patients with distant metastasis. Microsatellite instability (MSI) status was determined by a fragmentation assay and HER2 amplification was assessed by silver in situ hybridization. In addition, KRAS mutations were investigated by the Sanger sequencing method in 97 of 191 CRC cases. Results Mutations in KRAS, BRAF, and PIK3CA were found in 104 (54.5%), 6 (3.1%), and 25 (13.1%) cases of advanced CRC, respectively. MSI-high status and HER2 amplification were observed in 3 (1.6%) and 16 (8.4%) cases, respectively. PIK3CA mutations were more frequently found in KRAS mutant type (18.3%) than KRAS wild type (6.9%) (P = 0.020). In contrast, HER2 amplifications and BRAF mutations were associated with KRAS wild type with borderline significance (P = 0.052 and 0.094, respectively). In combined analyses with KRAS, BRAF and HER2 status, BRAF mutations or HER2 amplifications were associated with the worst prognosis in the wild type KRAS group (P = 0.004). When comparing the efficacy of detection methods, the results of real time PCR analysis revealed 56 of 97 (57.7%) CRC cases with KRAS mutations, whereas Sanger sequencing revealed 49 cases (50.5%). Conclusions KRAS mutations were found in 54.5% of advanced CRC patients. Our results support that subgrouping using PIK3CA and BRAF mutation or HER2 amplification status, in addition to KRAS mutation status, is helpful for managing advanced CRC patients. PMID

  2. Drought response transcriptomes are altered in poplar with reduced tonoplast sucrose transporter expression

    PubMed Central

    Xue, Liang-Jiao; Frost, Christopher J.; Tsai, Chung-Jui; Harding, Scott A.

    2016-01-01

    Transgenic Populus tremula x alba (717-1B4) plants with reduced expression of a tonoplast sucrose efflux transporter, PtaSUT4, exhibit reduced shoot growth compared to wild type (WT) under sustained mild drought. The present study was undertaken to determine whether SUT4-RNAi directly or indirectly altered poplar predisposition and/or response to changes in soil water availability. While sucrose and hexose levels were constitutively elevated in shoot organs, expression responses to drought were most altered in the root tips of SUT4-RNAi plants. Prior to any drought treatment, constitutively elevated transcript levels of abscisic acid biosynthetic genes and bark/vegetative storage proteins suggested altered metabolism in root tips of RNAi plants. Stronger drought-stimulation of stress-inducible genes encoding late-embryogenesis-abundant proteins in transgenic roots was consistent with increased vulnerability to soil drying. Transcript evidence suggested an RNAi effect on intercellular water trafficking by aquaporins in stem xylem during soil drying and recovery. Co-expression network analysis predicted altered integration of abscisic acid sensing/signaling with ethylene and jasmonate sensing/signaling in RNAi compared to WT roots. The overall conclusion is that steepened shoot-root sugar gradient in RNAi plants increased sensitivity of root tips to decreasing soil water availability. PMID:27641356

  3. Drought response transcriptomes are altered in poplar with reduced tonoplast sucrose transporter expression.

    PubMed

    Xue, Liang-Jiao; Frost, Christopher J; Tsai, Chung-Jui; Harding, Scott A

    2016-01-01

    Transgenic Populus tremula x alba (717-1B4) plants with reduced expression of a tonoplast sucrose efflux transporter, PtaSUT4, exhibit reduced shoot growth compared to wild type (WT) under sustained mild drought. The present study was undertaken to determine whether SUT4-RNAi directly or indirectly altered poplar predisposition and/or response to changes in soil water availability. While sucrose and hexose levels were constitutively elevated in shoot organs, expression responses to drought were most altered in the root tips of SUT4-RNAi plants. Prior to any drought treatment, constitutively elevated transcript levels of abscisic acid biosynthetic genes and bark/vegetative storage proteins suggested altered metabolism in root tips of RNAi plants. Stronger drought-stimulation of stress-inducible genes encoding late-embryogenesis-abundant proteins in transgenic roots was consistent with increased vulnerability to soil drying. Transcript evidence suggested an RNAi effect on intercellular water trafficking by aquaporins in stem xylem during soil drying and recovery. Co-expression network analysis predicted altered integration of abscisic acid sensing/signaling with ethylene and jasmonate sensing/signaling in RNAi compared to WT roots. The overall conclusion is that steepened shoot-root sugar gradient in RNAi plants increased sensitivity of root tips to decreasing soil water availability. PMID:27641356

  4. Transportation of young beef bulls alters circulating physiological parameters that may be effective biomarkers of stress.

    PubMed

    Buckham Sporer, K R; Weber, P S D; Burton, J L; Earley, B; Crowe, M A

    2008-06-01

    Transportation causes stress in cattle that may alter numerous physiological variables with a negative impact on production and health. The objectives of the current study were to investigate the physiological effects of truck transportation and to characterize a pattern of phenotypes in the circulation that may aid in the early identification of stress-susceptible animals that often succumb to severe respiratory disease. Thirty-six young beef bulls (Aberdeen Angus, n = 12; Friesian, n = 12; and Belgian Blue x Friesian, n = 12) were subjected to a 9-h truck transportation by road. Blood (10 mL) was collected at -24, 0, 4.5, 9.75, 14.25, 24, and 48 h relative to the initiation of transportation (0 h). Plasma was collected for the assay of various metabolic, inflammatory, and steroid variables, and total leukocyte counts were determined in whole blood at each time point. Body weight and rectal temperature were recorded at -24, 9.75, and 48 h. Transportation decreased measures of protein metabolism in the plasma, including albumin (P = 0.002), globulin (P < 0.001), urea (P = 0.006), and total protein (P < 0.001), and increased creatine kinase (P < 0.001). The energy substrate beta-hydroxybutyrate was not changed (P = 0.27). Acute phase proteins haptoglobin and fibrinogen were both decreased (P < 0.001), whereas total leukocyte counts were elevated (P = 0.002). Circulating steroid concentrations were altered, because a classical acute increase in plasma cortisol was observed with the onset of transit (P < 0.001), in association with a decrease in dehydroepiandrosterone (P = 0.07), resulting in a profound increase in cortisol:dehydroepiandrosterone ratio (P < 0.001). Plasma testosterone was decreased, whereas plasma progesterone was increased (P < 0.001) in association with the increase in cortisol (P < 0.001). There was also an effect of breed for all variables except plasma urea, creatine kinase, and testosterone, perhaps indicating that a genetic component

  5. Alterations in gut transport of minerals and in binding proteins during simulated weightlessness

    NASA Technical Reports Server (NTRS)

    Bikle, D. D.

    1984-01-01

    The structural components of the skeleton develop and are maintained in a 1 g environment, shaped by the mechanical load to which they are constantly exposed. Altering such a mechanical load by reducing the gravitational force imposed on the system, as in space flight, has profound effects on the skeleton and permits an exploration of the molecular events which regulate normal skeletal homeostasis. The objective was to determine whether simulated weightlessness reduced intestinal calcium transport, and if so, to determine the molecular mechanisms for such an effect. A nonstressful tail suspension in which the rats gained weight normally while suspended was used to simulate weightlessness. A significant change in intestinal calcium transport was not demonstrated. However, a cyclic change in bone formation with suspension was shown. Based on these observations, the objective changed to determination of the hormonal regulation of bone formation during simulated weightlessness.

  6. The Altered Renal and Hepatic Expression of Solute Carrier Transporters (SLCs) in Type 1 Diabetic Mice

    PubMed Central

    Xu, Chenghao; Zhu, Ling; Chan, Ting; Lu, Xiaoxi; Shen, Weiyong; Gillies, Mark C.; Zhou, Fanfan

    2015-01-01

    Diabetes mellitus is a chronic metabolic disorder that significantly affects human health and well-being. The Solute carrier transporters (SLCs), particularly the Organic anion/cation transporters (Oats/Octs/Octns), Organic anion transporting polypeptides (Oatps) and Oligopeptide transporters (Pepts) are essential membrane proteins responsible for cellular uptake of many endogenous and exogenous substances such as clinically important drugs. They are widely expressed in mammalian key organs especially the kidney and liver, in which they facilitate the influx of various drug molecules, thereby determining their distribution and elimination in body. The altered expression of SLCs in diabetes mellitus could have a profound and clinically significant influence on drug therapies. In this study, we extensively investigated the renal and hepatic expression of twenty essential SLCs in the type 1 diabetic Ins2Akita murine model that develops both hyperglycemia and diabetes-related complications using real-time PCR and immunoblotting analysis. We found that the renal expression of mOatp1a1, mOatp1a6, mOat1, mOat3, mOat5, mOct2 and mPept2 was decreased; while that of mPept1 was increased at the mRNA level in the diabetic mice compared with non-diabetic controls. We found up-regulated mRNA expression of mOatp1a4, mOatp1c1, mOctn2, mOct3 and mPept1 as well as down-regulation of mOatp1a1 in the livers of diabetic mice. We confirmed the altered protein expression of several SLCs in diabetic mice, especially the decreased renal and hepatic expression of mOatp1a1. We also found down-regulated protein expression of mOat3 and mOctn1 in the kidneys as well as increased protein expression of mOatp1a4 and mOct3 in the livers of diabetic mice. Our findings contribute to better understanding the modulation of SLC transporters in type 1 diabetes mellitus, which is likely to affect the pharmacokinetic performance of drugs that are transported by these transporters and therefore, forms the

  7. Chronic restraint stress induces intestinal inflammation and alters the expression of hexose and lipid transporters.

    PubMed

    Lee, Chooi Yeng

    2013-06-01

    Psychosocial stress is reported to be one of the main causes of obesity. Based on observations in studies that relate stress and gut inflammation to obesity, the present study hypothesized that chronic stress, via inflammation, alters the expression of nutrient transporters and contributes to the development of metabolic syndrome. Rats were exposed to restraint stress for 4 h/day for 5 days/week for eight consecutive weeks. Different segments of rat intestine were then collected and analysed for signs of pathophysiological changes and the expression of Niemann-Pick C1-like-1 (NPC1L1), sodium-dependent glucose transporter-1 (SLC5A1, previously known as SGLT1) and facilitative glucose transporter-2 (SLC2A2, previously known as GLUT2). In a separate experiment, the total anti-oxidant activity (TAA)-time profile of control isolated intestinal segments was measured. Stress decreased the expression of NPC1L1 in the ileum and upregulated SLC5A1 in both the jejunum and ileum and SLC2A2 in the duodenum. Inflammation and morphological changes were observed in the proximal region of the intestine of stressed animals. Compared with jejunal and ileal segments, the rate of increase in TAA was higher in the duodenum, indicating that the segment contained less anti-oxidants; anti-oxidants may function to protect the tissues. In conclusion, stress alters the expression of hexose and lipid transporters in the gut. The site-specific increase in the expression of SLC5A1 and SLC2A2 may be correlated with pathological changes in the intestine. The ileum may be protected, in part, by gut anti-oxidants. Collectively, the data suggest that apart from causing inflammation, chronic stress may promote sugar uptake and contribute to hyperglycaemia.

  8. Alteration of O-GlcNAcylation affects serine phosphorylation and regulates gene expression and activity of pyruvate kinase M2 in colorectal cancer cells.

    PubMed

    Chaiyawat, Parunya; Chokchaichamnankit, Daranee; Lirdprapamongkol, Kriengsak; Srisomsap, Chantragan; Svasti, Jisnuson; Champattanachai, Voraratt

    2015-10-01

    O-GlcNAcylation is a dynamic post-translational modification that has extensive crosstalk with phosphorylation either at the same or adjacent sites of various proteins. We have previously reported that O-GlcNAcylation level was increased in primary breast and colorectal cancer, but the interplay of the two modifications remains unclear. Therefore, we explored crosstalk of the modifications by RNA interference against O-GlcNAc transferase (OGT) in colorectal cancer cells. Two-dimensional immunoblotting and mass spectrometric analysis showed that the levels of O-GlcNAc and serine phosphorylation of many proteins including serine hydroxymethyltransferase, cytokeratin-8, pyruvate kinase M2 (PKM2), heterogeneous nuclear ribonucleoprotein L, and lamin-B1, were reduced in siOGT cells compared to siScramble cells. In HT29 cells, immunoprecipitated PKM2 revealed decreased O-GlcNAc and serine phosphorylation levels after siOGT knockdown, but increased levels after treatment with Thiamet-G, an inhibitor of O-GlcNAcase (OGA). In addition, when global O-GlcNAcylation was enhanced by treating cells with Thiamet-G, PKM2 expression level was upregulated, but PKM2-specific activity was decreased. On the other hand, in OGT knockdown cells, PKM2 expression level was downregulated, but PKM2-specific activity was increased. Moreover, the metastatic colorectal cancer cells, SW620, had more O-GlcNAc-PKM2 and showed lower PKM2-specific activity compared to the non-metastatic colorectal cancer SW480 cells. These results suggested roles of O-GlcNAcylation in modulating serine phosphorylation, as well as in regulating PKM2 activity and expression. Interfering levels of O-GlcNAcylation of PKM2 may be a novel target in controlling cancer metabolism and tumorigenesis of colorectal cancer.

  9. Altered transport of lindane caused by the retention of natural particles in saturated porous media.

    PubMed

    Ngueleu, Stéphane K; Grathwohl, Peter; Cirpka, Olaf A

    2014-07-01

    Attachment and straining of colloidal particles in porous media result in their reversible and irreversible retention. The retained particles may either increase the retention of hydrophobic pollutants by sorption onto the particles, or enhance pollutant transport when particles, loaded with the pollutants, are remobilized. The present study examines the effects of retained particles on the transport of the hydrophobic pesticide lindane (gamma-hexachlorocyclohexane) in saturated porous media. The lignite particles used have median diameters of about 3 μm, 1 μm, 0.8 μm, and 0.2 μm, respectively. Laboratory column experiments were analyzed by numerical modeling in order to identify and understand the processes involved in the transport of the particles and of lindane. Four scenarios were considered in which the solution containing lindane is injected either during or after the elution of the particles. The results show that lignite particles retained in a sandy porous medium alter the transport of the invading lindane. Particle retention was high in all scenarios and increased with increasing particle size. Remobilization of particles occurred due to a change in solution chemistry, and continuous particle detachment was observed over time. Numerical modeling of particle transport suggests that both reversible attachment and irreversible straining affected the transport of the particles. Lindane was retarded in all scenarios due to the strong particle retention in conjunction with the sorption of lindane onto the sand and onto retained particles, and the limited number of mobile particles carrying lindane. Moreover, it was found that intra-particle diffusion limited adsorption/desorption of lindane onto/from both limestone fragments of the sand and lignite particles. We assume that retention of lindane is reversible even though lindane recovery was incomplete over the duration of the experiments. The analysis of the effluent concentration suggests that retained

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

    PubMed Central

    Arregi, Igor; Falces, Jorge; Olazabal-Herrero, Anne; Alonso-Mariño, Marián; Taneva, Stefka G.; Rodríguez, José A.; Urbaneja, María A.; Bañuelos, Sonia

    2015-01-01

    Nucleophosmin (NPM) is a nucleocytoplasmic shuttling protein, normally enriched in nucleoli, that performs several activities related to cell growth. NPM mutations are characteristic of a subtype of acute myeloid leukemia (AML), where mutant NPM seems to play an oncogenic role. AML-associated NPM mutants exhibit altered subcellular traffic, being aberrantly located in the cytoplasm of leukoblasts. Exacerbated export of AML variants of NPM is mediated by the nuclear export receptor CRM1, and due, in part, to a mutationally acquired novel nuclear export signal (NES). To gain insight on the molecular basis of NPM transport in physiological and pathological conditions, we have evaluated the export efficiency of NPM in cells, and present new data indicating that, in normal conditions, wild type NPM is weakly exported by CRM1. On the other hand, we have found that AML-associated NPM mutants efficiently form complexes with CRM1HA (a mutant CRM1 with higher affinity for NESs), and we have quantitatively analyzed CRM1HA interaction with the NES motifs of these mutants, using fluorescence anisotropy and isothermal titration calorimetry. We have observed that the affinity of CRM1HA for these NESs is similar, which may help to explain the transport properties of the mutants. We also describe NPM recognition by the import machinery. Our combined cellular and biophysical studies shed further light on the determinants of NPM traffic, and how it is dramatically altered by AML-related mutations. PMID:26091065

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

    PubMed Central

    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

  12. Sources, transport and alterations of metal compounds: an overview. I. Arsenic, beryllium, cadmium, chromium, and nickel.

    PubMed Central

    Fishbein, L

    1981-01-01

    An overview is presented of the current state of knowledge of the salient aspects of the sources, transport, and alterations of arsenic, beryllium, cadmium, chromium, and nickel. This information is considered vital for a better assessment of the scope of potential human hazard to these ubiquitous toxicants and their compounds. Stress is focused on both natural and industrial activities, particularly on the latter's projected trends. Increasing use patterns per se of most of these metals, as well as aspects of waste disposal and the anticipated increased combustion of fossil fuels for power generation and space heating (particularly in the United States), are major causes of potential health concern. Additionally, attention is drawn to the need for increased research to fill the gaps in our knowledge in these vital areas, all in the hope of permitting a more facile identification and quantification of the potential hazard to exposure to these agents. PMID:7023934

  13. Conformational Exchange in a Membrane Transport Protein Is Altered in Protein Crystals

    SciTech Connect

    D Freed; P Horanyi; M Wiener; D Cafiso

    2011-12-31

    Successful macromolecular crystallography requires solution conditions that may alter the conformational sampling of a macromolecule. Here, site-directed spin labeling is used to examine a conformational equilibrium within BtuB, the Escherichia coli outer membrane transporter for vitamin B{sub 12}. Electron paramagnetic resonance (EPR) spectra from a spin label placed within the N-terminal energy coupling motif (Ton box) of BtuB indicate that this segment is in equilibrium between folded and unfolded forms. In bilayers, substrate binding shifts this equilibrium toward the unfolded form; however, EPR spectra from this same spin-labeled mutant indicate that this unfolding transition is blocked in protein crystals. Moreover, crystal structures of this spin-labeled mutant are consistent with the EPR result. When the free energy difference between substates is estimated from the EPR spectra, the crystal environment is found to alter this energy by 3 kcal/mol when compared to the bilayer state. Approximately half of this energy change is due to solutes or osmolytes in the crystallization buffer, and the remainder is contributed by the crystal lattice. These data provide a quantitative measure of how a conformational equilibrium in BtuB is modified in the crystal environment, and suggest that more-compact, less-hydrated substates will be favored in protein crystals.

  14. Conformational Exchange in a Membrane Transport Protein Is Altered in Protein Crystals

    SciTech Connect

    Freed, Daniel M.; Horanyi, Peter S.; Wiener, Michael C.; Cafiso, David S.

    2010-09-27

    Successful macromolecular crystallography requires solution conditions that may alter the conformational sampling of a macromolecule. Here, site-directed spin labeling is used to examine a conformational equilibrium within BtuB, the Escherichia coli outer membrane transporter for vitamin B{sub 12}. Electron paramagnetic resonance (EPR) spectra from a spin label placed within the N-terminal energy coupling motif (Ton box) of BtuB indicate that this segment is in equilibrium between folded and unfolded forms. In bilayers, substrate binding shifts this equilibrium toward the unfolded form; however, EPR spectra from this same spin-labeled mutant indicate that this unfolding transition is blocked in protein crystals. Moreover, crystal structures of this spin-labeled mutant are consistent with the EPR result. When the free energy difference between substates is estimated from the EPR spectra, the crystal environment is found to alter this energy by 3 kcal/mol when compared to the bilayer state. Approximately half of this energy change is due to solutes or osmolytes in the crystallization buffer, and the remainder is contributed by the crystal lattice. These data provide a quantitative measure of how a conformational equilibrium in BtuB is modified in the crystal environment, and suggest that more-compact, less-hydrated substates will be favored in protein crystals.

  15. Genetic and chemical reductions in protein phosphatase activity alter auxin transport, gravity response, and lateral root growth

    NASA Technical Reports Server (NTRS)

    Rashotte, A. M.; DeLong, A.; Muday, G. K.; Brown, C. S. (Principal Investigator)

    2001-01-01

    Auxin transport is required for important growth and developmental processes in plants, including gravity response and lateral root growth. Several lines of evidence suggest that reversible protein phosphorylation regulates auxin transport. Arabidopsis rcn1 mutant seedlings exhibit reduced protein phosphatase 2A activity and defects in differential cell elongation. Here we report that reduced phosphatase activity alters auxin transport and dependent physiological processes in the seedling root. Root basipetal transport was increased in rcn1 or phosphatase inhibitor-treated seedlings but showed normal sensitivity to the auxin transport inhibitor naphthylphthalamic acid (NPA). Phosphatase inhibition reduced root gravity response and delayed the establishment of differential auxin-induced gene expression across a gravity-stimulated root tip. An NPA treatment that reduced basipetal transport in rcn1 and cantharidin-treated wild-type plants also restored a normal gravity response and asymmetric auxin-induced gene expression, indicating that increased basipetal auxin transport impedes gravitropism. Increased auxin transport in rcn1 or phosphatase inhibitor-treated seedlings did not require the AGR1/EIR1/PIN2/WAV6 or AUX1 gene products. In contrast to basipetal transport, root acropetal transport was normal in phosphatase-inhibited seedlings in the absence of NPA, although it showed reduced NPA sensitivity. Lateral root growth also exhibited reduced NPA sensitivity in rcn1 seedlings, consistent with acropetal transport controlling lateral root growth. These results support the role of protein phosphorylation in regulating auxin transport and suggest that the acropetal and basipetal auxin transport streams are differentially regulated.

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

    PubMed

    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; 10(7) 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

  17. Altered hippocampal expression of glutamate receptors and transporters in GRM2 and GRM3 knockout mice.

    PubMed

    Lyon, Louisa; Kew, James N C; Corti, Corrado; Harrison, Paul J; Burnet, Philip W J

    2008-11-01

    Group II metabotropic glutamate receptors (mGluR2 and mGluR3, also called mGlu2 and mGlu3, encoded by GRM2 and GRM3, respectively) are therapeutic targets for several psychiatric disorders. GRM3 may also be a schizophrenia susceptibility gene. mGluR2-/- and mGluR3-/- mice provide the only unequivocal means to differentiate between these receptors, yet interpretation of in vivo findings may be complicated by secondary effects on expression of other genes. To address this issue, we examined the expression of NMDA receptor subunits (NR1, NR2A, NR2B) and glutamate transporters (EAAT1-3), as well as the remaining group II mGluR, in the hippocampus of mGluR2-/- and mGluR3-/- mice, compared with wild-type controls. mGluR2 mRNA was increased in mGluR3-/- mice, and vice versa. NR2A mRNA was increased in both knockout mice. EAAT1 (GLAST) mRNA and protein, and EAAT2 (GLT-1) protein, were reduced in mGluR3-/- mice, whereas EAAT3 (EAAC1) mRNA was decreased in mGluR2-/- mice. Transcripts for NR1 and NR2B were unchanged. The findings show a compensatory upregulation of the remaining group II metabotropic glutamate receptor in the knockout mice. Upregulation of NR2A expression suggests modified NMDA receptor signaling in mGluR2-/- and mGluR3-/- mice, and downregulation of glutamate transporter expression suggests a response to altered synaptic glutamate levels. The results show a mutual interplay between mGluR2 and mGluR3, and also provide a context in which to interpret behavioral and electrophysiological results in these mice. PMID:18720515

  18. Altered microtubule dynamics and vesicular transport in mouse and human MeCP2-deficient astrocytes.

    PubMed

    Delépine, Chloé; Meziane, Hamid; Nectoux, Juliette; Opitz, Matthieu; Smith, Amos B; Ballatore, Carlo; Saillour, Yoann; Bennaceur-Griscelli, Annelise; Chang, Qiang; Williams, Emily Cunningham; Dahan, Maxime; Duboin, Aurélien; Billuart, Pierre; Herault, Yann; Bienvenu, Thierry

    2016-01-01

    Rett syndrome (RTT) is a rare X-linked neurodevelopmental disorder, characterized by normal post-natal development followed by a sudden deceleration in brain growth with progressive loss of acquired motor and language skills, stereotypic hand movements and severe cognitive impairment. Mutations in the methyl-CpG-binding protein 2 (MECP2) cause more than 95% of classic cases. Recently, it has been shown that the loss of Mecp2 from glia negatively influences neurons in a non-cell-autonomous fashion, and that in Mecp2-null mice, re-expression of Mecp2 preferentially in astrocytes significantly improved locomotion and anxiety levels, restored respiratory abnormalities to a normal pattern and greatly prolonged lifespan compared with globally null mice. We now report that microtubule (MT)-dependent vesicle transport is altered in Mecp2-deficient astrocytes from newborn Mecp2-deficient mice compared with control wild-type littermates. Similar observation has been made in human MECP2 p.Arg294* iPSC-derived astrocytes. Importantly, administration of Epothilone D, a brain-penetrant MT-stabilizing natural product, was found to restore MT dynamics in Mecp2-deficient astrocytes and in MECP2 p.Arg294* iPSC-derived astrocytes in vitro. Finally, we report that relatively low weekly doses of Epothilone D also partially reversed the impaired exploratory behavior in Mecp2(308/y) male mice. These findings represent a first step toward the validation of an innovative treatment for RTT.

  19. Prodigiosin isolated from cell wall of Serratia marcescens alters expression of apoptosis-related genes and increases apoptosis in colorectal cancer cells.

    PubMed

    Hassankhani, Ramin; Sam, Mohammad Reza; Esmaeilou, Mohammad; Ahangar, Prinaz

    2015-01-01

    Colorectal cancer remains often refractory to classic therapies. In consequence, the search for new anti-tumor agents with minimal toxicity is of particular interest in colon cancer treatment. Prodigiosin as a secondary metabolite of Serratia marcescens induces apoptosis in various kinds of cancer cells with low toxicity on normal cells. In the present study, we evaluated the effect of prodigiosin on proliferation and expression of apoptotic-related genes in HT-29 cells. Malignant cells were treated to various concentrations of prodigiosin and proliferation rate, survivin, Bcl-2, Bax and Bad mRNA levels, caspase 3 activation and apoptosis were evaluated by different cellular and molecular techniques. Treatment of cells with increasing concentration of prodigiosin decreased significantly cell proliferation in a dose- and time-dependent manner. Following 48-h treatment, growth rate was measured to be 77 ± 6.8, 41.3 ± 3.1 and 46 ± 6.3 % for 100, 400 and 600 nM prodigiosin, respectively, compared to untreated cells. This molecule induced 61.7, 90 and 89 % decrease in survivin mRNA level as well as 1.9-, 2.8- and 2.2-fold increase in caspase 3 activation for indicated concentrations of prodigiosin, respectively. The level of Bcl-2 mRNA was inversely proportional to Bax and Bad mRNA levels. Low mRNA levels of Bcl-2 combined with high levels of Bax and Bad mRNAs were correlated to higher apoptosis rate in treated cells. Our data suggest that prodigiosin-induced apoptosis may ascribe to Bcl-2 and survivin inhibition in HT-29 cells and these genes may provide promising molecular targets of prodigiosin. Collectively, prodigiosin may have a great potential for colorectal cancer-directed therapy.

  20. Auxin Transport and Ribosome Biogenesis Mutant/Reporter Lines to Study Plant Cell Growth and Proliferation under Altered Gravity

    NASA Astrophysics Data System (ADS)

    Valbuena, Miguel A.; Manzano, Ana I.; van Loon, Jack JWA.; Saez-Vasquez, Julio; Carnero-Diaz, Eugenie; Herranz, Raul; Medina, F. J.

    2013-02-01

    We tested different Arabidopsis thaliana strains to check their availability for space use in the International Space Station (ISS). We used mutants and reporter gene strains affecting factors of cell proliferation and cell growth, to check variations induced by an altered gravity vector. Seedlings were grown either in a Random Positioning Machine (RPM), under simulated microgravity (μg), or in a Large Diameter Centrifuge (LDC), under hypergravity (2g). A combination of the two devices (μgRPM+LDC) was also used. Under all gravity alterations, seedling roots were longer than in control 1g conditions, while the levels of the nucleolar protein nucleolin were depleted. Alterations in the pattern of expression of PIN2, an auxin transporter, and of cyclin B1, a cell cycle regulator, were shown. All these alterations are compatible with previous space data, so the use of these strains will be useful in the next experiments in ISS, under real microgravity.

  1. The reactivity of chlorite surfaces: Microscopic alteration processes and the transport behaviour of uranium(VI)

    NASA Astrophysics Data System (ADS)

    Bosbach, D.; Brandt, F.; Arnold, T.; Krawczyk-Baersch, E.; Bernhard, G.

    2003-04-01

    The transport of U(VI) in phyllite rocks or on granitic fractures is significantly affected by the dissolution of chlorite and the re-precipitation of various secondary phases. However, in order to be able to predict the behaviour of radionuclides in these systems a sound understanding of the reaction kinetics of chlorite alteration/dissolution processes as well as the precipitation of secondary phases is required. We have studied the dissolution of chlorite with mixed-flow reactor experiments and in-situ AFM observations far from equilibrium over a broad pH range. Key parameters such as the reactive surface area as well as the stoichiometry and pH dependency of the dissolution reaction were determined. Speciation calculations indicate that no secondary phases have formed (except under neutral pH conditions). Under acidic conditions the brucite-like layer of the chlorite structure dissolves faster than the 2:1 TOT layer whereas above pH 8 a reverse dissolution behaviour was observed. Under acidic conditions (pH < 5) chlorite transforms to a vermiculite-like clay mineral, which has also been identified in field studies. In addition, static batch dissolution experiments with chlorite were performed in order to mimic more closely natural systems. In these experiments various secondary phases including hydrous ferrous oxides (HFO) were formed as coatings on chlorite surfaces and as colloids in solution. Batch adsorption experiments indicate that U(VI) has a strong affinity to HFO and that retardation of U(VI) occurs via adsorption to immobile HFO coatings on chlorite surfaces. Heterogeneous HFO formation seems to be favoured on {hk0} edge surfaces in the near neutral pH range. The formation mechanism of HFO coatings was studied systematically with titration experiments, in order to be able to quantify the homogeneous and heterogeneous formation of these secondary phases as a function of the geochemical conditions.

  2. The transmembrane sodium gradient influences ambient GABA concentration by altering the equilibrium of GABA transporters.

    PubMed

    Wu, Yuanming; Wang, Wengang; Richerson, George B

    2006-11-01

    Tonic inhibition is widely believed to be caused solely by "spillover" of GABA that escapes the synaptic cleft and activates extrasynaptic GABA(A) receptors. However, an exclusively vesicular source is not consistent with the observation that tonic inhibition can still occur after blocking vesicular release. Here, we made patch-clamp recordings from neurons in rat hippocampal cultures and measured the tonic current that was blocked by bicuculline or gabazine. During perforated patch recordings, the tonic GABA current was decreased by the GAT1 antagonist SKF-89976a. Zero calcium solution did not change the amount of tonic current, despite a large reduction in vesicular GABA release. Perturbations that would be expected to alter the transmembrane sodium gradient influenced the tonic current. For example, in zero calcium Ringer, TTX (which can decrease cytosolic [Na(+)]) reduced tonic current, whereas veratridine (which can increase cytosolic [Na(+)]) increased tonic current. Likewise, removal of extracellular sodium led to a large increase in tonic current. The increases in tonic current induced by veratridine and sodium removal were completely blocked by SKF89976a. When these experiments were repeated in hippocampal slices, similar results were obtained except that a GAT1- and GAT3-independent nonvesicular source(s) of GABA was found to contribute to the tonic current. We conclude that multiple sources can contribute to ambient GABA, including spillover and GAT1 reversal. The source of GABA release may be conceptually less important in determining the amount of tonic inhibition than the factors that control the equilibrium of GABA transporters.

  3. Infectious Prion Protein Alters Manganese Transport and Neurotoxicity in a Cell Culture Model of Prion Disease

    PubMed Central

    Martin, Dustin P.; Anantharam, Vellareddy; Jin, Huajun; Witte, Travis; Houk, Robert; Kanthasamy, Arthi; Kanthasamy, Anumantha G.

    2011-01-01

    Protein misfolding and aggregation are considered key features of many neurodegenerative diseases, but biochemical mechanisms underlying protein misfolding and the propagation of protein aggregates are not well understood. Prion disease is a classical neurodegenerative disorder resulting from the misfolding of endogenously expressed normal cellular prion protein (PrPC). Although the exact function of PrPC has not been fully elucidated, studies have suggested that it can function as a metal binding protein. Interestingly, increased brain manganese (Mn) levels have been reported in various prion diseases indicating divalent metals also may play a role in the disease process. Recently, we reported that PrPC protects against Mn-induced cytotoxicity in a neural cell culture model. To further understand the role of Mn in prion diseases, we examined Mn neurotoxicity in an infectious cell culture model of prion disease. Our results show CAD5 scrapie-infected cells were more resistant to Mn neurotoxicity as compared to uninfected cells (EC50 = 428.8 μM for CAD5 infected cells vs. 211.6 μM for uninfected cells). Additionally, treatment with 300 μM Mn in persistently infected CAD5 cells showed a reduction in mitochondrial impairment, caspase-3 activation, and DNA fragmentation when compared to uninfected cells. Scrapie-infected cells also showed significantly reduced Mn uptake as measured by inductively coupled plasma-mass spectrometry (ICP-MS), and altered expression of metal transporting proteins DMT1 and transferrin. Together, our data indicate that conversion of PrP to the pathogenic isoform enhances its ability to regulate Mn homeostasis, and suggest that understanding the interaction of metals with disease-specific proteins may provide further insight to protein aggregation in neurodegenerative diseases. PMID:21871919

  4. MDR1 Synonymous Polymorphisms Alter Transporter Specificity and Protein Stability in a Stable Epithelial Monolayer

    PubMed Central

    Fung, King Leung; Pan, James; Ohnuma, Shinobu; Lund, Paul E.; Pixley, Jessica N.; Kimchi-Sarfaty, Chava; Ambudkar, Suresh V.; Gottesman, Michael M.

    2016-01-01

    The drug efflux function of P-glycoprotein (P-gp) encoded by MDR1 can be influenced by genetic polymorphisms, including two synonymous changes in the coding region of MDR1. Here we report that the conformation of P-gp and its drug efflux activity can be altered by synonymous polymorphisms in stable epithelial monolayers expressing P-gp. Several cell lines with similar MDR1 DNA copy number were developed and termed LLC-MDR1-WT (expresses wild-type P-gp), LLC-MDR1-3H (expresses common haplotype P-gp), and LLC-MDR1-3HA (a mutant that carries a different valine codon in position 3435). These cell lines express similar levels of recombinant mRNA and protein. P-gp in each case is localized on the apical surface of polarized cells. However, the haplotype and its mutant P-gps fold differently from the wild-type, as determined by UIC2 antibody shift assays and limited proteolysis assays. Surface biotinylation experiments suggest that the non-wild-type P-gps have longer recycling times. Drug transport assays show that wild-type and haplotype P-gp respond differently to P-gp inhibitors that block efflux of rhodamine-123 or mitoxantrone. In addition, cytotoxicity assays show that the LLC-MDR1-3H cells are more resistant to mitoxantrone than the LLC-MDR1-WT cells after being treated with a P-gp inhibitor. Expression of polymorphic P-gp, however, does not affect the host cell’s morphology, growth rate, or monolayer formation. Also, ATPase activity assays indicate that neither basal nor drug-stimulated ATPase activities are affected in the variant P-gps. Taken together, our findings indicate that “silent” polymorphisms significantly change P-gp function, which would be expected to affect interindividual drug disposition and response. PMID:24305879

  5. Five Myths about Colorectal Cancer

    MedlinePlus

    ... ACS » Your Local Offices Close + - Text Size Five Myths About Colorectal Cancer In many cases, colorectal cancer ... screening tests you need, when you need them. Myth: Colorectal cancer is a man’s disease. Truth: Colorectal ...

  6. Allelic loss in colorectal carcinoma

    SciTech Connect

    Kern, S.E.; Fearon, E.R.; Tersmette, K.W.F.; Enterline, J.P.; Vogelstein, B.; Hamilton, S.R. ); Leppert, M.; Nakamura, Yusuke; White, R. )

    1989-06-02

    Clinical and pathological associations with molecular genetic alterations were studied in colorectal carcinomas from 83 patients. Fractional allelic loss, a measure of allelic deletions throughout the genome, and allelic deletions of specific chromosomal arms (the short arm of 17 and long arm of 18) each provided independent prognostic information by multivariate analysis when considered individually with Dukes' classification. Distant metastasis was significantly associated with high fractional allelic loss and with deletions of 17p and 18q. Mutations of ras proto-oncogenes and deletions of 5q had no prognostic importance. Statistically significant associations were also found between allelic losses and a family history of cancer, left-sided tumor location, and absence of extracellular tumor mucin. Allelic deletion analysis thus identified subsets of colorectal carcinoma with increased predilection for distant metastasis and cancer-related death. Further studies may define a subset of genetic alterations that can be used clinically to help assess prognosis.

  7. Altered colonic environment, a possible predisposition to colorectal cancer and colonic inflammatory bowel disease: rationale of dietary manipulation with emphasis on disaccharides.

    PubMed

    Szilagyi, A

    1998-03-01

    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 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. PMID:9559208

  8. Phosphorylation at serine 52 and 635 does not alter the transport properties of glucosinolate transporter AtGTR1

    PubMed Central

    Jørgensen, Morten Egevang; Olsen, Carl Erik; Halkier, Barbara Ann; Nour-Eldin, Hussam Hassan

    2016-01-01

    Little is known about how plants regulate transporters of defense compounds. In A. thaliana, glucosinolates are transported between tissues by NPF2.10 (AtGTR1) and NPF2.11 (AtGTR2). Mining of the PhosPhat4.0 database showed two cytosol exposed phosphorylation sites for AtGTR1 and one membrane-buried phosphorylation site for AtGTR2. In this study, we investigate whether mutation of the two potential regulatory sites of AtGTR1 affected transport of glucosinolates in Xenopus oocytes. Characterization of AtGTR1 phosphorylation mutants showed that phosphorylation of AtGTR1 - at the two reported phosphorylation sites - is not directly involved in regulating AtGTR1 transport activity. We hypothesize a role for AtGTR1-phosphorylation in regulating protein-protein interactions. PMID:26340317

  9. Prenatal transportation alters the metabolic response of Brahman bull calves exposed to a lipopolysaccharide (LPS) challenge

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This study was designed to determine if prenatal transportation influences the metabolic response to a postnatal lipopolysaccharide (LPS) challenge. Pregnant Brahman cows (n=96) matched by age and parity were separated into transported (TRANS; n=48; transported for 2 hours on gestational day 60, 80,...

  10. Chemoprevention of colorectal cancer

    PubMed Central

    LANGMAN, M; BOYLE, P

    1998-01-01

    Department of Medicine, Queen Elizabeth Hospital, Birmingham B15 2TH, UK P BOYLE Colorectal cancer is the fourth commonest form of cancer in men with 678 000 estimated new cases per year worldwide, representing 8.9% of all new cancers. The disease is most frequent in Occidental countries and particularly so in North America, Australia, New Zealand, and parts of Europe. Prospects for colorectal cancer control are bright and a number of possible approaches could prove fruitful. Among these, pharmaceutical measures seem to be valid and logical approaches to the prevention of colorectal cancer and diminishing its impact. Such approaches could concentrate in primary prevention in at-risk subjects or be applied in altering the course of precursor or established disease. Treatments used must fulfil basic requirements of biological plausibility and safety in continued use in large numbers of subjects. Those available include vitamins and minerals, and other drugs with potential as antioxidants, immune modulators or promoters of cell differentiation or apoptosis. Of the various regimens suggested, vitamin A supplementation may even predispose to adverse outcomes, and antioxidant vitamins in general have no coherent body of evidence to support their use. N-acetylcysteine and ursodeoxycholic acid have promising characteristics but there are as yet no clinical data to support the use of the former in gut epithelial cancer, and formal dose ranging studies must be carried out before the latter is submitted to large scale trial. Folate shows promising characteristics but non-steroidal anti-inflammatory drugs and vitamin D seem the most promising agents. Both seem to reduce the incidence of disease, and to reduce growth rates and/or induce differentiation or apoptosis in gut epithelial cancer cells. Both are also well understood pharmacologically. They may be preferred to newer selective compounds in the same class until these newer compounds are confirmed as safe for widespread

  11. 49 CFR 37.43 - Alteration of transportation facilities by public entities.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... that, to the maximum extent feasible, the path of travel to the altered area and the bathrooms.... Provided, that alterations to the path of travel, drinking fountains, telephones and bathrooms are not... personnel). (d) As used in this section, a “path of travel” includes a continuous, unobstructed way...

  12. 49 CFR 37.43 - Alteration of transportation facilities by public entities.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... that, to the maximum extent feasible, the path of travel to the altered area and the bathrooms.... Provided, that alterations to the path of travel, drinking fountains, telephones and bathrooms are not... personnel). (d) As used in this section, a “path of travel” includes a continuous, unobstructed way...

  13. 49 CFR 37.43 - Alteration of transportation facilities by public entities.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... that, to the maximum extent feasible, the path of travel to the altered area and the bathrooms.... Provided, that alterations to the path of travel, drinking fountains, telephones and bathrooms are not... personnel). (d) As used in this section, a “path of travel” includes a continuous, unobstructed way...

  14. 49 CFR 37.43 - Alteration of transportation facilities by public entities.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... that, to the maximum extent feasible, the path of travel to the altered area and the bathrooms.... Provided, that alterations to the path of travel, drinking fountains, telephones and bathrooms are not... personnel). (d) As used in this section, a “path of travel” includes a continuous, unobstructed way...

  15. 49 CFR 37.43 - Alteration of transportation facilities by public entities.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... this section apply to any alteration which begins (i.e., issuance of notice to proceed or work order... maximum physical accessibility feasible. Any altered features of the facility or portion of the facility... counted as expenditures required to provide an accessible path of travel include: (i) Costs...

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

    NASA Astrophysics Data System (ADS)

    Sun, Detong; Wan, Yongshan; Qiu, Chelsea

    2016-05-01

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

  17. Colorectal Carcinogenesis, Radiation Quality, and the Ubiquitin-Proteasome Pathway

    PubMed Central

    Datta, Kamal; Suman, Shubhankar; Kumar, Santosh; Fornace, Albert J

    2016-01-01

    Adult colorectal epithelium undergoes continuous renewal and maintains homeostatic balance through regulated cellular proliferation, differentiation, and migration. The canonical Wnt signaling pathway involving the transcriptional co-activator β-catenin is important for colorectal development and normal epithelial maintenance, and deregulated Wnt/β-catenin signaling has been implicated in colorectal carcinogenesis. Colorectal carcinogenesis has been linked to radiation exposure, and radiation has been demonstrated to alter Wnt/β-catenin signaling, as well as the proteasomal pathway involved in the degradation of the signaling components and thus regulation of β-catenin. The current review discusses recent progresses in our understanding of colorectal carcinogenesis in relation to different types of radiation and roles that radiation quality plays in deregulating β-catenin and ubiquitin-proteasome pathway (UPP) for colorectal cancer initiation and progression. PMID:26819641

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

    PubMed

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

    2015-01-01

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

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

    PubMed

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

    2015-01-01

    The contribution of hyphae to water transport in ectomycorrhizal (ECM) white spruce (Picea glauca) seedlings was examined by altering expression of a major water-transporting aquaporin in Laccaria bicolor. Picea glauca was inoculated with wild-type (WT), mock transgenic or L. bicolor aquaporin JQ585595-overexpressing (OE) strains and exposed to root temperatures ranging from 5 to 20°C to examine the root water transport properties, physiological responses and plasma membrane intrinsic protein (PIP) expression in colonized plants. Mycorrhization increased shoot water potential, transpiration, net photosynthetic rates, root hydraulic conductivity and root cortical cell hydraulic conductivity in seedlings. At 20°C, OE plants had higher root hydraulic conductivity compared with WT plants and the increases were accompanied by higher expression of P. glauca PIP GQ03401_M18.1 in roots. In contrast to WT L. bicolor, the effects of OE fungi on root and root cortical cell hydraulic conductivities were abolished at 10 and 5°C in the absence of major changes in the examined transcript levels of P. glauca root PIPs. The results provide evidence for the importance of fungal aquaporins in root water transport of mycorrhizal plants. They also demonstrate links between hyphal water transport, root aquaporin expression and root water transport in ECM plants. PMID:25323307

  20. Molecular alterations of Ras-Raf-mitogen-activated protein kinase and phosphatidylinositol 3-kinase-Akt signaling pathways in colorectal cancers from a tertiary hospital at Kuala Lumpur, Malaysia.

    PubMed

    Yip, Wai Kien; Choo, Chee Wei; Leong, Vincent Ching-Shian; Leong, Pooi Pooi; Jabar, Mohd Faisal; Seow, Heng Fong

    2013-10-01

    Molecular alterations in KRAS, BRAF, PIK3CA, and PTEN have been implicated in designing targeted therapy for colorectal cancer (CRC). The present study aimed to determine the status of these molecular alterations in Malaysian CRCs as such data are not available in the literature. We investigated the mutations of KRAS, BRAF, and PTEN, the gene amplification of PIK3CA, and the protein expression of PTEN and phosphatidylinositol 3-kinase (PI3K) catalytic subunit (p110α) by direct DNA sequencing, quantitative real-time PCR, and immunohistochemistry, respectively, in 49 CRC samples. The frequency of KRAS (codons 12, 13, and 61), BRAF (V600E), and PTEN mutations, and PIK3CA amplification was 25.0% (11/44), 2.3% (1/43), 0.0% (0/43), and 76.7% (33/43), respectively. Immunohistochemical staining demonstrated loss of PTEN protein in 54.5% (24/44) of CRCs and no significant difference in PI3K p110α expression between CRCs and the adjacent normal colonic mucosa (p = 0.380). PIK3CA amplification was not associated with PI3K p110α expression level, but associated with male cases (100% of male cases vs 56% of female cases harbored amplified PIK3CA, p = 0.002). PI3K p110α expression was significantly higher (p = 0.041) in poorly/moderately differentiated carcinoma compared with well-differentiated carcinoma. KRAS mutation, PIK3CA amplification, PTEN loss, and PI3K p110α expression did not correlate with Akt phosphorylation or Ki-67 expression. KRAS mutation, PIK3CA amplification, and PTEN loss were not mutually exclusive. This is the first report on CRC in Malaysia showing comparable frequency of KRAS mutation and PTEN loss, lower BRAF mutation rate, higher PIK3CA amplification frequency, and rare PTEN mutation, as compared with published reports.

  1. Integrated proteomic and genomic analysis of colorectal cancer

    Cancer.gov

    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

  2. Colorectal Cancer Prevention

    MedlinePlus

    ... Genetics of Colorectal Cancer Colorectal cancer is the second leading cause of death from cancer in the ... professional versions have detailed information written in technical language. The patient versions are written in easy-to- ...

  3. Diet and supplements and their impact on colorectal cancer

    PubMed Central

    Pericleous, Marinos; Mandair, Dalvinder

    2013-01-01

    Background Colorectal cancer is the third commonest cancer and the third leading cause of cancer death among men and women. It has been proposed that dietary factors are responsible for 70-90% of colorectal cancer and diet optimization may prevent most cases. Aim To evaluate the role of dietary components and supplements in colorectal cancer. Methods Bibliographical searches were performed in Pubmed for the terms “diet and colorectal cancer”, “diet and colon cancer”, “diet and rectal cancer”, “nutrition and colorectal cancer”, “probiotics and colorectal cancer”, “prebiotics and colorectal cancer”, “alcohol and cancer” and “colorectal cancer epidemiology”. Results Consumption of processed or red meat, especially when cooked at high temperatures may be associated with increased risk of colorectal cancer. The evidence for dietary fibre is unclear but foods that contain high amounts of fibre are usually rich in polyphenols which have been shown to alter molecular processes that can encourage colorectal carcinogenesis. Meta-analyses provide evidence on the benefits of circulating, diet-derived and supplemented, vitamin D and Calcium. We also found that diets rich in Folate may prevent colorectal carcinoma. The evidence on dietary micronutrients such as Zinc and Selenium in association with colorectal cancer is not conclusive. It has been suggested that there may be a direct association between alcohol intake and colorectal cancer. In vitro and in vivo studies have highlighted a possible protective role of prebiotics and probiotics. Conclusions The lack of randomized trials and the presence of confounding factors including smoking, physical activity, obesity and diabetes may often yield inconclusive results. Carefully designed randomized trials are recommended. PMID:24294513

  4. Effects of altered cytoplasmic domains on transport of the vesicular stomatitis virus glycoprotein are transferable to other proteins.

    PubMed Central

    Guan, J L; Ruusala, A; Cao, H; Rose, J K

    1988-01-01

    Alterations of the cytoplasmic domain of the vesicular stomatitis virus glycoprotein (G protein) were shown previously to affect transport of the protein from the endoplasmic reticulum, and recent studies have shown that this occurs without detectable effects on G protein folding and trimerization (R. W. Doms et al., J. Cell Biol., in press). Deletions within this domain slowed exit of the mutant proteins from the endoplasmic reticulum, and replacement of this domain with a foreign 12-amino-acid sequence blocked all transport out of the endoplasmic reticulum. To extend these studies, we determined whether such effects of cytoplasmic domain changes were transferable to other proteins. Three different assays showed that the effects of the mutations on transport of two membrane-anchored secretory proteins were the same as those observed with vesicular stomatitis virus G protein. In addition, possible effects on oligomerization were examined for both transported and nontransported forms of membrane-anchored human chorionic gonadotropin-alpha. These membrane-anchored forms, like the nonanchored human chorionic gonadotropin-alpha, had sedimentation coefficients consistent with a monomeric structure. Taken together, our results provide strong evidence that these cytoplasmic mutations affect transport by affecting interactions at or near the cytoplasmic side of the membrane. Images PMID:2841589

  5. Alterations in Adhesion, Transport, and Membrane Characteristics in an Adhesion-Deficient Pseudomonad

    PubMed Central

    DeFlaun, M. F.; Oppenheimer, S. R.; Streger, S.; Condee, C. W.; Fletcher, M.

    1999-01-01

    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. We 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. PMID:9925613

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

    NASA Technical Reports Server (NTRS)

    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.

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

    SciTech Connect

    DeFlaun, M.F.; Streger, S.; Condee, C.W.; Oppenheimer, S.R.; Fletcher, M.

    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.

  8. Gut microbiota imbalance and colorectal cancer

    PubMed Central

    Gagnière, Johan; Raisch, Jennifer; Veziant, Julie; Barnich, Nicolas; Bonnet, Richard; Buc, Emmanuel; Bringer, Marie-Agnès; Pezet, Denis; Bonnet, Mathilde

    2016-01-01

    The gut microbiota acts as a real organ. The symbiotic interactions between resident micro-organisms and the digestive tract highly contribute to maintain the gut homeostasis. However, alterations to the microbiome caused by environmental changes (e.g., infection, diet and/or lifestyle) can disturb this symbiotic relationship and promote disease, such as inflammatory bowel diseases and cancer. Colorectal cancer is a complex association of tumoral cells, non-neoplastic cells and a large amount of micro-organisms, and the involvement of the microbiota in colorectal carcinogenesis is becoming increasingly clear. Indeed, many changes in the bacterial composition of the gut microbiota have been reported in colorectal cancer, suggesting a major role of dysbiosis in colorectal carcinogenesis. Some bacterial species have been identified and suspected to play a role in colorectal carcinogenesis, such as Streptococcus bovis, Helicobacter pylori, Bacteroides fragilis, Enterococcus faecalis, Clostridium septicum, Fusobacterium spp. and Escherichia coli. The potential pro-carcinogenic effects of these bacteria are now better understood. In this review, we discuss the possible links between the bacterial microbiota and colorectal carcinogenesis, focusing on dysbiosis and the potential pro-carcinogenic properties of bacteria, such as genotoxicity and other virulence factors, inflammation, host defenses modulation, bacterial-derived metabolism, oxidative stress and anti-oxidative defenses modulation. We lastly describe how bacterial microbiota modifications could represent novel prognosis markers and/or targets for innovative therapeutic strategies. PMID:26811603

  9. Genomic Convergence Analysis of Schizophrenia: mRNA Sequencing Reveals Altered Synaptic Vesicular Transport in Post-Mortem Cerebellum

    PubMed Central

    Mudge, Joann; Miller, Neil A.; Khrebtukova, Irina; Lindquist, Ingrid E.; May, Gregory D.; Huntley, Jim J.; Luo, Shujun; Zhang, Lu; van Velkinburgh, Jennifer C.; Farmer, Andrew D.; Lewis, Sharon; Beavis, William D.; Schilkey, Faye D.; Virk, Selene M.; Black, C. Forrest; Myers, M. Kathy; Mader, Lar C.; Langley, Ray J.; Utsey, John P.; Kim, Ryan W.; Roberts, Rosalinda C.; Khalsa, Sat Kirpal; Garcia, Meredith; Ambriz-Griffith, Victoria; Harlan, Richard; Czika, Wendy; Martin, Stanton; Wolfinger, Russell D.; Perrone-Bizzozero, Nora I.; Schroth, Gary P.; Kingsmore, Stephen F.

    2008-01-01

    Schizophrenia (SCZ) is a common, disabling mental illness with high heritability but complex, poorly understood genetic etiology. As the first phase of a genomic convergence analysis of SCZ, we generated 16.7 billion nucleotides of short read, shotgun sequences of cDNA from post-mortem cerebellar cortices of 14 patients and six, matched controls. A rigorous analysis pipeline was developed for analysis of digital gene expression studies. Sequences aligned to approximately 33,200 transcripts in each sample, with average coverage of 450 reads per gene. Following adjustments for confounding clinical, sample and experimental sources of variation, 215 genes differed significantly in expression between cases and controls. Golgi apparatus, vesicular transport, membrane association, Zinc binding and regulation of transcription were over-represented among differentially expressed genes. Twenty three genes with altered expression and involvement in presynaptic vesicular transport, Golgi function and GABAergic neurotransmission define a unifying molecular hypothesis for dysfunction in cerebellar cortex in SCZ. PMID:18985160

  10. Role of EP4 receptor and prostaglandin transporter in prostaglandin E2-induced alteration in colonic epithelial barrier integrity.

    PubMed

    Lejeune, Manigandan; Leung, Pearl; Beck, Paul L; Chadee, Kris

    2010-11-01

    Prostaglandin E(2) (PGE(2)) is a proinflammatory lipid mediator produced in excess in inflammatory bowel disease (IBD). PGE(2) couples to and signals via four different E-prostanoid (EP) receptors, namely EP1, EP2, EP3, and EP4. In this study, we determined a role for PGE(2) and EP4 receptors in altering colonic epithelial barrier integrity. In healthy colonic mucosa, EP4 receptors were localized on apical plasma membrane of epithelial cells at the tip of mucosal folds, whereas, in patients with IBD and in rats with dextran sodium sulfate (DSS)-induced colitis, they were diffusely overexpressed throughout the mucosa. Similarly, expression of EP4 receptor was polarized in T84 colonic epithelial monolayer and mimics the normal epithelium. Apical exposure of T84 monolayer with high levels of PGE(2) decreased barrier integrity, which was abrogated by an EP4 receptor antagonist. To reveal the mechanism of vectorial transport of basally produced PGE(2) toward apical EP4 receptors, we identified prostaglandin transporters (PGT) in human colonic epithelia. PGT were least expressed on epithelial cells at the colonic mucosal folds of control subjects but overexpressed in epithelial cells of patients with IBD or animals with DSS-induced colitis. T84 monolayer also expressed PGT, which increased twofold following stimulation with TNF-α. Importantly, in T84 monolayer stimulated with TNF-α, there was a corresponding increase in the uptake and vectorial transport of (3)H-PGE(2) to the apical surface. Knockdown or pharmacological inhibition of PGT significantly decreased vectorial transport of (3)H-PGE(2). These studies unravel a mechanism whereby EP4 receptor and PGT play a role in PGE(2)-induced alteration of epithelial barrier integrity in colitis.

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

    USGS Publications Warehouse

    Worthington, Thomas A.; Brewer, Shannon K.; Farless, Nicole; Grabowski, Timothy B.; Gregory, Mark S.

    2014-01-01

    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.

  12. Phosphate depletion modulates auxin transport in Triticum aestivum leading to altered root branching

    PubMed Central

    Talboys, Peter J.; Healey, John R.; Withers, Paul J. A.; Jones, Davey L.

    2014-01-01

    Understanding the mechanisms by which nutritional signals impact upon root system architecture is a key facet in the drive for greater nutrient application efficiency in agricultural systems. Cereal plants reduce their rate of lateral root emergence under inorganic phosphate (Pi) shortage; this study uses molecular and pharmacological techniques to dissect this Pi response in Triticum aestivum. Plants were grown in coarse sand washed in high- or low-Pi nutrient solution before being assessed for their root branching density and expression of AUX/IAA and PIN genes. Seedlings were also grown on media containing [14C]indole acetic acid to measure basipetal auxin transport. Seedlings grown in low-Pi environments displayed less capacity to transport auxin basipetally from the seminal root apex, a reduction in root expression of PIN auxin transporter genes, and perturbed expression of a range of AUX/IAA auxin response genes. Given the known importance of basipetally transported auxin in stimulating lateral root initiation, it is proposed here that, in T. aestivum, Pi availability directly influences lateral root production through modulation of PIN expression. Understanding such processes is important in the drive for greater efficiency in crop use of Pi fertilizers in agricultural settings. PMID:25086590

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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 ...

  14. Altered hepatic transport of immunoglobulin A in mice lacking the J chain

    PubMed Central

    1995-01-01

    We have created J chain knockout mice to define the physiologic role of the J chain in immunoglobulin synthesis and transport. The J chain is covalently associated with pentameric immunoglobulin (Ig) M and dimeric IgA and is also expressed in most IgG-secreting cells. J chain- deficient mice have normal serum IgM and IgG levels but markedly elevated serum IgA. Although polymeric IgA was present in the mutant mice, a larger proportion of their serum IgA was monomeric than was found in wild-type mouse serum. Bile and fecal IgA levels were decreased in J chain-deficient mice compared with wild-type mice, suggesting inefficient transport of J chain-deficient IgA by hepatic polymeric immunoglobulin receptors (pIgR). The pIgR-mediated transport of serum-derived IgA from wild-type and mutant mice was assessed in Madin-Darby canine kidney (MDCK) cells transfected with the pIgR. These studies revealed selective transport by pIgR-expressing MDCK cells of wild-type IgA but not J chain-deficient IgA. We conclude that although the J chain is not required for IgA dimerization, it does affect the efficiency of polymerization or have a role in maintaining IgA dimer stability. Furthermore, the J chain is essential for efficient hepatic pIgR transport of IgA. PMID:7500036

  15. Inhibition of Nucleotide Sugar Transport in Trypanosoma brucei Alters Surface Glycosylation*

    PubMed Central

    Liu, Li; Xu, Yu-Xin; Caradonna, Kacey L.; Kruzel, Emilia K.; Burleigh, Barbara A.; Bangs, James D.; Hirschberg, Carlos B.

    2013-01-01

    Nucleotide sugar transporters (NSTs) are indispensible for the biosynthesis of glycoproteins by providing the nucleotide sugars needed for glycosylation in the lumen of the Golgi apparatus. Mutations in NST genes cause human and cattle diseases and impaired cell walls of yeast and fungi. Information regarding their function in the protozoan parasite, Trypanosoma brucei, a causative agent of African trypanosomiasis, is unknown. Here, we characterized the substrate specificities of four NSTs, TbNST1–4, which are expressed in both the insect procyclic form (PCF) and mammalian bloodstream form (BSF) stages. TbNST1/2 transports UDP-Gal/UDP-GlcNAc, TbNST3 transports GDP-Man, and TbNST4 transports UDP-GlcNAc, UDP-GalNAc, and GDP-Man. TbNST4 is the first NST shown to transport both pyrimidine and purine nucleotide sugars and is demonstrated here to be localized at the Golgi apparatus. RNAi-mediated silencing of TbNST4 in the procyclic form caused underglycosylated surface glycoprotein EP-procyclin. Similarly, defective glycosylation of the variant surface glycoprotein (VSG221) as well as the lysosomal membrane protein p67 was observed in Δtbnst4 BSF T. brucei. Relative infectivity analysis showed that defects in glycosylation of the surface coat resulting from tbnst4 deletion were insufficient to impact the ability of this parasite to infect mice. Notably, the fact that inactivation of a single NST gene results in measurable defects in surface glycoproteins in different life cycle stages of the parasite highlights the essential role of NST(s) in glycosylation of T. brucei. Thus, results presented in this study provide a framework for conducting functional analyses of other NSTs identified in T. brucei. PMID:23443657

  16. Inhibition of nucleotide sugar transport in Trypanosoma brucei alters surface glycosylation.

    PubMed

    Liu, Li; Xu, Yu-Xin; Caradonna, Kacey L; Kruzel, Emilia K; Burleigh, Barbara A; Bangs, James D; Hirschberg, Carlos B

    2013-04-12

    Nucleotide sugar transporters (NSTs) are indispensible for the biosynthesis of glycoproteins by providing the nucleotide sugars needed for glycosylation in the lumen of the Golgi apparatus. Mutations in NST genes cause human and cattle diseases and impaired cell walls of yeast and fungi. Information regarding their function in the protozoan parasite, Trypanosoma brucei, a causative agent of African trypanosomiasis, is unknown. Here, we characterized the substrate specificities of four NSTs, TbNST1-4, which are expressed in both the insect procyclic form (PCF) and mammalian bloodstream form (BSF) stages. TbNST1/2 transports UDP-Gal/UDP-GlcNAc, TbNST3 transports GDP-Man, and TbNST4 transports UDP-GlcNAc, UDP-GalNAc, and GDP-Man. TbNST4 is the first NST shown to transport both pyrimidine and purine nucleotide sugars and is demonstrated here to be localized at the Golgi apparatus. RNAi-mediated silencing of TbNST4 in the procyclic form caused underglycosylated surface glycoprotein EP-procyclin. Similarly, defective glycosylation of the variant surface glycoprotein (VSG221) as well as the lysosomal membrane protein p67 was observed in Δtbnst4 BSF T. brucei. Relative infectivity analysis showed that defects in glycosylation of the surface coat resulting from tbnst4 deletion were insufficient to impact the ability of this parasite to infect mice. Notably, the fact that inactivation of a single NST gene results in measurable defects in surface glycoproteins in different life cycle stages of the parasite highlights the essential role of NST(s) in glycosylation of T. brucei. Thus, results presented in this study provide a framework for conducting functional analyses of other NSTs identified in T. brucei. PMID:23443657

  17. Chemical transport during formation and alteration of Martian impact and volcanic deposits

    NASA Technical Reports Server (NTRS)

    Newsom, H. E.

    1992-01-01

    Much of the surface of Mars, including volcanic and cratered terrains, probably experienced alteration and degassing processes. These processes may have depleted or enriched many important elements in surface materials, including bedrock, dust, and soils. The composition of the martian soil may represent the best estimate, for some elements, of the average composition of the martian crust, similar to the composition of loess created by glacial action on the Earth. The martian soil may represent the only convenient, globally or regionally averaged sample of the martian crust. In order to understand the composition of the source material for the soil, however, we need to understand the contributions of volcanic vs. impact sources for this material and the chemical fractionations involved in its production. The processes to be addressed include degassing of volcanic deposits, as observed in the Valley of Ten Thousand Smokes at Katmai, Alaska, and degassing of meltbearing impact ejecta as inferred for suevite ejecta sheets at the Ries Crater, and alteration or palagonitization of volcanic deposits, as documented for volcanos in British Columbia and many other volcanic terrains, and impact crater deposits. The process of palagonitization has been the subject of several studies with reference to Mars, and palagonite is a good analogue for the spectroscopic properties of the martian dust. The role of impact in cratering has not been as well studied, although other researchers have established that both degassing and alteration are common features of impact crater deposits. Other relevant sources of experimental data include the extensive literature on the corrosion of nuclear waste glass and leaching of shocked materials.

  18. Colorectal Cancer

    MedlinePlus

    ... malignant tumor and enter the bloodstream or the lymphatic system where they travel to other organs in the body. Among other things, the lymphatic system transports white blood cells that fight infection. When ...

  19. Activation of guanylate cyclase-C attenuates stretch responses and sensitization of mouse colorectal afferents

    PubMed Central

    Feng, Bin; Kiyatkin, Michael E.; La, Jun-Ho; Ge, Pei; Solinga, Robert; Silos-Santiago, Inmaculada; Gebhart, G.F.

    2013-01-01

    Irritable bowel syndrome (IBS) is characterized by altered bowel habits, persistent pain and discomfort, and typically colorectal hypersensitivity. Linaclotide, a peripherally-restricted 14-amino acid peptide approved for the treatment of IBS with constipation, relieves constipation and reduces IBS-associated pain in these patients presumably by activation of guanylate cyclase-C (GC-C), which stimulates production and release of cyclic guanosine monophosphate (cGMP) from intestinal epithelial cells. We investigated whether activation of GC-C by the endogenous agonist uroguanylin or the primary downstream effector of that activation, cGMP, directly modulates responses and sensitization of mechanosensitive colorectal primary afferents. The distal 2 cm of mouse colorectum with attached pelvic nerve was harvested, pinned flat mucosal side up for in vitro single-fiber recordings and the encoding properties of mechanosensitive afferents (serosal, mucosal, muscular and muscular-mucosal) to probing and circumferential stretch studied. Both cGMP (10–300μM) and uroguanylin (1–1000nM) applied directly to colorectal receptive endings significantly reduced responses of muscular and muscular-mucosal afferents to stretch; serosal and mucosal afferents were not affected. Sensitized responses (i.e., increased responses to stretch) of muscular and muscular-mucosal afferents were reversed by cGMP, returning responses to stretch to control. Blocking the transport of cGMP from colorectal epithelia by probenecid, a mechanism validated by studies in cultured intestinal T84 cells, abolished the inhibitory effect of uroguanylin on muscular-mucosal afferents. These results suggest that GC-C agonists like linaclotide alleviate colorectal pain and hypersensitivity by dampening stretch-sensitive afferent mechanosensitivity and normalizing afferent sensitization. PMID:23739979

  20. Solutes alter the conformation of the ligand binding loops in outer membrane transporters.

    PubMed

    Kim, Miyeon; Xu, Qi; Murray, David; Cafiso, David S

    2008-01-15

    The binding and recognition of ligands by bacterial outer membrane transport proteins is mediated in part by interactions made through their extracellular loops. Here, site-directed spin labeling (SDSL) and electron paramagnetic resonance (EPR) spectroscopy were used to examine the effect of stabilizing solutes on the extracellular loops in BtuB, the vitamin B12 transporter, and FecA, the ferric citrate transporter. EPR spectra from the extracellular loops of FecA and BtuB arise from dynamic backbone segments, and distance measurements made by double electron-electron resonance indicate that the second extracellular loop in BtuB samples a wide range of conformations. These conformations are dramatically restricted upon substrate binding. In addition, the EPR spectra from nitroxide labels attached to the extracellular loops in BtuB and FecA are highly sensitive to solutes, and at every site examined the motion of the label is significantly reduced in the presence of stabilizing osmolytes, such as polyethylene glycols. For the second extracellular loop in BtuB, the solute-induced structural changes are small, but they are sufficient to bring spin-labeled side chains into tertiary contact with other portions of the protein. The spectroscopic changes seen by SDSL suggest that high concentrations of stabilizing solutes, such as those used to generate membrane protein crystals, result in a more compact and ordered state of the protein than is seen under more physiological conditions.

  1. Chronic hypoxia enhances adenosine release in rat PC12 cells by altering adenosine metabolism and membrane transport.

    PubMed

    Kobayashi, S; Zimmermann, H; Millhorn, D E

    2000-02-01

    Acute exposure to hypoxia causes a release of adenosine (ADO) that is inversely related to the O2 levels in oxygen-sensitive pheochromocytoma (PC12) cells. In the current study, chronic exposure (48 h) of PC12 cells to moderate hypoxia (5% O2) significantly enhanced the release of ADO during severe, acute hypoxia (1% O2). Investigation into the intra- and extracellular mechanisms underpinning the secretion of ADO in PC12 cells chronically exposed to hypoxia revealed changes in gene expression and activities of several key enzymes associated with ADO production and metabolism, as well as the down-regulation of a nucleoside transporter. Decreases in the enzymatic activities of ADO kinase and ADO deaminase accompanied by an increase in those of cytoplasmic and ecto-5'-nucleotidases bring about an increased capacity to produce intra- and extracellular ADO. This increased potential to generate ADO and decreased capacity to metabolize ADO indicate that PC12 cells shift toward an ADO producer phenotype during hypoxia. The reduced function of the rat equilibrative nucleoside transporter rENT1 also plays a role in controlling extracellular ADO levels. The hypoxia-induced alterations in the ADO metabolic enzymes and the rENT1 transporter seem to increase the extracellular concentration of ADO. The biological significance of this regulation is unclear but is likely to be associated with modulating cellular activity during hypoxia. PMID:10646513

  2. Prenatal alcohol exposure alters methyl metabolism and programs serotonin transporter and glucocorticoid receptor expression in brain

    PubMed Central

    Ngai, Ying Fai; Sulistyoningrum, Dian C.; O'Neill, Ryan; Innis, Sheila M.; Weinberg, Joanne

    2015-01-01

    Prenatal alcohol exposure (PAE) programs the fetal hypothalamic-pituitary-adrenal (HPA) axis, resulting in HPA dysregulation and hyperresponsiveness to stressors in adulthood. Molecular mechanisms mediating these alterations are not fully understood. Disturbances in one-carbon metabolism, a source of methyl donors for epigenetic processes, contributes to alcoholic liver disease. We assessed whether PAE affects one-carbon metabolism (including Mtr, Mat2a, Mthfr, and Cbs mRNA) and programming of HPA function genes (Nr3c1, Nr3c2, and Slc6a4) in offspring from ethanol-fed (E), pair-fed (PF), and ad libitum-fed control (C) dams. At gestation day 21, plasma total homocysteine and methionine concentrations were higher in E compared with C dams, and E fetuses had higher plasma methionine concentrations and lower whole brain Mtr and Mat2a mRNA compared with C fetuses. In adulthood (55 days), hippocampal Mtr and Cbs mRNA was lower in E compared with C males, whereas Mtr, Mat2a, Mthfr, and Cbs mRNA were higher in E compared with C females. We found lower Nr3c1 mRNA and lower nerve growth factor inducible protein A (NGFI-A) protein in the hippocampus of E compared with PF females, whereas hippocampal Slc6a4 mRNA was higher in E than C males. By contrast, hypothalamic Slc6a4 mRNA was lower in E males and females compared with C offspring. This was accompanied by higher hypothalamic Slc6a4 mean promoter methylation in E compared with PF females. These findings demonstrate that PAE is associated with alterations in one-carbon metabolism and has long-term and region-specific effects on gene expression in the brain. These findings advance our understanding of mechanisms of HPA dysregulation associated with PAE. PMID:26180184

  3. Osmotically induced cell volume changes alter anterograde and retrograde transport, Golgi structure, and COPI dissociation.

    PubMed

    Lee, T H; Linstedt, A D

    1999-05-01

    Physiological conditions that impinge on constitutive traffic and affect organelle structure are not known. We report that osmotically induced cell volume changes, which are known to occur under a variety of conditions, rapidly inhibited endoplasmic reticulum (ER)-to-Golgi transport in mammalian cells. Both ER export and ER Golgi intermediate compartment (ERGIC)-to-Golgi trafficking steps were blocked, but retrograde transport was active, and it mediated ERGIC and Golgi collapse into the ER. Extensive tubulation and relatively rapid Golgi resident redistribution were observed under hypo-osmotic conditions, whereas a slower redistribution of the same markers, without apparent tubulation, was observed under hyperosmotic conditions. The osmotic stress response correlated with the perturbation of COPI function, because both hypo- and hyperosmotic conditions slowed brefeldin A-induced dissociation of betaCOP from Golgi membranes. Remarkably, Golgi residents reemerged after several hours of sustained incubation in hypotonic or hypertonic medium. Reemergence was independent of new protein synthesis but required PKC, an activity known to mediate cell volume recovery. Taken together these results indicate the existence of a coupling between cell volume and constitutive traffic that impacts organelle structure through independent effects on anterograde and retrograde flow and that involves, in part, modulation of COPI function. PMID:10233155

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

    SciTech Connect

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

    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.

  5. Multidrug Transporters and Alterations in Sterol Biosynthesis Contribute to Azole Antifungal Resistance in Candida parapsilosis.

    PubMed

    Berkow, Elizabeth L; Manigaba, Kayihura; Parker, Josie E; Barker, Katherine S; Kelly, Stephen L; Rogers, P David

    2015-10-01

    While much is known concerning azole resistance in Candida albicans, considerably less is understood about Candida parapsilosis, an emerging species of Candida with clinical relevance. We conducted a comprehensive analysis of azole resistance in a collection of resistant C. parapsilosis clinical isolates in order to determine which genes might play a role in this process within this species. We examined the relative expression of the putative drug transporter genes CDR1 and MDR1 and that of ERG11. In isolates overexpressing these genes, we sequenced the genes encoding their presumed transcriptional regulators, TAC1, MRR1, and UPC2, respectively. We also sequenced the sterol biosynthesis genes ERG3 and ERG11 in these isolates to find mutations that might contribute to this phenotype in this Candida species. Our findings demonstrate that the putative drug transporters Cdr1 and Mdr1 contribute directly to azole resistance and suggest that their overexpression is due to activating mutations in the genes encoding their transcriptional regulators. We also observed that the Y132F substitution in ERG11 is the only substitution occurring exclusively among azole-resistant isolates, and we correlated this with specific changes in sterol biosynthesis. Finally, sterol analysis of these isolates suggests that other changes in sterol biosynthesis may contribute to azole resistance in C. parapsilosis.

  6. Tuber physiology and properties of starch from tubers of transgenic potato plants with altered plastidic adenylate transporter activity.

    PubMed

    Geigenberger, P; Stamme, C; Tjaden, J; Schulz, A; Quick, P W; Betsche, T; Kersting, H J; Neuhaus, H E

    2001-04-01

    We showed recently that antisense plants with decreased activity of the plastidic ATP/ADP-transporter protein exhibit drastically reduced levels of starch and a decreased amylose/amylopectin ratio, whereas sense plants with increased activity of the transporter possessed more starch than wild-type plants and an increased amylose/amylopectin ratio. In this paper we investigate the effect of altered plastidic ATP/ADP-transporter protein expression on primary metabolism and granule morphology in more detail. Tuber tissues from antisense and sense plants exhibited substantially increased respiratory activity compared with the wild type. Tubers from antisense plants contained markedly increased levels of free sugars, UDP-Glc, and hexose phosphates, whereas phosphoenolpyruvate, isocitrate, ATP, ADP, AMP, UTP, UDP, and inorganic pyrophosphate levels were slightly decreased. In contrast, tubers from sense plants revealed a slight increase in adenine and uridine nucleotides and in the levels of inorganic pyrophosphate, whereas no significant changes in the levels of soluble sugars and metabolites were observed. Antisense tubers contained 50% reduced levels of ADP-Glc, whereas sense tubers contained up to 2-fold increased levels of this sole precursor for starch biosynthesis. Microscopic examination of starch grain morphology revealed that the size of starch grains from antisense tubers was substantially smaller (50%) compared with the wild type. The large starch grains from sense tubers appeared of a more angular morphology, which differed to the more ellipsoid shape of wild type grains. The results suggest a close interaction between plastidial adenylate transport and starch biosynthesis, indicating that ADP-Glc pyrophosphorylase is ATP-limited in vivo and that changes in ADP-Glc concentration determine starch yield, as well as granule morphology. Possible factors linking starch synthesis and respiration are discussed.

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

    SciTech Connect

    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.

  8. Pathophysiological mechanisms of death resistance in colorectal carcinoma

    PubMed Central

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

    2015-01-01

    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. PMID:26557002

  9. Synchronous trifocal colorectal cancer

    PubMed Central

    Charalampoudis, Petros; Kykalos, Stylianos; Stamopoulos, Paraskevas; Kouraklis, Gregory

    2016-01-01

    Synchronous colorectal cancers (SCRCs) have been increasingly diagnosed due to emerging diagnostic modalities. The presence of three or more synchronous colorectal cancers has, however, only rarely been reported. A 76-year-old white man presented for management of two concurrent colorectal adenocarcinomas in the left colon evidenced on total colonoscopy. Preoperative abdominal ultrasonography and thoracoabdominal computed tomography were negative for metastatic disease. The patient underwent an elective left hemicolectomy. The pathology report ultimately showed the presence of three moderately differentiated, distinct colorectal cancers. The patient experienced an uneventful recovery. PMID:27695171

  10. Colorectal neoplasm and acromegaly.

    PubMed

    Bhansali, Anil; Dutta, Pinaki; Bhat, Mohammad Hayat; Sinha, S K; Kochar, R; Vaiphi, K

    2006-01-01

    The risk for colorectal carcinoma in acromegaly remains controversial. In our earlier study, we have demonstrated that the risk of colorectal carcinoma in Asian Indians with acromegaly is not increased and after this report, routine colonoscopy in our patients with acromegaly was abandoned. Subsequently, two consecutive young men aged 30 and 35, one 6 years after and other at the time of diagnosis of acromegaly had colorectal carcinoma respectively. None of them had family history of colonic neoplasm. These two younger patients with no other predisposition for colorectal neoplasm suggests that colonoscopy should be done in all patients with acromegaly at diagnosis and they should remain under surveillance.

  11. Synchronous trifocal colorectal cancer

    PubMed Central

    Charalampoudis, Petros; Kykalos, Stylianos; Stamopoulos, Paraskevas; Kouraklis, Gregory

    2016-01-01

    Synchronous colorectal cancers (SCRCs) have been increasingly diagnosed due to emerging diagnostic modalities. The presence of three or more synchronous colorectal cancers has, however, only rarely been reported. A 76-year-old white man presented for management of two concurrent colorectal adenocarcinomas in the left colon evidenced on total colonoscopy. Preoperative abdominal ultrasonography and thoracoabdominal computed tomography were negative for metastatic disease. The patient underwent an elective left hemicolectomy. The pathology report ultimately showed the presence of three moderately differentiated, distinct colorectal cancers. The patient experienced an uneventful recovery.

  12. Macrophages block insulin action in adipocytes by altering expression of signaling and glucose transport proteins.

    PubMed

    Lumeng, Carey N; Deyoung, Stephanie M; Saltiel, Alan R

    2007-01-01

    Obesity leads to a proinflammatory state with immune responses that include infiltration of adipose tissue with macrophages. These macrophages are believed to alter insulin sensitivity in adipocytes, but the mechanisms that underlie this effect have not been characterized. We have explored the interaction between macrophages and adipocytes in the context of both indirect and direct coculture. Macrophage-secreted factors blocked insulin action in adipocytes via downregulation of GLUT4 and IRS-1, leading to a decrease in Akt phosphorylation and impaired insulin-stimulated GLUT4 translocation to the plasma membrane. GLUT1 was upregulated with a concomitant increase in basal glucose uptake. These changes recapitulate those seen in adipose tissue from insulin-resistant humans and animal models. TNF-alpha-neutralizing antibodies partially reversed the insulin resistance produced by macrophage-conditioned media. Peritoneal macrophages and macrophage-enriched stromal vascular cells from adipose tissue also attenuated responsiveness to insulin in a manner correlating with inflammatory cytokine secretion. Adipose tissue macrophages from obese mice have an F4/80(+)CD11b(+)CD68(+)CD14(-) phenotype and form long cellular extensions in culture. Peritoneal macrophages take on similar characteristics in direct coculture with adipocytes and induce proinflammatory cytokines, suggesting that macrophage activation state is influenced by contact with adipocytes. Thus both indirect/secreted and direct/cell contact-mediated factors derived from macrophages influence insulin sensitivity in adipocytes.

  13. Alterations in serotonin receptors and transporter immunoreactivities in the hippocampus in the rat unilateral hypoxic-induced epilepsy model.

    PubMed

    An, Sung-Jin; Kim, Duk-Soo

    2011-11-01

    Unilateral hypoxic-ischemia results in the frequent occurrence of interictal spikes, and occasionally sustained ictal discharges accompanied by a reduction in paired-pulse inhibition within the non-lesioned dentate gyrus. To elucidate the roles of serotonin (5-hydroxytryptamine [5-HT]) in an epileptogenic insult, we investigated the changes in 5-HT receptors and serotonin transporter (5-HTT) immunoreactivities within the lesioned and contralateral hippocampus following unilateral hypoxic-ischemia. During epileptogenic periods following hypoxic-ischemia, both 5-HT(1A) and 5HT(1B) receptor immunoreactivities were decreased within the lesioned and the non-lesioned hippocampus. However, 5-HTT immunoreactivity was transiently increased within the hippocampus bilaterally. These findings indicate that alteration of the 5-HT system results in a "diaschisis" pattern, and may contribute to neuronal death and the development of emotional disorders in epileptic patients accompanied by psychological stress.

  14. Colonic microbiota alters host susceptibility to infectious colitis by modulating inflammation, redox status, and ion transporter gene expression.

    PubMed

    Ghosh, S; Dai, C; Brown, K; Rajendiran, E; Makarenko, S; Baker, J; Ma, C; Halder, S; Montero, M; Ionescu, V A; Klegeris, A; Vallance, B A; Gibson, D L

    2011-07-01

    Individuals vary in their resistance to enteric infections. The role of the intestinal microbiota in altering susceptibility to enteric infection is relatively unknown. Previous studies have identified that C3H/HeOuJ mice suffer 100% mortality during Citrobacter rodentium-induced colitis, whereas C57BL/6 mice recover from infection. The basis for their differences in susceptibility is unclear and has been mainly attributed to differences in host genetics. This study investigated the role of the intestinal microbiota in altering susceptibility to C. rodentium-induced colitis. When the feces of C57BL/6 mice were gavaged into antibiotic treated C3H/HeOuJ mice, the C57BL/6 microflora led to a complete reversal in mortality patterns where 100% of the C3H/HeOuJ mice survived infection. This protection corresponded with reduced colonic pathology and less systemic pathogen load and was associated with increased inflammatory and redox responses with reduced epithelial cell death. C3H/HeOuJ mice are normally susceptible to infection-induced dehydration due to defective expression of colonic ion transporters such as Dra, CA IV, and CA I; expression of these genes was normalized when C3H/HeOuJ mice were colonized with the C57BL/6 microflora. Together, these data reveal that the colonic microbiota play a critical role in protecting against intestinal infection by inducing proinflammatory and prooxidant responses that control pathogen load as well as ion transporter gene expression previously shown to prevent fatal dehydration. Protection of mice from lethal colitis was associated with higher levels of bacteria from Bacteroidetes. This study reveals that the microbiota is sufficient to overcome inherent genetic susceptibility patterns in C3H/HeOuJ mice that cause mortality during C. rodentium infection.

  15. Prenatal transportation stress alters temperament and serum cortisol concentrations in suckling Brahman calves.

    PubMed

    Littlejohn, B P; Price, D M; Banta, J P; Lewis, A W; Neuendorff, D A; Carroll, J A; Vann, R C; Welsh, T H; Randel, R D

    2016-02-01

    This experiment examined the relationship between prenatal stress and subsequent calf temperament through weaning. The prenatal stressor used was repeated transportation of pregnant Brahman cows for 2 h at 60 ± 5, 80 ± 5, 100 ± 5, 120 ± 5, and 140 ± 5 d of gestation. Prenatally stressed calves ( = 41) were compared with controls ( = 44; dams did not undergo transportation during pregnancy) from 2 wk of age until weaning (average age at weaning = 174.8 ± 1.3 d). Temperament was defined by pen score (PS; 1 = calm and 5 = excitable), exit velocity (EV; m/sec), and temperament score (TS; (PS + EV)/2) and was recorded for each calf on d -168, -140, -112, -84, -56, -28, and 0 relative to weaning (d 0 = weaning). Cortisol concentrations were determined in serum samples obtained on d -168, -140, -28, and 0 relative to weaning. Birth weight and weaning weight were not different between treatment groups ( > 0.1). Pen score was greater ( = 0.03) in prenatally stressed calves (2.84 ± 0.21) relative to controls (2.31 ± 0.21). Exit velocity was greater ( < 0.01) in prenatally stressed calves (2.1 ± 0.14 m/sec) than in controls (1.61 ± 0.14 m/sec). Exit velocity was affected by a treatment × calf sex interaction ( = 0.04) and was greater in prenatally stressed females. Exit velocity was also affected by day ( < 0.0001). Temperament score was greater ( = 0.01) in prenatally stressed calves (2.45 ± 0.16) than in controls (1.95 ± 0.16). Temperament score was affected by day ( < 0.01). Basal cortisol concentrations were greater ( = 0.04) in prenatally stressed calves (15.87 ± 1.04 ng/mL) than in controls (13.42 ± 1.03 ng/mL). Basal cortisol concentrations were greater ( < 0.01) in females (16.61 ± 1.06 ng/mL) than in males (12.68 ± 1.02 ng/mL). Cortisol concentrations were positively correlated ( < 0.01) with PS ( = 0.55, < 0.01), EV ( = 0.4, < 0.01), and TS ( = 0.55, < 0.01). Overall, suckling Brahman calves that were prenatally stressed were more temperamental and

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

    PubMed

    Nath, Aritro; Chan, Christina

    2016-01-01

    Reprogramming of cellular metabolism is a hallmark feature of cancer cells. While a distinct set of processes drive metastasis when compared to tumorigenesis, it is yet unclear if genetic alterations in metabolic pathways are associated with metastatic progression of human cancers. Here, we analyzed the mutation, copy number variation and gene expression patterns of a literature-derived model of metabolic genes associated with glycolysis (Warburg effect), fatty acid metabolism (lipogenesis, oxidation, lipolysis, esterification) and fatty acid uptake in >9000 primary or metastatic tumor samples from the multi-cancer TCGA datasets. Our association analysis revealed a uniform pattern of Warburg effect mutations influencing prognosis across all tumor types, while copy number alterations in the electron transport chain gene SCO2, fatty acid uptake (CAV1, CD36) and lipogenesis (PPARA, PPARD, MLXIPL) genes were enriched in metastatic tumors. Using gene expression profiles, we established a gene-signature (CAV1, CD36, MLXIPL, CPT1C, CYP2E1) that strongly associated with epithelial-mesenchymal program across multiple cancers. Moreover, stratification of samples based on the copy number or expression profiles of the genes identified in our analysis revealed a significant effect on patient survival rates, thus confirming prominent roles of fatty acid uptake and metabolism in metastatic progression and poor prognosis of human cancers. PMID:26725848

  17. Effects of human alterations on the hydrodynamics and sediment transport in the Sacramento-San Joaquin Delta, California

    USGS Publications Warehouse

    Marineau, Mathieu D.; Wright, Scott A.

    2015-01-01

    The Sacramento-San Joaquin Delta, California, (Delta) has been significantly altered since the mid-nineteenth century. Many existing channels have been widened or deepened and new channels have been created for navigation and water conveyance. Tidal marshes have been drained and leveed to form islands that have subsided, some of which have permanently flooded. To understand how these alterations have affected hydrodynamics and sediment transport in the Delta, we analysed measurements from 27 sites, along with other spatial data, and previous literature. Results show that: (a) the permanent flooding of islands results in an increase in the shear velocity of channels downstream, (b) artificial widening and deepening of channels generally results in a decrease in shear velocity except when the channel is also located downstream of a flooded island, (c) 1.5 Mt/year of sediment was deposited in the Delta (1997–2010), and of this deposited sediment, 0.31 Mt/year (21%) was removed through dredging.

  18. Effects of human alterations on the hydrodynamics and sediment transport in the Sacramento-San Joaquin Delta, California

    NASA Astrophysics Data System (ADS)

    Marineau, M. D.; Wright, S. A.

    2015-03-01

    The Sacramento-San Joaquin Delta, California, (Delta) has been significantly altered since the mid-nineteenth century. Many existing channels have been widened or deepened and new channels have been created for navigation and water conveyance. Tidal marshes have been drained and leveed to form islands that have subsided, some of which have permanently flooded. To understand how these alterations have affected hydrodynamics and sediment transport in the Delta, we analysed measurements from 27 sites, along with other spatial data, and previous literature. Results show that: (a) the permanent flooding of islands results in an increase in the shear velocity of channels downstream, (b) artificial widening and deepening of channels generally results in a decrease in shear velocity except when the channel is also located downstream of a flooded island, (c) 1.5 Mt/year of sediment was deposited in the Delta (1997-2010), and of this deposited sediment, 0.31 Mt/year (21%) was removed through dredging.

  19. Postnatal manganese exposure alters dopamine transporter function in adult rats: Potential impact on nonassociative and associative processes.

    PubMed

    McDougall, S A; Reichel, C M; Farley, C M; Flesher, M M; Der-Ghazarian, T; Cortez, A M; Wacan, J J; Martinez, C E; Varela, F A; Butt, A E; Crawford, C A

    2008-06-23

    In the present study, we examined whether exposing rats to a high-dose regimen of manganese chloride (Mn) during the postnatal period would depress presynaptic dopamine functioning and alter nonassociative and associative behaviors. To this end, rats were given oral supplements of Mn (750 microg/day) on postnatal days (PD) 1-21. On PD 90, dopamine transporter (DAT) immunoreactivity and [3H]dopamine uptake were assayed in the striatum and nucleus accumbens, while in vivo microdialysis was used to measure dopamine efflux in the same brain regions. The effects of postnatal Mn exposure on nigrostriatal functioning were evaluated by assessing rotorod performance and amphetamine-induced stereotypy in adulthood. In terms of associative processes, both cocaine-induced conditioned place preference (CPP) and sucrose-reinforced operant responding were examined. Results showed that postnatal Mn exposure caused persistent declines in DAT protein expression and [3H]dopamine uptake in the striatum and nucleus accumbens, as well as long-term reductions in striatal dopamine efflux. Rotorod performance did not differ according to exposure condition, however Mn-exposed rats did exhibit substantially more amphetamine-induced stereotypy than vehicle controls. Mn exposure did not alter performance on any aspect of the CPP task (preference, extinction, or reinstatement testing), nor did Mn affect progressive ratio responding (a measure of motivation). Interestingly, acquisition of a fixed ratio task was impaired in Mn-exposed rats, suggesting a deficit in procedural learning. In sum, these results indicate that postnatal Mn exposure causes persistent declines in various indices of presynaptic dopaminergic functioning. Mn-induced alterations in striatal functioning may have long-term impact on associative and nonassociative behavior.

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

    PubMed

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

    2016-05-01

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

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

    PubMed

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

    2016-05-01

    High (37)Ar activity concentration in soil gas is proposed as a key evidence for the detection of underground nuclear explosion by the Comprehensive Nuclear Test-Ban Treaty. However, such a detection is challenged by the natural background of (37)Ar in the subsurface, mainly due to Ca activation by cosmic rays. A better understanding and improved capability to predict (37)Ar activity concentration in the subsurface and its spatial and temporal variability is thus required. A numerical model integrating (37)Ar production and transport in the subsurface is developed, including variable soil water content and water infiltration at the surface. A parameterized equation for (37)Ar production in the first 15 m below the surface is studied, taking into account the major production reactions and the moderation effect of soil water content. Using sensitivity analysis and uncertainty quantification, a realistic and comprehensive probability distribution of natural (37)Ar activity concentrations in soil gas is proposed, including the effects of water infiltration. Site location and soil composition are identified as the parameters allowing for a most effective reduction of the possible range of (37)Ar activity concentrations. The influence of soil water content on (37)Ar production is shown to be negligible to first order, while (37)Ar activity concentration in soil gas and its temporal variability appear to be strongly influenced by transient water infiltration events. These results will be used as a basis for practical CTBTO concepts of operation during an OSI. PMID:26939033

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

    SciTech Connect

    Sickle-Santanello, B.J.; O'Dwyer, P.J.; Mojzisik, C.; Tuttle, S.E.; Hinkle, G.H.; Rousseau, M.; Schlom, J.; Colcher, D.; Thurston, M.O.; Nieroda, C.

    1987-10-01

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

  3. Serum-derived immunoglobulins alter amyloid beta transport across a blood-brain barrier in vitro model.

    PubMed

    Poetsch, V; Bennani-Baiti, B; Neuhaus, W; Muchitsch, E M; Noe, C R

    2010-04-01

    Since passive immunization with serum-derived immunoglobulins (intravenous immunoglobulins) showed several positive effects in some patients with Alzheimer's disease (AD), intravenous immunoglobulins (IVIG) are discussed as a possible treatment option. IVIG, an antibody product derived from human plasma, contains natural antibodies against amyloid beta(Abeta) peptide. Until now it is not known, how IVIG interferes with pathogenesis in AD, but several proposed mechanisms are in discussion. Receptor types which are involved in transport processes at the BBB are LRP, RAGE and hFcRn. We were looking for an in vitro BBB model expressing these receptors and studied the alteration of transport of Abeta peptides across this model under the influence of immunoglobulins. Cell line ECV304 was found to be suitable for our experiments. We found evidence for involvement of an improved clearance of Abeta across the BBB as well as a decreased Abeta influx from blood to the brain probably following complex formation of immunoglobulins with free Abeta in the periphery. Furthermore, we were able to confirm the activity of IVIG preparations which acted the same way but showed slightly less efficacy in comparison to monoclonal anti-Abeta antibodies. Based on these results we suggest multiple mechanisms responsible for the efficacy of immunotherapy in Alzheimer's disease.

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

    PubMed Central

    Pastor, Victoria; Gamir, Jordi; Camañes, Gemma; Cerezo, Miguel; Sánchez-Bel, Paloma; Flors, Victor

    2014-01-01

    Disruption of the high-affinity nitrate transporter NRT2.1 activates the priming defense 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 defense 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 defense 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. PMID:24910636

  5. ATP-binding cassette transporter A7 (ABCA7) loss of function alters Alzheimer amyloid processing.

    PubMed

    Satoh, Kanayo; Abe-Dohmae, Sumiko; Yokoyama, Shinji; St George-Hyslop, Peter; Fraser, Paul E

    2015-10-01

    The ATP-binding cassette transporter A7 (ABCA7) has been identified as a susceptibility factor of late onset Alzheimer disease in genome-wide association studies. ABCA7 has been shown to mediate phagocytosis and affect membrane trafficking. The current study examined the impact of ABCA7 loss of function on amyloid precursor protein (APP) processing and generation of amyloid-β (Aβ). Suppression of endogenous ABCA7 in several different cell lines resulted in increased β-secretase cleavage and elevated Aβ. ABCA7 knock-out mice displayed an increased production of endogenous murine amyloid Aβ42 species. Crossing ABCA7-deficient animals to an APP transgenic model resulted in significant increases in the soluble Aβ as compared with mice expressing normal levels of ABCA7. Only modest changes in the amount of insoluble Aβ and amyloid plaque densities were observed once the amyloid pathology was well developed, whereas Aβ deposition was enhanced in younger animals. In vitro studies indicated a more rapid endocytosis of APP in ABCA7 knock-out cells that is mechanistically consistent with the increased Aβ production. These in vitro and in vivo findings indicate a direct role of ABCA7 in amyloid processing that may be associated with its primary biological function to regulate endocytic pathways. Several potential loss-of-function ABCA7 mutations and deletions linked to Alzheimer disease that in some instances have a greater impact than apoE allelic variants have recently been identified. A reduction in ABCA7 expression or loss of function would be predicted to increase amyloid production and that may be a contributing factor in the associated Alzheimer disease susceptibility. PMID:26260791

  6. Serotonin transporter polymorphism alters citalopram effects on human pain responses to physical pain.

    PubMed

    Ma, Yina; Wang, Chenbo; Luo, Siyang; Li, Bingfeng; Wager, Tor D; Zhang, Wenxia; Rao, Yi; Han, Shihui

    2016-07-15

    Humans exhibit substantial inter-individual differences in pain perception, which contributes to variability in analgesic efficacy. Individual differences in pain sensitivity have been linked with variation in the serotonin transporter gene (5-HTTLPR), and selective serotonin reuptake inhibitors (SSRIs) such as citalopram have been increasingly used as treatments for multiple pain conditions. We combined genotyping, pharmacological challenge, and neuroimaging during painful electrical stimulation to reveal how serotonin genetics and pharmacology interact to influence pain perception and its underlying neurobiological mechanisms. In a double-blind, placebo-controlled procedure, we acutely administrated citalopram (30mgpo) to short/short (s/s) and long/long (l/l) healthy male 5-HTTLPR homozygotes during functional MRI with painful and non-painful electrical stimulation. 5-HTTLPR genotype modulated citalopram effects on pain-related brain responses in the thalamus, cerebellum, anterior insula, midcingulate cortex and inferior frontal cortex. Specifically, citalopram significantly reduced pain-related brain responses in l/l but not in s/s homozygotes. Moreover, the interaction between 5-HTTLPR genotype and pain-related brain activity was a good predictor of the citalopram-induced reductions in pain reports. The genetic modulations of citalopram effects on brain-wide pain processing were paralleled by significant effects on the Neurological Pain Signature, a multivariate brain pattern validated to be sensitive and specific to physical pain. This work provides neurobiological mechanism by which genetic variation shapes brain responses to pain perception and treatment efficacy. These findings have important implications for the types of individuals for whom serotonergic treatments provide effective pain relief, which is critical for advancing personalized pain treatment. PMID:27132044

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

    PubMed

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

    2014-10-14

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

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

    PubMed

    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, P<0.05). Upon insulin stimulation, we reported an increase in Akt (Th308 and s473 sites) and AS160 phosphorylation, which was positively (P<0.05) correlated with GLUT4 protein content in the healthy atria. During diabetes, active cell surface GLUT-4 and -8 content was downregulated in the atria (by 70% and 90%, respectively, P<0.05). Akt and AS160 phosphorylation was not impaired in the diabetic atria, suggesting the presence of an intact insulin 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.

  9. Loss of Slc26a9 anion transporter alters intestinal electrolyte and HCO3(-) transport and reduces survival in CFTR-deficient mice.

    PubMed

    Liu, Xuemei; Li, Taolang; Riederer, Brigitte; Lenzen, Henrike; Ludolph, Lisa; Yeruva, Sunil; Tuo, Biguang; Soleimani, Manoocher; Seidler, Ursula

    2015-06-01

    Slc26a9 is an anion transporter that is strongly expressed in the stomach and lung. Slc26a9 variants were recently found associated with a higher incidence of meconium ileus in cystic fibrosis (CF) infants, raising the question whether Slc26a9 is expressed in the intestine and what its functional role is. Slc26a9 messenger RNA (mRNA) was found highly expressed in the mucosae of the murine and human upper gastrointestinal tract, with an abrupt decrease in expression levels beyond the duodenum. Absence of SLC26a9 expression strongly increased the intestinally related mortality in cystic fibrosis transmembrane conductance regulator (CFTR)-deficient mice. Proximal duodenal JHCO3(-) and fluid secretion were reduced in the absence of Slc26a9 expression. In the proximal duodenum of young Slc26a9 KO mice, the glands and villi/crypts were elongated and proliferation was enhanced. This difference was lost with ageing, as were the alterations in fluid movement, whereas the reduction in JHCO3(-) remained. Laser dissection followed by qPCR suggested Slc26a9 expression to be crypt-predominant in the duodenum. In summary, deletion of Slc26a9 caused bicarbonate secretory and fluid absorptive changes in the proximal duodenal mucosa and increased the postweaning death rates in CFTR-deficient mice. Functional alterations in the duodenum were most prominent at young ages. We assume that the association of meconium ileus and Slc26a9 variants may be related to maldigestion and impaired downstream signaling caused by loss of upper GI tract digestive functions, aggravating the situation of lack of secretion and sticky mucus at the site of obstruction in CF intestine.

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

    SciTech Connect

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

    2012-12-29

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

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

    SciTech Connect

    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.

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

    NASA Astrophysics Data System (ADS)

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

    2006-05-01

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

  13. Reduced phototropism in pks mutants may be due to altered auxin-regulated gene expression or reduced lateral auxin transport.

    PubMed

    Kami, Chitose; Allenbach, Laure; Zourelidou, Melina; Ljung, Karin; Schütz, Frédéric; Isono, Erika; Watahiki, Masaaki K; Yamamoto, Kotaro T; Schwechheimer, Claus; Fankhauser, Christian

    2014-02-01

    Phototropism allows plants to orient their photosynthetic organs towards the light. In Arabidopsis, phototropins 1 and 2 sense directional blue light such that phot1 triggers phototropism in response to low fluence rates, while both phot1 and phot2 mediate this response under higher light conditions. Phototropism results from asymmetric growth in the hypocotyl elongation zone that depends on an auxin gradient across the embryonic stem. How phototropin activation leads to this growth response is still poorly understood. Members of the phytochrome kinase substrate (PKS) family may act early in this pathway, because PKS1, PKS2 and PKS4 are needed for a normal phototropic response and they associate with phot1 in vivo. Here we show that PKS proteins are needed both for phot1- and phot2-mediated phototropism. The phototropic response is conditioned by the developmental asymmetry of dicotyledonous seedlings, such that there is a faster growth reorientation when cotyledons face away from the light compared with seedlings whose cotyledons face the light. The molecular basis for this developmental effect on phototropism is unknown; here we show that PKS proteins play a role at the interface between development and phototropism. Moreover, we present evidence for a role of PKS genes in hypocotyl gravi-reorientation that is independent of photoreceptors. pks mutants have normal levels of auxin and normal polar auxin transport, however they show altered expression patterns of auxin marker genes. This situation suggests that PKS proteins are involved in auxin signaling and/or lateral auxin redistribution.

  14. Dietary omega 3 fatty acid alters prostaglandin synthesis, glucose transport and protein turnover in skeletal muscle of healthy and diabetic rats.

    PubMed Central

    Sohal, P S; Baracos, V E; Clandinin, M T

    1992-01-01

    The present study was designed to determine if dietary-fat-induced alterations in the fatty acid composition of skeletal-muscle lipid alters insulin-dependent and basal muscle metabolism, including glucose and amino acid transport, prostaglandin (PG) synthesis and protein turnover. Rats were fed on high-fat semi-purified diets providing 19% or 1% omega 3 fatty acids in the form of fish oil, for 6 weeks. After 3 weeks, half of the rats were made diabetic by a single injection of streptozotocin (50 mg/kg body wt.). After a further 3 weeks, contralateral epitrochlearis and extensor digitorum longus (EDL) muscles from each rat were incubated in vitro. High levels of dietary omega 3 fatty acids decreased PGE2 and PGF2 alpha synthesis in EDL and epitrochlearis muscle (P less than 0.0001). Diabetes and insulin had no effect on PG synthesis. Diet did not alter basal glucose or amino acid transport in EDL muscle from healthy or diabetic rats. Insulin increased glucose and amino acid transport (P less than 0.0001); the increase in glucose transport by insulin was significantly greater in muscles of rats fed on high levels of omega 3 fatty acids (P less than 0.05). Epitrochlearis from rats fed on high levels of omega 3 fatty acids showed decreased net protein degradation in the presence and absence of insulin, owing to decreased rates of protein degradation and synthesis. The data suggest that high levels of dietary omega 3 fatty acids that alter muscle membrane composition also result in alterations in glucose transport and the metabolism of muscle protein. PMID:1530573

  15. Inherited Colorectal Cancer Syndromes

    PubMed Central

    Kastrinos, Fay; Syngal, Sapna

    2011-01-01

    Colorectal cancer is the most common gastrointestinal malignancy and the second leading cause of cancer death in both men and women in the United States. Most colorectal cancer cases diagnosed annually are due to sporadic events but up to 5% are attributed to known monogenic disorders including Lynch syndrome, Familial Adenomatous Polyposis, MYH-associated polyposis, and the rare hamartomatous polyposis syndromes. These inherited colorectal cancer syndromes confer a markedly increased risk for the development of multiple cancers and predictive genetic testing is available to identify mutation carriers and at-risk family members. Through personalized strategies for diagnosis and management, a substantial reduction in morbidity and mortality has been appreciated among patients at highest risk for the development of colorectal cancer. PMID:22157284

  16. Colorectal Cancer Coalition

    MedlinePlus

    ... Reports Press Room Contact Us Sign Up We fight for Moms Dads Uncles Aunts Friends Brothers Sisters ... on Congress. Take Action Your Guide in the Fight Free resource for stage III & stage IV colorectal ...

  17. Tests for Colorectal Cancer

    MedlinePlus

    ... to look for colorectal cancer Imaging tests use sound waves, x-rays, magnetic fields, or radioactive substances to ... has spread to the liver. Ultrasound Ultrasound uses sound waves and their echoes to create images of the ...

  18. Chemoprevention of colorectal cancer.

    PubMed

    Lang, Michaela; Gasche, Christoph

    2015-01-01

    Colorectal cancer has become one of the most prevalent malignant diseases for both men and women. Patients with inflammatory bowel diseases or certain inherited cancer syndromes are at high risk of developing colorectal cancer and have naturally the highest need for cancer prevention. In familial adenomatous polyposis (FAP) and Lynch syndrome, most of the underlying germline mutations can be detected by DNA sequencing, and medical counselling of affected individuals involves both surveillance tests and chemopreventive measures. However, as the mechanisms leading to colorectal cancer differ in these high-risk groups, the molecular action of chemopreventive drugs needs to be adjusted to the certain pathway of carcinogenesis. In the last decades, a number of drugs have been tested, including sulindac, aspirin, celecoxib, and mesalazine, but some of them are still controversially discussed. This review summarizes the advances and current standards of colorectal cancer prevention in patients with inflammatory bowel disease, FAP and Lynch syndrome. PMID:25531498

  19. Epidemiology of colorectal cancer

    PubMed Central

    Marley, Andrew R; Nan, Hongmei

    2016-01-01

    Colorectal cancer is currently the third deadliest cancer in the United States and will claim an estimated 49,190 U.S. lives in 2016. The purpose of this review is to summarize our current understanding of this disease, based on nationally published statistics and information presented in peer-reviewed journal articles. Specifically, this review will cover the following topics: descriptive epidemiology (including time and disease trends both in the United States and abroad), risk factors (environmental, genetic, and gene-environment interactions), screening, prevention and control, and treatment. Landmark discoveries in colorectal cancer risk factor research will also be presented. Based on the information reviewed for this report, we suggest that future U.S. public health efforts aim to increase colorectal cancer screening among African American communities, and that future worldwide colorectal cancer epidemiology studies should focus on researching nutrient-gene interactions towards the goal of improving personalized treatment and prevention strategies. PMID:27766137

  20. Dependence receptors and colorectal cancer.

    PubMed

    Mehlen, Patrick; Tauszig-Delamasure, Servane

    2014-11-01

    The research on colorectal cancer (CRC) biology has been leading the oncology field since the early 1990s. The search for genetic alterations has allowed the identification of the main tumour suppressors or oncogenes. Recent work obtained in CRC has unexpectedly proposed the existence of novel category of tumour suppressors, the so-called 'dependence receptors'. These transmembrane receptors behave as Dr Jekyll and Mr Hyde with two opposite sides: they induce a positive signalling (survival, proliferation, differentiation) in presence of their ligand, but are not inactive in the absence of their ligand and rather trigger apoptosis when unbound. This trait confers them a conditional tumour suppressor activity: they eliminate cells that grow abnormally in an environment offering a limited quantity of ligand. This review will describe how receptors such as deleted in colorectal carcinoma (DCC), uncoordinated 5 (UNC5), rearranged during transfection (RET) or TrkC constrain CRC progression and how this dependence receptor paradigm may open up therapeutical perspectives. PMID:25163468

  1. Update on Hereditary Colorectal Cancer.

    PubMed

    DA Silva, Felipe Carneiro; Wernhoff, Patrik; Dominguez-Barrera, Constantino; Dominguez-Valentin, Mev

    2016-09-01

    In the past two decades, significant advances have been made in our understanding of colorectal (CRC) tumors with DNA mismatch (MMR) repair deficiency. The knowledge from molecular and genetic alterations in a variety of clinical conditions has refined the disease terminology and classification. Hereditary non-polyposis colorectal cancer (HNPCC) encompasses a spectrum of conditions that have significant phenotypic overlapping that makes clinical diagnosis a challenging task. Distinguishing among the HNPCC disorders is clinically important, as the approach to surveillance for patients and their at-risk family members differs according to risks for colonic and extracolonic cancer associated with each syndrome. Prospective and next-generation studies will provide valuable clinical information regarding the natural history of disease that will help differentiate the Lynch syndrome mimics and guide diagnosis and management for heterogeneous conditions currently grouped under the category of familial CRC. The review is intended to present and discuss the molecular nature of various conditions related to MMR deficiency and discusses the tools and strategies that have been used in detecting these conditions. PMID:27630275

  2. Colorectal carcinoma: Pathologic aspects

    PubMed Central

    Fleming, Matthew; Ravula, Sreelakshmi; Tatishchev, Sergei F.

    2012-01-01

    Colorectal carcinoma is one of the most common cancers and one of the leading causes of cancer-related death in the United States. Pathologic examination of biopsy, polypectomy and resection specimens is crucial to appropriate patient managemnt, prognosis assessment and family counseling. Molecular testing plays an increasingly important role in the era of personalized medicine. This review article focuses on the histopathology and molecular pathology of colorectal carcinoma and its precursor lesions, with an emphasis on their clinical relevance. PMID:22943008

  3. New Molecular Features of Colorectal Cancer Identified - Office of Cancer Clinical Proteomics Research

    Cancer.gov

    Investigators from the National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium (CPTAC) who comprehensively analyzed 95 human colorectal tumor samples, have determined how gene alterations identified in previous analyses of the same samples

  4. Risks of Colorectal Cancer Screening

    MedlinePlus

    ... Genetics of Colorectal Cancer Colorectal cancer is the second leading cause of death from cancer in the ... professional versions have detailed information written in technical language. The patient versions are written in easy-to- ...

  5. 6 Common Cancers - Colorectal Cancer

    MedlinePlus

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

  6. MTDH genetic variants in colorectal cancer patients

    PubMed Central

    Gnosa, Sebastian; Ticha, Ivana; Haapaniemi, Staffan; Sun, Xiao-Feng

    2016-01-01

    The colorectal carcinogenesis is a complex process encompassing genetic alterations. The oncoprotein AEG-1, encoded by the MTDH gene, was shown previously to be involved in colorectal cancer (CRC). The aim of this study was to determine the frequency and the spectrum of MTDH variants in tumor tissue, and their relationship to clinicopathological variables in CRC patients. The study included tumors from 356 unselected CRC patients. Mutation analysis of the MTDH gene, including coding region and adjacent intronic sequences, was performed by direct DNA sequencing. The corresponding normal colorectal tissue was analyzed in the carriers of exonic variant to confirm germline or somatic origin. We detected 42 intronic variants, where 25 were novel. Furthermore, we found 8 exonic variants of which four, one missense (c.977C > G-germline) and three frameshift mutations (c.533delA-somatic, c.1340dupA-unknown origin, c.1731delA-unknown origin), were novel. In silico prediction analyses suggested four deleterious variants (c.232G > T, c.533delA, c.1340dupA, and c.1731delA). There were no correlations between the MTDH variants and tumor stage, differentiation or patient survival. We described several novel exonic and intronic variants of the MTDH gene. The detection of likely pathogenic truncating mutations and alterations in functional protein domains indicate their clinical significance, although none of the variants had prognostic potential. PMID:26983693

  7. Prenatal transportation alters the acute phase response (APR) of bull calves exposed to a lipopolysaccharide (LPS) challenge

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This study was designed to determine if prenatal transportation influences the acute phase response (APR) to a postnatal Lipopolysaccharide (LPS) challenge. Pregnant Brahman cows (n=96) matched by age and parity were separated into transported (TRANS; n=48; transported for 2 hours on gestational day...

  8. Colorectal Cancer and Basement Membranes: Clinicopathological Correlations

    PubMed Central

    Mylonas, Charalampos C.; Lazaris, Andreas C.

    2014-01-01

    Colorectal cancer (CRC) is the third most commonly diagnosed cancer in males and the second in females. In 2008, an estimated 1.2 million people were diagnosed with and 608,700 people died of CRC. Besides diagnosis and treatment, prognosis is an important matter for cancer patients. Today, clinicopathological correlations have many applications in cancer prognostication. Examples include the prediction of the medium patient survival and the screening for patients suitable for specific therapeutic approaches. Apart from traditional prognostic factors, such as tumor stage and grade, new markers may be useful in clinical practice. Possible markers may result from the study of basement membranes (BMs). BM seems to play a role in the pathogenesis of colorectal cancer, so BM alterations may have prognostic significance as well. The purpose of this review is to briefly describe BMs and their relationship with CRC, in the aspect of clinicopathological correlations. PMID:25614736

  9. Missense Polymorphisms in the Adenomatous Polyposis Coli Gene and Colorectal Cancer Risk

    PubMed Central

    Cleary, Sean P.; Kim, Hyeja; Croitoru, Marina E.; Redston, Mark; Knight, Julia A.; Gallinger, Steven; Gryfe, Robert

    2009-01-01

    PURPOSE Whereas truncating germline mutations of the adenomatous polyposis coli (APC) gene give rise to familial adenomatous polyposis, missense polymorphisms of APC may confer a weaker risk for colorectal cancer. METHODS We sequenced the entire open reading frame of the APC gene and tested for two common MYH mutations in a population-based series of patients with colorectal cancer and 5 to 99 adenomas. Missense adenomatous polyposis coli alterations identified in this colorectal cancer multiple-polyp population were analyzed in a population-based series of patients with colorectal cancer and healthy control subjects. RESULTS Germline APC or mutY human homologue (MYH) alterations were identified in 16 of 39 colorectal cancer-multiple polyp patients. Four missense APC gene alterations (S130G, E1317Q, Dl822V, G2502S) were observed in 13 individuals and 3 additional patients carried presumed pathogenic (APC Y94X, biallelic MYH Y165C and heterozygous MYH G382D) mutations. When independently assessed in 971 patients with colorectal cancer and 954 healthy control subjects, none of the identified missense APC alterations conferred a significantly increased risk for colorectal cancer, odds ratio (95 percent confidence intervals): S130G=3.1 (0.29–32.25), E1317Q= 1.08 (0.59–2.74), G2502S= 1 (0.65–1.63), D1822V (heterozygous)=0.79 (0.64–0.98), D1822V (homozygous) =0.82 (0.63–1.27). CONCLUSIONS Germline missense APC alterations observed in 33 percent of patients with multiple colorectal neoplasms seemed to play a limited role in colorectal cancer risk when independently assessed by a population-based, case-control analysis. PMID:18612690

  10. Schisandra chinensis Peptidoglycan-Assisted Transmembrane Transport of Lignans Uniquely Altered the Pharmacokinetic and Pharmacodynamic Mechanisms in Human HepG2 Cell Model

    PubMed Central

    Chyau, Charng-Cherng; Ker, Yaw-Bee; Chang, Chi-Huang; Huang, Shiau-Huei; Wang, Hui-Er; Peng, Chiung-Chi; Peng, Robert Y.

    2014-01-01

    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”. PMID:24475039

  11. Clinical aspects of urea cycle dysfunction and altered brain energy metabolism on modulation of glutamate receptors and transporters in acute and chronic hyperammonemia.

    PubMed

    Natesan, Vijayakumar; Mani, Renuka; Arumugam, Ramakrishnan

    2016-07-01

    In living organisms, nitrogen arise primarily as ammonia (NH3) and ammonium (NH4(+)), which is a main component of the nucleic acid pool and proteins. Although nitrogen is essential for growth and maintenance in animals, but when the nitrogenous compounds exceeds the normal range which can quickly lead to toxicity and death. Urea cycle is the common pathway for the disposal of excess nitrogen through urea biosynthesis. Hyperammonemia is a consistent finding in many neurological disorders including congenital urea cycle disorders, reye's syndrome and acute liver failure leads to deleterious effects. Hyperammonemia and liver failure results in glutamatergic neurotransmission which contributes to the alteration in the function of the glutamate-nitric oxide-cGMP pathway, modulates the important cerebral process. Even though ammonia is essential for normal functioning of the central nervous system (CNS), in particular high concentrations of ammonia exposure to the brain leads to the alterations of glutamate transport by the transporters. Several glutamate transporters have been recognized in the central nervous system and each has a unique physiological property and distribution. The loss of glutamate transporter activity in brain during acute liver failure and hyperammonemia is allied with increased extracellular brain glutamate concentrations which may be conscientious for the cerebral edema and ultimately cell death. PMID:27261594

  12. The transparent testa4 mutation prevents flavonoid synthesis and alters auxin transport and the response of Arabidopsis roots to gravity and light.

    PubMed

    Buer, Charles S; Muday, Gloria K

    2004-05-01

    We examined whether flavonoids act as endogenous auxin transport regulators during gravity vector and light intensity changes in Arabidopsis thaliana roots. Flavonoid deficient transparent testa4 [tt4(2YY6)] seedlings had elevated root basipetal auxin transport compared with the wild type, consistent with the absence of a negative auxin transport regulator. The tt4(2YY6) roots had delayed gravitropism that was chemically complemented with a flavonoid intermediate. Flavonoid accumulation was found in wild-type columella cells, the site of gravity perception, and in epidermal and cortical cells, the site of differential growth, but flavonoid accumulation was absent in tt4(2YY6) roots. Flavonoid accumulation was higher in gravity-stimulated root tips as compared with vertical controls, with maximum differences coinciding with the timing of gravitropic bending, and was located in epidermal cells. Exogenous indole-3-acetic acid (IAA) also elevated flavonoid accumulation, suggesting that flavonoid changes in response to gravity might be partly as a result of changing IAA distribution. Acropetal IAA transport was also elevated in roots of tt4(2YY6). Flavonoid synthesis was repressed in the dark, as were differences in root acropetal transport in tt4(2YY6). These results are consistent with light- and gravity-induced flavonoid stimulation that alters auxin transport in roots and dependent physiological processes, including gravitropic bending and root development.

  13. The role of pyrrole formation in the alteration of neurofilament transport induced during exposure to 2,5-hexanedione.

    PubMed

    Pyle, S J; Amarnath, V; Graham, D G; Anthony, D C

    1992-07-01

    Exposure to the gamma-diketone, 2,5-hexanedione (HD), results in the accumulation of neurofilaments within the distal axon and is associated with acceleration of neurofilament transport within the proximal axon. The epsilon-amino groups of lysyl residues react with HD forming pyrrole adducts, followed by pyrrole-mediated protein crosslinking. Both reaction steps have been proposed as mechanisms causing neurofilament accumulation and acceleration of transport. In order to assess the importance of these steps on neurofilament transport, we compared transport in the optic system of rats exposed to HD and 3-acetyl-2,5-hexanedione (AcHD), a non-toxic analog of HD which forms pyrroles but does not crosslink proteins. Control, HD-treated, and AcHD-treated rats received intraoptic injections of [35S]-methionine and were exposed to saline, HD, or AcHD by intraperitoneal injections before and during the period of neurofilament transport. Neurofilament triplet proteins in the optic nerve and tract were identified by polyacrylamide gel electrophoresis followed by fluorography. The rate of neurofilament transport was accelerated in HD-treated animals over that of controls. However, despite higher levels of protein-bound pyrroles in AcHD-treated animals, the rate of transport was indistinguishable from that of controls. These findings indicate that pyrrole formation alone is not sufficient to cause acceleration of neurofilament transport.

  14. Management of Colorectal Trauma

    PubMed Central

    2011-01-01

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

  15. [Nutrition and colorectal cancer].

    PubMed

    Ströhle, Alexander; Maike, Wolters; Hahn, Andreas

    2007-01-01

    Diet plays an important role in the pathogenesis of colorectal cancer. Current prospective cohort studies and metaanalysis enable a reevaluation of how food or nutrients such as fiber and fat influence cancer risk. Based on the evidence criteria of the WHO/FAD, risk reduction by a high intake of fruit is assessed as possible, while a lowered risk by a high vegetable intake is probable. Especially raw vegetables and fruits seem to exert anticancer properties. The evidence of a risk reducing effect of whole grain relating to colorectal cancer is assessed as probable whereas the evidence of an increased risk by high consumption of refined white flour products and sweets is (still) insufficient despite some evidences. There is a probable risk reducing effect of milk and dairy products. e available data on eggs and red meat indicate a possible risk increasing influence. Stronger clues for a risk increasing effect have been shown for meat products leading to an evidence assessed as probable. Owing to varied interpretations of the data on fiber, the evidence of a risk reducing effect relating to colorectal cancer is assessed as possible or insufficient. The available data on alcohol consumption indicate a possible risk increasing effect. In contrast to former evaluations, diets rich in fat seem to increase colorectal cancer risk only indirectly as part of a hypercaloric diet by advancing the obesity risk. Thus, the evidence of obesity, especially visceral obesity, as a risk of colorectal cancer is judged as convincing today. Prospective cohort studies suggest that people who get higher than average amounts of folic acid from multivitamin supplements have lower risks of colorectal cancer. The evidence for a risk reducing effect of calcium, selenium, vitamin D and vitamin E on colorectal cancer is insufficient. As primary prevention, a diet rich in vegetables, fruits, whole grain products, and legumes added by low-fat dairy products, fish, and poultry can be recommended. In

  16. Serrated colorectal cancer: Molecular classification, prognosis, and response to chemotherapy

    PubMed Central

    Murcia, Oscar; Juárez, Miriam; Hernández-Illán, Eva; Egoavil, Cecilia; Giner-Calabuig, Mar; Rodríguez-Soler, María; Jover, Rodrigo

    2016-01-01

    Molecular advances support the existence of an alternative pathway of colorectal carcinogenesis that is based on the hypermethylation of specific DNA regions that silences tumor suppressor genes. This alternative pathway has been called the serrated pathway due to the serrated appearance of tumors in histological analysis. New classifications for colorectal cancer (CRC) were proposed recently based on genetic profiles that show four types of molecular alterations: BRAF gene mutations, KRAS gene mutations, microsatellite instability, and hypermethylation of CpG islands. This review summarizes what is known about the serrated pathway of CRC, including CRC molecular and clinical features, prognosis, and response to chemotherapy. PMID:27053844

  17. Prediction of Altered Bile Acid Disposition Due to Inhibition of Multiple Transporters: An Integrated Approach Using Sandwich-Cultured Hepatocytes, Mechanistic Modeling, and Simulation.

    PubMed

    Guo, Cen; Yang, Kyunghee; Brouwer, Kenneth R; St Claire, Robert L; Brouwer, Kim L R

    2016-08-01

    Transporter-mediated alterations in bile acid disposition may have significant toxicological implications. Current methods to predict interactions are limited by the interplay of multiple transporters, absence of protein in the experimental system, and inaccurate estimates of inhibitor concentrations. An integrated approach was developed to predict altered bile acid disposition due to inhibition of multiple transporters using the model bile acid taurocholate (TCA). TCA pharmacokinetic parameters were estimated by mechanistic modeling using sandwich-cultured human hepatocyte data with protein in the medium. Uptake, basolateral efflux, and biliary clearance estimates were 0.63, 0.034, and 0.074 mL/min/g liver, respectively. Cellular total TCA concentrations (Ct,Cells) were selected as the model output based on sensitivity analysis. Monte Carlo simulations of TCA Ct,Cells in the presence of model inhibitors (telmisartan and bosentan) were performed using inhibition constants for TCA transporters and inhibitor concentrations, including cellular total inhibitor concentrations ([I]t,cell) or unbound concentrations, and cytosolic total or unbound concentrations. For telmisartan, the model prediction was accurate with an average fold error (AFE) of 0.99-1.0 when unbound inhibitor concentration ([I]u) was used; accuracy dropped when total inhibitor concentration ([I]t) was used. For bosentan, AFE was 1.2-1.3 using either [I]u or [I]t This difference was evaluated by sensitivity analysis of the cellular unbound fraction of inhibitor (fu,cell,inhibitor), which revealed higher sensitivity of fu,cell,inhibitor for predicting TCA Ct,Cells when inhibitors exhibited larger ([I]t,cell/IC50) values. In conclusion, this study demonstrated the applicability of a framework to predict hepatocellular bile acid concentrations due to drug-mediated inhibition of transporters using mechanistic modeling and cytosolic or cellular unbound concentrations. PMID:27233294

  18. Radioimmunodetection of colorectal cancer

    SciTech Connect

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

    1980-03-15

    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 /sup 131/I at a total dose of at least 1.0 ..mu..Ci. 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 /sup 131/I-labeled anti-CEA IgG, while two colonic carcinoma patients received normal goat IgG labelled with /sup 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.

  19. Radioimmunodetection of colorectal cancer.

    PubMed

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

    1980-03-15

    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 muCi. 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-labelled 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 appraent 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.

  20. Low speed wind tunnel investigation of span load alteration, forward-located spoilers, and splines as trailing-vortex-hazard alleviation devices on a transport aircraft model

    NASA Technical Reports Server (NTRS)

    Croom, D. R.; Dunham, R. E., Jr.

    1975-01-01

    The effectiveness of a forward-located spoiler, a spline, and span load alteration due to a flap configuration change as trailing-vortex-hazard alleviation methods was investigated. For the transport aircraft model in the normal approach configuration, the results indicate that either a forward-located spoiler or a spline is effective in reducing the trailing-vortex hazard. The results also indicate that large changes in span loading, due to retraction of the outboard flap, may be an effective method of reducing the trailing-vortex hazard.

  1. Colorectal tumors: the histology report.

    PubMed

    Lanza, Giovanni; Messerini, Luca; Gafà, Roberta; Risio, Mauro

    2011-03-01

    Epithelial colorectal tumors are common pathologic entities. Their histology report should be comprehensive of a series of pathologic parameters essential for the correct clinical management of the patients. Diagnostic histologic criteria of adenomatous, serrated, inflammatory, and hamartomatous polyps and of polyposis syndromes are discussed. In addition, the pathologic features of early and advanced colorectal cancer are described and a checklist is given. Finally, molecular prognostic and predictive factors currently employed in the treatment of colorectal cancer are discussed.

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

    PubMed

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

    2013-01-25

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

  3. Acute changes in cellular zinc alters zinc uptake rates prior to zinc transporter gene expression in Jurkat cells.

    PubMed

    Holland, Tai C; Killilea, David W; Shenvi, Swapna V; King, Janet C

    2015-12-01

    A coordinated network of zinc transporters and binding proteins tightly regulate cellular zinc levels. Canonical responses to zinc availability are thought to be mediated by changes in gene expression of key zinc transporters. We investigated the temporal relationships of actual zinc uptake with patterns of gene expression in membrane-bound zinc transporters in the human immortalized T lymphocyte Jurkat cell line. Cellular zinc levels were elevated or reduced with exogenous zinc sulfate or N,N,N',N-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN), respectively. Excess zinc resulted in a rapid 44 % decrease in the rate of zinc uptake within 10 min. After 120 min, the expression of metallothionein (positive control) increased, as well as the zinc exporter, ZnT1; however, the expression of zinc importers did not change during this time period. Zinc chelation with TPEN resulted in a rapid twofold increase in the rate of zinc uptake within 10 min. After 120 min, the expression of ZnT1 decreased, while again the expression of zinc importers did not change. Overall, zinc transporter gene expression kinetics did not match actual changes in cellular zinc uptake with exogenous zinc or TPEN treatments. This suggests zinc transporter regulation may be the initial response to changes in zinc within Jurkat cells.

  4. Folic acid and sodium butyrate prevent tumorigenesis in a mouse model of colorectal cancer.

    PubMed

    Lu, Rong; Wang, Xia; Sun, Dan-Feng; Tian, Xiao-Qing; Zhao, Shu-Liang; Chen, Ying-Xuan; Fang, Jing-Yuan

    2008-11-01

    Colorectal cancer is a leading cause of morbidity and mortality worldwide, and its incidence has been increasing in recent years. The role of epigenetic modifications, including DNA methylation and histone modifications, has only recently been investigated. In this study, the effects of epigenetic agents such as folic acid (FA) and sodium butyrate (NaBu) on the development of colorectal cancer induced by 1,2-dimethylhydrazine (DMH) using ICR mice was examined. Of the mice treated in a chemopreventive manner with epigenetic agents, FA and NaBu, 15-50% developed colorectal cancer at 24 weeks compared with a 95% incidence of colorectal cancer in DMH-treated control mice. Folate deficiency can alter cytosine methylation in DNA leading to inappropriate activation of the proto-oncogene c-myc. We detected lower levels of p21(WAF1) gene expression in colorectal cancer samples, as well as significantly lower levels of acetylated histone H3, compared with samples from corresponding normal colorectal mucosa. In contrast, administration of NaBu increased levels of p21(WAF1) mRNA and p21(WAF1) protein, and was associated with an accumulation of histone acetylation. In summary, our results show that FA and NaBu reduce the incidence of colorectal cancer induced by DMH-induced in ICR mice, and therefore we hypothesize that targeting epigenetic targets should be further investigated for the prevention of colorectal cancer in humans.

  5. Targeting mTOR network in colorectal cancer therapy

    PubMed Central

    Wang, Xiao-Wen; Zhang, Yan-Jie

    2014-01-01

    The mechanistic target of rapamycin (mTOR) integrates growth factor signals with cellular nutrient and energy levels and coordinates cell growth, proliferation and survival. A regulatory network with multiple feedback loops has evolved to ensure the exquisite regulation of cell growth and division. Colorectal cancer is the most intensively studied cancer because of its high incidence and mortality rate. Multiple genetic alterations are involved in colorectal carcinogenesis, including oncogenic Ras activation, phosphatidylinositol 3-kinase pathway hyperactivation, p53 mutation, and dysregulation of wnt pathway. Many oncogenic pathways activate the mTOR pathway. mTOR has emerged as an effective target for colorectal cancer therapy. In vitro and preclinical studies targeting the mTOR pathway for colorectal cancer chemotherapy have provided promising perspectives. However, the overall objective response rates in major solid tumors achieved with single-agent rapalog therapy have been modest, especially in advanced metastatic colorectal cancer. Combination regimens of mTOR inhibitor with agents such as cytotoxic chemotherapy, inhibitors of vascular endothelial growth factor, epidermal growth factor receptor and Mitogen-activated protein kinase kinase (MEK) inhibitors are being intensively studied and appear to be promising. Further understanding of the molecular mechanism in mTOR signaling network is needed to develop optimized therapeutic regimens. In this paper, oncogenic gene alterations in colorectal cancer, as well as their interaction with the mTOR pathway, are systematically summarized. The most recent preclinical and clinical anticancer therapeutic endeavors are reviewed. New players in mTOR signaling pathway, such as non-steroidal anti-inflammatory drug and metformin with therapeutic potentials are also discussed here. PMID:24764656

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

    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

  8. Biology of colorectal cancer

    PubMed Central

    Arvelo, Francisco; Sojo, Felipe; Cotte, Carlos

    2015-01-01

    Colorectal cancer is a serious health problem, a challenge for research, and a model for studying the molecular mechanisms involved in its development. According to its incidence, this pathology manifests itself in three forms: family, hereditary, and most commonly sporadic, apparently not associated with any hereditary or familial factor. For the types having inheritance patterns and a family predisposition, the tumours develop through defined stages ranging from adenomatous lesions to the manifestation of a malignant tumour. It has been established that environmental and hereditary factors contribute to the development of colorectal cancer, as indicated by the accumulation of mutations in oncogenes, genes which suppress and repair DNA, signaling the existence of various pathways through which the appearance of tumours may occur. In the case of the suppressive and mutating tracks, these are characterised by genetic disorders related to the phenotypical changes of the morphological progression sequence in the adenoma/carcinoma. Moreover, alternate pathways through mutation in BRAF and KRAS genes are associated with the progression of polyps to cancer. This review surveys the research done at the cellular and molecular level aimed at finding specific alternative therapeutic targets for fighting colorectal cancer. PMID:25932044

  9. Transportation.

    ERIC Educational Resources Information Center

    Crank, Ron

    This instructional unit is one of 10 developed by students on various energy-related areas that deals specifically with transportation and energy use. Its objective is for the student to be able to discuss the implication of energy usage as it applies to the area of transportation. Some topics covered are efficiencies of various transportation…

  10. Using Genetics to Identify Hereditary Colorectal Polyposis and Cancer Syndromes in Your Patient.

    PubMed

    Macaron, Carole; Heald, Brandie; Burke, Carol A

    2015-10-01

    The majority of patients with colorectal polyps and cancer do not have a Mendelian cause of the disease. Age, lifestyle, and environmental factors interact with complex genetic traits to contribute to the etiology. However, approximately 5-10 % of patients with colorectal cancer (CRC) and more than 40 % of patients meeting specific clinical features of the hereditary polyposis syndromes have a discoverable, actionable genetic cause which will significantly alter their medical management. PMID:26292665

  11. Adenosine protects Sprague Dawley rats from high-fat diet and repeated acute restraint stress-induced intestinal inflammation and altered expression of nutrient transporters.

    PubMed

    Lee, C Y

    2015-04-01

    This study investigated the effect of repeated acute restraint stress and high-fat diet (HFD) on intestinal expression of nutrient transporters, concomitant to intestinal inflammation. The ability of adenosine to reverse any change was examined. Six-week-old male Sprague Dawley rats were divided into eight groups: control or non-stressed (C), rats exposed to restraint stress for 6 h per day for 14 days (S), control rats fed with HFD (CHF) and restraint-stressed rats fed with HFD (SHF); four additional groups received the same treatments and were also given 50 mg/l adenosine dissolved in drinking water. Fasting blood glucose, plasma insulin, adiponectin and corticosterone were measured. Intestinal expression of SLC5A1, SLC2A2, NPC1L1 and TNF-α was analysed. Histological evaluation was conducted to observe for morphological and anatomical changes in the intestinal tissues. Results showed that HFD feeding increased glucose and insulin levels, and repeated acute restraint stress raised the corticosterone level by 22%. Exposure to both stress and HFD caused a further increase in corticosterone to 41%, while decreasing plasma adiponectin level. Restraint stress altered intestinal expression of SLC5A1, SLC2A2 and NPC1L1. These changes were enhanced in SHF rats. Adenosine was found to alleviate HFD-induced increase in glucose and insulin levels, suppress elevation of corticosterone in S rats and improve the altered nutrient transporters expression profiles. It also prevented upregulation of TNF-α in the intestine of SHF rats. In summary, a combination of stress and HFD exaggerated stress- and HFD-induced pathophysiological changes in the intestine, and biochemical parameters related to obesity. Adenosine attenuated the elevation of corticosterone and altered expression of SLC5A1, NPC1L1 and TNF-α.

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed Central

    Rebouche, C J; Engel, A G

    1984-01-01

    The human primary carnitine deficiency syndromes are potentially fatal disorders affecting children and adults. The molecular etiologies of these syndromes have not been determined. In this investigation, we considered the hypothesis that these syndromes result from defective transport of carnitine into tissues, particularly skeletal muscle. The problem was approached by mathematical modeling, by using the technique of kinetic compartmental analysis. A tracer dose of L-[methyl-3H]carnitine was administered intravenously to six normal subjects, one patient with primary muscle carnitine deficiency (MCD), and four patients with primary systemic carnitine deficiency (SCD). Specific radioactivity was followed in plasma for 28 d. A three-compartment model (extracellular fluid, muscle, and "other tissues") was adopted. Rate constants, fluxes, pool sizes, and turnover times were calculated. Results of these calculations indicated reduced transport of carnitine into muscle in both forms of primary carnitine deficiency. However, in SCD, the reduced rate of carnitine transport was attributed to reduced plasma carnitine concentration. In MCD, the results are consistent with an intrinsic defect in the transport process. Abnormal fluctuations of the plasma carnitine, but of a different form, occurred in MCD and SCD. The significance of these are unclear, but in SCD they suggest abnormal regulation of the muscle/plasma carnitine concentration gradient. In 8 of 11 subjects, carnitine excretion was less than dietary carnitine intake. Carnitine excretion rates calculated by kinetic compartmental analysis were higher than corresponding rates measured directly, indicating degradation of carnitine. However, we found no radioactive metabolites of L-[methyl-3H]carnitine in urine. These observations suggest that dietary carnitine was metabolized in the gastrointestinal tract. PMID:6707204

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

    PubMed Central

    Ramos-Chávez, Lucio A.; Rendón-López, Christian R. R.; Zepeda, Angélica; Silva-Adaya, Daniela; Del Razo, Luz M.; Gonsebatt, María E.

    2015-01-01

    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 (CNS). 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. PMID:25709567

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

    PubMed

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

    2015-06-01

    Hyperimmunized hens are an effective means of generating large quantities of antigen specific egg antibodies that have use as oral supplements. In this study, we attempted to create a peptide specific antibody that produced outcomes similar to those of the human pharmaceutical, sevelamer HCl, used in the treatment of hyperphosphatemia (a sequela of chronic renal disease). Egg antibodies were generated against 8 different human intestinal sodium-dependent phosphate cotransporter 2b (NaPi2b) peptides, and hNaPi2b peptide egg antibodies were screened for their ability to inhibit phosphate transport in human intestinal Caco-2 cell line. Antibody produced against human peptide sequence TSPSLCWT (anti-h16) was specific for its peptide sequence, and significantly reduced phosphate transport in human Caco-2 cells to 25.3±11.5% of control nonspecific antibody, when compared to nicotinamide, a known inhibitor of phosphate transport (P≤0.05). Antibody was then produced against the mouse-specific peptide h16 counterpart (mouse sequence TSPSYCWT, anti-m16) for further analysis in a murine model. When anti-m16 was fed to mice (1% of diet as dried egg yolk powder), egg yolk immunoglobulin (IgY) was detected using immunohistochemical staining in mouse ileum, and egg anti-m16 IgY colocalized with a commercial goat anti-NaPi2b antibody. The effectiveness of anti-m16 egg antibody in reducing serum phosphate, when compared to sevelamer HCl, was determined in a mouse feeding study. Serum phosphate was reduced 18% (P<0.02) in mice fed anti-m16 (1% as dried egg yolk powder) and 30% (P<0.0001) in mice fed sevelamer HCl (1% of diet) when compared to mice fed nonspecific egg immunoglobulin. The methods described and the findings reported show that oral egg antibodies are useful and easy to prepare reagents for the study and possible treatment of select diseases.

  16. Glutamate transporters alterations in the reorganizing dentate gyrus are associated with progressive seizure activity in chronic epileptic rats.

    PubMed

    Gorter, Jan A; Van Vliet, Erwin A; Proper, Evelien A; De Graan, Pierre N E; Ghijsen, Wim E J M; Lopes Da Silva, Fernando H; Aronica, Eleonora

    2002-01-21

    The expression of glial and neuronal glutamate transporter proteins was investigated in the hippocampal region at different time points after electrically induced status epilepticus (SE) in the rat. This experimental rat model for mesial temporal lobe epilepsy is characterized by cell loss, gliosis, synaptic reorganization, and chronic seizures after a latent period. Despite extensive gliosis, immunocytochemistry revealed only an up-regulation of both glial transporters localized at the outer aspect of the inner molecular layer (iml) in chronic epileptic rats. The neuronal EAAC1 transporter was increased in many somata of individual CA1-3 neurons and granule cells that had survived after SE; this up-regulation was still present in the chronic epileptic phase. In contrast, a permanent decrease of EAAC1 immunoreactivity was observed in the iml of the dentate gyrus. This permanent decrease in EAAC1 expression, which was only observed in rats that experienced progressive spontaneous seizure activity, could lead to abnormal glutamate levels in the iml once new abnormal glutamatergic synaptic contacts are formed by means of sprouted mossy fibers. Considering the steady growth of reorganizing mossy fibers in the iml, the absence of a glutamate reuptake mechanism in this region could contribute to progression of spontaneous seizure activity, which occurs with a similar time course.

  17. Ca2+ Transport in Membrane Vesicles from Pinto Bean Leaves and Its Alteration after Ozone Exposure 1

    PubMed Central

    Castillo, Federico J.; Heath, Robert L.

    1990-01-01

    The influence of ozone on Ca2+ transport in plant membranes from pinto bean (Phaseolus vulgaris L. var Pinto) leaves was investigated in vitro by means of a filtration method using purified vesicles. Two transport mechanisms located at the plasma membrane are involved in a response to ozone: (a) passive Ca2+ influx into the cell and (b) active Ca2+ efflux driven by an ATP-dependent system, which has two components: a primary Ca2+ transport directly linked to ATP which is partially activated by calmodulin and a H+/Ca2+ antiport coupled to activity of a H+-ATPase. The passive Ca2+ permeability is increased by ozone. A triangular pulse of ozone stimulates a higher influx of Ca2+ than does a square wave, even though the total dose was the same (0.6 microliter per liter × hour). Leaves exposed to a square wave did not exhibit visible injury and were still able to recover from oxidant stress by activation of calmodulin-dependent Ca2+ extrusion mechanisms. On the other hand, leaves exposed to a triangular wave of ozone, exhibit visible injury and lost the ability of extruding Ca2+ out of the cell. PMID:16667780

  18. Genetic deficiency of carnitine/organic cation transporter 2 (slc22a5) is associated with altered tissue distribution of its substrate pyrilamine in mice.

    PubMed

    Kato, Sayaka; Kato, Yukio; Nakamura, Tadakatsu; Sugiura, Tomoko; Kubo, Yoshiyuki; Deguchi, Yoshiharu; Tsuji, Akira

    2009-12-01

    Carnitine/organic cation transporter 2 (OCTN2) recognizes various cationic compounds as substrates in vitro, but information on its pharmacokinetic role in vivo is quite limited. This paper demonstrates altered tissue distribution of the OCTN2 substrate pyrilamine in juvenile visceral steatosis (jvs) mice, which have a hereditary defect of the octn2 gene. At 30 min after intravenous injection of pyrilamine, the tissue-to-plasma concentration ratio (K(p)) in the heart and pancreas was higher, whereas the K(p) in kidney and testis was lower in jvs mice compared with wild-type mice. Pyrilamine transport studies in isolated heart slices confirmed higher accumulation, together with lower efflux, of pyrilamine in the heart of jvs mice. The higher accumulation in heart slices of jvs mice was abolished by lowering the temperature, by increasing the substrate concentration, and in the presence of other H(1) antagonists or another OCTN2 substrate, carnitine, suggesting that OCTN2 extrudes pyrilamine from heart tissue. On the other hand, the lower distribution to the kidney of jvs mice was probably due to down-regulation of a basolateral transporter coupled with OCTN2, because, in jvs mice, (i) the K(p) of pyrilamine in kidney assessed immediately after intravenous injection (approximately 1 min) was also lower, (ii) the urinary excretion of pyrilamine was lower, and (iii) the uptake of pyrilamine in kidney slices was lower. The renal uptake of pyrilamine was saturable (K(m) approximately 236 microM) and was strongly inhibited by cyproheptadine, astemizole, ebastine and terfenadine. The present study thus indicates that genetic deficiency of octn2 alters pyrilamine disposition tissue-dependently. PMID:19821448

  19. Epigenetics and Colorectal Cancer Pathogenesis

    PubMed Central

    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. PMID:24216997

  20. MicroRNA Methylation in Colorectal Cancer.

    PubMed

    Kaur, Sippy; Lotsari-Salomaa, Johanna E; Seppänen-Kaijansinkko, Riitta; Peltomäki, Päivi

    2016-01-01

    Epigenetic alterations such as DNA methylation, histone modifications and non-coding RNA (including microRNA) associated gene silencing have been identified as a major characteristic in human cancers. These alterations may occur more frequently than genetic mutations and play a key role in silencing tumor suppressor genes or activating oncogenes, thereby affecting multiple cellular processes. In recent years, studies have shown that microRNAs, that act as posttranscriptional regulators of gene expression are frequently deregulated in colorectal cancer (CRC), via aberrant DNA methylation. Over the past decade, technological advances have revolutionized the field of epigenetics and have led to the identification of numerous epigenetically dysregulated miRNAs in CRC, which are regulated by CpG island hypermethylation and DNA hypomethylation. In addition, aberrant DNA methylation of miRNA genes holds a great promise in several clinical applications such as biomarkers for early screening, prognosis, and therapeutic applications in CRC. PMID:27573897

  1. Distinct alterations in ATP-binding cassette transporter expression in liver, kidney, small intestine, and brain in adjuvant-induced arthritic rats.

    PubMed

    Kawase, Atsushi; Norikane, Sari; Okada, Ayaka; Adachi, Mamiko; Kato, Yukio; Iwaki, Masahiro

    2014-08-01

    Pathophysiological changes of infection or inflammation are associated with alterations in the production of numerous absorption, distribution, metabolism and excretion-related proteins. However, little information is available on the effects of inflammation on the expression levels and activities of ATP-binding cassette (ABC) transporters. We examined the effect of acute (on day 7) and chronic (on day 21) inflammation on the expression of ABC transporters in some major tissues in rat. Adjuvant-induced arthritis (AA) in rats was used as an animal model for inflammation. The mRNA levels of mdr1a and mdr1b encoding P-glycoprotein (P-gp) decreased significantly in livers of AA rats on day 21. Hepatic protein levels of P-gp, Mrp2, and Bcrp decreased significantly in membranes but not homogenates of AA rats after 7 days and after 21 days of treatment with adjuvant. Contrary to liver, protein levels of P-gp and Mrp2, but not Bcrp in kidney, increased significantly in membranes. The biliary excretion of rhodamine 123 was decreased in rats with chronic inflammation owing to decreases in efflux activities of P-gp. Our results showed that the expression of transporters in response to inflammation was organ dependent. In particular, hepatic and renal P-gp and Mrp2 exhibited opposite changes in membrane protein levels.

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

    PubMed

    Zhang, Ying; Zhao, Xin; Chang, Yanzhong; Zhang, Yuanyuan; Chu, Xi; Zhang, Xuan; Liu, Zhenyi; Guo, Hui; Wang, Na; Gao, Yonggang; Zhang, Jianping; Chu, Li

    2016-06-15

    Liver fibrosis is the principal cause of morbidity and mortality in patients with iron overload. Calcium channel blockers (CCBs) can antagonize divalent cation entry into renal and myocardial cells and inhibit fibrogenic gene expression. We investigated the potential of CCBs to resolve iron overload-associated hepatic fibrosis. Kunming mice were assigned to nine groups (n=8 per group): control, iron overload, deferoxamine, high and low dose verapamil, high and low dose nimodipine, and high and low dose diltiazem. Iron deposition and hepatic fibrosis were measured in mouse livers. Expression levels of molecules associated with transmembrane iron transport were determined by molecular biology approaches. In vitro HSC-T6 cells were randomized into nine groups (the same groups as the mice). Changes in proliferation, apoptosis, and metalloproteinase expression in cells were detected to assess the anti-fibrotic effects of CCBs during iron overload conditions. We found that CCBs reduced hepatic iron content, intracellular iron deposition, the number of hepatic fibrotic areas, collagen expression levels, and hydroxyproline content. CCBs rescued abnormal expression of α1C protein in L-type voltage-dependent calcium channel (LVDCC) and down-regulated divalent metal transporter-1 (DMT-1) expression in mouse livers. In iron-overloaded HSC-T6 cells, CCBs reduced iron deposition, inhibited proliferation, induced apoptosis, and elevated expression of matrix metalloproteinase-13 (MMP-13) and tissue inhibitor of metalloproteinase-1 (TIMP-1). CCBs are potential therapeutic agents that can be used to address hepatic fibrosis during iron overload. They resolve hepatic fibrosis probably correlated with regulating transmembrane iron transport and inhibiting HSC growth. PMID:27095094

  3. Mouse model of type II Bartter's syndrome. II. Altered expression of renal sodium- and water-transporting proteins.

    PubMed

    Wagner, Carsten A; Loffing-Cueni, Dominique; Yan, Qingshang; Schulz, Nicole; Fakitsas, Panagiotis; Carrel, Monique; Wang, Tong; Verrey, Francois; Geibel, John P; Giebisch, Gerhard; Hebert, Steven C; Loffing, Johannes

    2008-06-01

    Bartter's syndrome represents a group of hereditary salt- and water-losing renal tubulopathies caused by loss-of-function mutations in proteins mediating or regulating salt transport in the thick ascending limb (TAL) of Henle's loop. Mutations in the ROMK channel cause type II antenatal Bartter's syndrome that presents with maternal polyhydramnios and postnatal life-threatening volume depletion. We have developed a colony of Romk null mice showing a Bartter-like phenotype and with increased survival to adulthood, suggesting the activation of compensatory mechanisms. To test the hypothesis that upregulation of Na(+)-transporting proteins in segments distal to the TAL contributes to compensation, we studied expression of salt-transporting proteins in ROMK-deficient (Romk(-/-)) mice. Plasma aldosterone was 40% higher and urinary PGE(2) excretion was 1.5-fold higher in Romk(-/-) compared with wild-type littermates. Semiquantitative immunoblotting of kidney homogenates revealed decreased abundances of proximal tubule Na(+)/H(+) exchanger (NHE3) and Na(+)-P(i) cotransporter (NaPi-IIa) and TAL-specific Na(+)-K(+)-2Cl(-)-cotransporter (NKCC2/BSC1) in Romk(-/-) mice, while the distal convoluted tubule (DCT)-specific Na(+)-Cl(-) cotransporter (NCC/TSC) was markedly increased. The abundance of the alpha-,beta-, and gamma-subunits of the epithelial Na(+) channel (ENaC) was slightly increased, although only differences for gamma-ENaC reached statistical significance. Morphometry revealed a fourfold increase in the fractional volume of DCT but not of connecting tubule (CNT) and collecting duct (CCD). Consistently, CNT and CD of Romk(-/-) mice revealed no apparent increase in the luminal abundance of the ENaC compared with those of wild-type mice. These data suggest that the loss of ROMK-dependent Na(+) absorption in the TAL is compensated predominately by upregulation of Na(+) transport in downstream DCT cells. These adaptive changes in Romk(-/-) mice may help to limit renal Na

  4. Obesity and age-related alterations in the gene expression of zinc-transporter proteins in the human brain.

    PubMed

    Olesen, R H; Hyde, T M; Kleinman, J E; Smidt, K; Rungby, J; Larsen, A

    2016-01-01

    The incidence of Alzheimer's disease (AD) is increasing. Major risk factors for AD are advancing age and diabetes. Lately, obesity has been associated with an increased risk of dementia. Obese and diabetic individuals are prone to decreased circulating levels of zinc, reducing the amount of zinc available for crucial intracellular processes. In the brain, zinc co-localizes with glutamate in synaptic vesicles, and modulates NMDA receptor activity. Intracellular zinc is involved in apoptosis and fluctuations in cytoplasmic Zn(2+) affect modulation of intracellular signaling. The ZNT and ZIP proteins participate in intracellular zinc homeostasis. Altered expression of zinc-regulatory proteins has been described in AD patients. Using microarray data from human frontal cortex (BrainCloud), this study investigates expression of the SCLA30A (ZNT) and SCLA39A (ZIP) families of genes in a Caucasian and African-American sample of 145 neurologically and psychiatrically normal individuals. Expression of ZNT3 and ZNT4 were significantly reduced with increasing age, whereas expression of ZIP1, ZIP9 and ZIP13 were significantly increased. Increasing body mass index (BMI) correlated with a significant reduction in ZNT1 expression similar to what is seen in the early stages of AD. Increasing BMI also correlated with reduced expression of ZNT6. In conclusion, we found that the expression of genes that regulate intracellular zinc homeostasis in the human frontal cortex is altered with increasing age and affected by increasing BMI. With the increasing rates of obesity throughout the world, these findings warrant continuous scrutiny of the long-term consequences of obesity on brain function and the development of neurodegenerative diseases. PMID:27300264

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

    PubMed

    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. PMID:24361445

  6. Obesity and age-related alterations in the gene expression of zinc-transporter proteins in the human brain

    PubMed Central

    Olesen, R H; Hyde, T M; Kleinman, J E; Smidt, K; Rungby, J; Larsen, A

    2016-01-01

    The incidence of Alzheimer's disease (AD) is increasing. Major risk factors for AD are advancing age and diabetes. Lately, obesity has been associated with an increased risk of dementia. Obese and diabetic individuals are prone to decreased circulating levels of zinc, reducing the amount of zinc available for crucial intracellular processes. In the brain, zinc co-localizes with glutamate in synaptic vesicles, and modulates NMDA receptor activity. Intracellular zinc is involved in apoptosis and fluctuations in cytoplasmic Zn2+ affect modulation of intracellular signaling. The ZNT and ZIP proteins participate in intracellular zinc homeostasis. Altered expression of zinc-regulatory proteins has been described in AD patients. Using microarray data from human frontal cortex (BrainCloud), this study investigates expression of the SCLA30A (ZNT) and SCLA39A (ZIP) families of genes in a Caucasian and African-American sample of 145 neurologically and psychiatrically normal individuals. Expression of ZNT3 and ZNT4 were significantly reduced with increasing age, whereas expression of ZIP1, ZIP9 and ZIP13 were significantly increased. Increasing body mass index (BMI) correlated with a significant reduction in ZNT1 expression similar to what is seen in the early stages of AD. Increasing BMI also correlated with reduced expression of ZNT6. In conclusion, we found that the expression of genes that regulate intracellular zinc homeostasis in the human frontal cortex is altered with increasing age and affected by increasing BMI. With the increasing rates of obesity throughout the world, these findings warrant continuous scrutiny of the long-term consequences of obesity on brain function and the development of neurodegenerative diseases. PMID:27300264

  7. A Bed Load Monitoring System for Real Time Sediment Transport and Bed Morphology during Channel Altering Events

    NASA Astrophysics Data System (ADS)

    Curran, J. C.; Waters, K. A.; Cannatelli, K.

    2014-12-01

    A new technique is presented that provides continuous measurement of sediment movement over the length of a flume. Real-time measurements of bed changes over a reach are a missing piece needed to link bed morphology with sediment transport processes during unsteady flows when the bed adjusts quickly to changing transport rates or visual observation of the bed is precluded by fine sediment in the water column. A bed load monitoring system (BLMS) was developed that records the sediment and water loads over discrete bed lengths throughout a flow event. It was designed for laboratory application where controlled measurement methods are possible. Upon data processing, the BLMS provides a continuous measure of the sediment load across the bed from which sediment movement rates through the reach, including areas of temporary aggradation or degradation, can be reconstructed. Examples are provided of how the bed load monitoring system has been applied during sediment feed and sediment recirculation experiments to further the interpretation of channel processes occurring during large flows. We detail the use of the BLMS to measure bed slopes during unsteady flows and to measure the movement of sediment downstream following different methods of dam removal. We evaluate the BLMS for use where DEM differencing was also applied to illustrate the information provided by each measurement method. Exciting implications of future research that incorporates a BLMS include a more informed management of river systems as a result of improved temporal predictions of sediment movement and the associated changes in channel slope and morphology.

  8. Mutations in the Plasmodium falciparum chloroquine resistance transporter, PfCRT, enlarge the parasite's food vacuole and alter drug sensitivities.

    PubMed

    Pulcini, Serena; Staines, Henry M; Lee, Andrew H; Shafik, Sarah H; Bouyer, Guillaume; Moore, Catherine M; Daley, Daniel A; Hoke, Matthew J; Altenhofen, Lindsey M; Painter, Heather J; Mu, Jianbing; Ferguson, David J P; Llinás, Manuel; Martin, Rowena E; Fidock, David A; Cooper, Roland A; Krishna, Sanjeev

    2015-09-30

    Mutations in the Plasmodium falciparum chloroquine resistance transporter, PfCRT, are the major determinant of chloroquine resistance in this lethal human malaria parasite. Here, we describe P. falciparum lines subjected to selection by amantadine or blasticidin that carry PfCRT mutations (C101F or L272F), causing the development of enlarged food vacuoles. These parasites also have increased sensitivity to chloroquine and some other quinoline antimalarials, but exhibit no or minimal change in sensitivity to artemisinins, when compared with parental strains. A transgenic parasite line expressing the L272F variant of PfCRT confirmed this increased chloroquine sensitivity and enlarged food vacuole phenotype. Furthermore, the introduction of the C101F or L272F mutation into a chloroquine-resistant variant of PfCRT reduced the ability of this protein to transport chloroquine by approximately 93 and 82%, respectively, when expressed in Xenopus oocytes. These data provide, at least in part, a mechanistic explanation for the increased sensitivity of the mutant parasite lines to chloroquine. Taken together, these findings provide new insights into PfCRT function and PfCRT-mediated drug resistance, as well as the food vacuole, which is an important target of many antimalarial drugs.

  9. Metabolism-Induced CaCO3 Biomineralization During Reactive Transport in a Micromodel: Implications for Porosity Alteration.

    PubMed

    Singh, Rajveer; Yoon, Hongkyu; Sanford, Robert A; Katz, Lynn; Fouke, Bruce W; Werth, Charles J

    2015-10-20

    The ability of Pseudomonas stutzeri strain DCP-Ps1 to drive CaCO3 biomineralization has been investigated in a microfluidic flowcell (i.e., micromodel) that simulates subsurface porous media. Results indicate that CaCO3 precipitation occurs during NO3(-) reduction with a maximum saturation index (SIcalcite) of ∼1.56, but not when NO3(-) was removed, inactive biomass remained, and pH and alkalinity were adjusted to SIcalcite ∼ 1.56. CaCO3 precipitation was promoted by metabolically active cultures of strain DCP-Ps1, which at similar values of SIcalcite, have a more negative surface charge than inactive strain DCP-Ps1. A two-stage NO3(-) reduction (NO3(-) → NO2(-) → N2) pore-scale reactive transport model was used to evaluate denitrification kinetics, which was observed in the micromodel as upper (NO3(-) reduction) and lower (NO2(-) reduction) horizontal zones of biomass growth with CaCO3 precipitation exclusively in the lower zone. Model results are consistent with two biomass growth regions and indicate that precipitation occurred in the lower zone because the largest increase in pH and alkalinity is associated with NO2(-) reduction. CaCO3 precipitates typically occupied the entire vertical depth of pores and impacted porosity, permeability, and flow. This study provides a framework for incorporating microbial activity in biogeochemistry models, which often base biomineralization only on SI (caused by biotic or abiotic reactions) and, thereby, underpredict the extent of this complex process. These results have wide-ranging implications for understanding reactive transport in relevance to groundwater remediation, CO2 sequestration, and enhanced oil recovery.

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

    PubMed Central

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

    2008-01-01

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

  11. Robotics in colorectal surgery.

    PubMed

    Hance, J; Rockall, T; Darzi, A

    2004-01-01

    Minimally invasive surgery has been shown to offer many advantages to general surgical patients but has not been widely adopted for colorectal disease. Initial fears surrounding the oncological safety of laparoscopic colectomies have largely subsided but the technical challenges still remain. Surgical robots or telemanipulators present the laparoscopic surgeon with unrivaled dexterity and vision, which may allow colonic resections to be completed with greater ease. Although initial studies suggest promising results using currently available systems, it will take further time for patient benefits to be proven, therefore justifying the greater expense of operating with this new technology.

  12. [Genetics of colorectal cancer].

    PubMed

    Balaguer, Francesc

    2012-09-01

    Colorectal cancer (CRC) is one of the most frequent neoplasms in developed countries and up to 5% of all cases occur in the context of a hereditary syndrome. These hereditary forms often require a high index of suspicion for their diagnosis and specific and specialized management. Moreover, a diagnosis of hereditary CRC has major consequences not only for the patient--for whom there are highly effective preventive measures--but also for the patient's relatives, who may carry the same condition. The most significant advances in the field of hereditary CRC have been produced in the diagnosis and characterization of Lynch's syndrome and serrated polyposis syndrome.

  13. [Genetics of colorectal cancer].

    PubMed

    Balaguer, Francesc

    2013-10-01

    Up to 5% of all cases of colorectal cancer (CRC) are due to a known hereditary syndrome. These hereditary forms often require a high degree of suspicion for their diagnosis and specific and specialized management. Moreover, a diagnosis of hereditary CRC has important consequences, not only for patients-for whom highly effective preventive measures are available-, but also for their relatives, who may be carriers of the same condition. The most significant advances in the field of hereditary CRC have been produced in the diagnosis and characterization of these syndromes and in the discovery of new causative genes.

  14. Primary Prevention of Colorectal Cancer

    PubMed Central

    Chan, Andrew T.; Giovannucci, Edward L.

    2010-01-01

    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 the 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 the maintenance of a reasonable level of physical activity are associated with markedly lower risks of colorectal cancer. Medications such as aspirin and non-steroidal anti-inflammatory drugs and post-menopausal hormones for women are associated with significant 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. PMID:20420944

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

    NASA Astrophysics Data System (ADS)

    Lee, T.-Y.; Huang, J.-C.; Kao, S.-J.; Tung, C.-P.

    2013-04-01

    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 analogous to typical Oceania

  16. Rab7 Mutants Associated with Charcot-Marie-Tooth Disease Cause Delayed Growth Factor Receptor Transport and Altered Endosomal and Nuclear Signaling*

    PubMed Central

    BasuRay, Soumik; Mukherjee, Sanchita; Romero, Elsa G.; Seaman, Matthew N. J.; Wandinger-Ness, Angela

    2013-01-01

    Rab7 belongs to the Ras superfamily of small GTPases and is a master regulator of early to late endocytic membrane transport. Four missense mutations in the late endosomal Rab7 GTPase (L129F, K157N, N161T, and V162M) cause the autosomal dominant peripheral neuropathy Charcot-Marie-Tooth type 2B (CMT2B) disease. As yet, the pathological mechanisms connecting mutant Rab7 protein expression to altered neuronal function are undefined. Here, we analyze the effects of Rab7 CMT2B mutants on epidermal growth factor (EGF)-dependent intracellular signaling and trafficking. Three different cell lines expressing Rab7 CMT2B mutants and stimulated with EGF exhibited delayed trafficking of EGF to LAMP1-positive late endosomes and lysosomes and slowed EGF receptor (EGFR) degradation. Expression of all Rab7 CMT2B mutants altered the Rab7 activation cycle, leading to enhanced and prolonged EGFR signaling as well as variable increases in p38 and ERK1/2 activation. However, due to reduced nuclear translocation of p38 and ERK1/2, the downstream nuclear activation of Elk-1 was decreased along with the expression of immediate early genes like c-fos and Egr-1 by the disease mutants. In conclusion, our results demonstrate that Rab7 CMT2B mutants impair growth factor receptor trafficking and, in turn, alter p38 and ERK1/2 signaling from perinuclear, clustered signaling endosomes. The resulting down-regulation of EGFR-dependent nuclear transcription that is crucial for normal axon outgrowth and peripheral innervation offers a crucial new mechanistic insight into disease pathogenesis that is relevant to other neurodegenerative diseases. PMID:23188822

  17. Early-life stress induces persistent alterations in 5-HT1A receptor and serotonin transporter mRNA expression in the adult rat brain

    PubMed Central

    Bravo, Javier A.; Dinan, Timothy G.; Cryan, John F.

    2014-01-01

    Early-life experience plays a major role in the stress response throughout life. Neonatal maternal separation (MS) is an animal model of depression with an altered serotonergic response. We hypothesize that this alteration may be caused by differences in 5-HT1A receptor and serotonin transporter (SERT) mRNA expression in brain areas involved in the control of emotions, memory, and fear as well as in regions controlling the central serotonergic tone. To test this, Sprague–Dawley rats were subjected to MS for 3 h daily during postnatal days 2–12. As control, age matched rats were non-separated (NS) from their dams. When animals reached adulthood (11–13 weeks) brain was extracted and mRNA expression of 5-HT1A receptor in amygdala, hippocampus and dorsal raphé nucleus (DRN) and SERT in the DRN was analyzed through in situ hybridisation. Densitometric analysis revealed that MS increased 5-HT1A receptor mRNA expression in the amygdala, and reduced its expression in the DRN, but no changes were observed in the hippocampus in comparison to NS controls. Also, MS reduced SERT mRNA expression in the DRN when compared to NS rats. These results suggest that early-life stress induces persistent changes in 5-HT1A receptor and SERT mRNA expression in key brain regions involved in the development of stress-related psychiatric disorders. The reduction in SERT mRNA indicates an alteration that is in line with clinical findings such as polymorphic variants in individuals with higher risk of depression. These data may help to understand how early-life stress contributes to the development of mood disorders in adulthood. PMID:24782706

  18. Sublethal exposure to azamethiphos causes neurotoxicity, altered energy allocation and high mortality during simulated live transport in American lobster.

    PubMed

    Couillard, C M; Burridge, L E

    2015-05-01

    In the Bay of Fundy, New Brunswick, sea lice outbreaks in caged salmon are treated with pesticides including Salmosan(®), applied as bath treatments and then released into the surrounding seawater. The effect of chronic exposure to low concentrations of this pesticide on neighboring lobster populations is a concern. Adult male lobsters were exposed to 61 ngL(-1) of azamethiphos (a.i. in Salmosan(®) formulation) continuously for 10 days. In addition to the direct effects of pesticide exposure, effects on the ability to cope with shipping conditions and the persistence of the effects after a 24h depuration period in clean seawater were assessed. Indicators of stress and hypoxia (serum total proteins, hemocyanin and lactate), oxidative damage (protein carbonyls in gills and serum) and altered energy allocation (hepatosomatic and gonadosomatic indices, hepatopancreas lipids) were assessed in addition to neurotoxicity (chlolinesterase activity in muscle). Directly after exposure, azamethiphos-treated lobsters had inhibition of muscle cholinesterase, reduced gonadosomatic index and enhanced hepatosomatic index and hepatopancreas lipid content. All these responses persisted after 24-h depuration, increasing the risk of cumulative impacts with further exposure to chemical or non-chemical stressors. In both control and treated lobsters exposed to simulated shipment conditions, concentrations of protein and lactate in serum, and protein carbonyls in gills increased. However, mortality rate was higher in azamethiphos-treated lobsters (33 ± 14%) than in controls (2.6 ± 4%). Shipment and azamethiphos had cumulative impacts on serum proteins. Both direct effects on neurological function and energy allocation and indirect effect on ability to cope with shipping stress could have significant impacts on lobster population and/or fisheries.

  19. G-actin guides p53 nuclear transport: potential contribution of monomeric actin in altered localization of mutant p53.

    PubMed

    Saha, Taniya; Guha, Deblina; Manna, Argha; Panda, Abir Kumar; Bhat, Jyotsna; Chatterjee, Subhrangsu; Sa, Gaurisankar

    2016-01-01

    p53 preserves genomic integrity by restricting anomaly at the gene level. Till date, limited information is available for cytosol to nuclear shuttling of p53; except microtubule-based trafficking route, which utilizes minus-end directed motor dynein. The present study suggests that monomeric actin (G-actin) guides p53 traffic towards the nucleus. Histidine-tag pull-down assay using purified p53(1-393)-His and G-actin confirms direct physical association between p53 and monomeric G-actin. Co-immunoprecipitation data supports the same. Confocal imaging explores intense perinuclear colocalization between p53 and G-actin. To address atomistic details of the complex, constraint-based docked model of p53:G-actin complex was generated based on crystal structures. MD simulation reveals that p53 DNA-binding domain arrests very well the G-actin protein. Docking benchmark studies have been carried out for a known crystal structure, 1YCS (complex between p53DBD and BP2), which validates the docking protocol we adopted. Co-immunoprecipitation study using "hot-spot" p53 mutants suggested reduced G-actin association with cancer-associated p53 conformational mutants (R175H and R249S). Considering these findings, we hypothesized that point mutation in p53 structure, which diminishes p53:G-actin complexation results in mutant p53 altered subcellular localization. Our model suggests p53Arg249 form polar-contact with Arg357 of G-actin, which upon mutation, destabilizes p53:G-actin interaction and results in cytoplasmic retention of p53R249S. PMID:27601274

  20. G-actin guides p53 nuclear transport: potential contribution of monomeric actin in altered localization of mutant p53

    PubMed Central

    Saha, Taniya; Guha, Deblina; Manna, Argha; Panda, Abir Kumar; Bhat, Jyotsna; Chatterjee, Subhrangsu; Sa, Gaurisankar

    2016-01-01

    p53 preserves genomic integrity by restricting anomaly at the gene level. Till date, limited information is available for cytosol to nuclear shuttling of p53; except microtubule-based trafficking route, which utilizes minus-end directed motor dynein. The present study suggests that monomeric actin (G-actin) guides p53 traffic towards the nucleus. Histidine-tag pull-down assay using purified p53(1–393)-His and G-actin confirms direct physical association between p53 and monomeric G-actin. Co-immunoprecipitation data supports the same. Confocal imaging explores intense perinuclear colocalization between p53 and G-actin. To address atomistic details of the complex, constraint-based docked model of p53:G-actin complex was generated based on crystal structures. MD simulation reveals that p53 DNA-binding domain arrests very well the G-actin protein. Docking benchmark studies have been carried out for a known crystal structure, 1YCS (complex between p53DBD and BP2), which validates the docking protocol we adopted. Co-immunoprecipitation study using “hot-spot” p53 mutants suggested reduced G-actin association with cancer-associated p53 conformational mutants (R175H and R249S). Considering these findings, we hypothesized that point mutation in p53 structure, which diminishes p53:G-actin complexation results in mutant p53 altered subcellular localization. Our model suggests p53Arg249 form polar-contact with Arg357 of G-actin, which upon mutation, destabilizes p53:G-actin interaction and results in cytoplasmic retention of p53R249S. PMID:27601274

  1. Sublethal exposure to azamethiphos causes neurotoxicity, altered energy allocation and high mortality during simulated live transport in American lobster.

    PubMed

    Couillard, C M; Burridge, L E

    2015-05-01

    In the Bay of Fundy, New Brunswick, sea lice outbreaks in caged salmon are treated with pesticides including Salmosan(®), applied as bath treatments and then released into the surrounding seawater. The effect of chronic exposure to low concentrations of this pesticide on neighboring lobster populations is a concern. Adult male lobsters were exposed to 61 ngL(-1) of azamethiphos (a.i. in Salmosan(®) formulation) continuously for 10 days. In addition to the direct effects of pesticide exposure, effects on the ability to cope with shipping conditions and the persistence of the effects after a 24h depuration period in clean seawater were assessed. Indicators of stress and hypoxia (serum total proteins, hemocyanin and lactate), oxidative damage (protein carbonyls in gills and serum) and altered energy allocation (hepatosomatic and gonadosomatic indices, hepatopancreas lipids) were assessed in addition to neurotoxicity (chlolinesterase activity in muscle). Directly after exposure, azamethiphos-treated lobsters had inhibition of muscle cholinesterase, reduced gonadosomatic index and enhanced hepatosomatic index and hepatopancreas lipid content. All these responses persisted after 24-h depuration, increasing the risk of cumulative impacts with further exposure to chemical or non-chemical stressors. In both control and treated lobsters exposed to simulated shipment conditions, concentrations of protein and lactate in serum, and protein carbonyls in gills increased. However, mortality rate was higher in azamethiphos-treated lobsters (33 ± 14%) than in controls (2.6 ± 4%). Shipment and azamethiphos had cumulative impacts on serum proteins. Both direct effects on neurological function and energy allocation and indirect effect on ability to cope with shipping stress could have significant impacts on lobster population and/or fisheries. PMID:25499691

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

    PubMed Central

    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

  3. [Hereditary and familial colorectal cancer].

    PubMed

    Balaguer, Francesc

    2014-09-01

    Up to 5% of all colorectal cancer cases are caused by a known hereditary syndrome. These hereditary types often need a higher degree of clinical suspicion to be diagnosed and require specific and specialized management. In addition, diagnosing hereditary colorectal cancer has significant consequences not only for the patient, for whom there are effective preventative measures, but also for their families, who could be carriers of the condition. The most significant advances in the field of colorectal cancer have come from the diagnosis and characterization of these syndromes.

  4. Alterations in the mitochondrial alternative NAD(P)H Dehydrogenase NDB4 lead to changes in mitochondrial electron transport chain composition, plant growth and response to oxidative stress.

    PubMed

    Smith, Chevaun; Barthet, Michelle; Melino, Vanessa; Smith, Penelope; Day, David; Soole, Kathleen

    2011-07-01

    The branched respiratory electron transport chain of plants contains a non-phosphorylating alternative pathway consisting of type II NAD(P)H dehydrogenases on both sides of the inner membrane linked through the ubiquinone pool to an alternative oxidase (AOX). T-DNA and RNA interference (RNAi) were used to reduce gene expression to characterize the external NAD(P)H dehydrogenase NDB4 in Arabidopsis. The ndb4 lines showed different levels of suppression of NDB4 protein, leading to increases in NBD2 and AOX1a mRNA and protein levels in all lines. These changes were associated with lower reactive oxygen species formation and an altered phenotype, including changes in growth rate, root : shoot ratios and leaf area. The general growth pattern for the ndb4 mutants was decreased leaf area early in development (6-15 d) followed by a prompt subsequent increase in leaf area that exceeded the leaf area of the wild type by maturity (the 10-12 rosette stage). This pattern was most evident for the RNAi lines that had increased mitochondrial electron transport capacity. The RNAi lines also exhibited better tolerance to salinity stress, with better growth rates and lower shoot Na⁺ content compared with controls when grown under saline conditions. We hypothesize that these differences reflect the enhanced expression of NDB2 and AOX in the ndb4 mutant plants.

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

    PubMed Central

    Lei, Qiong; Feng, Chao; Gao, Yinan; Zheng, Xiaodong; Zhao, Yu; Wang, Zhi; Kong, Jin

    2015-01-01

    Background 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. Results 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. Conclusion 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. PMID:26562158

  6. Toxicological effects of particulate matter (PM2.5) on rats: Bioaccumulation, antioxidant alterations, lipid damage, and ABC transporter activity.

    PubMed

    Ribeiro, Joaquim de Paula; Kalb, Ana Cristina; Campos, Paula Peixoto; Cruz, Alex Rubén Huaman De La; Martinez, Pablo Elias; Gioda, Adriana; Souza, Marta Marques de; Gioda, Carolina Rosa

    2016-11-01

    Previous studies have demonstrated the harmful effects of atmospheric pollutants on cardiac systems because of the presence of particulate matter (PM), a complex mixture of numerous substances including trace metals. In this study, the toxicity of PM2.5 from two regions, rural (PM2.5 level of 8.5 ± 4.0 μg m(-3)) and industrial (PM2.5 level of 14.4 ± 4.1 μg m(-3)) in Brazil, was investigated through in vivo experiments in rats. Metal accumulation and biochemical responses were evaluated after rats were exposed to three different concentrations of PM2.5 in saline extract (10× dilution, 5× dilution, and concentrated). The experimental data showed the bioaccumulation of diverse trace metals in the hearts of groups exposed to PM2.5 from both regions. Furthermore, mobilization of the antioxidant defenses and an increase in lipid peroxidation of the cardiac tissue was observed in response to the industrial and rural area PM2.5. Glutathione-S-transferase activity was increased in groups exposed to the 5× and concentrated rural PM2.5. Additionally, ATP-binding cassette (ABC) transporter activity in the cardiac tissue exposed to PM2.5 was reduced in response to the 5× dilution of the rural and industrial region PM2.5. Histological analysis showed a decrease in the percentage of cardiac cells in the heart at all tested concentrations. The results indicate that exposure to different concentrations of PM2.5 from both sources causes biochemical and histological changes in the heart with consequent damage to biological structures; these factors can favor the development of cardiac diseases.

  7. Toxicological effects of particulate matter (PM2.5) on rats: Bioaccumulation, antioxidant alterations, lipid damage, and ABC transporter activity.

    PubMed

    Ribeiro, Joaquim de Paula; Kalb, Ana Cristina; Campos, Paula Peixoto; Cruz, Alex Rubén Huaman De La; Martinez, Pablo Elias; Gioda, Adriana; Souza, Marta Marques de; Gioda, Carolina Rosa

    2016-11-01

    Previous studies have demonstrated the harmful effects of atmospheric pollutants on cardiac systems because of the presence of particulate matter (PM), a complex mixture of numerous substances including trace metals. In this study, the toxicity of PM2.5 from two regions, rural (PM2.5 level of 8.5 ± 4.0 μg m(-3)) and industrial (PM2.5 level of 14.4 ± 4.1 μg m(-3)) in Brazil, was investigated through in vivo experiments in rats. Metal accumulation and biochemical responses were evaluated after rats were exposed to three different concentrations of PM2.5 in saline extract (10× dilution, 5× dilution, and concentrated). The experimental data showed the bioaccumulation of diverse trace metals in the hearts of groups exposed to PM2.5 from both regions. Furthermore, mobilization of the antioxidant defenses and an increase in lipid peroxidation of the cardiac tissue was observed in response to the industrial and rural area PM2.5. Glutathione-S-transferase activity was increased in groups exposed to the 5× and concentrated rural PM2.5. Additionally, ATP-binding cassette (ABC) transporter activity in the cardiac tissue exposed to PM2.5 was reduced in response to the 5× dilution of the rural and industrial region PM2.5. Histological analysis showed a decrease in the percentage of cardiac cells in the heart at all tested concentrations. The results indicate that exposure to different concentrations of PM2.5 from both sources causes biochemical and histological changes in the heart with consequent damage to biological structures; these factors can favor the development of cardiac diseases. PMID:27567156

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

    NASA Astrophysics Data System (ADS)

    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.

  9. Get Tested for Colorectal Cancer

    MedlinePlus

    ... of fiber . Talk with your doctor about taking aspirin every day. Taking aspirin every day can lower your risk of colorectal ... 50 to 59, ask your doctor if daily aspirin is right for you . Previous section Get Tested ...

  10. Population screening for colorectal cancer.

    PubMed

    2006-09-01

    Each year in the UK, around 16,000 people die from colorectal cancer. At disease presentation, around 55% of people have advanced cancer that has spread to lymph nodes, metastasised to other organs or is so locally advanced that surgery is unlikely to be curative (Dukes' stage C or D). Overall 5-year survival for colorectal cancer in the UK is around 47-51% (compared to 64% in the USA), but only 7% at most in those presenting with metastatic disease. These facts underlie the current introduction of national bowel screening programmes in the UK. Here we assess the role of screening of the general population in reducing mortality from colorectal cancer. We do not consider the screening arrangements needed for high-risk populations, including those with inflammatory bowel disease or a strong family history of colorectal cancer. PMID:17009566

  11. Stem cells, colorectal cancer and cancer stem cell markers correlations.

    PubMed

    Cherciu, Irina; Bărbălan, A; Pirici, D; Mărgăritescu, C; Săftoiu, A

    2014-01-01

    : The idea of stem cells as being progenitors of cancer was initially controversial, but later supported by research in the field of leukemia and solid tumors. Afterwards, it was established that genetic abnormalities can affect the stem and progenitor cells, leading to uncontrolled replication and deregulated differentiation. These alterations will cause the changeover to cancerous stem cells (CSC) having two main characteristics: tumor initiation and maintenance. This review will focus on the colorectal cancer stem cell (CR-CSCs) theory which provides a better understanding of different tumor processes: initiation, aggressive growth, recurrence, treatment resistance and metastasis. A search in PubMed/Medline was performed using the following keywords: colorectal cancer stem cells (CR-CSCs), colorectal neoplasms stem cells, colorectal cancer stem cell (CR-CSCs) markers, etc. Electronic searches were supplemented by hand searching reference lists, abstracts and proceedings from meetings. Isolation of CR-CSCs can be achieved by targeting and selecting subpopulation of tumor cells based on expression of one or multiple cell surface markers associated with cancer self-renewal, markers as: CD133, CD166, CD44, CD24, beta1 integrin-CD29, Lgr5, EpCAM (ESA), ALDH-1, Msi-1, DCAMLK1 or EphB receptors. The identification and localization of CR-CSCs through different markers will hopefully lead to a better stratification of prognosis and treatment response, as well as the development of new effective strategies for cancer management.

  12. Potential role of probiotics on colorectal cancer prevention

    PubMed Central

    2012-01-01

    Background Colorectal cancer represents the most common malignancy of the gastrointestinal tract. Owing to differences in dietary habits and lifestyle, this neoplasm is more common in industrialized countries than in developing ones. Evidence from a wide range of sources supports the assumption that the link between diet and colorectal cancer may be due to an imbalance of the intestinal microflora. Discussion Probiotic bacteria are live microorganisms that, when administered in adequate amounts, confer a healthy benefit on the host, and they have been investigated for their protective anti-tumor effects. In vivo and molecular studies have displayed encouraging findings that support a role of probiotics in colorectal cancer prevention. Summary Several mechanisms could explain the preventive action of probiotics against colorectal cancer onset. They include: alteration of the intestinal microflora; inactivation of cancerogenic compounds; competition with putrefactive and pathogenic microbiota; improvement of the host’s immune response; anti-proliferative effects via regulation of apoptosis and cell differentiation; fermentation of undigested food; inhibition of tyrosine kinase signaling pathways. PMID:23173670

  13. Mucosal adherent bacterial dysbiosis in patients with colorectal adenomas

    PubMed Central

    Lu, Yingying; Chen, Jing; Zheng, Junyuan; Hu, Guoyong; Wang, Jingjing; Huang, Chunlan; Lou, Lihong; Wang, Xingpeng; Zeng, Yue

    2016-01-01

    Recent reports have suggested that the gut microbiota is involved in the progression of colorectal cancer (CRC). The composition of gut microbiota in CRC precursors has not been adequately described. To characterize the structure of adherent microbiota in this disease, we conducted pyrosequencing-based analysis of 16S rRNA genes to determine the bacterial profile of normal colons (healthy controls) and colorectal adenomas (CRC precursors). Adenoma mucosal biopsy samples and adjacent normal colonic mucosa from 31 patients with adenomas and 20 healthy volunteers were profiled using the Illumina MiSeq platform. Principal coordinate analysis (PCoA) showed structural segregation between colorectal adenomatous tissue and control tissue. Alpha diversity estimations revealed higher microbiota diversity in samples from patients with adenomas. Taxonomic analysis illustrated that abundance of eight phyla (Firmicutes, Proteobacteria, Bacteroidetes, Actinobacteria, Chloroflexi, Cyanobacteria, Candidate-division TM7, and Tenericutes) was significantly different. In addition, Lactococcus and Pseudomonas were enriched in preneoplastic tissue, whereas Enterococcus, Bacillus, and Solibacillus were reduced. However, both PCoA and cluster tree analyses showed similar microbiota structure between adenomatous and adjacent non-adenoma tissues. These present findings provide preliminary experimental evidence supporting that colorectal preneoplastic lesion may be the most important factor leading to alterations in bacterial community composition. PMID:27194068

  14. Biomolecular markers as determinants of patients selection for adjuvant chemotherapy of sporadic colorectal cancers.

    PubMed

    Sudoyo, Aru W

    2010-01-01

    Colorectal cancer (CRC) is a disease classified and based on genetic alteration resulting from interaction of environmental factors, individual cancer susceptibility and accumulated somatic changes of the colorectal epithelium. Advanced knowledge in genetics and epigenetics of colorectal cancer develops a hypothesis that various clinical manifestations of colorectal cancer are caused by different carcinogenesis pathways. Different carcinogenesis pathways and types of colorectal cancer appear to bring effects on different response against chemotherapy and prognosis. Chemotherapy is mainly provided for patients with stage III CRC which are also the largest proportion of CRC patients in Indonesia. However, it is also provided for some patients with high risk stage II CRC. Classically, clinical factors have been generally accepted as prognostic factors including depth of tumor invasion, regional nodal metastasis, vascular invasion, poor differentiation, and serologic tumor marker such as carcinoembryonic antigen (CEA). However, clinical and histopathological factors themselves do not provide accurate prediction for colorectal cancer prognosis and treatment. A biomolecular marker is necessary to provide such prediction. Numerous studies have been conducted to evaluate the molecular biological markers in order to determine either the possibility of successful treatment for colorectal cancer (predictive factor) or life-expectancy (prognostic factor). Results of several studies demonstrate different status of some molecular markers to determine successful treatment between stage II and stage III colorectal cancer. Certainly, such finding should be followed up but it shall be accepted that there will be a shift of paradigm of CRC treatment. Therefore, the success of colorectal cancer, excluding the patient's socioeconomic factors and the surgeon's skill, will depend extremely on molecular parameter and not only the stage.

  15. Immunotherapy for colorectal cancer.

    PubMed

    Koido, Shigeo; Ohkusa, Toshifumi; Homma, Sadamu; Namiki, Yoshihisa; Takakura, Kazuki; Saito, Keisuke; Ito, Zensho; Kobayashi, Hiroko; Kajihara, Mikio; Uchiyama, Kan; Arihiro, Seiji; Arakawa, Hiroshi; Okamoto, Masato; Gong, Jianlin; Tajiri, Hisao

    2013-12-14

    The incidence of colorectal cancer (CRC) is on the rise, and the prognosis for patients with recurrent or metastatic disease is extremely poor. Although chemotherapy and radiation therapy can improve survival rates, it is imperative to integrate alternative strategies such as immunotherapy to improve outcomes for patients with advanced CRC. In this review, we will discuss the effect of immunotherapy for inducing cytotoxic T lymphocytes and the major immunotherapeutic approaches for CRC that are currently in clinical trials, including peptide vaccines, dendritic cell-based cancer vaccines, whole tumor cell vaccines, viral vector-based cancer vaccines, adoptive cell transfer therapy, antibody-based cancer immunotherapy, and cytokine therapy. The possibility of combination therapies will also be discussed along with the challenges presented by tumor escape mechanisms. PMID:24379570

  16. Robotics in Colorectal Surgery

    PubMed Central

    Weaver, Allison; Steele, Scott

    2016-01-01

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

  17. Association of genetic variants in lncRNA H19 with risk of colorectal cancer in a Chinese population

    PubMed Central

    Wang, Haixiao; Du, Mulong; Zhu, Lingjun; Chu, Haiyan; Zhang, Zhengdong; Wang, Meilin

    2016-01-01

    Objective The long non-coding RNA (lncRNA) gene, H19, has been involving in multiple biological functions, which also plays a vital role in colorectal cancer carcinogenesis. However, the association between genetic variants in H19 and colorectal cancer susceptibility has not been reported. In this study, we aim to explore whether H19 polymorphisms are related to the susceptibility of colorectal cancer. Methods We conducted a case-control study to evaluate the association between four selected single nucleotide polymorphisms (SNPs) (rs2839698, rs3024270, rs217727, and rs2735971) in H19 and the risk of colorectal cancer in a Chinese population. Results We found that individuals with rs2839698 A allele had a significantly increased risk of colorectal cancer, compared to those carrying G allele [odds ratio (OR) = 1.20, 95% confidence interval (CI) = 1.05–1.36 in additive model]. Further stratified analyses revealed that colon tumor site, well differentiated grade and Duke's stage of C/D were significantly associated with colorectal cancer risk (P < 0.05). Additionally, bioinformatic analysis showed that rs2839698 may change the crucial folding structures and alter the target microRNAs of H19. Conclusions Our results provided the evidence that rs2839698 in H19 was associated with elevated risk of colorectal cancer, which may be a potential biomarker for predicting colorectal cancer susceptibility. PMID:27027436

  18. Anacetrapib and dalcetrapib differentially alters HDL metabolism and macrophage-to-feces reverse cholesterol transport at similar levels of CETP inhibition in hamsters.

    PubMed

    Briand, François; Thieblemont, Quentin; Muzotte, Elodie; Burr, Noémie; Urbain, Isabelle; Sulpice, Thierry; Johns, Douglas G

    2014-10-01

    Cholesteryl ester transfer protein (CETP) inhibitors dalcetrapib and anacetrapib differentially alter LDL- and HDL-cholesterol levels, which might be related to the potency of each drug to inhibit CETP activity. We evaluated the effects of both drugs at similar levels of CETP inhibition on macrophage-to-feces reverse cholesterol transport (RCT) in hamsters. In normolipidemic hamsters, both anacetrapib 30 mg/kg QD and dalcetrapib 200 mg/kg BID inhibited CETP activity by ~60%. After injection of 3H-cholesteryl oleate labeled HDL, anacetrapib and dalcetrapib reduced HDL-cholesteryl esters fractional catabolic rate (FCR) by 30% and 26% (both P<0.001 vs. vehicle) respectively, but only dalcetrapib increased HDL-derived 3H-tracer fecal excretion by 30% (P<0.05 vs. vehicle). After 3H-cholesterol labeled macrophage intraperitoneal injection, anacetrapib stimulated 3H-tracer appearance in HDL, but both drugs did not promote macrophage-derived 3H-tracer fecal excretion. In dyslipidemic hamsters, both anacetrapib 1 mg/kg QD and dalcetrapib 200 mg/kg BID inhibited CETP activity by ~65% and reduced HDL-cholesteryl ester FCR by 36% (both P<0.001 vs. vehicle), but only anacetrapib increased HDL-derived 3H-tracer fecal excretion significantly by 39%. After 3H-cholesterol labeled macrophage injection, only anacetrapib 1 mg/kg QD stimulated macrophage-derived 3H-tracer appearance in HDL. These effects remained weaker than those observed with anacetrapib 60 mg/kg QD, which induced a maximal inhibition of CETP and stimulation of macrophage-derived 3H-tracer fecal excretion. In contrast, dalcetrapib 200 mg/kg BID reduced macrophage-derived 3H-tracer fecal excretion by 23% (P<0.05 vs. vehicle). In conclusion, anacetrapib and dalcetrapib differentially alter HDL metabolism and RCT in hamsters. A stronger inhibition of CETP may be required to promote macrophage-to-feces reverse cholesterol transport in dyslipidemic hamsters.

  19. Colorectal cancer carcinogenesis: a review of mechanisms

    PubMed Central

    Tariq, Kanwal; Ghias, Kulsoom

    2016-01-01

    Colorectal cancer (CRC) is the second most common cancer in women and the third most common in men globally. CRC arises from one or a combination of chromosomal instability, CpG island methylator phenotype, and microsatellite instability. Genetic instability is usually caused by aneuploidy and loss of heterozygosity. Mutations in the tumor suppressor or cell cycle genes may also lead to cellular transformation. Similarly, epigenetic and/or genetic alterations resulting in impaired cellular pathways, such as DNA repair mechanism, may lead to microsatellite instability and mutator phenotype. Non-coding RNAs, more importantly microRNAs and long non-coding RNAs have also been implicated at various CRC stages. Understanding the specific mechanisms of tumorigenesis and the underlying genetic and epigenetic traits is critical in comprehending the disease phenotype. This paper reviews these mechanisms along with the roles of various non-coding RNAs in CRCs. PMID:27144067

  20. Liver disease with altered bile acid transport in Niemann-Pick C mice on a high-fat, 1% cholesterol diet.

    PubMed

    Erickson, Robert P; Bhattacharyya, Achyut; Hunter, Robert J; Heidenreich, Randall A; Cherrington, Nathan J

    2005-08-01

    Cholestatic hepatitis is frequently found in Niemann-Pick C (NPC) disease. We studied the influence of diet and the low density lipoprotein receptor (LDLR, Ldlr in mice, known to be the source of most of the stored cholesterol) on liver disease in the mouse model of NPC. Npc1-/- mice of both sexes, with or without the Ldlr knockout, were fed a 18% fat, 1% cholesterol ("high-fat") diet and were evaluated by chemical and histological methods. Bile acid transporters [multidrug resistance protein (Mrps) 1-5; Ntcp, Bsep, and OatP1, 2, and 4] were quantitated by real-time RT-PCR. Many mice died prematurely (within 6 wk) with hepatomegaly. Histopathology showed an increase in macrophage and hepatocyte lipids independent of Ldlr genotype. Non-zone-dependent diffuse fibrosis was found in the surviving mice. Serum alanine aminotransferase was elevated in Npc1-/- mice on the regular diet and frequently became markedly elevated with the high-fat diet. Serum cholesterol was increased in the controls but not the Npc1-/- mice on the high-fat diet; it was massively increased in the Ldlr-/- mice. Esterified cholesterol was greatly increased by the high-fat diet, independent of Ldlr genotype. gamma-Glutamyltransferase was also elevated in Npc1-/- mice, more so on the high-fat diet. Mrps 1-5 were elevated in Npc1-/- liver and became more elevated with the high-fat diet; Ntcp, Bsep, and OatP2 were elevated in Npc1-/- liver and were suppressed by the high-fat diet. In conclusion, Npc1-/- mice on a high-fat diet provide an animal model of NPC cholestatic hepatitis and indicate a role for altered bile acid transport in its pathogenesis.

  1. Laparoscopic Colorectal Training Gap in Colorectal and Surgical Residents

    PubMed Central

    Soliman, Mark; Williamson, Paul; Ferrara, Andrea

    2016-01-01

    Background and Objectives: Laparoscopic colorectal surgery is an established safe procedure with demonstrated benefits. Proficiency in this specialty correlates with the volume of cases. We examined training in this surgical field for both general surgery and colon and rectal surgery residents to determine whether the number of cases needed for proficiency is being realized. Methods: We examined the Accreditation Council for Graduate Medical Education (ACGME) and American Board of Colorectal Surgeons (ABCRS) operative statistics for graduating general surgery and colon and rectal surgery residents. Results: Although the number of advanced laparoscopy cases had increased for general surgery residents, there was still a significant gap in case volume between the average number of laparoscopic colorectal operations performed by graduating general surgery residents (21.6) and those performed by graduating colon and rectal surgery residents (81.9) in 2014. Conclusion: There is a gap between general surgery and colon and rectal surgery residency training for laparoscopic colorectal surgery. General surgery residents are not meeting the volume of cases necessary for proficiency in colorectal surgery. This deficit represents a structural difference in training. PMID:27493468

  2. Homocysteinylation of neuronal proteins contributes to folate deficiency-associated alterations of differentiation, vesicular transport, and plasticity in hippocampal neuronal cells.

    PubMed

    Akchiche, Nassila; Bossenmeyer-Pourié, Carine; Kerek, Racha; Martin, Nicolas; Pourié, Grégory; Koziel, Violette; Helle, Déborah; Alberto, Jean-Marc; Ortiou, Sandrine; Camadro, Jean-Michel; Léger, Thibaut; Guéant, Jean-Louis; Daval, Jean-Luc

    2012-10-01

    Despite the key role in neuronal development of a deficit in the methyl donor folate, little is known on the underlying mechanisms. We therefore studied the consequences of folate deficiency on proliferation, differentiation, and plasticity of the rat H19-7 hippocampal cell line. Folate deficit reduced proliferation (17%) and sensitized cells to differentiation-associated apoptosis (+16%). Decreased production (-58%) of S-adenosylmethionine (the universal substrate for transmethylation reactions) and increased expression of histone deacetylases (HDAC4,6,7) would lead to epigenomic changes that may impair the differentiation process. Cell polarity, vesicular transport, and synaptic plasticity were dramatically affected, with poor neurite outgrowth (-57%). Cell treatment by an HDAC inhibitor (SAHA) led to a noticeable improvement of cell polarity and morphology, with longer processes. Increased homocysteine levels (+55%) consecutive to folate shortage produced homocysteinylation, evidenced by coimmunoprecipitations and mass spectrometry, and aggregation of motor proteins dynein and kinesin, along with functional alterations, as reflected by reduced interactions with partner proteins. Prominent homocysteinylation of key neuronal proteins and subsequent aggregation certainly constitute major adverse effects of folate deficiency, affecting normal development with possible long-lasting consequences.

  3. Repeated stress-induced expression pattern alterations of the hippocampal chloride transporters KCC2 and NKCC1 associated with behavioral abnormalities in female mice.

    PubMed

    Tsukahara, Takao; Masuhara, Masaaki; Iwai, Haruki; Sonomura, Takahiro; Sato, Tomoaki

    2015-09-11

    The balance of cation-chloride co-transporters, particularly KCC2 and NKCC1, is critical for GABAergic inhibitory signaling. However, KCC2/NKCC1 balance is disrupted in many neurodegenerative diseases. Moreover, correlations between chronic stress, KCC2 and NKCC1 in the hippocampus remain poorly understood. Despite the fact that emotional disorders in humans are far more prevalent in women, there have been relatively few studies about female subjects. Here we investigated behaviors and expression patterns of KCC2 and NKCC1 in the hippocampi of female mice under chronic stress. Repeated stress (RS) was induced in experimental mice by repeated forced water administration. Then, expression patterns of GABAergic signaling molecules were identified by immunohistochemical analysis and performance was assessed using several behavioral tests. The results of semi-quantitative analysis showed that RS decreased KCC2 expression and increased NKCC1 expression in membranes of granular and pyramidal cells in the hippocampus. The novel object recognition (NOR) test and sociability test revealed that RS induced cognitive and sociability deficits, whereas RS increased the time spent in the open arms of the elevated plus maze test and induced attention deficits in other tests. In summary, RS induced alterations in membrane KCC2/NKCC1 balance in the hippocampus of female mice, which may contribute to GABAergic disinhibition associated with cognitional, sociability and attention deficits. PMID:26239662

  4. ALTERED RESPONSE TO GRAVITY Is a Peripheral Membrane Protein That Modulates Gravity-Induced Cytoplasmic Alkalinization and Lateral Auxin Transport in Plant Statocytes

    PubMed Central

    Boonsirichai, Kanokporn; Sedbrook, John C.; Chen, Rujin; Gilroy, Simon; Masson, Patrick H.

    2003-01-01

    ARG1 (ALTERED RESPONSE TO GRAVITY) is required for normal root and hypocotyl gravitropism. Here, we show that targeting ARG1 to the gravity-perceiving cells of roots or hypocotyls is sufficient to rescue the gravitropic defects in the corresponding organs of arg1-2 null mutants. The cytosolic alkalinization of root cap columella cells that normally occurs very rapidly upon gravistimulation is lacking in arg1-2 mutants. Additionally, vertically grown arg1-2 roots appear to accumulate a greater amount of auxin in an expanded domain of the root cap compared with the wild type, and no detectable lateral auxin gradient develops across mutant root caps in response to gravistimulation. We also demonstrate that ARG1 is a peripheral membrane protein that may share some subcellular compartments in the vesicular trafficking pathway with PIN auxin efflux carriers. These data support our hypothesis that ARG1 is involved early in gravitropic signal transduction within the gravity-perceiving cells, where it influences pH changes and auxin distribution. We propose that ARG1 affects the localization and/or activity of PIN or other proteins involved in lateral auxin transport. PMID:14507996

  5. KRAS, BRAF, PIK3CA, and PTEN mutations: implications for targeted therapies in metastatic colorectal cancer.

    PubMed

    De Roock, Wendy; De Vriendt, Veerle; Normanno, Nicola; Ciardiello, Fortunato; Tejpar, Sabine

    2011-06-01

    The discovery of mutant KRAS as a predictor of resistance to epidermal growth-factor receptor (EGFR) monoclonal antibodies brought a major change in the treatment of metastatic colorectal cancer. This seminal finding also highlighted our sparse knowledge about key signalling pathways in colorectal tumours. Drugs that inhibit oncogenic alterations such as phospho-MAP2K (also called MEK), phospho-AKT, and mutant B-RAF seem promising as single treatment or when given with EGFR inhibitors. However, our understanding of the precise role these potential drug targets have in colorectal tumours, and the oncogenic dependence that tumours might have on these components, has not progressed at the same rate. As a result, patient selection and prediction of treatment effects remain problematic. We review the role of mutations in genes other than KRAS on the efficacy of anti-EGFR therapy, and discuss strategies to target these oncogenic alterations alone or in combination with receptor tyrosine-kinase inhibition.

  6. Top-down morphogenesis of colorectal tumors

    PubMed Central

    Shih, Ie-Ming; Wang, Tian-Li; Traverso, Giovanni; Romans, Kathy; Hamilton, Stanley R.; Ben-Sasson, Shmuel; Kinzler, Kenneth W.; Vogelstein, Bert

    2001-01-01

    One of the fundamental tenets of oncology is that tumors arise from stem cells. In the colon, stem cells are thought to reside at the base of crypts. In the early stages of tumorigenesis, however, dysplastic cells are routinely found at the luminal surface of the crypts whereas the cells at the bases of these same crypts appear morphologically normal. To understand this discrepancy, we evaluated the molecular characteristics of cells isolated from the bases and orifices of the same crypts in small colorectal adenomas. We found that the dysplastic cells at the tops of the crypts often exhibited genetic alterations of adenomatous polyposis coli (APC) and neoplasia-associated patterns of gene expression. In contrast, cells located at the base of these same crypts did not contain such alterations and were not clonally related to the contiguous transformed cells above them. These results imply that development of adenomatous polyps proceeds through a top-down mechanism. Genetically altered cells in the superficial portions of the mucosae spread laterally and downward to form new crypts that first connect to preexisting normal crypts and eventually replace them. PMID:11226292

  7. Gut mucosal microbiome across stages of colorectal carcinogenesis

    PubMed Central

    Nakatsu, Geicho; Li, Xiangchun; Zhou, Haokui; Sheng, Jianqiu; Wong, Sunny Hei; Wu, William Ka Kai; Ng, Siew Chien; Tsoi, Ho; Dong, Yujuan; Zhang, Ning; He, Yuqi; Kang, Qian; Cao, Lei; Wang, Kunning; Zhang, Jingwan; Liang, Qiaoyi; Yu, Jun; Sung, Joseph J. Y.

    2015-01-01

    Gut microbial dysbiosis contributes to the development of colorectal cancer (CRC). Here we catalogue the microbial communities in human gut mucosae at different stages of colorectal tumorigenesis. We analyse the gut mucosal microbiome of 47 paired samples of adenoma and adenoma-adjacent mucosae, 52 paired samples of carcinoma and carcinoma-adjacent mucosae and 61 healthy controls. Probabilistic partitioning of relative abundance profiles reveals that a metacommunity predominated by members of the oral microbiome is primarily associated with CRC. Analysis of paired samples shows differences in community configurations between lesions and the adjacent mucosae. Correlations of bacterial taxa indicate early signs of dysbiosis in adenoma, and co-exclusive relationships are subsequently more common in cancer. We validate these alterations in CRC-associated microbiome by comparison with two previously published data sets. Our results suggest that a taxonomically defined microbial consortium is implicated in the development of CRC. PMID:26515465

  8. Effects of octreotide on responses to colorectal distension in the rat

    PubMed Central

    Su, X; Burton, M; Gebhart, G

    2001-01-01

    BACKGROUND AND AIMS—It has been suggested that the analgesic effect of the somatostatin analogue octreotide in visceral pain involves peripheral mechanisms. We evaluated the effect of octreotide on responses to noxious colorectal distension in rats.
METHODS—In a behavioural study, pressor and electromyographic responses to colorectal distension were evaluated before and after intravenous or intrathecal administration of octreotide. In pelvic nerve afferent fibre recordings, responses of mechanosensitive fibres innervating the colon to noxious colorectal distension (80 mm Hg, 30 seconds) were tested before and after octreotide.
RESULTS—Octreotide was ineffective in attenuating responses to colorectal distension in either normal or acetic acid inflamed colon when administered intravenously but attenuated responses when given intrathecally. Administration of octreotide over a broad dose range (0.5 µg/kg to 2.4 mg/kg) did not alter responses of afferent fibres to noxious colorectal distension in untreated, or acetic acid or zymosan treated colons.
CONCLUSIONS—In the rat, octreotide has no peripheral (pelvic nerve) modulatory action in visceral nociception. The antinociceptive effect of octreotide in this model of visceral nociception is mediated by an action at central sites.


Keywords: octreotide; colorectal distension; electromyographic responses; afferent fibres; visceral pain; analgesic effect; rat PMID:11302968

  9. Colorectal cancer in Portugal.

    PubMed

    Pinto, Carlos Gouveia; Paquete, Ana Teresa; Pissarra, Irene

    2010-01-01

    Increasing diagnosis and deaths caused by colorectal cancer (CRC) warrant closer examination of affected patients and focus on management of CRC in Portugal. In order to assess the extent and quality of the information available in Portugal, we first analyse Portuguese cancer registries and then the management of CRC by discussing the diagnostic process and medical care provided, especially pharmaceuticals. Other cancer indications are mentioned in order to illustrate current approaches of cancer in Portugal. Current national data on cancer patients are scarce and there are divergencies in methods of data collection and treatment amongst regional cancer registries. However, the available data is sufficient enough to understand the dimension of CRC, with age-standardised incidence of 37 per 100,000 and mortality of 31 per 100,000 annually. An ongoing project is restructuring health services to improve efficiency and quality, however, some problems exist. The regional inequity of access to health care facilities and long waiting times for diagnostic examinations and surgery are major examples. Despite the non-availability of clinical guidelines, a pilot screening programme started at the beginning of 2009 in the Centre Region of the country. It is hoped that this overview will provide the basis for discussion on improvements in CRC management in Portugal and lead to better outcomes.

  10. Immunotherapy of Colorectal Cancer.

    PubMed

    Jäger, Dirk; Halama, Niels; Zörnig, Inka; Klug, Paula; Krauss, Jürgen; Haag, Georg-Martin

    2016-01-01

    It is known that the immune response, reflected by high T cell infiltrates in primary tumors and metastases, influences the clinical course of colorectal cancer (CRC). Therefore, immunotherapy concepts have been adapted from other tumor entities, which typically rely on the activation of T cells in the tumor microenvironment (e.g. blockade of the immune checkpoint molecules PD-1 and CTLA-4). However, most of the strategies using the approved checkpoint inhibitors and/or combination strategies have more or less failed to produce impressive results in early phase trials in CRC. Therefore, a number of novel targets for checkpoint inhibition are currently in early phase clinical testing (TIM-3, Lag-3, OX40, GITR, 4-1BB, CD40, CD70). A simple activation of infiltrating T cells will not, however, lead to a meaningful anti-tumor response without modulating the environmental factors in CRC. Thus, it is absolutely necessary to improve our understanding of the complex regulation of the tumor microenvironment in CRC to design individual combination treatments leading to effective immune control. PMID:27259331

  11. Animal Models of Colorectal Cancer

    PubMed Central

    Johnson, Robert L.; Fleet, James C.

    2012-01-01

    Colorectal cancer is a heterogeneous disease that afflicts a large number of people in the United States. The use of animal models has the potential to increase our understanding of carcinogenesis, tumor biology, and the impact of specific molecular events on colon biology. In addition, animal models with features of specific human colorectal cancers can be used to test strategies for cancer prevention and treatment. In this review we provide an overview of the mechanisms driving human cancer, we discuss the approaches one can take to model colon cancer in animals, and we describe a number of specific animal models that have been developed for the study of colon cancer. We believe that there are many valuable animal models to study various aspects of human colorectal cancer. However, opportunities for improving upon these models exist. PMID:23076650

  12. Animal models of colorectal cancer.

    PubMed

    Johnson, Robert L; Fleet, James C

    2013-06-01

    Colorectal cancer is a heterogeneous disease that afflicts a large number of people in the USA. The use of animal models has the potential to increase our understanding of carcinogenesis, tumor biology, and the impact of specific molecular events on colon biology. In addition, animal models with features of specific human colorectal cancers can be used to test strategies for cancer prevention and treatment. In this review, we provide an overview of the mechanisms driving human cancer, we discuss the approaches one can take to model colon cancer in animals, and we describe a number of specific animal models that have been developed for the study of colon cancer. We believe that there are many valuable animal models to study various aspects of human colorectal cancer. However, opportunities for improving upon these models exist.

  13. Colorectal cancers and chlorinated water

    PubMed Central

    El-Tawil, Ahmed Mahmoud

    2016-01-01

    Published reports have revealed increased risk of colorectal cancers in people exposed to chlorinated drinking water or chemical derivatives of chlorination. Oestrogen plays a dual positive functions for diminishing the possibilities of such risk by reducing the entrance, and increasing the excretion, of these chemicals. In addition, there are supplementary measures that could be employed in order to reduce this risk further, such as boiling the drinking water, revising the standard concentrations of calcium, magnesium and iron in the public drinking water and prescribing oestrogen in susceptible individuals. Hypo-methylation of genomic DNA could be used as a biological marker for screening for the potential development of colorectal cancers. PMID:27096035

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

    SciTech Connect

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

    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.

  15. Colorectal Cancer Risk Prediction Models

    Cancer.gov

    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.

  16. The Mendelian colorectal cancer syndromes

    PubMed Central

    2015-01-01

    A small minority of colorectal cancers (CRCs) (≤5%) are caused by a single, inherited faulty gene. These diseases, the Mendelian colorectal cancer (CRC) syndromes, have been central to our understanding of colorectal carcinogenesis in general. Most of the approximately 13 high-penetrance genes that predispose to CRC primarily predispose to colorectal polyps, and each gene is associated with a specific type of polyp, whether conventional adenomas (APC, MUTYH, POLE, POLD1, NTHL1), juvenile polyps (SMAD4, BMPR1A), Peutz-Jeghers hamartomas (LKB1/STK11) and mixed polyps of serrated and juvenile types (GREM1). Lynch syndrome (MSH2, MLH1, MSH6, PMS2), by contrast, is associated primarily with cancer risk. Major functional pathways are consistently inactivated in the Mendelian CRC syndromes: certain types of DNA repair (proofreading of DNA replication errors, mismatch repair and base excision repair) and signalling (bone morphogenetic protein (BMP), Wnt signalling and mTOR). The inheritance of the CRC syndromes also varies: most are dominant but some of the DNA repair deficiencies are recessive. Some of the Mendelian CRC genes are especially important because they play a role through somatic inactivation in sporadic CRC (APC, MLH1, SMAD4, POLE). Additional Mendelian CRC genes may remain to be discovered and searches for these genes are ongoing, especially in patients with multiple adenomas and hyperplastic polyps. PMID:26169059

  17. What's New in Colorectal Cancer Research and Treatment?

    MedlinePlus

    ... Next Topic Additional resources for colorectal cancer What’s new in colorectal cancer research? Research is always going ... ways to find colorectal cancer early by studying new types of screening tests and improving the ones ...

  18. Percentage of Adults Who Receive Colorectal Cancer Screening as Appropriate

    MedlinePlus

    ... Appropriate Percentage of Adults Who Receive Colorectal Cancer Screening as Appropriate Colorectal cancer is the second leading ... Percentage of Adults Who Receive Recommended Colorectal Cancer Screening by Age Group 78pm-ubty Download these data » ...

  19. Colorectal adenocarcinoma in Crohn's disease.

    PubMed Central

    Ribeiro, M B; Greenstein, A J; Sachar, D B; Barth, J; Balasubramanian, S; Harpaz, N; Heimann, T M; Aufses, A H

    1996-01-01

    OBJECTIVE: The authors' aim was to review the clinical features and estimate the long-term survival of patients with colorectal carcinoma complicating Crohn's disease. SUMMARY BACKGROUND DATA: Recent studies have demonstrated a significantly increased risk of colorectal carcinoma in patients with Crohns disease. METHODS: The authors reviewed retrospectively the medical records of 30 patients with Crohn's disease admitted to The Mount Sinai Hospital between 1960 and 1989 in whom colorectal adenocarcinoma developed. All patients were operated on and follow-up was complete for all patients to 10 years after operation, to the time of death, or to the closing date of the study in December 1989. RESULTS: The 30 patients in the series had 33 colorectal adenocarcinomas; three patients (10%) presented with two synchronous cancers. The patients were relatively young (mean age, 53 years) and had long-standing Crohn's disease (duration >20 years in 87%). The 5-year actuarial survival was 44% for the overall series: 100% for stage A, 86% for stage B, 60% for stage C. All five patients with excluded bowel tumor died of large bowel cancer within 2.4 years; by contrast, the actuarial 5-year survival for patients with in-continuity tumors was 56%. CONCLUSIONS: The incidence, characteristics, and prognosis of colorectal carcinoma complicating Crohn's disease are similar to the features of cancer in ulcerative colitis, including young age, multiple neoplasms, long duration of disease, and greater than a 50% 5-year survival rate (without excluded loops). These observations suggest the advisability of surveillance programs for Crohn's disease of the colon similar to those for ulcerative colitis of comparable duration and extent. PMID:8597513

  20. Identification and characterization of RET fusions in advanced colorectal cancer

    PubMed Central

    Garrett, Christopher R.; Seery, Tara; Sanford, Eric M.; Balasubramanian, Sohail; Ross, Jeffrey S.; Stephens, Philip J.; Miller, Vincent A.; Ali, Siraj M.; Chiu, Vi K.

    2015-01-01

    There is an unmet clinical need for molecularly directed therapies available for metastatic colorectal cancer. Comprehensive genomic profiling has the potential to identify actionable genomic alterations in colorectal cancer. Through comprehensive genomic profiling we prospectively identified 6 RET fusion kinases, including two novel fusions of CCDC6-RET and NCOA4-RET, in metastatic colorectal cancer (CRC) patients. RET fusion kinases represent a novel class of oncogenic driver in CRC and occurred at a 0.2% frequency without concurrent driver mutations, including KRAS, NRAS, BRAF, PIK3CA or other fusion tyrosine kinases. Multiple RET kinase inhibitors were cytotoxic to RET fusion kinase positive cancer cells and not RET fusion kinase negative CRC cells. The presence of a RET fusion kinase may identify a subset of metastatic CRC patients with a high response rate to RET kinase inhibition. This is the first characterization of RET fusions in CRC patients and highlights the therapeutic significance of prospective comprehensive genomic profiling in advanced CRC. PMID:26078337

  1. Identification and characterization of RET fusions in advanced colorectal cancer.

    PubMed

    Le Rolle, Anne-France; Klempner, Samuel J; Garrett, Christopher R; Seery, Tara; Sanford, Eric M; Balasubramanian, Sohail; Ross, Jeffrey S; Stephens, Philip J; Miller, Vincent A; Ali, Siraj M; Chiu, Vi K

    2015-10-01

    There is an unmet clinical need for molecularly directed therapies available for metastatic colorectal cancer. Comprehensive genomic profiling has the potential to identify actionable genomic alterations in colorectal cancer. Through comprehensive genomic profiling we prospectively identified 6 RET fusion kinases, including two novel fusions of CCDC6-RET and NCOA4-RET, in metastatic colorectal cancer (CRC) patients. RET fusion kinases represent a novel class of oncogenic driver in CRC and occurred at a 0.2% frequency without concurrent driver mutations, including KRAS, NRAS, BRAF, PIK3CA or other fusion tyrosine kinases. Multiple RET kinase inhibitors were cytotoxic to RET fusion kinase positive cancer cells and not RET fusion kinase negative CRC cells. The presence of a RET fusion kinase may identify a subset of metastatic CRC patients with a high response rate to RET kinase inhibition. This is the first characterization of RET fusions in CRC patients and highlights the therapeutic significance of prospective comprehensive genomic profiling in advanced CRC. PMID:26078337

  2. Microbiota regulation of inflammatory bowel disease and colorectal cancer

    PubMed Central

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

    2013-01-01

    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. PMID:24071482

  3. Current concepts in colorectal cancer prevention

    PubMed Central

    Thompson, Patricia A; Gerner, Eugene W

    2009-01-01

    Colorectal cancer chemoprevention, or chemoprophylaxis, is a drug-based approach to prevent colorectal cancer. Preventing colorectal adenomas with currently available agents demonstrates the promise of pharmacologic strategies directed at critical regulatory pathways. However, agent toxicity, lesion breakthrough and competing efficacy from endoscopy procedures challenge population-based implementation. This article reviews the role of colorectal cancer chemoprevention in the context of existing screening and surveillance guidelines and practice. Emphasis is placed on the role of the colorectal adenoma as a cancer precursor and its surrogacy in assessing individual risk and for evaluating chemoprevention efficacy. We discuss the importance of risk stratification for identifying subjects at moderate-to-high risk for colorectal cancer who are most likely to benefit from chemoprevention at an acceptable level of risk. PMID:19673624

  4. Epigenetic silencing of monoallelically methylated miRNA loci in precancerous colorectal lesions

    PubMed Central

    Menigatti, M; Staiano, T; Manser, C N; Bauerfeind, P; Komljenovic, A; Robinson, M; Jiricny, J; Buffoli, F; Marra, G

    2013-01-01

    Epigenetic silencing of protein-encoding genes is common in early-stage colorectal tumorigenesis. Less is known about the methylation-mediated silencing of genes encoding microRNAs (miRNAs), which are also important epigenetic modulators of gene expression. Using quantitative PCR, we identified 56 miRNAs that were expressed in normal colorectal mucosa and in HT29 colorectal cancer cells treated with demethylating agents but not in untreated HT29 cells, suggesting that they probably undergo methylation-induced silencing during colorectal tumorigenesis. One of these, miR-195, had recently been reported to be underexpressed in colorectal cancers and to exert tumor-suppressor effects in colorectal cancer cells. We identified the transcription start site (TSS) for primary miRNA (pri-miR)-497/195, the primary precursor that yields miR-195 and another candidate on our list, miR-497, and a single CpG island upstream to the TSS, which controls expression of both miRNAs. Combined bisulfite restriction analysis and bisulfite genomic sequencing studies revealed monoallelic methylation of this island in normal colorectal mucosa (50/50 samples) and full methylation in most colorectal adenomas (38/50; 76%). The hypermethylated precancerous lesions displayed significantly downregulated expression of both miRNAs. Similar methylation patterns were observed at two known imprinted genes, MEG3 and GNAS-AS1, which encode several of the 56 miRNAs on our list. Imprinting at these loci was lost in over half the adenomas (62% at MEG3 and 52% at GNAS-AS1). Copy-number alterations at MEG3, GNAS-AS1 and pri-miR-497/195, which are frequent in colorectal cancers, were less common in adenomas and confined to tumors displaying differential methylation at the involved locus. Our data show that somatically acquired, epigenetic changes at monoallelically methylated regions encoding miRNAs are relatively frequent in sporadic colorectal adenomas and might contribute to the onset and progression of

  5. Epigenetic silencing of monoallelically methylated miRNA loci in precancerous colorectal lesions.

    PubMed

    Menigatti, M; Staiano, T; Manser, C N; Bauerfeind, P; Komljenovic, A; Robinson, M; Jiricny, J; Buffoli, F; Marra, G

    2013-01-01

    Epigenetic silencing of protein-encoding genes is common in early-stage colorectal tumorigenesis. Less is known about the methylation-mediated silencing of genes encoding microRNAs (miRNAs), which are also important epigenetic modulators of gene expression. Using quantitative PCR, we identified 56 miRNAs that were expressed in normal colorectal mucosa and in HT29 colorectal cancer cells treated with demethylating agents but not in untreated HT29 cells, suggesting that they probably undergo methylation-induced silencing during colorectal tumorigenesis. One of these, miR-195, had recently been reported to be underexpressed in colorectal cancers and to exert tumor-suppressor effects in colorectal cancer cells. We identified the transcription start site (TSS) for primary miRNA (pri-miR)-497/195, the primary precursor that yields miR-195 and another candidate on our list, miR-497, and a single CpG island upstream to the TSS, which controls expression of both miRNAs. Combined bisulfite restriction analysis and bisulfite genomic sequencing studies revealed monoallelic methylation of this island in normal colorectal mucosa (50/50 samples) and full methylation in most colorectal adenomas (38/50; 76%). The hypermethylated precancerous lesions displayed significantly downregulated expression of both miRNAs. Similar methylation patterns were observed at two known imprinted genes, MEG3 and GNAS-AS1, which encode several of the 56 miRNAs on our list. Imprinting at these loci was lost in over half the adenomas (62% at MEG3 and 52% at GNAS-AS1). Copy-number alterations at MEG3, GNAS-AS1 and pri-miR-497/195, which are frequent in colorectal cancers, were less common in adenomas and confined to tumors displaying differential methylation at the involved locus. Our data show that somatically acquired, epigenetic changes at monoallelically methylated regions encoding miRNAs are relatively frequent in sporadic colorectal adenomas and might contribute to the onset and progression of

  6. Enema ion compositions for enhancing colorectal drug delivery.

    PubMed

    Maisel, Katharina; Chattopadhyay, Sumon; Moench, Thomas; Hendrix, Craig; Cone, Richard; Ensign, Laura M; Hanes, Justin

    2015-07-10

    Delivering drugs to the colorectum by enema has advantages for treating or preventing both local and systemic diseases. However, the properties of the enema itself are not typically exploited for improving drug delivery. Sodium ions are actively pumped out of the lumen of the colon, which is followed by osmotically-driven water absorption, so we hypothesized that this natural mechanism could be exploited to drive nanoparticles and drugs to the colorectal tissue surface. Here, we report that sodium-based, absorption-inducing (hypotonic) enemas rapidly transport hydrophilic drugs and non-mucoadhesive, mucus penetrating nanoparticles (MPP), deep into the colorectal folds to reach virtually the entire colorectal epithelial surface. In contrast, isotonic and secretion-inducing (hypertonic) vehicles led to non-uniform, poor surface coverage. Sodium-based enemas induced rapid fluid absorption even when moderately hyper-osmolal (~350 mOsm) compared to blood (~300 mOsm), which suggests that active sodium absorption plays a key role in osmosis-driven fluid uptake. We then used tenofovir, an antiretroviral drug in clinical trials for preventing HIV, to test the effects of enema composition on local and systemic drug delivery. We found that strongly hypotonic and hypertonic enemas caused rapid systemic drug uptake, whereas moderately hypotonic enemas with ion compositions similar to feces resulted in high local tissue levels with minimal systemic drug exposure. Similarly, moderately hypotonic enemas provided improved local drug retention in colorectal tissue, whereas hypertonic and isotonic enemas provided markedly reduced drug retention in colorectal tissue. Lastly, we found that moderately hypotonic enema formulations caused little to no detectable epithelial damage, while hypertonic solutions caused significant damage, including epithelial sloughing; the epithelial damage caused increased systemic drug absorption and penetration of MPP into colorectal tissue, a potential

  7. Epidemiology and molecular genetics of colorectal cancer in iran: a review.

    PubMed

    Malekzadeh, Reza; Bishehsari, Faraz; Mahdavinia, Mahboobeh; Ansari, Reza

    2009-03-01

    Although the incidence of colorectal cancer in Iranian older age subjects is currently very low compared to Western population, the younger generation is experiencing an accelerated rate approaching the Western rates and the burden of disease will increase dramatically in near future. The high frequency of positive family history of colorectal cancer in Iranian patients indicates that a significant number of colorectal cancers in Iran arise in family members and relatives of colorectal cancer patients. It is clear that the familial clustering of colorectal cancer is more often seen in younger probands and cancer located in the right side of the colon. These epidemiologic findings call for a broader attempt to promote public awareness and screening strategies in those families with a member affected by colorectal cancer, especially at younger age or with proximal tumors. Based on our present understanding, the possibility of preventing or curing most colon and rectal cancers is now plausible. The molecular biology of colon cancer has been the subject of many researches and is better understood than those for any other solid cancer and have established an important example for cancer research. It is now clear that colorectal cancer develops as the result of genetic and epigenetic alterations that lead to malignant transformation of normal mucosa. In spite of these scientific progresses and the fact that screening can reduce the rate of death by detecting early cancer or premalignant polyps, the rate of screening is very low globally and negligible in Iran and many other developing countries which is due to cost, resistance by physicians, patients, and the healthcare system. In Iran screening should at least be started in family members at earlier age with colonoscopy as the preferred modality of screening method. PMID:19249887

  8. [Signet ring cell colorectal carcinom - case report].

    PubMed

    Matkovčík, Z; Hlad, J

    2015-08-01

    Signet ring cell colorectal carcinoma is a rare aggressive tumor. The incidence of this desease is very low in young patients and accounts up to 1% of all surgical patients with colorectal cancer. The infrequency of the disease among young patients makes the diagnosis more difficult and the prognosis less favourable. Biopsy results are crucial for verification of signet ring cell carcinoma. Treatment is similar as in other types of colorectal cancer. We report a case of signet ring cell colon cancer in a 22 years old female patient.The aim of this paper is to point out this rare case of infrequent colorectal cancer in a young female patient. PMID:26395957

  9. Altered Profile of Secondary Metabolites in the Root Exudates of Arabidopsis ATP-Binding Cassette Transporter Mutants1[C][W][OA

    PubMed Central

    Badri, Dayakar V.; Loyola-Vargas, Victor M.; Broeckling, Corey D.; De-la-Peña, Clelia; Jasinski, Michal; Santelia, Diana; Martinoia, Enrico; Sumner, Lloyd W.; Banta, Lois M.; Stermitz, Frank; Vivanco, Jorge M.

    2008-01-01

    Following recent indirect evidence suggesting a role for ATP-binding cassette (ABC) transporters in root exudation of phytochemicals, we identified 25 ABC transporter genes highly expressed in the root cells most likely to be involved in secretion processes. Of these 25 genes, we also selected six full-length ABC transporters and a half-size transporter for in-depth molecular and biochemical analyses. We compared the exuded root phytochemical profiles of these seven ABC transporter mutants to those of the wild type. There were three nonpolar phytochemicals missing in various ABC transporter mutants compared to the wild type when the samples were analyzed by high-performance liquid chromatography-mass spectrometry. These data suggest that more than one ABC transporter can be involved in the secretion of a given phytochemical and that a transporter can be involved in the secretion of more than one secondary metabolite. The primary and secondary metabolites present in the root exudates of the mutants were also analyzed by gas chromatography-mass spectrometry, which allowed for the identification of groups of compounds differentially found in some of the mutants compared to the wild type. For instance, the mutant Atpdr6 secreted a lower level of organic acids and Atmrp2 secreted a higher level of amino acids as compared to the wild type. We conclude that the release of phytochemicals by roots is partially controlled by ABC transporters. PMID:18065561

  10. Therapeutic targets in the Wnt signaling pathway: Feasibility of targeting TNIK in colorectal cancer.

    PubMed

    Masuda, Mari; Sawa, Masaaki; Yamada, Tesshi

    2015-12-01

    The genetic and epigenetic alterations occurring during the course of multistage colorectal carcinogenesis have been extensively studied in the last few decades. One of the most notable findings is that the great majority of colorectal cancers (>80%) have mutations in the adenomatous polyposis coli (APC) tumor suppressor gene. Loss of functional APC protein results in activation of canonical Wnt/β-catanin signaling and initiates intestinal carcinogenesis. Mutational inactivation of APC is the first genetic event, but colorectal cancer cells retain their dependency on constitutive Wnt signal activation even after accumulation of other genetic events. Accordingly, pharmacological blocking of Wnt signaling has been considered an attractive therapeutic approach for colorectal cancer. Several therapeutics targeting various molecular components of the Wnt signaling pathway, including porcupine, frizzled receptors and co-receptor, tankyrases, and cAMP response element binding protein (CREB)-binding protein (CBP), have been developed, and some of those are currently being evaluated in early-phase clinical trials. Traf2- and Nck-interacting protein kinase (TNIK) has been identified as a regulatory component of the T-cell factor-4 and β-catenin transcriptional complex independently by two research groups. TNIK regulates Wnt signaling in the most downstream part of the pathway, and its inhibition is expected to block the signal even in colorectal cancer cells with APC gene mutation. Here we discuss some of the TNIK inhibitors under preclinical development. PMID:26542362

  11. Sildenafil inhibits the growth of human colorectal cancer in vitro and in vivo

    PubMed Central

    Mei, Xiao-Long; Yang, Yang; Zhang, Yao-Jun; Li, Yong; Zhao, Jin-Ming; Qiu, Jian-Ge; Zhang, Wen-Ji; Jiang, Qi-Wei; Xue, You-Qiu; Zheng, Di-Wei; Chen, Yao; Qin, Wu-Ming; Wei, Meng-Ning; Shi, Zhi

    2015-01-01

    Colorectal cancer is the third most common human cancer with frequent overexpression of the cGMP-specific phosphodiesterase 5 (PDE5). In the present study, we investigated that the anticancer effect of sildenafil on human colorectal cancer in vitro and in vivo, which is a potent and selective inhibitor of PDE5 for the treatment of erectile dysfunction and pulmonary arterial hypertension in the clinic. Sildenafil significantly induced cell growth inhibition, cell cycle arrest and apoptosis of human colorectal cancer with increased intracellular reactive oxidative specie (ROS) levels, which were accompanied by obvious alterations of related proteins such as CDKs, Cyclins and PARP etc. Pretreatment with ROS scavenger N-acetyl-L-cysteine could reverse sildenafil-induced ROS accumulation and cell apoptosis. Inhibition of the activity of protein kinase G with KT-5823 could enhance sildenafil-induced apoptosis. Furthermore, sildenafil caused the reduction of xenograft models of human colorectal cancer in nude mice. Overall, these findings suggest that sildenafil has the potential to be used for treatment of human colorectal cancer. PMID:26807313

  12. Accumulation of arachidonic acid-containing phosphatidylinositol at the outer edge of colorectal cancer

    PubMed Central

    Hiraide, Takanori; Ikegami, Koji; Sakaguchi, Takanori; Morita, Yoshifumi; Hayasaka, Takahiro; Masaki, Noritaka; Waki, Michihiko; Sugiyama, Eiji; Shinriki, Satoru; Takeda, Makoto; Shibasaki, Yasushi; Miyazaki, Shinichiro; Kikuchi, Hirotoshi; Okuyama, Hiroaki; Inoue, Masahiro; Setou, Mitsutoshi; Konno, Hiroyuki

    2016-01-01

    Accumulating evidence indicates that cancer cells show specific alterations in phospholipid metabolism that contribute to tumour progression in several types of cancer, including colorectal cancer. Questions still remain as to what lipids characterize the outer edge of cancer tissues and whether those cancer outer edge-specific lipid compositions emerge autonomously in cancer cells. Cancer tissue-originated spheroids (CTOSs) that are composed of pure primary cancer cells have been developed. In this study, we aimed to seek out the cancer cell-autonomous acquisition of cancer outer edge-characterizing lipids in colorectal cancer by analysing phospholipids in CTOSs derived from colorectal cancer patients with matrix-assisted laser desorption/ionization (MALDI)-imaging mass spectrometry (IMS). A signal at m/z 885.5 in negative ion mode was detected specifically at the surface regions. The signal was identified as an arachidonic acid (AA)-containing phosphatidylinositol (PI), PI(18:0/20:4), by tandem mass spectrometry analysis. Quantitative analysis revealed that the amount of PI(18:0/20:4) in the surface region of CTOSs was two-fold higher than that in the medial region. Finally, PI(18:0/20:4) was enriched at the cancer cells/stromal interface in colorectal cancer patients. These data imply a possible importance of AA-containing PI for colorectal cancer progression, and suggest cells expressing AA-containing PI as potential targets for anti-cancer therapy. PMID:27435310

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

    PubMed Central

    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

    2015-01-01

    Background 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. Methods 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. Results 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 < 0.05 = in wild-type C57BL/6 and mice with DMH treatment). BBR intervention reversed the F. 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. Conclusions 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. PMID:26397137

  14. Identification of novel tumor suppressor proteases by degradome profiling of colorectal carcinomas

    PubMed Central

    Fraile, Julia M.; Ordóñez, Gonzalo R.; Quirós, Pedro M.; Astudillo, Aurora; Galván, José A.; Colomer, Dolors; López-Otín, Carlos; Freije, José M.P.; Puente, Xose S.

    2013-01-01

    Proteolytic enzymes play important roles during tumor development and progression through their ability to promote cell growth or by facilitating the invasion of surrounding tissues. The human genome contains more than 570 protease-coding genes, many of them forming functional networks, which has forced the use of global strategies for the analysis of this group of enzymes. In this study, we have designed a new quantitative PCR-based device for profiling the entire degradome in human malignancies. We have used this method to evaluate protease expression levels in colorectal carcinomas with the finding that most proteases with altered expression in these tumors exert their function in the extracellular compartment. In addition, we have found that among genes encoding repressed proteases there was a higher proportion with somatic mutations in colorectal cancer when compared to genes coding for upregulated proteases (14% vs. 4%, p<0.05). One of these genes, MASP3, is consistently repressed in colorectal carcinomas as well as in colorectal cancer cell lines when compared to normal colonic mucosa. Functional analysis of this gene revealed that ectopic expression of MASP3 reduces cell proliferation in vitro and restrains subcutaneous tumor growth, whereas its downregulation induces an increase in the tumorigenic potential of colorectal cancer cells. These results provide new insights into the diversity of proteases associated with cancer and support the utility of degradome profiling to identify novel proteases with tumor-defying functions.

  15. Survivorship Care Plan in Promoting Physical Activity in Breast or Colorectal Cancer Survivors in Wisconsin

    ClinicalTrials.gov

    2016-08-19

    Cancer Survivor; Healthy Subject; Stage I Colorectal Cancer; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage IIA Breast Cancer; Stage IIA Colorectal Cancer; Stage IIB Breast Cancer; Stage IIB Colorectal Cancer; Stage IIC Colorectal Cancer; Stage IIIA Breast Cancer; Stage IIIA Colorectal Cancer; Stage IIIB Breast Cancer; Stage IIIB Colorectal Cancer; Stage IIIC Breast Cancer; Stage IIIC Colorectal Cancer

  16. Stem cells and colorectal carcinogenesis

    PubMed Central

    Stoian, M; Stoica, V; Radulian, G

    2016-01-01

    Abstract Colorectal cancer represents an important cause of mortality and morbidity. Unfortunately, the physiopathology is still under study. There are theories about carcinogenesis and it is known that not only a single factor is responsible for the development of a tumor, but several conditions. Stem cells are a promising target for the treatment of colorectal cancer, along with the environment that has an important role. It has been postulated that mutations within the adult colonic stem cells may induce neoplastic changes. This theory is based on the observation that within a colon cancer, less than 1% of the neoplastic cells have the ability to regenerate the tumor and therefore they are responsible for recurrence. It is important to know that a new way of treatment needs to be found, since these cells are resistant to chemotherapy and radiotherapy.

  17. General aspects of colorectal cancer.

    PubMed

    Centelles, Josep J

    2012-01-01

    Colorectal cancer (CRC) is one of the main causes of death. Cancer is initiated by several DNA damages, affecting proto-oncogenes, tumour suppressor genes, and DNA repairing genes. The molecular origins of CRC are chromosome instability (CIN), microsatellite instability (MSI), and CpG island methylator phenotype (CIMP). A brief description of types of CRC cancer is presented, including sporadic CRC, hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndromes, familiar adenomatous polyposis (FAP), MYH-associated polyposis (MAP), Peutz-Jeghers syndrome (PJS), and juvenile polyposis syndrome (JPS). Some signalling systems for CRC are also described, including Wnt-β-catenin pathway, tyrosine kinase receptors pathway, TGF-β pathway, and Hedgehog pathway. Finally, this paper describes also some CRC treatments.

  18. The diagnostics of colorectal cancer.

    PubMed

    Swiderska, Magdalena; Choromańska, Barbara; Dąbrowska, Ewelina; Konarzewska-Duchnowska, Emilia; Choromańska, Katarzyna; Szczurko, Grzegorz; Myśliwiec, Piotr; Dadan, Jacek; Ladny, Jerzy Robert; Zwierz, Krzysztof

    2014-01-01

    Colorectal cancer (CRC) is one of the most frequent human malignant neoplasms. CRC has an estimated incidence of more than 1,000,000 new cases annually worldwide. Approximately one out of three people who develop CRC dies from the disease. Furthermore, CRC often affects inhabitants of industrialized countries in comparison to less developed countries. Several markers of colon cancer, including CEA, CA-19-9, TPS, TAG-72 and lysosomal hydrolases, have been identified and are now being adopted in routine clinical practice. Increased values of these markers are often the first signal of recurrence or metastases, which is useful in prediction and prognosis of clinical outcome of patients with CRC. Determination of the activity of lysosomal exoglycosidases in body fluids may bring some hope of improving diagnosis of colorectal cancer. However, it has to be remembered that currently the most effective diagnostic method of CRC is endoscopy. PMID:24876814

  19. Fascin expression in colorectal carcinomas

    PubMed Central

    Ozerhan, Ismail Hakki; Ersoz, Nail; Onguru, Onder; Ozturk, Mustafa; Kurt, Bulent; Cetiner, Sadettin

    2010-01-01

    PURPOSE The purpose of this study was to investigate the significance of fascin expression in colorectal carcinoma. METHODS This is a retrospective study of 167 consecutive, well-documented cases of primary colorectal adenocarcinoma for which archival material of surgical specimens from primary tumor resections were available. We chose a representative tissue sample block and examined fascin expression by immunohistochemistry using a primary antibody against “fascin”. We calculated the “immunohistochemical score (IHS)” of fascin for each case, which was calculated from the multiplication of scores for the percentage of stained cells and the staining intensity. RESULTS Fascin immunoreactivity was observed in 59 (35.3%) of all cases with strong reactivity in 24 (14.4%), moderate reactivity in 25 (14.9%) and weak reactivity in 10 (6.0%) cases. Strong/moderate immunoreactivities were mostly observed in invasive fronts of the tumors or in both invasive and other areas. Fascin immunoreactivity scores were significantly higher in tumors with lymph node metastasis (p:0.002) and advanced stage presentation (p:0.007). There was no relation between fascin expression and age, gender, depth of invasion, distant metastasis or histological grade (p>0.05). There was a higher and statistically significant correlation between fascin immunoreactivity in the invasive borders of tumors and lymph node metastasis (r:0.747, p:0.005). In stage III/IV tumors, two-year survival was 92.2% in tumors without fascin immunoreactivity, and only 60.0% in tumors with a fascin IHS>10 (p:0.003). CONCLUSION These findings suggest that fascin is heterogeneously expressed in approximately one third of colorectal carcinomas with a significant association with lymph node metastasis, tumor stage and location. Moreover, these results indicate that fascin may have a role in the lymph node metastasis of colorectal carcinomas. PMID:20186299

  20. Colorectal hepatic metastasis: Evolving therapies

    PubMed Central

    Macedo, Francisco Igor B; Makarawo, Tafadzwa

    2014-01-01

    The approach for colorectal hepatic metastasis has advanced tremendously over the past decade. Multidrug chemotherapy regimens have been successfully introduced with improved outcomes. Concurrently, adjunct multimodal therapies have improved survival rates, and increased the number of patients eligible for curative liver resection. Herein, we described major advancements of surgical and oncologic management of such lesions, thereby discussing modern chemotherapeutic regimens, adjunct therapies and surgical aspects of liver resection. PMID:25067997

  1. Systemic Treatment of Colorectal Cancer

    PubMed Central

    Wolpin, Brian M.; Mayer, Robert J.

    2008-01-01

    Colorectal cancer is the fourth most common non-cutaneous malignancy in the United States and the second most frequent cause of cancer-related death. Over the past 12 years, significant progress has been made in the systemic treatment of this malignant condition. Six new chemotherapeutic agents have been introduced, increasing median overall survival for patients with metastatic colorectal cancer from less than 9 months with no treatment to approximately 24 months. For patients with stage III (lymph node positive) colon cancer, an overall survival benefit for fluorouracil-based chemotherapy has been firmly established, and recent data have shown further efficacy for the inclusion of oxaliplatin in such adjuvant treatment programs. For patients with stage II colon cancer, the use of adjuvant chemotherapy remains controversial, but may be appropriate in a subset of individuals at higher risk for disease recurrence. Ongoing randomized clinical trials are evaluating how best to combine currently available therapies, while smaller studies are evaluating new agents, with the goal of continued progress in prolonging life among patients with metastatic colorectal cancer and increasing cure rates among those with resectable disease. PMID:18471507

  2. Cathepsin B promotes colorectal tumorigenesis, cell invasion, and metastasis

    PubMed Central

    Bian, Benjamin; Mongrain, Sébastien; Cagnol, Sébastien; Langlois, Marie‐Josée; Boulanger, Jim; Bernatchez, Gérald; Carrier, Julie C.; Boudreau, François

    2015-01-01

    Cathepsin B is a cysteine proteinase that primarily functions as an endopeptidase within endolysosomal compartments in normal cells. However, during tumoral expansion, the regulation of cathepsin B can be altered at multiple levels, thereby resulting in its overexpression and export outside of the cell. This may suggest a possible role of cathepsin B in alterations leading to cancer progression. The aim of this study was to determine the contribution of intracellular and extracellular cathepsin B in growth, tumorigenesis, and invasion of colorectal cancer (CRC) cells. Results show that mRNA and activated levels of cathepsin B were both increased in human adenomas and in CRCs of all stages. Treatment of CRC cells with the highly selective and non‐permeant cathepsin B inhibitor Ca074 revealed that extracellular cathepsin B actively contributed to the invasiveness of human CRC cells while not essential for their growth in soft agar. Cathepsin B silencing by RNAi in human CRC cells inhibited their growth in soft agar, as well as their invasion capacity, tumoral expansion, and metastatic spread in immunodeficient mice. Higher levels of the cell cycle inhibitor p27Kip1 were observed in cathepsin B‐deficient tumors as well as an increase in cyclin B1. Finally, cathepsin B colocalized with p27Kip1 within the lysosomes and efficiently degraded the inhibitor. In conclusion, the present data demonstrate that cathepsin B is a significant factor in colorectal tumor development, invasion, and metastatic spreading and may, therefore, represent a potential pharmacological target for colorectal tumor therapy. © 2015 The Authors. Molecular Carcinogenesis, published by Wiley Periodicals, Inc. PMID:25808857

  3. Loss of heterozygosity and mutational analyses of the ACTRII gene locus in human colorectal tumors.

    PubMed

    Olaru, Andreea; Mori, Yuriko; Yin, Jing; Wang, Suna; Kimos, Martha C; Perry, Kellie; Xu, Yan; Sato, Fumiaki; Selaru, Florin M; Deacu, Elena; Sterian, Anca; Shibata, David; Abraham, John M; Meltzer, Stephen J

    2003-12-01

    The activin type II receptorgene (ACTRII) is mutated in 58.1% of microsatellite-unstable (MSI-H) colorectal cancers and is a close relative of the TGFbeta-1 type II receptor, which is known to be involved in both MSI-H and non-MSI-H colorectal carcinogenesis. We therefore sought to determine whether ACTRII was involved in non-MSI-H colorectal cancers. We evaluated ACTRII inactivation by allelic deletion, loss of mRNA expression, or somatic mutation in 51 non-MSI-H colon cancers. Loss of heterozygosity (LOH) at the ACTRII locus (2q23.1) was found in 9 (17.6%) of 51 primary tumors. Loss of ACTRII mRNA expression was seen in one (14.3%) of the seven LOH-positive primary tumors from which total RNA was available. We also performed DNA sequencing analysis of tumors showing LOH. One LOH-positive primary tumor exhibited a novel germline missense sequence alteration (amino acid substitution, 117 Ile to Phe) that was not found in 23 additional normal individuals, implying that this alteration is not a frequent polymorphism. We conclude that ACTRII is probably involved in both non-MSI-H and MSI-H colorectal carcinogenesis, but more frequently in the latter subgroup.

  4. Colorectal cancer in Jordan: prevention and care.

    PubMed

    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.

  5. Tailored Telephone Counseling Increases Colorectal Cancer Screening

    ERIC Educational Resources Information Center

    Rawl, Susan M.; Christy, Shannon M.; Monahan, Patrick O.; Ding, Yan; Krier, Connie; Champion, Victoria L.; Rex, Douglas

    2015-01-01

    To compare the efficacy of two interventions to promote colorectal cancer screening participation and forward stage movement of colorectal cancer screening adoption among first-degree relatives of individuals diagnosed with adenomatous polyps. One hundred fifty-eight first-degree relatives of individuals diagnosed with adenomatous polyps were…

  6. Dairy products, polymorphisms in the vitamin D receptor gene and colorectal adenoma recurrence.

    PubMed

    Hubner, Richard A; Muir, Kenneth R; Liu, Jo-Fen; Logan, Richard F A; Grainge, Matthew J; Houlston, Richard S

    2008-08-01

    Vitamin D receptor (VDR) activation inhibits proliferation and angiogenesis in the colorectal epithelium, and inhibits metastasis of colorectal tumors. Polymorphisms in the VDR gene alter receptor cellular levels and functioning, and may confer altered susceptibility to colorectal neoplasia. We aimed to investigate the influence of VDR polymorphisms and dietary factors impacting on vitamin D metabolism on colorectal adenoma (CRA) recurrence. Data on dietary intakes of calcium, vitamin D and dairy products were collected from 853 participants in the United Kingdom Colorectal Adenoma Prevention trial, a randomized trial of aspirin and folate for CRA recurrence prevention. The VDR Cdx2, FokI, BsmI, ApaI and TaqI polymorphisms were genotyped in 546 participants with available DNA, and gene-diet interaction analyses performed in 480. Dairy product intake was inversely related to CRA recurrence risk independent of calcium and vitamin D [relative risk (RR) = 0.64; 95% confidence intervals (CIs): 0.47-0.88, for subjects in the highest compared to lowest intake tertile, p(trend) = 0.005]. Milk accounted for 60% of dairy product intake, and on analysis of milk and nonmilk dairy products separately recurrence risk in individuals in the highest tertile of milk intake was half that of lowest tertile individuals (RR = 0.52; 95% CI: 0.38-0.72, p(trend) = 3.2 x 10(-5)), whereas nonmilk dairy products did not influence recurrence. VDR polymorphism genotypes and haplotypes did not directly alter recurrence risk, but the reduction in risk associated with high dairy product intake was confined to individuals with ApaI aA/AA genotype (p(interaction) = 0.02). These findings indicate dairy products, and in particular milk, have chemopreventive activity against CRA recurrence. PMID:18470879

  7. RPS7 inhibits colorectal cancer growth via decreasing HIF-1α-mediated glycolysis

    PubMed Central

    Li, Dawei; Li, Jiajia; Cheng, Xi; Wang, Ziliang

    2016-01-01

    Ribosomal protein S7 (RPS7) acts as a tumor suppressor in primary tumorigenesis but its role in cancer metabolism remains unclear. In this study, we demonstrate that RPS7 inhibits the colorectal cancer (CRC) cell glycolysis by suppressing the expression of hypoxia-inducible transcription factor-1α (HIF-1α) and the metabolic promoting proteins glucose transporter 4 (GLUT4) and lactate dehydrogenase B (LDHB). Further study found that the enhanced expression of HIF-1α abrogates the overexpression effects of RPS7 on CRC. In vivo assays also demonstrate that RPS7 suppresses colorectal cancer tumorigenesis and glycolysis. Clinically, the tissue microarray (TMA) analysis discloses the negative regulatory association between RPS7 and HIF-1α in colorectal cancer. Meanwhile, overexpression of RPS7 in colorectal cancer tissues predicts good overall survival and progression-free survival, but high expression level of HIF-1α indicates poor overall survival and progression-free survival. Overall, we reveal that RPS7 inhibits colorectal cancer glycolysis through HIF-1α-associated signaling and may be a promising biomarker for prognosis prediction and a potential target for therapeutic treatment. PMID:26735579

  8. Molecular Diagnostic Applications in Colorectal Cancer

    PubMed Central

    Huth, Laura; Jäkel, Jörg; Dahl, Edgar

    2014-01-01

    Colorectal cancer, a clinically diverse disease, is a leading cause of cancer-related death worldwide. Application of novel molecular diagnostic tests, which are summarized in this article, may lead to an improved survival of colorectal cancer patients. Distinction of these applications is based on the different molecular principles found in colorectal cancer (CRC). Strategies for molecular analysis of single genes (as KRAS or TP53) as well as microarray based techniques are discussed. Moreover, in addition to the fecal occult blood testing (FOBT) and colonoscopy some novel assays offer approaches for early detection of colorectal cancer like the multitarget stool DNA test or the blood-based Septin 9 DNA methylation test. Liquid biopsy analysis may also exhibit great diagnostic potential in CRC for monitoring developing resistance to treatment. These new diagnostic tools and the definition of molecular biomarkers in CRC will improve early detection and targeted therapy of colorectal cancer.

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

    PubMed

    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.

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

    PubMed

    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. PMID:25665006

  11. Identification of diagnostic markers in colorectal cancer via integrative epigenomics and genomics data.

    PubMed

    Kok-Sin, Teow; Mokhtar, Norfilza Mohd; Ali Hassan, Nur Zarina; Sagap, Ismail; Mohamed Rose, Isa; Harun, Roslan; Jamal, Rahman

    2015-07-01

    Apart from genetic mutations, epigenetic alteration is a common phenomenon that contributes to neoplastic transformation in colorectal cancer. Transcriptional silencing of tumor-suppressor genes without changes in the DNA sequence is explained by the existence of promoter hypermethylation. To test this hypothesis, we integrated the epigenome and transcriptome data from a similar set of colorectal tissue samples. Methylation profiling was performed using the Illumina InfiniumHumanMethylation27 BeadChip on 55 paired cancer and adjacent normal epithelial cells. Fifteen of the 55 paired tissues were used for gene expression profiling using the Affymetrix GeneChip Human Gene 1.0 ST array. Validation was carried out on 150 colorectal tissues using the methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) technique. PCA and supervised hierarchical clustering in the two microarray datasets showed good separation between cancer and normal samples. Significant genes from the two analyses were obtained based on a ≥2-fold change and a false discovery rate (FDR) p-value of <0.05. We identified 1,081 differentially hypermethylated CpG sites and 36 hypomethylated CpG sites. We also found 709 upregulated and 699 downregulated genes from the gene expression profiling. A comparison of the two datasets revealed 32 overlapping genes with 27 being hypermethylated with downregulated expression and 4 hypermethylated with upregulated expression. One gene was found to be hypomethylated and downregulated. The most enriched molecular pathway identified was cell adhesion molecules that involved 4 overlapped genes, JAM2, NCAM1, ITGA8 and CNTN1. In the present study, we successfully identified a group of genes that showed methylation and gene expression changes in well-defined colorectal cancer tissues with high purity. The integrated analysis gives additional insight regarding the regulation of colorectal cancer-associated genes and their underlying mechanisms that

  12. Identification of diagnostic markers in colorectal cancer via integrative epigenomics and genomics data

    PubMed Central

    KOK-SIN, TEOW; MOKHTAR, NORFILZA MOHD; HASSAN, NUR ZARINA ALI; SAGAP, ISMAIL; ROSE, ISA MOHAMED; HARUN, ROSLAN; JAMAL, RAHMAN

    2015-01-01

    Apart from genetic mutations, epigenetic alteration is a common phenomenon that contributes to neoplastic transformation in colorectal cancer. Transcriptional silencing of tumor-suppressor genes without changes in the DNA sequence is explained by the existence of promoter hypermethylation. To test this hypothesis, we integrated the epigenome and transcriptome data from a similar set of colorectal tissue samples. Methylation profiling was performed using the Illumina InfiniumHumanMethylation27 BeadChip on 55 paired cancer and adjacent normal epithelial cells. Fifteen of the 55 paired tissues were used for gene expression profiling using the Affymetrix GeneChip Human Gene 1.0 ST array. Validation was carried out on 150 colorectal tissues using the methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) technique. PCA and supervised hierarchical clustering in the two microarray datasets showed good separation between cancer and normal samples. Significant genes from the two analyses were obtained based on a ≥2-fold change and a false discovery rate (FDR) P-value of <0.05. We identified 1,081 differentially hypermethylated CpG sites and 36 hypomethylated CpG sites. We also found 709 upregulated and 699 downregulated genes from the gene expression profiling. A comparison of the two datasets revealed 32 overlapping genes with 27 being hypermethylated with downregulated expression and 4 hypermethylated with upregulated expression. One gene was found to be hypomethylated and downregulated. The most enriched molecular pathway identified was cell adhesion molecules that involved 4 overlapped genes, JAM2, NCAM1, ITGA8 and CNTN1. In the present study, we successfully identified a group of genes that showed methylation and gene expression changes in well-defined colorectal cancer tissues with high purity. The integrated analysis gives additional insight regarding the regulation of colorectal cancer-associated genes and their underlying mechanisms that

  13. Red Meat and Colorectal Cancer

    PubMed Central

    2015-01-01

    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. PMID:26779313

  14. Endoluminal Therapy in Colorectal Cancer.

    PubMed

    Kelley, Katherine A; Tsikitis, V Liana

    2016-09-01

    Appropriate endoscopic resection for colorectal polyps can present a challenge to endoscopists, as these lesions may harbor malignancy. With recent advances in endoscopy, however, we are now entering an exciting frontier of endoscopic therapy for gastrointestinal lesions. These techniques include endoluminal mucosal resection and endoscopic submucosal dissection, which may be utilized on several colonic lesions. This article will discuss these principle endoscopic techniques, their outcomes, and briefly highlight their influence on endoscopic interventions, including transanal endoscopic microsurgery and natural orifice transluminal endoscopic surgery. PMID:27582646

  15. Inflammatory networks underlying colorectal cancer.

    PubMed

    Lasry, Audrey; Zinger, Adar; Ben-Neriah, Yinon

    2016-03-01

    Inflammation is emerging as one of the hallmarks of cancer, yet its role in most tumors remains unclear. Whereas a minority of solid tumors are associated with overt inflammation, long-term treatment with non-steroidal anti-inflammatory drugs is remarkably effective in reducing cancer rate and death. This indicates that inflammation might have many as-yet-unrecognized facets, among which an indolent course might be far more prevalent than previously appreciated. In this Review, we explore the various inflammatory processes underlying the development and progression of colorectal cancer and discuss anti-inflammatory means for its prevention and treatment.

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

    PubMed

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

    2016-04-19

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

  17. Genetic architecture of colorectal cancer.

    PubMed

    Peters, Ulrike; Bien, Stephanie; Zubair, Niha

    2015-10-01

    Colorectal cancer (CRC) is a complex disease that develops as a consequence of both genetic and environmental risk factors. A small proportion (3-5%) of cases arise from hereditary syndromes predisposing to early onset CRC as a result of mutations in over a dozen well defined genes. In contrast, CRC is predominantly a late onset 'sporadic' disease, developing in individuals with no obvious hereditary syndrome. In recent years, genome wide association studies have discovered that over 40 genetic regions are associated with weak effects on sporadic CRC, and it has been estimated that increasingly large genome wide scans will identify many additional novel genetic regions. Subsequent experimental validations have identified the causally related variant(s) in a limited number of these genetic regions. Further biological insight could be obtained through ethnically diverse study populations, larger genetic sequencing studies and development of higher throughput functional experiments. Along with inherited variation, integration of the tumour genome may shed light on the carcinogenic processes in CRC. In addition to summarising the genetic architecture of CRC, this review discusses genetic factors that modify environmental predictors of CRC, as well as examples of how genetic insight has improved clinical surveillance, prevention and treatment strategies. In summary, substantial progress has been made in uncovering the genetic architecture of CRC, and continued research efforts are expected to identify additional genetic risk factors that further our biological understanding of this disease. Subsequently these new insights will lead to improved treatment and prevention of colorectal cancer. PMID:26187503

  18. Evolving management of colorectal cancer

    PubMed Central

    van Zijp, Jochem van der Voort; Hoekstra, Harald J; Basson, Marc D

    2008-01-01

    This article reviews recent advances in surgical techniques and adjuvant therapies for colorectal cancer, including total mesorectal excision, the resection of liver and lung metastasis and advances in chemoradiation and foreshadows some interventions that may lie just beyond the frontier. In particular, little is known about the intracellular and extracellular cascades that may influence colorectal cancer cell adhesion and metastasis. Although the phosphorylation of focal adhesion kinases and focal adhesion associated proteins in response to integrin-mediated cell matrix binding (”outside in integrin signaling”) is well described, the stimulation of cell adhesion by intracellular signals activated by pressure prior to adhesion represents a different signal paradigm. However, several studies have suggested that increased pressure and shear stress activate cancer cell adhesion. Further studies of the pathways that regulate integrin-driven cancer cell adhesion may identify ways to disrupt these signals or block integrin-mediated adhesion so that adhesion and eventual metastasis can be prevented in the future. PMID:18609678

  19. A hemagglutinin isolated from Northeast China black beans induced mitochondrial dysfunction and apoptosis in colorectal cancer cells.

    PubMed

    Dan, Xiuli; Ng, Tzi Bun; Wong, Jack Ho; Chan, Yau Sang; Cheung, Randy Chi Fai; Chan, Wai Yee

    2016-09-01

    Incidence of colorectal cancer is closely related with the lifestyle, especially the dietary habits of patients. Epidemiological researches have demonstrated a negative correlation between legume consumption and colorectal cancer incidence. Lectins/hemagglutinins are a type of carbohydrate binding proteins which are abundantly stored in legumes. Their eminent pH-stability allows them to survive digestion and remain active in the intestine where they may have direct contact with colorectal tumors. It is therefore interesting to explore the direct interaction between lectins/hemagglutinins and colorectal cancer. In the present research, we reported a detailed research on the interaction between a hemagglutinin isolated from an edible legume with two colorectal cancer cell lines. This hemagglutinin (NCBBH) was found to first bind to tumor cell membrane as early as 30min post treatment and was gradually transported inside the cytoplasm within 3h, with some of it localized in the Golgi apparatus and some in the lysosomes. After its entrance, the hemagglutinin induced aggregation of the Golgi apparatus, which in turn adversely affected the transportation of protein from endoplasmic reticulum (ER) to the Golgi apparatus, resulting in protein accumulation in ER and ER stress. The hemagglutinin-treated cells also manifested severe mitochondrial malformation and membrane depolarization, accompanied by obvious apoptosis characteristics, like chromatin condensation, phosphatidylserine exposure and caspase activation. Collectively, our results indicate that the hemaggltuinin could successfully enter the cytoplasm of colorectal cancer cells and adversely affect their growth, providing a mechanism in support of the application of edible legumes to the prevention and treatment of colorectal cancer. PMID:27235832

  20. Evaluating patient-derived colorectal cancer xenografts as preclinical models by comparison with patient clinical data.

    PubMed

    Nunes, Manoel; Vrignaud, Patricia; Vacher, Sophie; Richon, Sophie; Lièvre, Astrid; Cacheux, Wulfran; Weiswald, Louis-Bastien; Massonnet, Gerald; Chateau-Joubert, Sophie; Nicolas, André; Dib, Colette; Zhang, Weidong; Watters, James; Bergstrom, Donald; Roman-Roman, Sergio; Bièche, Ivan; Dangles-Marie, Virginie

    2015-04-15

    Development of targeted therapeutics required translationally relevant preclinical models with well-characterized cancer genome alterations. Here, by studying 52 colorectal patient-derived tumor xenografts (PDX), we examined key molecular alterations of the IGF2-PI3K and ERBB-RAS pathways and response to cetuximab. PDX molecular data were compared with that published for patient colorectal tumors in The Cancer Genome Atlas. We demonstrated a significant pattern of mutual exclusivity of genomic abnormalities in the IGF2-PI3K and ERBB-RAS pathways. The genomic anomaly frequencies observed in microsatellite stable PDX reproduce those detected in nonhypermutated patient tumors. We found frequent IGF2 upregulation (16%), which was mutually exclusive with IRS2, PIK3CA, PTEN, and INPP4B alterations, supporting IGF2 as a potential drug target. In addition to maintaining the genomic and histologic diversity, correct preclinical models need to reproduce drug response observed in patients. Responses of PDXs to cetuximab recapitulate also clinical data in patients, with partial or complete response in 15% (8 of 52) of PDXs and response strictly restricted to KRAS wild-type models. The response rate reaches 53% (8 of 15) when KRAS, BRAF, and NRAS mutations are concomitantly excluded, proving a functional cross-validation of predictive biomarkers obtained retrospectively in patients. Collectively, these results show that, because of their clinical relevance, colorectal PDXs are appropriate tools to identify both new targets, like IGF2, and predictive biomarkers of response/resistance to targeted therapies.

  1. Dietary Plant Lectins Appear to Be Transported from the Gut to Gain Access to and Alter Dopaminergic Neurons of Caenorhabditis elegans, a Potential Etiology of Parkinson's Disease.

    PubMed

    Zheng, Jolene; Wang, Mingming; Wei, Wenqian; Keller, Jeffrey N; Adhikari, Binita; King, Jason F; King, Michael L; Peng, Nan; Laine, Roger A

    2016-01-01

    Lectins from dietary plants have been shown to enhance drug absorption in the gastrointestinal tract of rats, be transported trans-synaptically as shown by tracing of axonal and dendritic paths, and enhance gene delivery. Other carbohydrate-binding protein toxins are known to traverse the gut intact in dogs. Post-feeding rhodamine- or TRITC-tagged dietary lectins, the lectins were tracked from gut to dopaminergic neurons (DAergic-N) in transgenic Caenorhabditis elegans (C. elegans) [egIs1(Pdat-1:GFP)] where the mutant has the green fluorescent protein (GFP) gene fused to a dopamine transport protein gene labeling DAergic-N. The lectins were supplemented along with the food organism Escherichia coli (OP50). Among nine tested rhodamine/TRITC-tagged lectins, four, including Phaseolus vulgaris erythroagglutinin (PHA-E), Bandeiraea simplicifolia (BS-I), Dolichos biflorus agglutinin (DBA), and Arachis hypogaea agglutinin (PNA), appeared to be transported from gut to the GFP-DAergic-N. Griffonia Simplicifolia and PHA-E, reduced the number of GFP-DAergic-N, suggesting a toxic activity. PHA-E, BS-I, Pisum sativum (PSA), and Triticum vulgaris agglutinin (Succinylated) reduced fluorescent intensity of GFP-DAergic-N. PHA-E, PSA, Concanavalin A, and Triticum vulgaris agglutinin decreased the size of GFP-DAergic-N, while BS-I increased neuron size. These observations suggest that dietary plant lectins are transported to and affect DAergic-N in C. elegans, which support Braak and Hawkes' hypothesis, suggesting one alternate potential dietary etiology of Parkinson's disease (PD). A recent Danish study showed that vagotomy resulted in 40% lower incidence of PD over 20 years. Differences in inherited sugar structures of gut and neuronal cell surfaces may make some individuals more susceptible in this conceptual disease etiology model. PMID:27014695

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

    PubMed

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

    2015-11-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2015-04-01

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

  4. Tests to Detect Colorectal Cancer and Polyps

    MedlinePlus

    ... be acceptable screening tests for colorectal cancer: High-sensitivity fecal occult blood tests (FOBT). Both polyps and ... higher than that of gFOBT or FIT. Test sensitivity for adenomas is low. False-positive test results ...

  5. TAS-102 for Metastatic Colorectal Cancer

    Cancer.gov

    A summary of results from an international phase III trial that compared TAS-102 with placebo in patients with metastatic colorectal cancer whose disease progressed following prior treatments or who had health conditions that prevented the re-administrati

  6. Nutritional status assessment in colorectal cancer patients.

    PubMed

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

    2013-01-01

    The present study intended to evaluate the nutritional status of Portuguese colorectal patients and associated it with surgery type as well as quality of life outcomes. Malnutrition can affect up to 85% of cancer patients and specifically 30-60% in colorectal cancer and can significantly influence health outcomes. A sample of 50 colorectal cancer patients was evaluated in what refers to several anthropometric measures, food intake, clinical history, complications rate before and after surgery procedure. The sample was divided between convention and fast-track procedures. Most of the individuals were overweight or obese but had lost weight on the past six months. Despite mild, there were signs of malnutrition in this sample with high losses of fat free mass, weight and also fat mass during the hospitalization period. These results reinforce the importance of malnutrition assessment in colorectal patients as well as consider weight loss on the past months and body composition in order to complement nutritional status evaluation.

  7. Genetics and Genetic Biomarkers in Sporadic Colorectal Cancer

    PubMed Central

    Carethers, John M.; Jung, Barbara H.

    2015-01-01

    Sporadic colorectal cancer (CRC) is a somatic genetic disease in which pathogenesis is influenced by the local colonic environment and the patient’s genetic background. Consolidating the knowledge of genetic and epigenetic events that occur with initiation, progression, and metastasis of sporadic CRC has identified some biomarkers that might be utilized to predict behavior and prognosis beyond staging, and inform treatment approaches. Modern next generation sequencing of sporadic CRCs has confirmed prior identified genetic alterations, and has classified new alterations. Each patient’s CRC is genetically unique, propelled by 2 to 8 driver gene alterations that have accumulated within the CRC since initiation. Commonly observed alterations across sporadic CRCs have allowed classification into a: (1) hypermutated group that includes defective DNA mismatch repair with microsatellite instability (MSI) and POLE mutations in ~15%, containing multiple frameshifted genes and BRAFV600E; (2) non-hypermutated group with multiple somatic copy number alterations and aneuploidy in ~85%, containing oncogenic activation of KRAS and PIK3CA and mutation and loss of heterozygosity of tumor suppressor genes such as APC and TP53; (3) CpG Island Methylator Phenotype CRCs in ~20% that overlap greatly with MSI CRCs and some non-hypermutated CRCs; and (4) elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) in ~60% that associates with metastatic behavior in both hypermutated and non-hypermutated groups. Components from these classifications are now used as diagnostic, prognostic and treatment biomarkers. Additional common biomarkers may come from genome-wide association studies and microRNAs among other sources, as well as from the unique alteration profile of an individual CRC to apply a precision medicine approach to care. PMID:26216840

  8. Mutations in the circadian gene CLOCK in colorectal cancer.

    PubMed

    Alhopuro, Pia; Björklund, Mikael; Sammalkorpi, Heli; Turunen, Mikko; Tuupanen, Sari; Biström, Mia; Niittymäki, Iina; Lehtonen, Heli J; Kivioja, Teemu; Launonen, Virpi; Saharinen, Juha; Nousiainen, Kari; Hautaniemi, Sampsa; Nuorva, Kyösti; Mecklin, Jukka-Pekka; Järvinen, Heikki; Orntoft, Torben; Arango, Diego; Lehtonen, Rainer; Karhu, Auli; Taipale, Jussi; Aaltonen, Lauri A

    2010-07-01

    The circadian clock regulates daily variations in physiologic processes. CLOCK acts as a regulator in the circadian apparatus controlling the expression of other clock genes, including PER1. Clock genes have been implicated in cancer-related functions; in this work, we investigated CLOCK as a possible target of somatic mutations in microsatellite unstable colorectal cancers. Combining microarray gene expression data and public gene sequence information, we identified CLOCK as 1 of 790 putative novel microsatellite instability (MSI) target genes. A total of 101 MSI colorectal carcinomas (CRC) were sequenced for a coding microsatellite in CLOCK. The effect of restoring CLOCK expression was studied in LS180 cells lacking wild-type CLOCK by stably expressing GST-CLOCK or glutathione S-transferase empty vector and testing the effects of UV-induced apoptosis and radiation by DNA content analysis using flow cytometry. Putative novel CLOCK target genes were searched by using ChIP-seq. CLOCK mutations occurred in 53% of MSI CRCs. Restoring CLOCK expression in cells with biallelic CLOCK inactivation resulted in protection against UV-induced apoptosis and decreased G(2)-M arrest in response to ionizing radiation. Using ChIP-Seq, novel CLOCK-binding elements were identified near DNA damage genes p21, NBR1, BRCA1, and RAD50. CLOCK is shown to be mutated in cancer, and altered response to DNA damage provides one plausible mechanism of tumorigenesis.

  9. Biomarker-directed Targeted Therapy in Colorectal Cancer

    PubMed Central

    Carethers, John M.

    2015-01-01

    With advances in the understanding of the biology and genetics of colorectal cancer (CRC), diagnostic biomarkers that may predict the existence or future presence of cancer or a hereditary condition, and prognostic and treatment biomarkers that may direct the approach to therapy have been developed. Biomarkers can be ascertained and assayed from any tissue that may demonstrate the diagnostic or prognostic value, including from blood cells, epithelial cells via buccal swab, fresh or archival cancer tissue, as well as from cells shed into fecal material. For CRC, current examples of biomarkers for screening and surveillance include germline testing for suspected hereditary CRC syndromes, and stool DNA tests for screening average at-risk patients. Molecular biomarkers for CRC that may alter patient care and treatment include the presence or absence of microsatellite instability, the presence or absence of mutant KRAS, BRAF or PIK3CA, and the level of expression of 15-PGDH in the colorectal mucosa. Molecularly targeted therapies and some general therapeutic approaches rely on biomarker information. Additional novel biomarkers are on the horizon that will undoubtedly further the approach to precision or individualized medicine. PMID:26609516

  10. Abdominal metastases from colorectal cancer: intraperitoneal therapy

    PubMed Central

    Guend, Hamza; Patel, Sunil

    2015-01-01

    Patients with peritoneal metastasis from colorectal cancer represent a distinct subset with regional disease rather than systemic disease. They often have poorer survival outcomes with systemic chemotherapy. Optimal cytoreductive surgery and intraperitoneal chemotherapy (IPC) offers such patients a more directed therapy with improved survival. In this review, we discuss the diagnosis, evaluation and classification, as well as rational for treatment of peritoneal carcinomatosis (PC) secondary to colorectal cancer. PMID:26697203

  11. Substitution of a single amino acid residue in the aromatic/arginine selectivity filter alters the transport profiles of tonoplast aquaporin homologs.

    PubMed

    Azad, Abul Kalam; Yoshikawa, Naoki; Ishikawa, Takahiro; Sawa, Yoshihiro; Shibata, Hitoshi

    2012-01-01

    Aquaporins are integral membrane proteins that facilitate the transport of water and some small solutes across cellular membranes. X-ray crystallography of aquaporins indicates that four amino acids constitute an aromatic/arginine (ar/R) pore constriction known as the selectivity filter. On the basis of these four amino acids, tonoplast aquaporins called tonoplast intrinsic proteins (TIPs) are divided into three groups in Arabidopsis. Herein, we describe the characterization of two group I TIP1s (TgTIP1;1 and TgTIP1;2) from tulip (Tulipa gesneriana). TgTIP1;1 and TgTIP1;2 have a novel isoleucine in loop E (LE2 position) of the ar/R filter; the residue at LE2 is a valine in all group I TIPs from model plants. The homologs showed mercury-sensitive water channel activity in a fast kinetics swelling assay upon heterologous expression in Pichia pastoris. Heterologous expression of both homologs promoted the growth of P. pastoris on ammonium or urea as sole sources of nitrogen and decreased growth and survival in the presence of H(2)O(2). TgTIP1;1- and TgTIP1;2-mediated H(2)O(2) conductance was demonstrated further by a fluorescence assay. Substitutions in the ar/R selectivity filter of TgTIP1;1 showed that mutants that mimicked the ar/R constriction of group I TIPs could conduct the same substrates that were transported by wild-type TgTIP1;1. In contrast, mutants that mimicked group II TIPs showed no evidence of urea or H(2)O(2) conductance. These results suggest that the amino acid residue at LE2 position is critical for the transport selectivity of the TIP homologs and group I TIPs might have a broader spectrum of substrate selectivity than group II TIPs.

  12. 2,4-Dichlorophenoxyacetic acid alters intracellular pH and ion transport in the outer mantle epithelium of the bivalve Anodonta cygnea.

    PubMed

    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.

  13. Industrial risk factors for colorectal cancer

    SciTech Connect

    Lashner, B.A.; Epstein, S.S. )

    1990-01-01

    Colorectal cancer is the second most common malignancy in the United States, and its incidence rates have sharply increased recently, especially in males. Industrial exposures, both occupational and environmental, are important colorectal cancer risk factors that are generally unrecognized by clinicians. Migration studies have documented that colorectal cancer is strongly associated with environmental risk factors. The causal role of occupational exposures is evidenced by a substantial literature associating specific work practices with increased colorectal cancer risks. Industrially related environmental exposures, including polluted drinking water and ionizing radiation, have also been associated with excess risks. Currently, there is a tendency to attribute colorectal cancer, largely or exclusively, to dietary and other lifestyle factors, thus neglecting these industrially related effects. Concerted efforts are needed to recognize the causal role of industrial risk factors and to encourage government and industry to reduce carcinogenic exposures. Furthermore, cost-effective screening programs for high-risk population groups are critically needed to further reduce deaths from colorectal cancer. 143 references.

  14. Circulating Omentin as a Novel Biomarker for Colorectal Cancer Risk: Data from the EPIC-Potsdam Cohort Study.

    PubMed

    Aleksandrova, Krasimira; di Giuseppe, Romina; Isermann, Berend; Biemann, Ronald; Schulze, Matthias; Wittenbecher, Clemens; Fritsche, Andreas; Lehmann, Rainer; Menzel, Juliane; Weikert, Cornelia; Pischon, Tobias; Boeing, Heiner

    2016-07-01

    Omentin is a novel biomarker shown to exert metabolic, inflammatory, and immune-related properties and thereby could be implicated in the risk of colorectal cancer. So far, the association between omentin and colorectal cancer risk has not been evaluated in prospective cohort studies. We investigated the association between prediagnostic plasma omentin concentrations and risk of colorectal cancer in a case-cohort comprising 251 incident colorectal cancer cases diagnosed over a mean follow-up time of 10.4 years and 2,295 persons who remained free of cancer in the European Prospective Investigation into Cancer and Nutrition-Potsdam study. Hazard ratios as a measure of relative risk (RR) and 95% confidence intervals (CI) were computed using a Prentice-modified Cox regression. In a multivariable model adjusted for age, sex, education, dietary and lifestyle factors, body mass index (BMI), and waist circumference, higher omentin concentrations were associated with a higher colorectal cancer risk (RRcontinuously per doubling of omentin concentrations = 1.98; 95% CI, 1.45-2.73). Additional adjustment for metabolic biomarkers, including glycated hemoglobin, high-density lipoprotein cholesterol, and C-reactive protein, did not alter the results. In stratified analyses, the positive association between omentin and colorectal cancer risk was retained in participants with BMI < 30 (RRcontinuously per doubling of omentin concentrations = 2.26; 95% CI, 1.57-3.27), whereas among participants with BMI ≥ 30 no association was revealed (RRcontinuously per doubling of omentin concentrations = 1.07; 95% CI, 0.63-1.83; Pinteraction = 0.005). These novel findings provide the first lines of evidence for an independent association between prediagnostic omentin concentrations and colorectal cancer risk and suggest a potential interaction with the adiposity state of the individual. Cancer Res; 76(13); 3862-71. ©2016 AACR. PMID:27216184

  15. Diet and Colorectal Cancer Risk: Baseline Dietary Knowledge of Colorectal Patients

    ERIC Educational Resources Information Center

    Dyer, K. J.; Fearon, K. C. H.; Buckner, K.; Richardson, R. A.

    2004-01-01

    Objective: To establish the dietary knowledge, attitudes and potential barriers to change of patients attending a colorectal outpatient clinic. Design: Use of a semistructured interview to generate qualitative and quantitative data. Setting: A regional colorectal outpatient clinic within Edinburgh. Method: Patients attending clinic with colorectal…

  16. Variation in the association between colorectal cancer susceptibility loci and colorectal polyps by polyp type.

    PubMed

    Burnett-Hartman, Andrea N; Newcomb, Polly A; Hutter, Carolyn M; Peters, Ulrike; Passarelli, Michael N; Schwartz, Malaika R; Upton, Melissa P; Zhu, Lee-Ching; Potter, John D; Makar, Karen W

    2014-07-15

    We conducted a case-control study of the association between subsets of colorectal polyps, including adenomas and serrated polyps, and single-nucleotide polymorphisms (SNPs) related to colorectal cancer through prior genome-wide association studies (GWAS). Participants were enrollees in the Group Health Cooperative (Seattle, Washington) aged 24-79 years who received a colonoscopy from 1998 to 2007, donated a buccal or blood sample, and completed a structured questionnaire. We performed genotyping of 13 colorectal cancer susceptibility SNPs. Polytomous logistic regression models were used to estimate odds ratios and 95% confidence intervals for associations between polyps and the colorectal cancer risk allele for each SNP under a log-additive model. Analyses included 781 controls, 489 cases with adenoma, 401 cases with serrated polyps, and 188 cases with both polyp types. The following SNPs were associated with advanced adenomas: rs10936599, rs10795668, rs16892766, and rs9929218 (P < 0.05). For nonadvanced adenomas and for serrated polyps overall, only rs961253 was statistically significant (P < 0.05). These associations were in the same directions as those in prior colorectal cancer GWAS. No SNP was significantly associated with hyperplastic polyps, and only rs6983267 was significantly associated with sessile serrated polyps, but this association was opposite of that found in colorectal cancer GWAS. Our results suggest that the association between colorectal cancer susceptibility SNPs and colorectal polyps varies by polyp type.

  17. Mutations in the Plasmodium falciparum chloroquine resistance transporter, PfCRT, enlarge the parasite’s food vacuole and alter drug sensitivities

    PubMed Central

    Pulcini, Serena; Staines, Henry M.; Lee, Andrew H.; Shafik, Sarah H.; Bouyer, Guillaume; Moore, Catherine M.; Daley, Daniel A.; Hoke, Matthew J.; Altenhofen, Lindsey M.; Painter, Heather J.; Mu, Jianbing; Ferguson, David J. P.; Llinás, Manuel; Martin, Rowena E.; Fidock, David A.; Cooper, Roland A.; Krishna, Sanjeev

    2015-01-01

    Mutations in the Plasmodium falciparum chloroquine resistance transporter, PfCRT, are the major determinant of chloroquine resistance in this lethal human malaria parasite. Here, we describe P. falciparum lines subjected to selection by amantadine or blasticidin that carry PfCRT mutations (C101F or L272F), causing the development of enlarged food vacuoles. These parasites also have increased sensitivity to chloroquine and some other quinoline antimalarials, but exhibit no or minimal change in sensitivity to artemisinins, when compared with parental strains. A transgenic parasite line expressing the L272F variant of PfCRT confirmed this increased chloroquine sensitivity and enlarged food vacuole phenotype. Furthermore, the introduction of the C101F or L272F mutation into a chloroquine-resistant variant of PfCRT reduced the ability of this protein to transport chloroquine by approximately 93 and 82%, respectively, when expressed in Xenopus oocytes. These data provide, at least in part, a mechanistic explanation for the increased sensitivity of the mutant parasite lines to chloroquine. Taken together, these findings provide new insights into PfCRT function and PfCRT-mediated drug resistance, as well as the food vacuole, which is an important target of many antimalarial drugs. PMID:26420308

  18. Targeted nanoparticles for colorectal cancer.

    PubMed

    Cisterna, Bruno A; Kamaly, Nazila; Choi, Won Il; Tavakkoli, Ali; Farokhzad, Omid C; Vilos, Cristian

    2016-09-01

    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 take advantage of differentially expressed molecules on the surface of tumor cells, providing effective release of cytotoxic drugs. Several efforts have recently reported the use of diverse molecules as ligands on the surface of nanoparticles to interact with the tumor cells, enabling the effective delivery of antitumor agents. Here, we present recent advances in targeted nanoparticles against CRC and discuss the promising use of ligands and cellular targets in potential strategies for the treatment of CRCs. PMID:27529192

  19. 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.

    PubMed

    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

  20. 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.

    PubMed

    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

  1. Genomic instability and cellular stress in organ biopsies and peripheral blood lymphocytes from patients with colorectal cancer and predisposing pathologies

    PubMed Central

    Lombardi, Sara; Fuoco, Ilenia; di Fluri, Giorgia; Costa, Francesco; Ricchiuti, Angelo; Biondi, Graziano; Nardini, Vincenzo; Scarpato, Roberto

    2015-01-01

    Inflammatory bowel disease (IBD) and polyps, are common colorectal pathologies in western society and are risk factors for development of colorectal cancer (CRC). Genomic instability is a cancer hallmark and is connected to changes in chromosomal structure, often caused by double strand break formation (DSB), and aneuploidy. Cellular stress, may contribute to genomic instability. In colorectal biopsies and peripheral blood lymphocytes of patients with IBD, polyps and CRC, we evaluated 1) genomic instability using the γH2AX assay as marker of DSB and micronuclei in mononuclear lymphocytes kept under cytodieresis inhibition, and 2) cellular stress through expression and cellular localization of glutathione-S-transferase omega 1 (GSTO1). Colon biopsies showed γH2AX increase starting from polyps, while lymphocytes already from IBD. Micronuclei frequency began to rise in lymphocytes of subjects with polyps, suggesting a systemic genomic instability condition. Colorectal tissues lost GSTO1 expression but increased nuclear localization with pathology progression. Lymphocytes did not change GSTO1 expression and localization until CRC formation, where enzyme expression was increased. We propose that the growing genomic instability found in our patients is connected with the alteration of cellular environment. Evaluation of genomic damage and cellular stress in colorectal pathologies may facilitate prevention and management of CRC. PMID:26046795

  2. Characterizing metabolic changes in human colorectal cancer.

    PubMed

    Williams, Michael D; Zhang, Xing; Park, Jeong-Jin; Siems, William F; Gang, David R; Resar, Linda M S; Reeves, Raymond; Hill, Herbert H

    2015-06-01

    Colorectal cancer (CRC) remains a leading cause of cancer death worldwide, despite the fact that it is a curable disease when diagnosed early. The development of new screening methods to aid in early diagnosis or identify precursor lesions at risk for progressing to CRC will be vital to improving the survival rate of individuals predisposed to CRC. Metabolomics is an advancing area that has recently seen numerous applications to the field of cancer research. Altered metabolism has been studied for many years as a means to understand and characterize cancer. However, further work is required to establish standard procedures and improve our ability to identify distinct metabolomic profiles that can be used to diagnose CRC or predict disease progression. The present study demonstrates the use of direct infusion traveling wave ion mobility mass spectrometry to distinguish metabolic profiles from CRC samples and matched non-neoplastic epithelium as well as metastatic and primary tumors at different stages of disease (T1-T4). By directly infusing our samples, the analysis time was reduced significantly, thus increasing the speed and efficiency of this method compared to traditional metabolomics platforms. Partial least squares discriminant analysis was used to visualize differences between the metabolic profiles of sample types and to identify the specific m/z features that led to this differentiation. Identification of the distinct m/z features was made using the human metabolome database. We discovered alterations in fatty acid biosynthesis and oxidative, glycolytic, and polyamine pathways that distinguish tumors from non-malignant colonic epithelium as well as various stages of CRC. Although further studies are needed, our results indicate that colonic epithelial cells undergo metabolic reprogramming during their evolution to CRC, and the distinct metabolites could serve as diagnostic tools or potential targets in therapy or primary prevention. Graphical Abstract

  3. Characterizing metabolic changes in human colorectal cancer.

    PubMed

    Williams, Michael D; Zhang, Xing; Park, Jeong-Jin; Siems, William F; Gang, David R; Resar, Linda M S; Reeves, Raymond; Hill, Herbert H

    2015-06-01

    Colorectal cancer (CRC) remains a leading cause of cancer death worldwide, despite the fact that it is a curable disease when diagnosed early. The development of new screening methods to aid in early diagnosis or identify precursor lesions at risk for progressing to CRC will be vital to improving the survival rate of individuals predisposed to CRC. Metabolomics is an advancing area that has recently seen numerous applications to the field of cancer research. Altered metabolism has been studied for many years as a means to understand and characterize cancer. However, further work is required to establish standard procedures and improve our ability to identify distinct metabolomic profiles that can be used to diagnose CRC or predict disease progression. The present study demonstrates the use of direct infusion traveling wave ion mobility mass spectrometry to distinguish metabolic profiles from CRC samples and matched non-neoplastic epithelium as well as metastatic and primary tumors at different stages of disease (T1-T4). By directly infusing our samples, the analysis time was reduced significantly, thus increasing the speed and efficiency of this method compared to traditional metabolomics platforms. Partial least squares discriminant analysis was used to visualize differences between the metabolic profiles of sample types and to identify the specific m/z features that led to this differentiation. Identification of the distinct m/z features was made using the human metabolome database. We discovered alterations in fatty acid biosynthesis and oxidative, glycolytic, and polyamine pathways that distinguish tumors from non-malignant colonic epithelium as well as various stages of CRC. Although further studies are needed, our results indicate that colonic epithelial cells undergo metabolic reprogramming during their evolution to CRC, and the distinct metabolites could serve as diagnostic tools or potential targets in therapy or primary prevention. Graphical Abstract

  4. Altered serotonin and dopamine transporter availabilities in brain of depressed patients upon treatment with escitalopram: A [123 I]β-CIT SPECT study.

    PubMed

    Rominger, A; Cumming, P; Brendel, M; Xiong, G; Zach, C; Karch, S; Tatsch, K; Bartenstein, P; la Fougère, C; Koch, W; Pogarell, O

    2015-06-01

    Altered SERT and DAT availabilities during treatment with escitalopram were investigated with [(123)I]2β-carbomethoxy-3β-(4-iodophenyl)tropane (β-CIT) SPECT in a series of patients fulfilling the criteria for unipolar major depressive disorder (MDD). 27 patients (10m, 42±16y) with diagnosis of MDD were recruited for the study. All patients underwent neuropsychiatric testing for assessment of Hamilton Depression (HAM-D) and Beck Depression Inventory (BDI) scores. At baseline, [(123)I]β-CIT SPECT recordings were acquired 4h (SERT-weighted) and 20-24h p.i (DAT-weighted). Follow-up scans and neuropsychiatric testing were performed after six weeks of stable escitalopram medication. Voxel-wise parametric maps of specific/ non-specific ratios-1 (~BPND) were calculated. At baseline, DAT-weighted BPND was 5.06±0.81 in striatum and SERT-weighted BPND was 0.94±0.18 in thalamus. There were significant negative correlations with age for DAT in striatum (R=-0.60; p<0.01) and SERT in thalamus (R=-0.45; p<0.05). Under SSRI treatment there was an apparent 42% occupancy of SERT in thalamus (p<0.0001), whereas DAT availability increased significantly by 20% in striatum (p<0.001); higher apparent SERT occupancy in thalamus was associated with lesser DAT increase in striatum (R=-0.62; p<0.005). The low apparent SERT occupancy may be confounded by alterations in SERT expression during treatment. Thus, [(123)I]β-CIT SPECT revealed age-dependent declines in DAT and SERT availabilities in un-medicated MDD patients, comparable to that seen previously in healthy controls. At follow-up, the SSRI-evoked increase in DAT was less pronounced in the older patients, even though apparent SERT occupancy and clinical improvement were not age-dependent. Present findings may have implications for escitalopram dosage and side effect profile in younger MDD patients. PMID:25819144

  5. 4,4′-Methylenedianiline Alters Serotonergic Transport in a Novel, Sex-Specific Model of Pulmonary Arterial Hypertension in Rats

    PubMed Central

    Carroll-Turpin, Michelle; Hebert, Valeria; Chotibut, Tanya; Wensler, Heather; Krentzel, Dallas; Varner, Kurt James; Burn, Brendan R.; Chen, Yi-Fan; Abreo, Fleurette; Dugas, Tammy Renee

    2015-01-01

    Pulmonary arterial hypertension (PAH) is a cardiovascular disorder characterized by elevated pulmonary artery pressure as a result of arterial wall thickening. Patients are 3–4 times more likely to be women than men. This gender discrepancy demonstrates a need for an animal model with similar sex differences. 4,4′-Methylenedianiline (DAPM) is an aromatic amine used industrially in the synthesis of polyurethanes. Chronic, intermittent treatment of male and female rats with DAPM resulted in medial hyperplasia of pulmonary arterioles, exclusively in females, coupled to increases in pulmonary arterial pressures. Significant increases in plasma levels of endothelin-1 (ET-1) and serotonin, but decreases in nitrite (NO2−), were observed in females treated with DAPM. A decrease was observed in the serum ratio of the estrogen metabolites 2-hydroxyestradiol (2-OHE1)/16α-hydroxyestrogen (16α-OHE1). In females, ET-1,NO2− , and 2-OHE1/16α-OHE1 were significantly correlated with peak pressure gradient, an indirect measure of pulmonary arterial pressure. Expression of the serotonin transport protein (SERT) was significantly higher in the arteries of DAPM-treated females. In vitro, DAPM induced human pulmonary vascular smooth muscle cell proliferation and serotonin uptake, both of which were inhibited by treatment with the estrogen receptor antagonist ICI 182,780 or the selective serotonin reuptake inhibitor fluoxetine. DAPM also induced the release of serotonin from human pulmonary endothelial cells in culture, which is blocked by ICI 182,780. Taken together, this suggests that DAPM-mediated dysregulation of serotonin transport is estrogen-receptor dependent. Thus, DAPM-induced PAH pathology may be a new tool to clarify the sex selectivity of PAH disease pathogenesis. PMID:26116029

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

    USGS Publications Warehouse

    Harvey, R.W.; Metge, D.W.; Barber, L.B.; Aiken, G.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.

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

    PubMed

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

    2010-02-01

    The effects of a dilute (ionic strength=5x10(-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 microg/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 approximately 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.

  8. Metastatic Colorectal Cancer Resembling Severe Preeclampsia in Pregnancy

    PubMed Central

    Khangura, Raminder Kaur; Khangura, Charanpreet Kaur; Desai, Anagha; Goyert, Gregory; Sangha, Roopina

    2015-01-01

    Although colorectal cancer (CRC) is the third most common cancer in women, it is a rare malignancy in pregnancy. Symptoms of CRC such as fatigue, malaise, nausea, vomiting, rectal bleeding, anemia, altered bowel habits, and abdominal mass are often considered typical symptoms of pregnancy. Many cases of CRC are diagnosed in advanced stages due to missed warning signs of CRC, which may be misinterpreted as normal symptoms related to pregnancy. This report reviews 2 cases of CRC diagnosed within a 4-month interval at our institution. Both cases were initially thought to be atypical presentations of preeclampsia. Prenatal history, hospital course, and postpartum course were reviewed for both patients. CRC is often diagnosed at advanced stages in pregnancy. Common physiological symptoms of pregnancy should be scrutinized carefully and worked up appropriately, especially if symptoms remain persistent or increase in intensity or severity. PMID:26770850

  9. Clues to the pathogenesis of familial colorectal cancer

    SciTech Connect

    Aaltonen, L.A.; Peltomaeki, P.; Pylkkaenen, L.; Chappelle, A. de la ); Leach, F.S.; Powell, S.M.; Jen, J.; Hamilton, S.R.; Petersen, G.M.; Kinzler, K.W.; Vogelstein, B. Johns Hopkins Hospital, Baltimore, MD ); Sistonen, P. Finnish Red Cross Blood Transfusion Service, Helsinki ); Mecklin, J.P. ); Jaervinen, H. )

    1993-05-07

    A predisposition to colorectal cancer is shown to be linked to markers on chromosome 2 in some families. Molecular features of familial cancers were compared with those of sporadic colon cancers. Neither the familial nor sporadic cancers showed loss of heterozygosity for chromosome 2 markers, and the incidence of mutations in KRAS, P53, and APC was similar in the two groups of tumors. Most of the familial cancers, however, had widespread alterations in short repeated DNA sequences, suggesting that numerous replication errors had occurred during tumor development. Thirteen percent of sporadic cancers had identical abnormalities and these cancers shared biologic properties with the familial cases. These data suggest a mechanism for familial tumorigenesis different from that mediated by classic tumor suppressor genes. 22 refs., 2 figs., 2 tabs.

  10. Novel insights into Notum and glypicans regulation in colorectal cancer

    PubMed Central

    De Robertis, Mariangela; Arigoni, Maddalena; Loiacono, Luisa; Riccardo, Federica; Calogero, Raffaele Adolfo; Feodorova, Yana; Tashkova, Dessislava; Belovejdov, Vesselin; Sarafian, Victoria; Cavallo, Federica; Signori, Emanuela

    2015-01-01

    The connection between colorectal cancer (CRC) and Wnt signaling pathway activation is well known, but full elucidation of the underlying regulation of the Wnt/β-catenin pathway and its biological functions in CRC pathogenesis is still needed. Here, the azoxymethane/dextran sulfate sodium salt (AOM/DSS) murine model has been used as an experimental platform able to mimic human sporadic CRC development with predictable timing. We performed genome-wide expression profiling of AOM/DSS-induced tumors and normal colon mucosa to identify potential novel CRC biomarkers. Remarkably, the enhanced expression of Notum, a conserved feedback antagonist of Wnt, was observed in tumors along with alterations in Glypican-1 and Glypican-3 levels. These findings were confirmed in a set of human CRC samples. Here, we provide the first demonstration of significant changes in Notum and glypicans gene expression during CRC development and present evidence to suggest them as potential new biomarkers of CRC pathogenesis. PMID:26517809

  11. Mass Spectrometry-Based N-Glycomics of Colorectal Cancer

    PubMed Central

    Sethi, Manveen K.; Fanayan, Susan

    2015-01-01

    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. PMID:26690136

  12. Insight On Colorectal Carcinoma Infiltration by Studying Perilesional Extracellular Matrix.

    PubMed

    Nebuloni, Manuela; Albarello, Luca; Andolfo, Annapaola; Magagnotti, Cinzia; Genovese, Luca; Locatelli, Irene; Tonon, Giovanni; Longhi, Erika; Zerbi, Pietro; Allevi, Raffaele; Podestà, Alessandro; Puricelli, Luca; Milani, Paolo; Soldarini, Armando; Salonia, Andrea; Alfano, Massimo

    2016-03-04

    The extracellular matrix (ECM) from perilesional and colorectal carcinoma (CRC), but not healthy colon, sustains proliferation and invasion of tumor cells. We investigated the biochemical and physical diversity of ECM in pair-wised comparisons of healthy, perilesional and CRC specimens. Progressive linearization and degree of organization of fibrils was observed from healthy to perilesional and CRC ECM, and was associated with a steady increase of stiffness and collagen crosslinking. In the perilesional ECM these modifications coincided with increased vascularization, whereas in the neoplastic ECM they were associated with altered modulation of matrisome proteins, increased content of hydroxylated lysine and lysyl oxidase. This study identifies the increased stiffness and crosslinking of the perilesional ECM predisposing an environment suitable for CRC invasion as a phenomenon associated with vascularization. The increased stiffness of colon areas may represent a new predictive marker of desmoplastic region predisposing to invasion, thus offering new potential application for monitoring adenoma with invasive potential.

  13. Insight On Colorectal Carcinoma Infiltration by Studying Perilesional Extracellular Matrix

    PubMed Central

    Nebuloni, Manuela; Albarello, Luca; Andolfo, Annapaola; Magagnotti, Cinzia; Genovese, Luca; Locatelli, Irene; Tonon, Giovanni; Longhi, Erika; Zerbi, Pietro; Allevi, Raffaele; Podestà, Alessandro; Puricelli, Luca; Milani, Paolo; Soldarini, Armando; Salonia, Andrea; Alfano, Massimo

    2016-01-01

    The extracellular matrix (ECM) from perilesional and colorectal carcinoma (CRC), but not healthy colon, sustains proliferation and invasion of tumor cells. We investigated the biochemical and physical diversity of ECM in pair-wised comparisons of healthy, perilesional and CRC specimens. Progressive linearization and degree of organization of fibrils was observed from healthy to perilesional and CRC ECM, and was associated with a steady increase of stiffness and collagen crosslinking. In the perilesional ECM these modifications coincided with increased vascularization, whereas in the neoplastic ECM they were associated with altered modulation of matrisome proteins, increased content of hydroxylated lysine and lysyl oxidase. This study identifies the increased stiffness and crosslinking of the perilesional ECM predisposing an environment suitable for CRC invasion as a phenomenon associated with vascularization. The increased stiffness of colon areas may represent a new predictive marker of desmoplastic region predisposing to invasion, thus offering new potential application for monitoring adenoma with invasive potential. PMID:26940881

  14. Insight On Colorectal Carcinoma Infiltration by Studying Perilesional Extracellular Matrix.

    PubMed

    Nebuloni, Manuela; Albarello, Luca; Andolfo, Annapaola; Magagnotti, Cinzia; Genovese, Luca; Locatelli, Irene; Tonon, Giovanni; Longhi, Erika; Zerbi, Pietro; Allevi, Raffaele; Podestà, Alessandro; Puricelli, Luca; Milani, Paolo; Soldarini, Armando; Salonia, Andrea; Alfano, Massimo

    2016-01-01

    The extracellular matrix (ECM) from perilesional and colorectal carcinoma (CRC), but not healthy colon, sustains proliferation and invasion of tumor cells. We investigated the biochemical and physical diversity of ECM in pair-wised comparisons of healthy, perilesional and CRC specimens. Progressive linearization and degree of organization of fibrils was observed from healthy to perilesional and CRC ECM, and was associated with a steady increase of stiffness and collagen crosslinking. In the perilesional ECM these modifications coincided with increased vascularization, whereas in the neoplastic ECM they were associated with altered modulation of matrisome proteins, increased content of hydroxylated lysine and lysyl oxidase. This study identifies the increased stiffness and crosslinking of the perilesional ECM predisposing an environment suitable for CRC invasion as a phenomenon associated with vascularization. The increased stiffness of colon areas may represent a new predictive marker of desmoplastic region predisposing to invasion, thus offering new potential application for monitoring adenoma with invasive potential. PMID:26940881

  15. Methylator phenotype in colorectal cancer: A prognostic factor or not?

    PubMed

    Gallois, C; Laurent-Puig, P; Taieb, J

    2016-03-01

    Colorectal cancer (CRC) is due to different types of genetic alterations that are translated into different phenotypes. Among them, CpG island methylator phenotype (CIMP+) is the most recently involved in carcinogenesis of some CRC. The malignant transformation in this case is mainly due to the transcriptional inactivation of tumor suppressor genes. CIMP+ are reported to be more frequently found in the elderly and in women. The tumors are more frequently located in the proximal part of the colon, BRAF mutated and are associated with microsatellite instability (MSI) phenotype. All sporadic MSI CRC belong to the methylator phenotype, however some non MSI CRC may also harbor a methylator phenotype. The prognostic value of CIMP is not well known. Most studies show a worse prognosis in CIMP+ CRC, and adjuvant treatments seem to be more efficient. We review here the current knowledge on prognostic and predictive values in CIMP+ CRC. PMID:26702883

  16. Revisit dietary fiber on colorectal cancer: butyrate and its role on prevention and treatment.

    PubMed

    Encarnação, J C; Abrantes, A M; Pires, A S; Botelho, M F

    2015-09-01

    Colorectal cancer is still a major health problem worldwide. Based on the most recent released data by the World Health Organization GLOBOCAN in 2012, colorectal cancer is the third most prevalent type of cancer in males and the second in females. In 1999, it was published the first report showing evidence of a strong correlation between diet and cancer incidence, being its positive or negative impact intimately linked to dietary patterns. A diet rich in fiber is associated with a low risk of developing colorectal cancer. The fermentation of the dietary fiber by intestinal microflora results in production of butyrate, which plays a plurifunctional role on the colonocytes, and it has also been reported as a chemopreventive agent. However, there are limited studies focusing its anti-cancer potential. Here, we review the recent new insights that focus butyrate and its role in colorectal cancer prevention and treatment, from its synthesis, metabolism, and transport, through its involvement on several cancer-related signaling pathways, to the novel existing approaches for its clinical use.

  17. Pathophysiology of colorectal peritoneal carcinomatosis: Role of the peritoneum.

    PubMed

    Lemoine, Lieselotte; Sugarbaker, Paul; Van der Speeten, Kurt

    2016-09-14

    Colorectal cancer (CRC) is the third most common cancer and the fourth most common cause of cancer-related death worldwide. Besides the lymphatic and haematogenous routes of dissemination, CRC frequently gives rise to transcoelomic spread of tumor cells in the peritoneal cavity, which ultimately leads to peritoneal carcinomatosis (PC). PC is associated with a poor prognosis and bad quality of life for these patients in their terminal stages of disease. A loco-regional treatment modality for PC combining cytoreductive surgery and hyperthermic intraperitoneal peroperative chemotherapy has resulted in promising clinical results. However, this novel approach is associated with significant morbidity and mortality. A comprehensive understanding of the molecular events involved in peritoneal disease spread is paramount in avoiding unnecessary toxicity. The emergence of PC is the result of a molecular crosstalk between cancer cells and host elements, involving several well-defined steps, together known as the peritoneal metastatic cascade. Individual or clumps of tumor cells detach from the primary tumor, gain access to the peritoneal cavity and become susceptible to the regular peritoneal transport. They attach to the distant peritoneum, subsequently invade the subperitoneal space, where angiogenesis sustains proliferation and enables further metastatic growth. These molecular events are not isolated events but rather a continuous and interdependent process. In this manuscript, we review current data regarding the molecular mechanisms underlying the development of colorectal PC, with a special focus on the peritoneum and the role of the surgeon in peritoneal disease spread. PMID:27678351

  18. Pathophysiology of colorectal peritoneal carcinomatosis: Role of the peritoneum

    PubMed Central

    Lemoine, Lieselotte; Sugarbaker, Paul; Van der Speeten, Kurt

    2016-01-01

    Colorectal cancer (CRC) is the third most common cancer and the fourth most common cause of cancer-related death worldwide. Besides the lymphatic and haematogenous routes of dissemination, CRC frequently gives rise to transcoelomic spread of tumor cells in the peritoneal cavity, which ultimately leads to peritoneal carcinomatosis (PC). PC is associated with a poor prognosis and bad quality of life for these patients in their terminal stages of disease. A loco-regional treatment modality for PC combining cytoreductive surgery and hyperthermic intraperitoneal peroperative chemotherapy has resulted in promising clinical results. However, this novel approach is associated with significant morbidity and mortality. A comprehensive understanding of the molecular events involved in peritoneal disease spread is paramount in avoiding unnecessary toxicity. The emergence of PC is the result of a molecular crosstalk between cancer cells and host elements, involving several well-defined steps, together known as the peritoneal metastatic cascade. Individual or clumps of tumor cells detach from the primary tumor, gain access to the peritoneal cavity and become susceptible to the regular peritoneal transport. They attach to the distant peritoneum, subsequently invade the subperitoneal space, where angiogenesis sustains proliferation and enables further metastatic growth. These molecular events are not isolated events but rather a continuous and interdependent process. In this manuscript, we review current data regarding the molecular mechanisms underlying the development of colorectal PC, with a special focus on the peritoneum and the role of the surgeon in peritoneal disease spread. PMID:27678351

  19. Pathophysiology of colorectal peritoneal carcinomatosis: Role of the peritoneum

    PubMed Central

    Lemoine, Lieselotte; Sugarbaker, Paul; Van der Speeten, Kurt

    2016-01-01

    Colorectal cancer (CRC) is the third most common cancer and the fourth most common cause of cancer-related death worldwide. Besides the lymphatic and haematogenous routes of dissemination, CRC frequently gives rise to transcoelomic spread of tumor cells in the peritoneal cavity, which ultimately leads to peritoneal carcinomatosis (PC). PC is associated with a poor prognosis and bad quality of life for these patients in their terminal stages of disease. A loco-regional treatment modality for PC combining cytoreductive surgery and hyperthermic intraperitoneal peroperative chemotherapy has resulted in promising clinical results. However, this novel approach is associated with significant morbidity and mortality. A comprehensive understanding of the molecular events involved in peritoneal disease spread is paramount in avoiding unnecessary toxicity. The emergence of PC is the result of a molecular crosstalk between cancer cells and host elements, involving several well-defined steps, together known as the peritoneal metastatic cascade. Individual or clumps of tumor cells detach from the primary tumor, gain access to the peritoneal cavity and become susceptible to the regular peritoneal transport. They attach to the distant peritoneum, subsequently invade the subperitoneal space, where angiogenesis sustains proliferation and enables further metastatic growth. These molecular events are not isolated events but rather a continuous and interdependent process. In this manuscript, we review current data regarding the molecular mechanisms underlying the development of colorectal PC, with a special focus on the peritoneum and the role of the surgeon in peritoneal disease spread.

  20. Epigenetic regulation of miR-21 in colorectal cancer

    PubMed Central

    Ferraro, Angelo; Kontos, Christos K; Boni, Themis; Bantounas, Ioannis; Siakouli, Dimitra; Kosmidou, Vivian; Vlassi, Margarita; Spyridakis, Yannis; Tsipras, Iraklis; Zografos, George; Pintzas, Alexander

    2014-01-01

    Previous studies have uncovered several transcription factors that determine biological alterations in tumor cells to execute the invasion-metastasis cascade, including the epithelial-mesenchymal transition (EMT). We sought to investigate the role of miR-21 in colorectal cancer regulation. For this purpose, miR-21 expression was quantified in a panel of colorectal cancer cell lines and clinical specimens. High expression was found in cell lines with EMT properties and in the vast majority of human tumor specimens. We demonstrate in a cell-specific manner the occupancy of MIR-21 gene promoter by AP-1 and ETS1 transcription factors and, for the first time, the pattern of histone posttranslational modifications necessary for miR-21 overexpression. We also show that Integrin-β4 (ITGβ4), exclusively expressed in polarized epithelial cells, is a novel miR-21 target gene and plays a role in the regulation of EMT, since it is remarkably de-repressed after transient miR-21 silencing and downregulated after miR-21 overexpression. miR-21-dependent change of ITGβ4 expression significantly affects cell migration properties of colon cancer cells. Finally, in a subgroup of tumor specimens, ROC curve analysis performed on quantitative PCR data sets for miR-21, ITGβ4, and PDCD4 shows that the combination of high miR-21 with low ITGβ4 and PDCD4 expression is able to predict presence of metastasis. In conclusion, miR-21 is a key player in oncogenic EMT, its overexpression is controlled by the cooperation of genetic and epigenetic alterations, and its levels, along with ITGβ4 and PDCD4 expression, could be exploited as a prognostic tool for CRC metastasis. PMID:24149370

  1. Fusobacterium and Escherichia: models of colorectal cancer driven by microbiota and the utility of microbiota in colorectal cancer screening.

    PubMed

    Leung, Andrea; Tsoi, Ho; Yu, Jun

    2015-05-01

    Intestinal microbiota has emerging roles in the development of colorectal cancer (CRC). Intestinal dysbiosis, with altered levels of specific bacteria, is consistently seen in CRC. The heart of the debate lies in whether these bacteria are a cause or consequence of CRC. Two bacteria in particular, Fusobacterium nucleatum and Escherichia coli, have consistently been associated with CRC. This review will examine evidence supporting oncogenic roles of F. nucleatum and E. coli. The proposed mechanisms of tumor formation follow two models: bacterial induced chronic inflammation leads to cell proliferation and tumor formation and virulence factors directly induce tumor formation. This review will further examine the potential for microbiota as biomarkers in CRC, with a focus on F. nucleatum.

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

    SciTech Connect

    Zavarin, M.; Zhao, P.; Joseph, C.; Begg, J.; Boggs, M.; Dai, Z.; Kersting, A. B.

    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

  3. BRAF V600E mutation detection by immunohistochemistry in colorectal carcinoma.

    PubMed

    Affolter, Kajsa; Samowitz, Wade; Tripp, Sheryl; Bronner, Mary P

    2013-08-01

    The serine/threonine-protein kinase B-raf (BRAF) is an oncogene mutated in various neoplasms, including 5-15% of colorectal carcinomas. The T1799A point mutation, responsible for a large majority of these alterations, results in an amino acid substitution (V600E) causing the constitutive activation of a protein kinase cascade. BRAF V600E in MLH1 deficient tumors implicates somatic tumor-only methylation of the MLH1 promoter region instead of a germline MLH1 mutation. BRAF V600E also predicts poor prognosis in microsatellite stable colorectal cancers and may be a marker of resistance to anti-EGFR therapy in metastatic disease. Currently, only molecular methods are available for assessing BRAF mutational status. An immunohistochemical approach is evaluated here. Colon cancers from 2008 to 2012 tested by pyrosequencing for BRAF V600E mutation were selected. A total of 31 tumors with (n = 14) and without (n = 17) the BRAF V600E mutation were analyzed by immunohistochemistry using a commercially available antibody specific to the V600E-mutated protein. All 14 colorectal carcinomas with the BRAF V600E mutation demonstrated cytoplasmic positivity in tumor cells with the anti-BRAF antibody. In a minority of cases, staining intensity for the mutated tumor samples was weak (n = 2) or heterogeneous (n = 4); however, the majority of cases showed diffuse, strong cytoplasmic positivity (8 of 14 cases). None of the 17 BRAF wild-type colorectal cancers showed immunoreactivity to the antibody. The overall sensitivity and specificity of the immunohistochemical BRAF V600E assay was 100%. Detection of the BRAF V600E mutation in colorectal cancer by immunohistochemistry is a viable alternative to molecular methods.

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

    PubMed Central

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

    2015-01-01

    Objectives 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. Design Qualitative in-depth interview study. Setting and participants 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. Methods 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. Results 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. Conclusions Findings provide guidance for awareness campaigns on reducing stigma around appraising and discussing bowel movements, and the importance of intermittent

  5. Genetics of Colorectal Cancer (PDQ®)—Health Professional Version

    Cancer.gov

    Expert-reviewed information summary about the genetics of colorectal cancer, including information about specific genes and family cancer syndromes. The summary also contains information about screening for colorectal cancer and research aimed at prevention of this disease. Psychosocial issues associated with genetic testing and counseling of individuals who may have hereditary colorectal cancer syndrome are also discussed.

  6. Reduced arsenic accumulation in rice (Oryza sativa L.) shoot involves sulfur mediated improved thiol metabolism, antioxidant system and altered arsenic transporters.

    PubMed

    Dixit, Garima; Singh, Amit Pal; Kumar, Amit; Mishra, Seema; Dwivedi, Sanjay; Kumar, Smita; Trivedi, Prabodh Kumar; Pandey, Vivek; Tripathi, Rudra Deo

    2016-02-01

    Arsenic (As) contamination in rice is at alarming level as majority of rice growing regions are As contaminated such as South East Asia. Restricting the As in aerial parts of rice plant may be an effective strategy to reduce As contamination in food chain. Sulfur (S), an essential element for plant growth and development, plays a crucial role in diminishing heavy metal toxicity. Current study is designed to investigate the role of S to mitigate As toxicity in rice under different S regimes. High S (5 mM) treatment resulted in enhanced root As accumulation as well as prevented its entry in to shoot. Results of thiol metabolism indicate that As was complexed in plant roots through enhanced synthesis of phytochelatins. High S treatment also reduced the expression of OsLsi1 and OsLsi2, the potent transporters of As in rice. High S treatment enhanced the activities of antioxidant enzymes and mitigated the As induced oxidative stress. Thus from present study it is evident that proper supply of S nutrition may be helpful in prevention of As accumulation in aerial parts of plant as well as As induced toxicity. PMID:26741538

  7. Reduced arsenic accumulation in rice (Oryza sativa L.) shoot involves sulfur mediated improved thiol metabolism, antioxidant system and altered arsenic transporters.

    PubMed

    Dixit, Garima; Singh, Amit Pal; Kumar, Amit; Mishra, Seema; Dwivedi, Sanjay; Kumar, Smita; Trivedi, Prabodh Kumar; Pandey, Vivek; Tripathi, Rudra Deo

    2016-02-01

    Arsenic (As) contamination in rice is at alarming level as majority of rice growing regions are As contaminated such as South East Asia. Restricting the As in aerial parts of rice plant may be an effective strategy to reduce As contamination in food chain. Sulfur (S), an essential element for plant growth and development, plays a crucial role in diminishing heavy metal toxicity. Current study is designed to investigate the role of S to mitigate As toxicity in rice under different S regimes. High S (5 mM) treatment resulted in enhanced root As accumulation as well as prevented its entry in to shoot. Results of thiol metabolism indicate that As was complexed in plant roots through enhanced synthesis of phytochelatins. High S treatment also reduced the expression of OsLsi1 and OsLsi2, the potent transporters of As in rice. High S treatment enhanced the activities of antioxidant enzymes and mitigated the As induced oxidative stress. Thus from present study it is evident that proper supply of S nutrition may be helpful in prevention of As accumulation in aerial parts of plant as well as As induced toxicity.

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

    PubMed Central

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

    2015-01-01

    ABSTRACT 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. PMID:26398944

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

    PubMed

    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.

  10. Knockout of the norepinephrine transporter and pharmacologically diverse antidepressants prevent behavioral and brain neurotrophin alterations in two chronic stress models of depression

    PubMed Central

    Haenisch, Britta; Bilkei-Gorzo, Andras; Caron, Marc G.; Bönisch, Heinz

    2009-01-01

    Diverse factors such as changes in neurotrophins and brain plasticity have been proposed to be involved in the actions of antidepressant drugs (ADs). However, in mouse models of depression based on chronic stress, it is still unclear whether simultaneous changes in behavior and neurotrophin expression occur and whether these changes can be corrected or prevented comparably by chronic administration of ADs or genetic manipulations that produce antidepressant-like effects such as the knockout (KO) of the norepinephrine transporter (NET) gene. Here we show that chronic restraint or social defeat stress induce comparable effects on behavior and changes in the expression of neurotrophins in depression-related brain regions. Chronic stress caused down-regulation of BDNF, NGF and NT-3 in hippocampus and cerebral cortex and up-regulation of these targets in striatal regions. In wild-type mice, these effects could be prevented by concomitant chronic administration of five pharmacologically diverse ADs. In contrast, NETKO mice were resistant to stress-induced depressive-like changes in behavior and brain neurotrophin expression. Thus, the resistance of the NETKO mice to the stress-induced depression-associated behaviors and biochemical changes highlight the importance of noradrenergic pathways in the maintenance of mood. In addition, these mice represent a useful model to study depression-resistant behaviors, and they might help to provide deeper insights into the identification of downstream targets involved in the mechanisms of antidepressants. PMID:19694905

  11. Genomic diversity of colorectal cancer: Changing landscape and emerging targets.

    PubMed

    Ahn, Daniel H; Ciombor, Kristen K; Mikhail, Sameh; Bekaii-Saab, Tanios

    2016-07-01

    Improvements in screening and preventive measures have led to an increased detection of early stage colorectal cancers (CRC) where patients undergo treatment with a curative intent. Despite these efforts, a high proportion of patients are diagnosed with advanced stage disease that is associated with poor outcomes, as CRC remains one of the leading causes of cancer-related deaths in the world. The development of next generation sequencing and collaborative multi-institutional efforts to characterize the cancer genome has afforded us with a comprehensive assessment of the genomic makeup present in CRC. This knowledge has translated into understanding the prognostic role of various tumor somatic variants in this disease. Additionally, the awareness of the genomic alterations present in CRC has resulted in an improvement in patient outcomes, largely due to better selection of personalized therapies based on an individual's tumor genomic makeup. The benefit of various treatments is often limited, where recent studies assessing the genomic diversity in CRC have identified the development of secondary tumor somatic variants that likely contribute to acquired treatment resistance. These studies have begun to alter the landscape of treatment for CRC that include investigating novel targeted therapies, assessing the role of immunotherapy and prospective, dynamic assessment of changes in tumor genomic alterations that occur during the treatment of CRC.

  12. Genomic diversity of colorectal cancer: Changing landscape and emerging targets.

    PubMed

    Ahn, Daniel H; Ciombor, Kristen K; Mikhail, Sameh; Bekaii-Saab, Tanios

    2016-07-01

    Improvements in screening and preventive measures have led to an increased detection of early stage colorectal cancers (CRC) where patients undergo treatment with a curative intent. Despite these efforts, a high proportion of patients are diagnosed with advanced stage disease that is associated with poor outcomes, as CRC remains one of the leading causes of cancer-related deaths in the world. The development of next generation sequencing and collaborative multi-institutional efforts to characterize the cancer genome has afforded us with a comprehensive assessment of the genomic makeup present in CRC. This knowledge has translated into understanding the prognostic role of various tumor somatic variants in this disease. Additionally, the awareness of the genomic alterations present in CRC has resulted in an improvement in patient outcomes, largely due to better selection of personalized therapies based on an individual's tumor genomic makeup. The benefit of various treatments is often limited, where recent studies assessing the genomic diversity in CRC have identified the development of secondary tumor somatic variants that likely contribute to acquired treatment resistance. These studies have begun to alter the landscape of treatment for CRC that include investigating novel targeted therapies, assessing the role of immunotherapy and prospective, dynamic assessment of changes in tumor genomic alterations that occur during the treatment of CRC. PMID:27433082

  13. Genomic diversity of colorectal cancer: Changing landscape and emerging targets

    PubMed Central

    Ahn, Daniel H; Ciombor, Kristen K; Mikhail, Sameh; Bekaii-Saab, Tanios

    2016-01-01

    Improvements in screening and preventive measures have led to an increased detection of early stage colorectal cancers (CRC) where patients undergo treatment with a curative intent. Despite these efforts, a high proportion of patients are diagnosed with advanced stage disease that is associated with poor outcomes, as CRC remains one of the leading causes of cancer-related deaths in the world. The development of next generation sequencing and collaborative multi-institutional efforts to characterize the cancer genome has afforded us with a comprehensive assessment of the genomic makeup present in CRC. This knowledge has translated into understanding the prognostic role of various tumor somatic variants in this disease. Additionally, the awareness of the genomic alterations present in CRC has resulted in an improvement in patient outcomes, largely due to better selection of personalized therapies based on an individual’s tumor genomic makeup. The benefit of various treatments is often limited, where recent studies assessing the genomic diversity in CRC have identified the development of secondary tumor somatic variants that likely contribute to acquired treatment resistance. These studies have begun to alter the landscape of treatment for CRC that include investigating novel targeted therapies, assessing the role of immunotherapy and prospective, dynamic assessment of changes in tumor genomic alterations that occur during the treatment of CRC. PMID:27433082

  14. PREFERENCE FOR DISTINCT FUNCTIONAL CONFORMATIONS OF THE DOPAMINE TRANSPORTER ALTERS THE RELATIONSHIP BETWEEN SUBJECTIVE EFFECTS OF COCAINE AND STIMULATION OF MESOLIMBIC DOPAMINE

    PubMed Central

    Kohut, Stephen J.; Hiranita, Takato; Hong, Soo-Kyung; Ebbs, Aaron L.; Tronci, Valeria; Green, Jennifer; Garcés-Ramírez, Linda; Chun, Lauren E.; Mereu, Maddalena; Newman, Amy H.; Katz, Jonathan L.; Tanda, Gianluigi

    2014-01-01

    Background Subjective effects related to cocaine abuse are primarily mediated by blockade of the dopamine (DA) transporter (DAT). The present study assessed the hypothesis that different conformational equilibria of the DAT regulate differences in extracellular DA induced by structurally diverse DA uptake inhibitors (DUI) and their cocaine-like subjective effects. Methods The relationship between cocaine-like subjective effects and stimulation of mesolimbic-DA levels by standard-DUIs (cocaine, methylphenidate, WIN35,428), and atypical-DUIs (benztropine analogs: AHN1-055, AHN2-005, JHW-007) was investigated using cocaine-discrimination and DA-microdialysis procedures in rats. Results All drugs stimulated DA-levels showing different time-courses and maximal effects. Standard-DUIs, which preferentially bind to the outward-facing DAT-conformation, fully substituted for cocaine, consistently producing those subjective effects at DA levels of 100-125% over basal values, regardless of dose or pretreatment time. The atypical-DUIs, with DAT binding minimally affected by DAT conformation, produced inconsistent cocaine-like subjective effects. Full effects were obtained, if at all, only at a few doses and pretreatment times, and at DA-levels 600-700% greater than basal values. Importantly, the linear, time-independent, relationship between cocaine-like subjective effects and stimulation of DA-levels, obtained with standard DUIs was not obtained with the atypical-DUIs. Conclusions These results suggest a time-related desensitization process underlying the reduced cocaine subjective effects of atypical-DUIs that may be differentially induced by the binding modalities identified using molecular approaches. Since the DAT is the target of several drugs for treating neuropsychiatric disorders, such as ADHD, these results help to identify safe and effective medications with minimal cocaine-like subjective effects that contribute to abuse liability. PMID:24853388

  15. High-fat and fructose intake induces insulin resistance, dyslipidemia, and liver steatosis and alters in vivo macrophage-to-feces reverse cholesterol transport in hamsters.

    PubMed

    Briand, François; Thiéblemont, Quentin; Muzotte, Elodie; Sulpice, Thierry

    2012-04-01

    Reverse cholesterol transport (RCT) promotes the egress of cholesterol from peripheral tissues to the liver for biliary and fecal excretion. Although not demonstrated in vivo, RCT is thought to be impaired in patients with metabolic syndrome, in which liver steatosis prevalence is relatively high. Golden Syrian hamsters were fed a nonpurified (CON) diet and normal drinking water or a high-fat (HF) diet containing 27% fat, 0.5% cholesterol, and 0.25% deoxycholate as well as 10% fructose in drinking water for 4 wk. Compared to CON, the HF diet induced insulin resistance and dyslipidemia, with significantly higher plasma non-HDL-cholesterol concentrations and cholesteryl ester transfer protein activity. The HF diet induced severe liver steatosis, with significantly higher cholesterol and TG levels compared to CON. In vivo RCT was assessed by i.p. injecting ³H-cholesterol labeled macrophages. Compared to CON, HF hamsters had significantly greater ³H-tracer recoveries in plasma, but not HDL. After 72 h, ³H-tracer recovery in HF hamsters was 318% higher in liver and 75% lower in bile (P < 0.01), indicating that the HF diet impaired hepatic cholesterol fluxes. However, macrophage-derived cholesterol fecal excretion was 45% higher in HF hamsters than in CON hamsters. This effect was not related to intestinal cholesterol absorption, which was 89% higher in HF hamsters (P < 0.05), suggesting a possible upregulation of transintestinal cholesterol excretion. Our data indicate a significant increase in macrophage-derived cholesterol fecal excretion in a hamster model of metabolic syndrome, which may not compensate for the diet-induced dyslipidemia and liver steatosis.

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

    PubMed

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

    2010-12-01

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

  17. Altered antibiotic transport in OmpC mutants isolated from a series of clinical strains of multi-drug resistant E. coli.

    PubMed

    Lou, Hubing; Chen, Min; Black, Susan S; Bushell, Simon R; Ceccarelli, Matteo; Mach, Tivadar; Beis, Konstantinos; Low, Alison S; Bamford, Victoria A; Booth, Ian R; Bayley, Hagan; Naismith, James H

    2011-01-01

    Antibiotic-resistant bacteria, particularly gram negative species, present significant health care challenges. The permeation of antibiotics through the outer membrane is largely effected by the porin superfamily, changes in which contribute to antibiotic resistance. A series of antibiotic resistant E. coli isolates were obtained from a patient during serial treatment with various antibiotics. The sequence of OmpC changed at three positions during treatment giving rise to a total of four OmpC variants (denoted OmpC20, OmpC26, OmpC28 and OmpC33, in which OmpC20 was derived from the first clinical isolate). We demonstrate that expression of the OmpC K12 porin in the clinical isolates lowers the MIC, consistent with modified porin function contributing to drug resistance. By a range of assays we have established that the three mutations that occur between OmpC20 and OmpC33 modify transport of both small molecules and antibiotics across the outer membrane. This results in the modulation of resistance to antibiotics, particularly cefotaxime. Small ion unitary conductance measurements of the isolated porins do not show significant differences between isolates. Thus, resistance does not appear to arise from major changes in pore size. Crystal structures of all four OmpC clinical mutants and molecular dynamics simulations also show that the pore size is essentially unchanged. Molecular dynamics simulations suggest that perturbation of the transverse electrostatic field at the constriction zone reduces cefotaxime passage through the pore, consistent with laboratory and clinical data. This subtle modification of the transverse electric field is a very different source of resistance than occlusion of the pore or wholesale destruction of the transverse field and points to a new mechanism by which porins may modulate antibiotic passage through the outer membrane.

  18. Cluster altered magnetic and transport properties in Ge{sub 1−x−y}Mn{sub x}Eu{sub y}Te

    SciTech Connect

    Kilanski, L. Górska, M.; Szymczak, R.; Dobrowolski, W.; Podgórni, A.; Avdonin, A.; Domukhovski, V.

    2014-08-28

    Magnetic and transport properties of Ge{sub 1−x−y}Mn{sub x}Eu{sub y}Te crystals with chemical compositions 0.041 ≤ x ≤ 0.092 and 0.010 ≤ y ≤ 0.043 are studied. Ferromagnetic order is observed at 150 < T < 160 K. Aggregation of magnetic ions into clusters is found to be the source of almost constant, composition independent Curie temperatures in our samples. Magnetotransport studies show that below 25 K there is a negative magnetoresistance, which is not linear and has a minimum and above 60 K the magnetoresistance is positive and linear. Negative magnetoresistance detected at T < 25 K is found to be due to a tunneling of spin-polarized electrons between ferromagnetic clusters. A linear positive magnetoresistance is identified to be a geometrical effect related to the presence of ferromagnetic clusters inside the semiconductor matrix. The product of the polarization constant (P) and the inter-grain exchange constant (J), JP, varies between about 0.13 meV and 0.99 meV. A strong anomalous Hall effect is observed for T ≤ T{sub C}, where T{sub C} is the Curie temperature, with coefficients R{sub S} independent of temperature. The scaling analysis of the AHE leads to a conclusion that this effect is due to a skew scattering mechanism.

  19. Genetic Variants Associated with Colorectal Adenoma Susceptibility

    PubMed Central

    Abulí, Anna; Castells, Antoni; Bujanda, Luis; Lozano, Juan José; Bessa, Xavier; Hernández, Cristina; Álvarez-Urturi, Cristina; Pellisé, Maria; Esteban-Jurado, Clara; Hijona, Elizabeth; Burón, Andrea; Macià, Francesc; Grau, Jaume; Guayta, Rafael

    2016-01-01

    Background Common low-penetrance genetic variants have been consistently associated with colorectal cancer risk. Aim 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). Methods 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. Results 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. Conclusions 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. PMID:27078840

  20. Clinicopathologic Features of Colorectal Carcinoma in HIV-Positive Patients

    PubMed Central

    Sigel, Carlie; Cavalcanti, Marcela S.; Daniel, Tanisha; Vakiani, Efsevia; Shia, Jinru; Sigel, Keith

    2016-01-01

    Background Emerging evidence suggests differences in colo-rectal cancer in HIV-infected patients (HIV+) compared with HIV− patients. Microsatellite instability (MSI), occurring in a subset of colorectal cancer, is present at a higher rate in certain cancers in HIV+ patients. Colorectal cancer with MSI share some characteristics with those reported for HIV+ colorectal cancer. On this premise, we studied clinical and pathologic features of HIV+ colorectal cancer and evaluated for MSI using matched HIV− colorectal cancer controls. Methods Two nested, matched cohorts were identified from a hospital-based cohort of colorectal cancer patients. HIV+ colo-rectal cancers were identified and random control patients were matched for selected characteristics. Mismatch repair protein (MMR) IHC was performed as the detection method for MSI. Variables were compared between cases and controls using fixed-effects logit modeling to account for matching. Results We included 184 colorectal cancer samples (38 HIV+, 146 HIV− control). Median patient age at colorectal cancer onset was 55. When compared with HIV− colorectal cancer, HIV+patients were more likely to have smoked (P = 0.001), have right-sided colorectal cancer (37% vs. 14%; P = 0.003), and tumor-infiltrating lymphocytes (TIL) above 50/10 high-power fields (21% vs. 7%). There was no difference in MMR protein expression (P = 0.6). HIV+ colorectal cancer patients had reduced overall survival (P = 0.02) but no difference in progression-free survival. Conclusions HIV+ patients developed colorectal cancer at a lower median age than population estimates, had a higher frequency of right-sided disease, and increased TILs, suggesting potential biologic differences compared with uninfected patients. Impact Clinicopathologic differences in colorectal cancer of HIV+ persons may have implications for tumor pathogenesis. PMID:27197294

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

    PubMed

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

    2015-08-01

    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 (0-20μM) 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 CII and lowered CI:CII respiration ratio, an indication of decreased OXPHOS efficiency. The effects of Cu were less pronounced but more variable and included inhibition of CII-IV maximal respiration rates and stimulation of both CI and CIII basal respiration rates. Surprisingly, only CII and CIII indices exhibited significant 3-way interactions whereas 2-way interactions of acclimation either with Cu or HRO were portrayed mostly by CIV, and those of

  2. Systematic genomic identification of colorectal cancer genes delineating advanced from early clinical stage and metastasis

    PubMed Central

    2013-01-01

    Background Colorectal cancer is the third leading cause of cancer deaths in the United States. The initial assessment of colorectal cancer involves clinical staging that takes into account the extent of primary tumor invasion, determining the number of lymph nodes with metastatic cancer and the identification of metastatic sites in other organs. Advanced clinical stage indicates metastatic cancer, either in regional lymph nodes or in distant organs. While the genomic and genetic basis of colorectal cancer has been elucidated to some degree, less is known about the identity of specific cancer genes that are associated with advanced clinical stage and metastasis. Methods We compiled multiple genomic data types (mutations, copy number alterations, gene expression and methylation status) as well as clinical meta-data from The Cancer Genome Atlas (TCGA). We used an elastic-net regularized regression method on the combined genomic data to identify genetic aberrations and their associated cancer genes that are indicators of clinical stage. We ranked candidate genes by their regression coefficient and level of support from multiple assay modalities. Results A fit of the elastic-net regularized regression to 197 samples and integrated analysis of four genomic platforms identified the set of top gene predictors of advanced clinical stage, including: WRN, SYK, DDX5 and ADRA2C. These genetic features were identified robustly in bootstrap resampling analysis. Conclusions We conducted an analysis integrating multiple genomic features including mutations, copy number alterations, gene expression and methylation. This integrated approach in which one considers all of these genomic features performs better than any individual genomic assay. We identified multiple genes that robustly delineate advanced clinical stage, suggesting their possible role in colorectal cancer metastatic progression. PMID:24308539

  3. Precancerous Lesions in Colorectal Cancer

    PubMed Central

    Sandouk, Fayez; Al Jerf, Feras; Al-Halabi, M. H. D. Bassel

    2013-01-01

    Colorectal cancer (CRC) is the third most common cause of cancer death in the world. The incidence rate (ASR) and age distribution of this disease differ between most of African-Middle-Eastern (AMAGE) and North America and Europe for many reasons. However, in all areas, “CRC” is considered as one of the most preventable cancers, because it might develop from variant processes like polyps and IBD in addition to the genetic pathogenesis which became very well known in this disease. We tried in this paper to review all the possible reasons of the differences in incidence and age between the west and AMAGE. Also we reviewed all the mutations that lead to the hereditary and familiar clustering of this disease with the correlations with the surrounding food and environment of different areas. Then, we focused on the precancerous pathology of this disease with special focusing on early detection depending on new endoscopy technology and most important genetic studies. We lastly reviewed the evidence of some of the surveillance and put suggestions about future surveillance programs and how important those programs are on the psychological aspect of the patients and their families. PMID:23737765

  4. Ablative Therapies for Colorectal Polyps and Malignancy

    PubMed Central

    Hochwald, Steven N.; Nurkin, Steven

    2014-01-01

    Endoscopic techniques are gaining popularity in the management of colorectal polyps and occasionally superficial cancers. While their use is in many times palliative, they have proven to be curative in carefully selected patients with polyps or malignancies, with less morbidity than radical resection. However, one should note that data supporting local and ablative therapies for colorectal cancer is scarce and may be subject to publication bias. Therefore, for curative intent, these techniques should only be considered in highly select cases as higher rates of local recurrences have also been reported. The aim of this review is to explain the different modalities of local and ablative therapies specific to colorectal neoplasia and explain the indications and circumstances where they have been most successful. PMID:25089281

  5. The stability of colorectal cancer mathematical models

    NASA Astrophysics Data System (ADS)

    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.

  6. Tissue Specific Promoters in Colorectal Cancer

    PubMed Central

    Rama, A. R.; Aguilera, A.; Melguizo, C.; Caba, O.; Prados, J.

    2015-01-01

    Colorectal carcinoma is the third most prevalent cancer in the world. In the most advanced stages, the use of chemotherapy induces a poor response and is usually accompanied by other tissue damage. Significant progress based on suicide gene therapy has demonstrated that it may potentiate the classical cytotoxic effects in colorectal cancer. The inconvenience still rests with the targeting and the specificity efficiency. The main target of gene therapy is to achieve an effective vehicle to hand over therapeutic genes safely into specific cells. One possibility is the use of tumor-specific promoters overexpressed in cancers. They could induce a specific expression of therapeutic genes in a given tumor, increasing their localized activity. Several promoters have been assayed into direct suicide genes to cancer cells. This review discusses the current status of specific tumor-promoters and their great potential in colorectal carcinoma treatment. PMID:26648599

  7. Relationship between intestinal microbiota and colorectal cancer

    PubMed Central

    Cipe, Gokhan; Idiz, Ufuk Oguz; Firat, Deniz; Bektasoglu, Huseyin

    2015-01-01

    The human gastrointestinal tract hosts a complex and vast microbial community with up to 1011-1012 microorganisms colonizing the colon. The gut microbiota has a serious effect on homeostasis and pathogenesis through a number of mechanisms. In recent years, the relationship between the intestinal microbiota and sporadic colorectal cancer has attracted much scientific interest. Mechanisms underlying colonic carcinogenesis include the conversion of procarcinogenic diet-related factors to carcinogens and the stimulation of procarcinogenic signaling pathways in luminal epithelial cells. Understanding each of these mechanisms will facilitate future studies, leading to the development of novel strategies for the diagnosis, treatment, and prevention of colorectal cancer. In this review, we discuss the relationship between colorectal cancer and the intestinal microbiota. PMID:26483877

  8. [New advances in hereditary colorectal cancer].

    PubMed

    Moreira, Leticia

    2015-09-01

    Colorectal cancer is the most frequent malignancy in both sexes in Spain. Between 20% and 25% of affected individuals have a family history of the disease, and 5% to 6% have a germ mutation, i.e. the disease develops in the context of a hereditary syndrome. The importance of identifying patients with hereditary syndromes predisposing them to colorectal cancer lies in the possibility of applying preventive measures, screening, and more appropriate management of both patients and their families. The present article outlines the most important studies presented at the congress of the American Gastroenterological Association.

  9. Vitamin D Receptor Gene Polymorphism and the Risk of Colorectal Cancer: A Nested Case-Control Study

    PubMed Central

    Budhathoki, Sanjeev; Yamaji, Taiki; Iwasaki, Motoki; Sawada, Norie; Shimazu, Taichi; Sasazuki, Shizuka; Yoshida, Teruhiko; Tsugane, Shoichiro

    2016-01-01

    Epidemiological and experimental evidence suggest that vitamin D is protective against the risk of colorectal cancer. Polymorphisms in the gene encoding vitamin D receptor (VDR), which mediates most of the known cellular effects of vitamin D, have been suggested to alter this association. Here, using a tag SNP approach, we comprehensively evaluated the role of common genetic variants in VDR and their interaction with plasma vitamin D levels in relation to colorectal cancer risk in Japanese populations. A total of 356 colorectal cancer cases and 709 matched control subjects were selected from the participants of the Japan Public Health Center-based Prospective Cohort Study. Among these subjects, 29 VDR single nucleotide polymorphisms (SNPs) were selected and genotyped, and plasma vitamin D concentrations were measured. Conditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of colorectal cancer, with adjustment for potential confounding factors. Among the results, eight VDR SNPs, namely rs2254210, rs1540339, rs2107301, rs11168267, rs11574113, rs731236, rs3847987 and rs11574143, the latter 5 of which were located in the 3′ region, were nominally associated with the risk of colorectal cancer (P = 0.01–0.048). Furthermore, of the above 5 3′ region SNPs, the inverse associations for 3 SNPs (rs11574113, rs3847987 and rs11574143) appeared to be evident only in those with high plasma vitamin D concentration. However, neither of these direct and suggestive interaction analysis associations was significant after multiple testing adjustment. Overall, the findings of this study provide only limited support for an association between common genetic variations in VDR and colorectal cancer risk in the Japanese population. PMID:27736940

  10. Physician knowledge, perceptions of barriers, and patient colorectal cancer screening practices.

    PubMed

    Nichols, Claretha; Holt, Cheryl L; Shipp, Michele; Eloubeidi, Mohamad; Fouad, Mona N; Britt, Kristi

    2009-01-01

    Physician recommendation is a major determinant of colorectal cancer screening. The purpose of this study was to examine physician attitudes and self-reported colorectal cancer patient screening. In a physician survey, perceived patient barriers included preparation for the tests and patient dislike of the blood stool test. Physician semistructured interviews revealed that perception of patient barriers included cost, time off from work, and transportation. Most physicians reported low knowledge of insurance coverage for screening, and self-reported screening rates among physicians themselves were not optimal. Evidence-based interventions to increase physician recommendations for screening, such as reminder and tracking systems, may be of value. Interventions that target physician knowledge of insurance coverage and encourage physicians to adopt screening themselves could also be considered.

  11. Diet, microbiota, and colorectal cancer.

    PubMed

    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. PMID:25291132

  12. Sorafenib and Radiation: A Promising Combination in Colorectal Cancer

    SciTech Connect

    Suen, Andrew W.; Galoforo, Sandra; Marples, Brian; McGonagle, Michele; Downing, Laura; Martinez, Alvaro A.; Robertson, John M.; Wilson, George D.

    2010-09-01

    Purpose: To examine the combination of radiation and the multikinase inhibitor sorafenib in human colorectal cancer cell lines and xenografts. Methods and Materials: HT29 and SW48 colorectal cancer cells were studied in vitro using MTT assays to establish the optimal timing of radiation and sorafenib. This optimal timing was then investigated in clonogenic survival assays. Xenografts were established, and the effect of a 3-week schedule of daily radiation and sorafenib was studied by growth delay. Results: Sorafenib predominantly had minimal effects on cell growth or radiation response in MTT growth assays, though growth inhibition was significantly enhanced in HT29 cells when sorafenib was administered after radiation. The highest dose of sorafenib altered the {alpha} component of the cell survival curve in clonogenic assays. The combination of radiation and sorafenib was synergistic in SW48 xenografts, with a mean time to threshold tumor size of 11.4 {+-} 1.0 days, 37.0 {+-} 9.5 days, 15.5 {+-} 3.2 days, and 98.0 {+-} 11.7 days in the control, radiation, sorafenib, and combined treatment group, respectively. The effect on HT29 tumors was additive, with mean time to threshold volume of 12.6 {+-} 1.1 days, 61.0 {+-} 4.3 days, 42.6 {+-} 11.7 days, and 100.2 {+-} 12.4 days. Conclusions: Sorafenib had little effect on radiation response in vitro but was highly effective when combined with radiation in vivo, suggesting that inhibition of proliferation and interference with angiogenesis may be the basis for the interaction.

  13. 14 CFR 77.15 - Construction or alteration not requiring notice.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... TRANSPORTATION (CONTINUED) AIRSPACE OBJECTS AFFECTING NAVIGABLE AIRSPACE Notice of Construction or Alteration... Administrator for any of the following construction or alteration: (a) Any object that would be shielded...

  14. Advanced endoscopic technologies for colorectal cancer screening

    PubMed Central

    Obstein, Keith L; Valdastri, Pietro

    2013-01-01

    Colorectal cancer is the third most common cancer in men and the second most common cancer in women worldwide. Diagnosing colorectal has been increasingly successful due to advances in technology. Flexible endoscopy is considered to be an effective method for early diagnosis and treatment of gastrointestinal cancer, making it a popular choice for screening programs. However, millions of people who may benefit from endoscopic colorectal cancer screening fail to have the procedure performed. Main reasons include psychological barriers due to the indignity of the procedure, fear of procedure related pain, bowel preparation discomfort, and potential need for sedation. Therefore, an urgent need for new technologies addressing these issues clearly exists. In this review, we discuss a set of advanced endoscopic technologies for colorectal cancer screening that are either already available or close to clinical trial. In particular, we focus on visual-inspection-only advanced flexible colonoscopes, interventional colonoscopes with alternative propulsion mechanisms, wireless capsule colonoscopy, and technologies for intraprocedural bowel cleansing. Many of these devices have the potential to reduce exam related patient discomfort, obviate the need for sedation, increase diagnostic yield, reduce learning curves, improve access to screening, and possibly avert the need for a bowel preparation. PMID:23382621

  15. Colorectal Cancer Rates by Race and Ethnicity

    MedlinePlus

    ... getting colorectal cancer, followed by white, Hispanic, Asian/Pacific Islander (A/PI), and American Indian/Alaska Native ( ... white, Hispanic, American Indian/Alaska Native, and Asian/Pacific Islander women. Sources: CDC’s National Program of Cancer ...

  16. Local inflammatory response in colorectal cancer.

    PubMed

    Łaskowski, P; Klim, B; Ostrowski, K; Szkudlarek, M; Litwiejko-Pietryńczak, E; Kitlas, K; Nienartowicz, S; Dzięcioł, J

    2016-06-01

    Type and intensity of tumor-infiltrating lymphocytes (TILs) in close proximity to the primary tumor are prognostically significant in postoperative patients. High intensity of TILs is considered to be a prognostically beneficial factor. The research included 66 postoperative colorectal cancer patients. The control group comprised 20 colon segments. Monoclonal antibodies LCA, CD3, CD4, CD5, CD8, CD20, CD23 and CD138 were used to differentiate between T and B lymphocytes. Types of cells in the infiltrate were defined. We found greater numbers of T and B lymphocytes located in close proximity to the cancerous tissue when compared to the control group. T lymphocyte intensity in the inflammatory infiltrations was directly correlated with the size of resected tumors, presence of regional lymphatic node metastases and histological grade of malignancy. Lymphocytic infiltrations of greater intensity located in close proximity to the primary tumor were found in subjects with less advanced colorectal cancer. The research presented here proves direct dependence between the immune system and colorectal cancer. The presence of lymphocytes in the inflammatory infiltrations located in close proximity to the cancerous tissue has been proved to be prognostically beneficial. The obtained results support the application of immunotherapy in colorectal cancer treatment. PMID:27543872

  17. Diagnostics and Epidemiology of Colorectal Cancer.

    PubMed

    Kolligs, Frank T

    2016-06-01

    Colorectal cancer is one of the leading causes of cancer-related morbidity and mortality. Main risk factors include advanced age, family history, male sex, and lifestyle factors. Screening can reduce incidence and death from colorectal cancer. Therefore, prevention and early detection are crucial in order to detect and remove pre-neoplastic adenomas and to detect cancers at early stages. Colonoscopy, flexible sigmoidoscopy, and fecal occult blood tests are established tools for screening. Newer fecal immunochemical tests reveal higher sensitivities for advanced adenoma and cancer than guaiac-based hemoccult tests. Molecular stool and blood tests as well as virtual colonoscopy and colon capsule endoscopy are promising new developments so far not established as routine instruments for the prevention and early detection of colorectal cancer. Colonoscopy is the method of choice for the diagnosis of colorectal cancer and for adenoma removal. Prognosis is essentially dependent on the tumor stage at the time of the initial diagnosis. Proper staging based on imaging prior to therapy is a prerequisite. In rectal cancer, local staging is an essential requirement for the identification of appropriate candidates for neoadjuvant therapy. PMID:27493942

  18. URINARY MUTAGENICITY AND COLORECTAL ADENOMA RISK

    EPA Science Inventory

    Abstract

    We investigated urinary mutagenicity and colorectal adenoma risk in a clinic-based, case-control study of currently nonsmoking cases (n = 143) and controls (n = 156). Urinary organics were extracted by C18/methanol from 12-h overnight urine samples, and mutagenici...

  19. [Cyclooxygenase 2 inhibitors and colorectal cancer].

    PubMed

    Bernardeau-Mozer, Marianne; Chaussade, Stanislas

    2004-05-01

    Cyclooxygenase-2 (Cox2) is an inductible isoenzyme of cyclooxygenase undetectable in normal colonic mucosa and overexpressed in 80% colonic tumor. Several works in vitro and in vivo showed that Cox2 plays a key role in the multistep process of colorectal tumorigenesis such apoptosis inhibition of cellular proliferation and angiogenesis induction. So that Cox2 represent a potential molecular target in colorectal management and specific Cox2 inhibitors may be useful as chemopreventive as well as therapeutic agent in humans. In animals study Cox2 inhibitors was shown to be effective and in humans Cox2 inhibitors are approved by the Food and Drug Administration as an adjunct to endoscopic surveillance and surgery in patients with Familial Adenomatous Polyposis (FAP). The purpose of this article is to review the relationship between Cox2/Cox2 inhibitors and differents signaling pathways of colorectal carcinogenesis and to precise their possible molecular mechanisms of action. This work although review clinicals data of their efficacy as chemopreventive agent as well as therapeutic in the differents group at risk for colorectal cancer. PMID:15239336

  20. A Big Bang model of human colorectal tumor growth

    PubMed Central

    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

    2015-01-01

    What happens in the early, still undetectable human malignancy 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 sub-clones 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 revealed the absence of selective sweeps, uniformly high intra-tumor heterogeneity (ITH), and sub-clone 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 sub-clone mixing indicative of early malignant potential. This new model provides a quantitative framework to interpret tumor growth dynamics and the origins of ITH with significant clinical implications. PMID:25665006

  1. Opportunities for immunotherapy in microsatellite instable colorectal cancer.

    PubMed

    Westdorp, Harm; Fennemann, Felix L; Weren, Robbert D A; Bisseling, Tanya M; Ligtenberg, Marjolijn J L; Figdor, Carl G; Schreibelt, Gerty; Hoogerbrugge, Nicoline; Wimmers, Florian; de Vries, I Jolanda M

    2016-10-01

    Microsatellite instability (MSI), the somatic accumulation of length variations in repetitive DNA sequences called microsatellites, is frequently observed in both hereditary and sporadic colorectal cancer (CRC). It has been established that defects in the DNA mismatch repair (MMR) pathway underlie the development of MSI in CRC. After the inactivation of the DNA MMR pathway, misincorporations, insertions and deletions introduced by DNA polymerase slippage are not properly recognized and corrected. Specific genomic regions, including microsatellites, are more prone for DNA polymerase slippage and, therefore, more susceptible for the introduction of these mutations if the DNA MMR capacity is lost. Some of these susceptible genomic regions are located within the coding regions of genes. Insertions and deletions in these regions may alter their reading frame, potentially resulting in the transcription and translation of frameshift peptides with c-terminally altered amino acid sequences. These frameshift peptides are called neoantigens and are highly immunogenic, which explains the enhanced immunogenicity of MSI CRC. Neoantigens contribute to increased infiltration of tumor tissue with activated neoantigen-specific cytotoxic T lymphocytes, a hallmark of MSI tumors. Currently, neoantigen-based vaccination is being studied in a clinical trial for Lynch syndrome and in a trial for sporadic MSI CRC of advanced stage. In this Focussed Research Review, we summarize current knowledge on molecular mechanisms and address immunological features of tumors with MSI. Finally, we describe their implications for immunotherapeutic approaches and provide an outlook on next-generation immunotherapy involving neoantigens and combinatorial therapies in the setting of MSI CRC. PMID:27060000

  2. Altered levels of synapsin I, dopamine transporter, dynorphin A, and neuropeptide Y in the nucleus accumbens and striatum at post-puberty in rats treated neonatally with pregnenolone or DHEA.

    PubMed

    Muneoka, Katsumasa; Iwata, Masaaki; Shirayama, Yukihiko

    2009-10-01

    It is well documented that neonatal neurosteroid administration influences brain development. In our previous studies, administration of pregnenolone, the precursor of neurosteroids, during the neonatal period altered the activity of dopamine (DA) in the striatum. Furthermore, neonatal treatment with pregnenolone or dehydroepiandrosterone (DHEA) increased synapse-related protein synapsin I as well as neuropeptide Y (NPY) in the hippocampus. The present study examined the effects of neonatal treatment with pregnenolone or DHEA on synapsin I, DA transporter (DAT), dynorphin A, and NPY in the striatum and the core and shell of the nucleus accumbens at post-puberty. Administration of pregnenolone or DHEA during the neonatal period increased immunodensity of synapsin I in the dorsomedial or ventrolateral striatum. DAT immunodensity in the striatum and the nucleus accumbens core as well as dynorphin A immunodensity in the nucleus accumbens core were increased in DHEA-treated but not in pregnenolone-treated rats. In addition, the size, but not numbers, of NPY-positive cells in the nucleus accumbens core was increased in pregnenolone- and DHEA-treated rats. The results suggest that neurosteroid levels during the neonatal period have larger impact on synaptic formation, development of DA and NPY systems in the nigrostriatal rather than the mesolimbic pathway.

  3. Alterations in binding site density of dopamine transporter in the striatum, orbitofrontal cortex, and amygdala in early Parkinson's disease: compartment analysis for beta-CFT binding with positron emission tomography.

    PubMed

    Ouchi, Y; Yoshikawa, E; Okada, H; Futatsubashi, M; Sekine, Y; Iyo, M; Sakamoto, M

    1999-05-01

    We investigated changes in the kinetics in the binding of the dopamine transporter probe 2-beta-carbomethoxy-3beta-(4-[11C]fluorophenyl)tropane (beta-CFT) in living brain by compartmental analysis, using positron emission tomography in unmedicated patients with Parkinson's disease (PD) (Hoehn and Yahr stages I-II). With dynamic positron emission tomographic data from 90-minute acquisitions and metabolite-corrected arterial input functions, binding potentials (k3/k4) were calculated by using estimated rate constants (K1 - k4). In this analysis, the magnitude of the distribution volume (K1/k2) measured in the cerebellum, in which specific binding is negligible, was used as a constrained value for fitting in binding regions. Statistics showed that k3/k4 values in the striatum, the orbitofrontal cortex, and the amygdala were significantly lower in PD patients than in normal controls, whereas there were no differences in K1/k2 ratios and structural volumes between the groups. Correlation analysis showed that the putaminal and orbitofrontal binding levels were correlated positively with motor and mentation scores, respectively, of the Unified Parkinson's Disease Rating Scale. These results indicated that not only the striatal but also the orbitofrontal and amygdalar presynaptic dopaminergic functions were altered in early PD. The reductions in these mesocortical/mesolimbic functions might contribute to the mental and behavioral impairment observed in PD.

  4. Hyperspectral imaging fluorescence excitation scanning for detecting colorectal cancer: pilot study

    NASA Astrophysics Data System (ADS)

    Leavesley, Silas J.; Wheeler, Mikayla; Lopez, Carmen; Baker, Thomas; Favreau, Peter F.; Rich, Thomas C.; Rider, Paul F.; Boudreaux, Carole W.

    2016-03-01

    Optical spectroscopy and hyperspectral imaging have shown the theoretical potential to discriminate between cancerous and non-cancerous tissue with high sensitivity and specificity. To date, these techniques have not been able to be effectively translated to endoscope platforms. Hyperspectral imaging of the fluorescence excitation spectrum represents a new technology that may be well-suited for endoscopic implementation. However, the feasibility of detecting differences between normal and cancerous mucosa using fluorescence excitation-scanning hyperspectral imaging has not been evaluated. The objective of this pilot study was to evaluate the changes in the fluorescence excitation spectrum of resected specimen pairs of colorectal adenocarcinoma and normal colorectal mucosa. Patients being treated for colorectal adenocarcinoma were enrolled. Representative adenocarcinoma and normal colonic mucosa specimens were collected from each case. Specimens were flash frozen in liquid nitrogen. Adenocarcinoma was confirmed by histologic evaluation of H&E permanent sections. Hyperspectral image data of the fluorescence excitation of adenocarcinoma and surrounding normal tissue were acquired using a custom microscope configuration previously developed in our lab. Results demonstrated consistent spectral differences between normal and cancerous tissues over the fluorescence excitation spectral range of 390-450 nm. We conclude that fluorescence excitation-scanning hyperspectral imaging may offer an alternative approach for differentiating adenocarcinoma and surrounding normal mucosa of the colon. Future work will focus on expanding the number of specimen pairs analyzed and will utilize fresh tissues where possible, as flash freezing and reconstituting tissues may have altered the autofluorescence properties.

  5. Fast track in colo-rectal surgery. Preliminary experience in a rural hospital

    PubMed Central

    FRONTERA, D.; ARENA, L.; CORSALE, I.; FRANCIOLI, N.; MAMMOLITI, F.; BUCCIANELLI, E.

    2014-01-01

    Background “Fast Track surgery” is a therapeutic program of large application, despite some doubts about its applicability and real validity. Literature review shows that this approach to colo-rectal surgery, particularly video-assisted, can allow a rapid recovery, better performance and a faster postoperative functional autonomy of the work, which can be discharged without cause additional welfare costs; in addition it can be reproducible in different health reality. Purpose To analyze the possibility to apply the Fast Truck protocol in patients undergoing colorectal surgery in a rural hospital and non specialistic Unit of Surgery. Patients and methods We have conducted a prospective, randomized study on 80 patients subjected to colorectal surgery in the last year. Results The protocol was observed in 95% of cases, compliance with the Fast Track was high and general morbidity was limited (7.8%). Conclusion This “aggressive” approach, which has fundamentally altered the usual surgical behavior, seems to allow a mean length of stay significantly lower than in controls (p < 0.05) with positive implications for patients and containment of health care costs, even after discharge (no need for home care in 92% of cases, no early re-admittance to the hospital). Homogeneous protocols are desirable, as well as an increased enrollment, to consolidate these rehabilitation programs in order to provide a reference for all hospitals. PMID:25644732

  6. CCR5 blockage by maraviroc induces cytotoxic and apoptotic effects in colorectal cancer cells.

    PubMed

    Pervaiz, Asim; Ansari, Shariq; Berger, Martin R; Adwan, Hassan

    2015-05-01

    Alterations in the expression of C-C chemokine receptor type 5 (CCR5 or CD195) have been correlated with disease progression in different cancers. Recently, a few investigations have reported the blockage of this receptor by an antagonist (maraviroc) and its antineoplastic effects on tumor cell growth. However, little is known about the mechanistic reasons behind these antineoplastic effects of CCR5 blockage by maraviroc. In this study, we blocked the CCR5 receptor by maraviroc in SW480 and SW620 colorectal cancer cells to study the resulting changes in biological properties and related pathways. This blockage induced significantly reduced proliferation and a profound arrest in G1 phase of the cell cycle. Concomitantly, maraviroc caused significant signs of apoptosis at morphological level. Significant modulation of multiple apoptosis-relevant genes was also noticed at mRNA levels. In addition, we found remarkable increases in cleaved caspases at protein level. These modulations led us to propose a signaling pathway for the observed apoptotic effects. In conclusion, blocking the CCR5 by maraviroc induces significant cytotoxic and apoptotic effects in colorectal cancer cells. Thus, maraviroc can be considered a model compound, which may foster the development of further CCR5 antagonists to be used for the treatment of colorectal cancer.

  7. New Insights into the Mechanism of Action of Aspirin in the Prevention of Colorectal Neoplasia.

    PubMed

    Di Francesco, Luigia; López Contreras, Luilli Antonio; Sacco, Angela; Patrignani, Paola

    2015-01-01

    The results of clinical studies have shown that the chronic administration of aspirin, even at the lowdoses (75-100 mg daily) recommended for the prevention of cardiovascular disease, is associated with a reduction of cancer incidence and mortality, in particular colorectal cancer (CRC). The mechanism of action of aspirin as an antineoplastic agent remains controversial. However, data of clinical pharmacology and several features of the chemopreventive effect of aspirin, emerged from clinical trials, suggest that the antiplatelet effect of aspirin plays a central role in its anticancer effects. In addition to their contribution to tumor metastasis, platelets may play a role in the early phases of tumorigenesis. In response to lifestyle and environment factors, intestinal epithelial damage/ dysfunction may be associated with platelet activation, initially as a mechanism to repair the damage. However, if the platelet response is unconstrained, it may contribute to the development of chronic inflammation. Altogether these events lead to alter the normal functions of intestinal epithelial cells and may translate into cellular transformation through several mechanisms, including the overexpression of cyclooxygenase(COX)-2 and epidermal growth factor receptor (EGFR), which are considered early events in colorectal tumorigenesis. Thus, antiplatelet agents may play a role in the prevention of CRC by modifying epigenetic events involved in early phases of colorectal tumorigenesis. Finally, we carried out a critical review of the literature on off-target mechanisms of aspirin action as anticancer drug. PMID:26369679

  8. Frequent PTPRK-RSPO3 fusions and RNF43 mutations in colorectal traditional serrated adenoma.

    PubMed

    Sekine, Shigeki; Yamashita, Satoshi; Tanabe, Taro; Hashimoto, Taiki; Yoshida, Hiroshi; Taniguchi, Hirokazu; Kojima, Motohiro; Shinmura, Kazuya; Saito, Yutaka; Hiraoka, Nobuyoshi; Ushijima, Toshikazu; Ochiai, Atsushi

    2016-06-01

    The molecular mechanisms underlying the serrated pathway of colorectal tumourigenesis, particularly those related to traditional serrated adenomas (TSAs), are still poorly understood. In this study, we analysed genetic alterations in 188 colorectal polyps, including hyperplastic polyps, sessile serrated adenomas/polyps (SSA/Ps), TSAs, tubular adenomas, and tubulovillous adenomas by using targeted next-generation sequencing and reverse transcription-PCR. Our analyses showed that most TSAs (71%) contained genetic alterations in WNT pathway components. In particular, PTPRK-RSPO3 fusions (31%) and RNF43 mutations (24%) were frequently and almost exclusively observed in TSAs. Consistent with the WNT pathway activation, immunohistochemical analysis showed diffuse and focal nuclear accumulation of β-catenin in 53% and 30% of TSAs, respectively. APC mutations were observed in tubular and tubulovillous adenomas and in a subset of TSAs. BRAF mutations were exclusively and frequently encountered in serrated lesions. KRAS mutations were observed in all types of polyps, but were most commonly encountered in tubulovillous adenomas and TSAs. This study has demonstrated that TSAs frequently harbour genetic alterations that lead to WNT pathway activation, in addition to BRAF and KRAS mutations. In particular, PTPRK-RSPO3 fusions and RNF43 mutations were found to be characteristic genetic features of TSAs. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  9. Frequent PTPRK-RSPO3 fusions and RNF43 mutations in colorectal traditional serrated adenoma.

    PubMed

    Sekine, Shigeki; Yamashita, Satoshi; Tanabe, Taro; Hashimoto, Taiki; Yoshida, Hiroshi; Taniguchi, Hirokazu; Kojima, Motohiro; Shinmura, Kazuya; Saito, Yutaka; Hiraoka, Nobuyoshi; Ushijima, Toshikazu; Ochiai, Atsushi

    2016-06-01

    The molecular mechanisms underlying the serrated pathway of colorectal tumourigenesis, particularly those related to traditional serrated adenomas (TSAs), are still poorly understood. In this study, we analysed genetic alterations in 188 colorectal polyps, including hyperplastic polyps, sessile serrated adenomas/polyps (SSA/Ps), TSAs, tubular adenomas, and tubulovillous adenomas by using targeted next-generation sequencing and reverse transcription-PCR. Our analyses showed that most TSAs (71%) contained genetic alterations in WNT pathway components. In particular, PTPRK-RSPO3 fusions (31%) and RNF43 mutations (24%) were frequently and almost exclusively observed in TSAs. Consistent with the WNT pathway activation, immunohistochemical analysis showed diffuse and focal nuclear accumulation of β-catenin in 53% and 30% of TSAs, respectively. APC mutations were observed in tubular and tubulovillous adenomas and in a subset of TSAs. BRAF mutations were exclusively and frequently encountered in serrated lesions. KRAS mutations were observed in all types of polyps, but were most commonly encountered in tubulovillous adenomas and TSAs. This study has demonstrated that TSAs frequently harbour genetic alterations that lead to WNT pathway activation, in addition to BRAF and KRAS mutations. In particular, PTPRK-RSPO3 fusions and RNF43 mutations were found to be characteristic genetic features of TSAs. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID:26924569

  10. Implementation Intentions and Colorectal Screening

    PubMed Central

    Greiner, K. Allen; Daley, Christine M.; Epp, Aaron; James, Aimee; Yeh, Hung-Wen; Geana, Mugur; Born, Wendi; Engelman, Kimberly K.; Shellhorn, Jeremy; Hester, Christina M.; LeMaster, Joseph; Buckles, Daniel; Ellerbeck, Edward F.

    2015-01-01

    Background Low-income and racial/ethnic minority populations experience disproportionate colorectal cancer (CRC) burden and poorer survival. Novel behavioral strategies are needed to improve screening rates in these groups. Purpose To test a theoretically based “implementation intentions” intervention for improving CRC screening among unscreened adults in urban safety-net clinics. Design Randomized controlled trial. Setting/participants Adults (N=470) aged ≥50 years, due for CRC screening, from urban safety-net clinics were recruited. Intervention The intervention (conducted in 2009–2011) was delivered via touchscreen computers that tailored informational messages to decisional stage and screening barriers. The computer then randomized participants to generic health information on diet and exercise (Comparison group) or “implementation intentions” questions and planning (Experimental group) specific to the CRC screening test chosen (fecal immunochemical test or colonoscopy). Main outcome measures The primary study outcome was completion of CRC screening at 26 weeks based on test reports (analysis conducted in 2012–2013). Results The study population had a mean age of 57 years, and was 42% non-Hispanic African American, 28% non-Hispanic white, and 27% Hispanic. Those receiving the implementation intentions–based intervention had higher odds (AOR=1.83, 95% CI=1.23, 2.73) of completing CRC screening than the Comparison group. Those with higher self-efficacy for screening (AOR=1.57, 95% CI=1.03, 2.39), history of asthma (AOR=2.20, 95% CI=1.26, 3.84), no history of diabetes (AOR=1.86, 95% CI=1.21, 2.86), and reporting they had never heard that “cutting on cancer” makes it spread (AOR=1.78, 95% CI=1.16, 2.72) were more likely to complete CRC screening. Conclusions The results of this study suggest that programs incorporating an implementation intentions approach can contribute to successful completion of CRC screening even among very low-income and

  11. Surgical quality in colorectal cancer

    PubMed Central

    Plummer, Joseph M.; Williams, Nadia; Leake, Pierre-Anthony; Ferron-Boothe, Doreen; Meeks-Aitken, Nicola; Mitchell, Derek I.; McFarlane, Michael E.; East, Jeffery

    2015-01-01

    Objective To determine the quality of surgical management offered to patients with colorectal cancer (CRC) as measured by adequacy of nodal resections and compare variations across the major hospitals in Jamaica. Method Data was obtained from the CRC Registry of patients diagnosed and treated surgically for CRC during the 3-year period commencing January 1, 2011. Variables analyzed included tumor site, stage and number of lymph nodes resected across hospitals. Results During the period under review 60% (349) of 586 patients had resections and formed the basis of this study. Of these 49% were treated at the UHWI, 27% from the KPH and STH, 15% from CRH and MRH and 8% from a private laboratory (DPS). Patient distribution was similar at UHWI compared to the others with mean age (61 vs 62) and with slightly more women having surgery (53% Vs 54%) (UHWI vs Others). For tumor grade, margin status, lymphovascular and depth of invasion (majority T3) there was no difference between UHWI and the other sites, although a smaller percentage of tumors treated at UHWI had Crohn's like reaction (p = 0.01). There was a larger proportion of sigmoid cancer at UHWI while the reverse trend was seen in cancers of the rectum (p = 0.027). The tumors treated at UHWI have a larger median number of regional nodes when compared to the other facilities (14 vs 10; p < 0.001) and also more likely to have positive nodes, as were women and younger patients. Comparison across facilities revealed that the proportion of tumors classed as well differentiated, circumferential margin involvement, and having lymphovascular invasion were higher for specimens processed at the private facility (p = 0.021, 0.035, 0.01 respectively). Histopathology reports of tumors treated at UHWI and DPS had median 14 and 18 nodes respectively while at NPH laboratory and CRH they were 9 and 10 respectively (p < 0.001), whilst those of the ascending, descending, sigmoid colon and rectum had median 15, 11, 13, 11

  12. Genetic amplification of the NOTCH modulator LNX2 upregulates the WNT/β-catenin pathway in colorectal cancer

    PubMed Central

    Camps, Jordi; Pitt, Jason J.; Emons, Georg; Hummon, Amanda B.; Case, Chanelle M.; Grade, Marian; Jones, Tamara L.; Nguyen, Quang T.; Ghadimi, B. Michael; Beissbarth, Tim; Difilippantonio, Michael J.; Caplen, Natasha J.; Ried, Thomas

    2016-01-01

    Chromosomal copy number alterations (aneuploidy) define the genomic landscape of most cancer cells, but identification of the oncogenic drivers behind these imbalances remains an unfinished task. In this study, we conducted a systematic analysis of colorectal carcinomas that integrated genomic copy number changes and gene expression profiles. This analysis revealed 44 highly overexpressed genes mapping to localized amplicons on chromosome 13, gains of which occur often in colorectal cancers. RNAi-mediated silencing identified eight candidates whose loss of function reduced cell viability 20% or more in colorectal cancer cell lines. The functional space of the genes NUPL1, LNX2, POLR1D, POMP, SLC7A1, DIS3, KLF5, and GPR180 was established by global expression profiling after RNAi exposure. One candidate, LNX2, not previously known as an oncogene, was involved in regulating NOTCH signaling. Silencing LNX2 reduced NOTCH levels but also downregulated the transcription factor TCF7L2 and markedly reduced WNT signaling. LNX2 overexpression and chromosome 13 amplification therefore constitutively activates the WNT pathway, offering evidence of an aberrant NOTCH-WNT axis in colorectal cancer. PMID:23319804

  13. Molecular dissection of premalignant colorectal lesions reveals early onset of the CpG island methylator phenotype.

    PubMed

    Yamamoto, Eiichiro; Suzuki, Hiromu; Yamano, Hiro-o; Maruyama, Reo; Nojima, Masanori; Kamimae, Seiko; Sawada, Takeshi; Ashida, Masami; Yoshikawa, Kenjiro; Kimura, Tomoaki; Takagi, Ryo; Harada, Taku; Suzuki, Ryo; Sato, Akiko; Kai, Masahiro; Sasaki, Yasushi; Tokino, Takashi; Sugai, Tamotsu; Imai, Kohzoh; Shinomura, Yasuhisa; Toyota, Minoru

    2012-11-01

    The concept of the CpG island methylator phenotype (CIMP) in colorectal cancer (CRC) is widely accepted, although the timing of its occurrence and its interaction with other genetic defects are not fully understood. Our aim in this study was to unravel the molecular development of CIMP cancers by dissecting their genetic and epigenetic signatures in precancerous and malignant colorectal lesions. We characterized the methylation profile and BRAF/KRAS mutation status in 368 colorectal tissue samples, including precancerous and malignant lesions. In addition, genome-wide copy number aberrations, methylation profiles, and mutations of BRAF, KRAS, TP53, and PIK3CA pathway genes were examined in 84 colorectal lesions. Genome-wide methylation analysis of CpG islands and selected marker genes revealed that CRC precursor lesions are in three methylation subgroups: CIMP-high, CIMP-low, and CIMP-negative. Interestingly, a subset of CIMP-positive malignant lesions exhibited frequent copy number gains on chromosomes 7 and 19 and genetic defects in the AKT/PIK3CA pathway genes. Analysis of mixed lesions containing both precancerous and malignant components revealed that most aberrant methylation is acquired at the precursor stage, whereas copy number aberrations are acquired during the progression from precursor to malignant lesion. Our integrative genomic and epigenetic analysis suggests early onset of CIMP during CRC development and indicates a previously unknown CRC development pathway in which epigenetic instability associates with genomic alterations.

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

    PubMed Central

    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

    2016-01-01

    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. PMID:26892992

  15. Role of the Microbiota in Colorectal Cancer: Updates on Microbial Associations and Therapeutic Implications

    PubMed Central

    Coleman, Olivia I.; Nunes, Tiago

    2016-01-01

    Abstract Genetic, environmental, and dietary factors have been found to influence the development and progression of colorectal cancer (CRC). More recently, accumulating evidence associates the intestinal microbiota with the initiation and progression of this disease. While studies have shown that individuals with CRC display alterations in gut bacterial composition, it remains somewhat unclear whether such differences drive cancer development or whether they are a response to tumorigenesis. In this review, the authors assess new evidence linking the community structure or specific bacterial factors of the intestinal microbiota to CRC development and progression, with insights into therapeutic implications. PMID:27790385

  16. New registry: National Cancer Patient Registry--Colorectal Cancer.

    PubMed

    Wendy, L; Radzi, M

    2008-09-01

    Colorectal cancer is emerging as one of the commonest cancers in Malaysia. Data on colorectal cancer from the National Cancer Registry is very limited. Comprehensive information on all aspects of colorectal cancer, including demographic details, pathology and treatment outcome are needed as the management of colorectal cancer has evolved rapidly over the years involving several disciplines including gastroenterology, surgery, radiology, pathology and oncology. This registry will be an important source of information that can help the development of guidelines to improve colorectal cancer care relevant to this country. The database will initially recruit all colorectal cancer cases from eight hospitals. The data will be stored on a customized web-based case report form. The database has begun collecting data from 1 October 2007 and will report on its first year findings at the end of 2008. PMID:19230248

  17. Endometrial metastasis of colorectal cancer with coincident endometrial adenocarcinoma

    PubMed Central

    Colling, Richard; Lopes, Tito; Das, Nagiindra; Mathew, Joe

    2010-01-01

    Metastasis to the uterine corpus is uncommon and secondary colorectal tumours of the endometrium are rare. We describe a uterine tumour with components of both primary endometrial and metastatic colorectal carcinomata. In this case, a 72-year-old obese woman presented with a 2-week history of postmenopausal bleeding per vaginum and weight loss. She had an abdominoperineal resection 3 years previously for a Dukes stage B rectal carcinoma. A transvaginal ultrasonography showed a thickened endometrium. Histology immunophenotyping showed a CK7+, CK20+, CA125− and CEA+ colorectal metastasis (a profile consistent with her previous cancer) associated with a primary CK7+, CK20−, CA125+ and CEA− endometroid endometrial adenocarcinoma. We conclude this represents endometrial metastasis of colorectal carcinoma with coincident primary endometrial adenocarcinoma. We speculate as to whether the endometrial carcinoma arose de novo or was induced by the colorectal metastasis, or whether the primary endometrial tumour provided a fertile site for the colorectal metastasis. PMID:22791861

  18. New registry: National Cancer Patient Registry--Colorectal Cancer.

    PubMed

    Wendy, L; Radzi, M

    2008-09-01

    Colorectal cancer is emerging as one of the commonest cancers in Malaysia. Data on colorectal cancer from the National Cancer Registry is very limited. Comprehensive information on all aspects of colorectal cancer, including demographic details, pathology and treatment outcome are needed as the management of colorectal cancer has evolved rapidly over the years involving several disciplines including gastroenterology, surgery, radiology, pathology and oncology. This registry will be an important source of information that can help the development of guidelines to improve colorectal cancer care relevant to this country. The database will initially recruit all colorectal cancer cases from eight hospitals. The data will be stored on a customized web-based case report form. The database has begun collecting data from 1 October 2007 and will report on its first year findings at the end of 2008.

  19. Evolving approach and clinical significance of detecting DNA mismatch repair deficiency in colorectal carcinoma

    PubMed Central

    Shia, Jinru

    2016-01-01

    The last two decades have seen significant advancement in our understanding of colorectal tumors with DNA mismatch repair (MMR) deficiency. The ever-emerging revelations of new molecular and genetic alterations in various clinical conditions have necessitated constant refinement of disease terminology and classification. Thus, a case with the clinical condition of hereditary non-polyposis colorectal cancer as defined by the Amsterdam criteria may be one of Lynch syndrome characterized by a germline defect in one of the several MMR genes, one of the yet-to-be-defined “Lynch-like syndrome” if there is evidence of MMR deficiency in the tumor but no detectable germline MMR defect or tumor MLH1 promoter methylation, or “familial colorectal cancer type X” if there is no evidence of MMR deficiency. The detection of these conditions carries significant clinical implications. The detection tools and strategies are constantly evolving. The Bethesda guidelines symbolize a selective approach that uses clinical information and tumor histology as the basis to select high-risk individuals. Such a selective approach has subsequently been found to have limited sensitivity, and is thus gradually giving way to the alternative universal approach that tests all newly diagnosed colorectal cancers. Notably, the universal approach also has its own limitations; its cost-effectiveness in real practice, in particular, remains to be determined. Meanwhile, technological advances such as the next-generation sequencing are offering the promise of direct genetic testing for MMR deficiency at an affordable cost probably in the near future. This article reviews the up-to-date molecular definitions of the various conditions related to MMR deficiency, and discusses the tools and strategies that have been used in detecting these conditions. Special emphasis will be placed on the evolving nature and the clinical importance of the disease definitions and the detection strategies. PMID:25716099

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

    PubMed Central

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

    2016-01-01

    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. PMID:27187454

  1. Evolving approach and clinical significance of detecting DNA mismatch repair deficiency in colorectal carcinoma.

    PubMed

    Shia, Jinru

    2015-09-01

    The last two decades have seen significant advancement in our understanding of colorectal tumors with DNA mismatch repair (MMR) deficiency. The ever-emerging revelations of new molecular and genetic alterations in various clinical conditions have necessitated constant refinement of disease terminology and classification. Thus, a case with the clinical condition of hereditary non-polyposis colorectal cancer as defined by the Amsterdam criteria may be one of Lynch syndrome characterized by a germline defect in one of the several MMR genes, one of the yet-to-be-defined "Lynch-like syndrome" if there is evidence of MMR deficiency in the tumor but no detectable germline MMR defect or tumor MLH1 promoter methylation, or "familial colorectal cancer type X" if there is no evidence of MMR deficiency. The detection of these conditions carries significant clinical implications. The detection tools and strategies are constantly evolving. The Bethesda guidelines symbolize a selective approach that uses clinical information and tumor histology as the basis to select high-risk individuals. Such a selective approach has subsequently been found to have limited sensitivity, and is thus gradually giving way to the alternative universal approach that tests all newly diagnosed colorectal cancers. Notably, the universal approach also has its own limitations; its cost-effectiveness in real practice, in particular, remains to be determined. Meanwhile, technological advances such as the next-generation sequencing are offering the promise of direct genetic testing for MMR deficiency at an affordable cost probably in the near future. This article reviews the up-to-date molecular definitions of the various conditions related to MMR deficiency, and discusses the tools and strategies that have been used in detecting these conditions. Special emphasis will be placed on the evolving nature and the clinical importance of the disease definitions and the detection strategies.

  2. Circulating Non-coding RNA as Biomarkers in Colorectal Cancer.

    PubMed

    Ferracin, Manuela; Lupini, Laura; Mangolini, Alessandra; Negrini, Massimo

    2016-01-01

    Recent studies suggested that colorectal cancer influences the types and quantity of nucleic acids - especially microRNAs - detected in the bloodstream. Concentration of circulating (cell-free) microRNAs, and possibly of other non-coding RNAs, could therefore serve as valuable colorectal cancer biomarker and could deliver insight into the disease process. This chapter addresses the recent discoveries on circulating microRNA and long non-coding RNA as diagnostic or prognostic biomarkers in colorectal cancer. PMID:27573900

  3. RNF43 is frequently mutated in colorectal and endometrial cancers

    PubMed Central

    Giannakis, Marios; Hodis, Eran; Mu, Xinmeng Jasmine; Yamauchi, Mai; Rosenbluh, Joseph; Cibulskis, Kristian; Saksena, Gordon; Lawrence, Michael S.; Qian, ZhiRong; Nishihara, Reiko; Van Allen, Eliezer M.; Hahn, William C.; Gabriel, Stacey B.; Lander, Eric S.; Getz, Gad; Ogino, Shuji; Fuchs, Charles S.; Garraway, Levi A.

    2014-01-01

    We report somatic mutations of RNF43 in over 18% of colorectal adenocarcinomas and endometrial carcinomas. RNF43 encodes an E3 ubiquitin ligase that negatively regulates Wnt signaling. Truncating mutations of RNF43 are more prevalent in microsatellite-unstable tumors and show mutual exclusivity with inactivating APC mutations in colorectal adenocarcinomas. These results indicate that RNF43 is one of the most commonly mutated genes in colorectal and endometrial cancers. PMID:25344691

  4. Serum Vitamin D, Vitamin D Binding Protein, and Risk of Colorectal Cancer

    PubMed Central

    Anic, Gabriella M.; Weinstein, Stephanie J.; Mondul, Alison M.; Männistö, Satu; Albanes, Demetrius

    2014-01-01

    Background We previously reported a positive association between serum 25-hydroxyvitamin D (25(OH)D) and colorectal cancer risk. To further elucidate this association, we examined the molar ratio of 25(OH)D to vitamin D binding protein (DBP), the primary 25(OH)D transport protein, and whether DBP modified the association between 25(OH)D and colorectal cancer risk. Methods In a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, controls were 1∶1 matched to 416 colorectal cancer cases based on age and date of blood collection. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) for quartiles of 25(OH)D, DBP, and the molar ratio of 25(OH)D:DBP, a proxy for free, unbound circulating 25(OH)D. Results Comparing highest to lowest quartiles, DBP was not associated with colorectal cancer risk (OR = 0.91; 95% CI: 0.58, 1.42, p for trend  = 0.58); however, a positive risk association was observed for the molar ratio of 25(OH)D:DBP (OR = 1.44; 95% CI: 0.92, 2.26, p for trend  = 0.04). In stratified analyses, the positive association between 25(OH)D and colorectal cancer was stronger among men with DBP levels above the median (OR = 1.89; 95% CI: 1.07, 3.36, p for trend  = 0.01) than below the median (OR = 1.20; 95% CI: 0.68, 2.12, p for trend  = 0.87), although the interaction was not statistically significant (p for interaction  = 0.24). Conclusion Circulating DBP may influence the association between 25(OH)D and colorectal cancer in male smokers, with the suggestion of a stronger positive association in men with higher DBP concentrations. This finding should be examined in other populations, especially those that include women and non-smokers. PMID:25036524

  5. Comparison of T-cell receptor repertoire restriction in blood and tumor tissue of colorectal cancer patients

    PubMed Central

    2010-01-01

    Several immunotherapeutic approaches rely on antigen-specific T-cells. Restrictions in the T-cell receptor (TCR) repertoire were reported as indicator of anti-tumor cytotoxic T-lymphocyte (CTL) response in various tumor entities. It is unclear yet whether a TCR restriction in peripheral blood mirrors the tumor compartment. We compared the expression of TCR Vβ-families for the quantification of TCR repertoire alterations in blood and tissue samples from patients with colorectal carcinoma. Blood samples from patients with colorectal carcinoma and healthy volunteers and tissue samples of normal colonic mucosa and colorectal carcinoma were analyzed. Relative Vβ-family quantification was performed based on quantitative reverse transcribed PCR. Standard deviation and average mean of the single families were determined. Two variables describing the degree of Vβ-repertoire restriction were defined. Forty-eight blood samples and 37 tissue samples were analyzed. TCR repertoire restriction was higher in blood of tumor patients than in blood of healthy controls (p < 0.05). No difference in the degree of TCR repertoire restriction was found between carcinoma and unaffected colon tissue. We found no corresponding elevated TCR families among the different compartments blood, normal colon, and carcinoma tissue of the same patient. In conclusion, we observed a repertoire restriction in peripheral blood as well as in tumor tissue of cancer patients. However, in tumor tissue, repertoire alterations were comparable to normal mucosa, suggesting compartment-specific TCR distribution rather than alterations due to tumor-T-cell interaction questioning the presence of highly restricted clonal T-cell expansions in colorectal cancer as they have been described in other, assumingly more immunogenic tumor entities. PMID:20385014

  6. An in vivo molecular response analysis of colorectal cancer treated with Astragalus membranaceus extract

    PubMed Central

    TSENG, AILUN; YANG, CHIH-HSUEH; CHEN, CHIH-HAO; CHEN, CHANG-HAN; HSU, SHIH-LAN; LEE, MEI-HSIEN; LEE, HOONG-CHIEN; SU, LI-JEN

    2016-01-01

    The fact that many chemotherapeutic drugs cause chemoresistance and side effects during the course of colorectal cancer treatment necessitates development of novel cytotoxic agents aiming to attenuate new molecular targets. Here, we show that Astragalus membranaceus (Fischer) Bge. var. mongolicus (Bge.) Hsiao (AM), a traditional Chinese medicine, can inhibit tumor growth in vivo and elucidate the underlying molecular mechanisms. The antitumor effect of AM was assessed on the subcutaneous tumors of human colorectal cancer cell line HCT116 grafted into nude mice. The mice were treated with either water or 500 mg/kg AM once per day, before being sacrificed for extraction of tumors, which were then subjected to microarray expression profiling. The gene expression of the extraction was then profiled using microarray analysis. The identified genes differentially expressed between treated mice and controls reveal that administration of AM suppresses chromosome organization, histone modification, and regulation of macromolecule metabolic process. A separate analysis focused on differentially expressed microRNAs revealing involvement of macromolecule metabolism, and intracellular transport, as well as several cancer signaling pathways. For validation, the input of the identified genes to The Library of Integrated Network-based Cellular Signatures led to many chemopreventive agents of natural origin that produce similar gene expression profiles to that of AM. The demonstrated effectiveness of AM suggests a potential therapeutic drug for colorectal cancer. PMID:26719057

  7. MicroRNA-224 is associated with colorectal cancer progression and response to 5-fluorouracil-based chemotherapy by KRAS-dependent and -independent mechanisms

    PubMed Central

    Amankwatia, E B; Chakravarty, P; Carey, F A; Weidlich, S; Steele, R J C; Munro, A J; Wolf, C R; Smith, G

    2015-01-01

    Background: Colorectal cancers arise from benign adenomas, although not all adenomas progress to cancer and there are marked interpatient differences in disease progression. We have previously associated KRAS mutations with disease progression and reduced survival in colorectal cancer patients. Methods: We used TaqMan low-density array (TLDA) qRT–PCR analysis to identify miRNAs differentially expressed in normal colorectal mucosa, adenomas and cancers and in isogeneic KRAS WT and mutant HCT116 cells, and used a variety of phenotypic assays to assess the influence of miRNA expression on KRAS activity, chemosensitivity, proliferation and invasion. Results: MicroRNA-224 was differentially expressed in dysplastic colorectal disease and in isogeneic KRAS WT and mutant HCT116 cells. Antagomir-mediated miR-224 silencing in HCT116 KRAS WT cells phenocopied KRAS mutation, increased KRAS activity and ERK and AKT phosphorylation. 5-FU chemosensitivity was significantly increased in miR-224 knockdown cells, and in NIH3T3 cells expressing KRAS and BRAF mutant proteins. Bioinformatics analysis of predicted miR-224 target genes predicted altered cell proliferation, invasion and epithelial–mesenchymal transition (EMT) phenotypes that were experimentally confirmed in miR-224 knockdown cells. Conclusions: We describe a novel mechanism of KRAS regulation, and highlight the clinical utility of colorectal cancer-specific miRNAs as disease progression or clinical response biomarkers. PMID:25919696

  8. AQP1 expression alterations affect morphology and water transport in Schwann cells and hypoxia-induced up-regulation of AQP1 occurs in a HIF-1α-dependent manner.

    PubMed

    Zhang, J; Xiong, Y; Lu, L X; Wang, H; Zhang, Y F; Fang, F; Song, Y L; Jiang, H

    2013-11-12

    Aquaporin-1 (AQP1) is the principle water channel in the peripheral nervous system (PNS) and is specifically localized to Schwann cells in the PNS. However, the pathophysiological role of AQP1 in peripheral nerves is poorly understood. Here, we utilized RNA interference by lentiviral transduction to specifically down-regulate AQP1 expression and a lentiviral overexpression protocol to up-regulate AQP1 expression, in primary Schwann cell cultures. AQP1 gene silencing resulted in a cell shrinkage phenotype, while AQP1 gene overexpression caused a cell swelling phenotype, as validated by cell volume determinations. Secondly, we utilized an in vitro hypoxia model in Schwann cells to mimic in vivo facial nerve injury. We demonstrated that AQP1 expression was induced within 8h following hypoxia injury in vitro, and that AQP1 knockdown (KD) caused the cells to resist edema following hypoxia. Finally, we investigated the hypoxic regulation of the AQP1 gene, as well as the involvement of Hypoxia-inducible factor-1α (HIF-1α) in AQP1 modulation and we found that KD of HIF-1α decreased hypoxia-dependent induction of endogenous AQP1 expression at both the mRNA and protein levels. Taken together, these results indicate that (1) AQP1 is an important factor responsible for the fast water transport of cultured Schwann cells and is involved in cell plasticity; (2) AQP1 alterations may be a primary factor in hypoxia-induced peripheral nerve edema; (3) HIF-1α participates in the hypoxic induction of the AQP1 gene; (4) AQP1 inhibition might provide a new therapeutic alternative for the treatment of some forms of peripheral nerve edema.

  9. Gut Microbiota, Inflammation, and Colorectal Cancer.

    PubMed

    Brennan, Caitlin A; Garrett, Wendy S

    2016-09-01

    Colorectal cancer is the second-leading cause of cancer-related deaths in the United States and fourth-leading cause of cancer-related deaths worldwide. While cancer is largely considered to be a disease of genetic and environmental factors, increasing evidence has demonstrated a role for the microbiota (the microorganisms associated with the human body) in shaping inflammatory environments and promoting tumor growth and spread. Herein, we discuss both human data from meta'omics analyses and data from mechanistic studies in cell culture and animal models that support specific bacterial agents as potentiators of tumorigenesis-including Fusobacterium nucleatum, enterotoxigenic Bacteroides fragilis, and colibactin-producing Escherichia coli. Further, we consider how microbes can be used in diagnosing colorectal cancer and manipulating the tumor environment to encourage better patient outcomes in response to immunotherapy treatments. PMID:27607555

  10. BRAF Mutation in Colorectal Cancer: An Update

    PubMed Central

    Barras, David

    2015-01-01

    Colorectal cancer (CRC) is still one of the deadliest cancer-related diseases. About 10% of CRC patients are characterized by a mutation in the B-Raf proto-oncogene serine/threonine kinase (BRAF) gene resulting in a valine-to-glutamate change at the residue 600 (V600E). This mutation is also present in more than 60% of melanoma patients. BRAF inhibitors were developed and found to improve patient survival; however, most patients at the end of the track ultimately develop resistance to these inhibitors. Melanoma patients benefit from the combination of BRAF inhibitors with mitogen/extracellular signal-regulated kinase (MEK) inhibitors, among others. Unfortunately, colorectal patients do not respond much efficiently, which suggests different resistance mechanisms between the two cancer types. This review aims at shedding light on recent discoveries that improve our understanding of the BRAF mutation biology in CRC. PMID:26396549

  11. Plasminogen activators in human colorectal neoplasia.

    PubMed Central

    Gelister, J S; Mahmoud, M; Lewin, M R; Gaffney, P J; Boulos, P B

    1986-01-01

    A crucial step in the transition from adenomatous polyp to invasive colorectal cancer is the degradation of the epithelial basement membrane. Plasminogen activators may play a part in regulating the extracellular protease environment necessary for this to occur. Both functional and antigenic activity of the two principal activators of plasminogen, tissue plasminogen activator and urokinase, were measured in 30 colorectal cancers, matched samples of mucosa, and eight adenomatous polyps. Both polyps (p less than 0.01) and carcinomas (p less than 0.001) had raised urokinase activities compared with normal mucosa, the activity being highest in the carcinomas. Activity of tissue plasminogen activator, however, was diminished in both polyps (p less than 0.01) and carcinomas (p less than 0.001) compared with normal mucosa, the values being lowest in carcinomas. Plasmin generation by urokinase--in contrast with tissue plasminogen activator--is fibrin independent and thus less subject to physiological control. Images p730-a PMID:3094628

  12. Endoscopic submucosal dissection for colorectal neoplasms

    PubMed Central

    Takamaru, Hiroyuki; Mori, Genki; Yamada, Masayoshi; Kinjo, Yuzuru; So, Eriko; Abe, Seiichiro; Otake, Yosuke; Nakajima, Takeshi; Matsuda, Takahisa; Saito, Yutaka

    2014-01-01

    Endoscopic submucosal dissection (ESD) is an established therapeutic technique for the treatment of gastrointestinal neoplasms. Because it is typically completed as en bloc resection, this technique provides a complete specimen for precise pathological evaluation. On the other hand, ESD is not as widely applied in treating colorectal neoplasms as with gastric cancers, due to its technical difficulty, longer procedure time, and increased risk of perforation. However, some devices that facilitate ESD and improve the safety of the procedure have been recently reported, and the use of the technique has gradually spread worldwide. Endoscopists who begin to perform ESD need to recognize the indications of ESD, the technical issue involved in this procedure, and its associated complications. This review outlines the methods and certain types of devices used for colorectal ESD. PMID:25333002

  13. Biomarkers for colitis-associated colorectal cancer.

    PubMed

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

    2016-09-21

    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

  14. Biomarkers for colitis-associated colorectal cancer

    PubMed Central

    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

  15. Biomarkers for colitis-associated colorectal cancer

    PubMed Central

    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.

  16. What's new in hereditary colorectal cancer?

    PubMed

    Jass, Jeremy R

    2005-11-01

    Precancerous polyposes other than classic familial adenomatous polyposis and the condition hereditary nonpolyposis colorectal cancer, or Lynch syndrome, continue to present major diagnostic challenges for the anatomic pathologist. This editorial highlights the practical significance of novel insights and clinical guidelines in the recent literature, as well as in 4 contributions to this edition of the Archives of Pathology & Laboratory Medicine. The first section will address attenuated familial adenomatous polyposis and a newly recognized type of autosomal-recessive adenomatous polyposis associated with the DNA repair gene MYH. The remainder of the editorial discusses the role of the revised Bethesda guidelines in the diagnosis of hereditary nonpolyposis colorectal cancer and concludes with the recently identified serrated pathway syndrome.

  17. Television watching and risk of colorectal adenoma

    PubMed Central

    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) and 95% confidence intervals (CIs). Results: 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. Conclusions: Prolonged TV viewing is associated with modest increased risk of colorectal adenoma independent of leisure-time physical activity and minimally mediated by obesity. PMID:25590667

  18. N-glycosylation of Colorectal Cancer Tissues

    PubMed Central

    Balog, Crina I. A.; Stavenhagen, Kathrin; Fung, Wesley L. J.; Koeleman, Carolien A.; McDonnell, Liam A.; Verhoeven, Aswin; Mesker, Wilma E.; Tollenaar, Rob A. E. M.; Deelder, André M.; Wuhrer, Manfred

    2012-01-01

    Colorectal cancer is the third most common cancer worldwide with an annual incidence of ∼1 million cases and an annual mortality rate of ∼655,000 individuals. There is an urgent need for identifying novel targets to develop more sensitive, reliable, and specific tests for early stage detection of colon cancer. Post-translational modifications are known to play an important role in cancer progression and immune surveillance of tumors. In the present study, we compared the N-glycan profiles from 13 colorectal cancer tumor tissues and corresponding control colon tissues. The N-glycans were enzymatically released, purified, and labeled with 2-aminobenzoic acid. Aliquots were profiled by hydrophilic interaction liquid chromatography (HILIC-HPLC) with fluorescence detection and by negative mode MALDI-TOF-MS. Using partial least squares discriminant analysis to investigate the N-glycosylation changes in colorectal cancer, an excellent separation and prediction ability were observed for both HILIC-HPLC and MALDI-TOF-MS data. For structure elucidation, information from positive mode ESI-ion trap-MS/MS and negative mode MALDI-TOF/TOF-MS was combined. Among the features with a high separation power, structures containing a bisecting GlcNAc were found to be decreased in the tumor, whereas sulfated glycans, paucimannosidic glycans, and glycans containing a sialylated Lewis type epitope were shown to be increased in tumor tissues. In addition, core-fucosylated high mannose N-glycans were detected in tumor samples. In conclusion, the combination of HILIC and MALDI-TOF-MS profiling of N-glycans with multivariate statistical analysis demonstrated its potential for identifying N-glycosylation changes in colorectal cancer tissues and provided new leads that might be used as candidate biomarkers. PMID:22573871

  19. Incidence of colorectal neoplasms among male pilots

    PubMed Central

    Moshkowitz, Menachem; Toledano, Ohad; Galazan, Lior; Hallak, Aharon; Arber, Nadir; Santo, Erwin

    2014-01-01

    AIM: To assess the prevalence of colorectal neoplasms (adenomas, advanced adenomas and colorectal cancers) among Israeli military and commercial airline pilots. METHODS: Initial screening colonoscopy was performed on average-risk (no symptoms and no family history) airline pilots at the Integrated Cancer Prevention Center (ICPC) in the Tel-Aviv Medical Center. Visualized polyps were excised and sent for pathological examination. Advanced adenoma was defined as a lesion >10 mm in diameter, with high-grade dysplasia or villous histology. The results were compared with those of an age- and gender-matched random sample of healthy adults undergoing routine screening at the ICPC. RESULTS: There were 270 pilots (mean age 55.2 ± 7.4 years) and 1150 controls (mean age 55.7 ± 7.8 years). The prevalence of colorectal neoplasms was 15.9% among the pilots and 20.6% among the controls (P = 0.097, χ2 test). There were significantly more hyperplastic polyps among pilots (15.5% vs 9.4%, P = 0.004) and a trend towards fewer adenomas (14.8% vs 20.3% P = 0.06). The prevalence of advanced lesions among pilots and control groups was 5.9% and 4.7%, respectively (P = 0.49), and the prevalence of cancer was 0.7% and 0.69%, respectively (P = 0.93). CONCLUSION: There tends to be a lower colorectal adenoma, advanced adenoma and cancer prevalence but a higher hyperplastic polyp prevalence among pilots than the general population. PMID:25083084

  20. Colorectal Cancer with Uncommon Metastatic Spread

    PubMed Central

    Dellavedova, Luca; Calcagno, Anna; Roncoroni, Lucia; Maffioli, Lorenzo Stefano

    2015-01-01

    The prevalence of bone metastases from colorectal cancer (CRC) is quite low and the presence of isolated osseous metastases at the time of diagnosis or the onset of bone metastases without other organ involvement during follow-up is even lower. Here, we present an interesting case of diffuse skeletal metastases from CRC in which both the atypical presentation of the metastatic spread and the presence of infective comorbidities created some troubles in getting the final diagnosis. PMID:26420997

  1. Future of Minimally Invasive Colorectal Surgery.

    PubMed

    Whealon, Matthew; Vinci, Alessio; Pigazzi, Alessio

    2016-09-01

    Minimally invasive surgery is slowly taking over as the preferred operative approach for colorectal diseases. However, many of the procedures remain technically difficult. This article will give an overview of the state of minimally invasive surgery and the many advances that have been made over the last two decades. Specifically, we discuss the introduction of the robotic platform and some of its benefits and limitations. We also describe some newer techniques related to robotics. PMID:27582647

  2. Colorectal cancer risk in hamartomatous polyposis syndromes

    PubMed Central

    Campos, Fábio Guilherme; Figueiredo, Marleny Novaes; Martinez, Carlos Augusto Real

    2015-01-01

    Colorectal cancer (CRC) is a major cause of morbidity and mortality around the world, and approximately 5% of them develop in a context of inherited mutations leading to some form of familial colon cancer syndromes. Recognition and characterization of these patients have contributed to elucidate the genetic basis of CRC. Polyposis Syndromes may be categorized by the predominant histological structure found within the polyps. The aim of the present paper is to review the most important clinical features of the Hamartomatous Polyposis Syndromes, a rare group of genetic disorders formed by the peutz-Jeghers syndrome, juvenil polyposis syndrome and PTEN Hamartoma Tumor Syndrome (Bannayan-Riley-Ruvalacaba and Cowden Syndromes). A literature search was performed in order to retrieve the most recent and important papers (articles, reviews, clinical cases and clinical guidelines) regarding the studied subject. We searched for terms such as “hamartomatous polyposis syndromes”, “Peutz-Jeghers syndrome”, “juvenile polyposis syndrome”, “juvenile polyp”, and “PTEN hamartoma tumour syndrome” (Cowden syndrome, Bananyan-Riley-Ruvalcaba). The present article reports the wide spectrum of disease severity and extraintestinal manifestations, with a special focus on their potential to develop colorectal and other neoplasia. In the literature, the reported colorectal cancer risk for Juvenile Polyposis, Peutz-Jeghers and PTEN Hamartoma Tumor Syndromes are 39%-68%, 39%-57% and 18%, respectively. A review regarding cancer surveillance recommendations is also presented. PMID:25848489

  3. Colorectal cancer risk in hamartomatous polyposis syndromes.

    PubMed

    Campos, Fábio Guilherme; Figueiredo, Marleny Novaes; Martinez, Carlos Augusto Real

    2015-03-27

    Colorectal cancer (CRC) is a major cause of morbidity and mortality around the world, and approximately 5% of them develop in a context of inherited mutations leading to some form of familial colon cancer syndromes. Recognition and characterization of these patients have contributed to elucidate the genetic basis of CRC. Polyposis Syndromes may be categorized by the predominant histological structure found within the polyps. The aim of the present paper is to review the most important clinical features of the Hamartomatous Polyposis Syndromes, a rare group of genetic disorders formed by the peutz-Jeghers syndrome, juvenil polyposis syndrome and PTEN Hamartoma Tumor Syndrome (Bannayan-Riley-Ruvalacaba and Cowden Syndromes). A literature search was performed in order to retrieve the most recent and important papers (articles, reviews, clinical cases and clinical guidelines) regarding the studied subject. We searched for terms such as "hamartomatous polyposis syndromes", "Peutz-Jeghers syndrome", "juvenile polyposis syndrome", "juvenile polyp", and "PTEN hamartoma tumour syndrome" (Cowden syndrome, Bananyan-Riley-Ruvalcaba). The present article reports the wide spectrum of disease severity and extraintestinal manifestations, with a special focus on their potential to develop colorectal and other neoplasia. In the literature, the reported colorectal cancer risk for Juvenile Polyposis, Peutz-Jeghers and PTEN Hamartoma Tumor Syndromes are 39%-68%, 39%-57% and 18%, respectively. A review regarding cancer surveillance recommendations is also presented.

  4. Circulating tumor cells in colorectal cancer patients.

    PubMed

    Torino, Francesco; Bonmassar, Enzo; Bonmassar, Laura; De Vecchis, Liana; Barnabei, Agnese; Zuppi, Cecilia; Capoluongo, Ettore; Aquino, Angelo

    2013-11-01

    The availability of sensitive methods has allowed the detailed study of circulating tumor cells only recently. Evolving evidence support the prognostic and predictive role of these cells in patients affected by several solid tumors, including colorectal cancer. Ongoing studies are aimed at confirming that the molecular characterization of circulating tumor cells in peripheral blood and in bone marrow of patients is a powerful tool to improve the patient risk-stratification, to monitor activity of the drugs, to develop more appropriate targeted therapies and tailored treatments. In parallel, results from these correlative studies promise to gain a better biological understanding of the metastatic process. The clinical utility of the detection of circulating tumor cells in patients affected by colorectal cancer is still hampered by a number of specific hurdles. Improvement in sensitivity and specificity of the available methods of detection, standardization of these methods and functional characterization of circulating tumor cells in well designed and statistically well powered studies are the key steps to reach these ambitious objectives in colorectal cancer patients as well.

  5. Colorectal cancer screening with virtual colonoscopy

    NASA Astrophysics Data System (ADS)

    Ge, Yaorong; Vining, David J.; Ahn, David K.; Stelts, David R.

    1999-05-01

    Early detection and removal of colorectal polyps have been proven to reduce mortality from colorectal carcinoma (CRC), the second leading cause of cancer deaths in the United States. Unfortunately, traditional techniques for CRC examination (i.e., barium enema, sigmoidoscopy, and colonoscopy) are unsuitable for mass screening because of either low accuracy or poor public acceptance, costs, and risks. Virtual colonoscopy (VC) is a minimally invasive alternative that is based on tomographic scanning of the colon. After a patient's bowel is optimally cleansed and distended with gas, a fast tomographic scan, typically helical computed tomography (CT), of the abdomen is performed during a single breath-hold acquisition. Two-dimensional (2D) slices and three-dimensional (3D) rendered views of the colon lumen generated from the tomographic data are then examined for colorectal polyps. Recent clinical studies conducted at several institutions including ours have shown great potential for this technology to be an effective CRC screening tool. In this paper, we describe new methods to improve bowel preparation, colon lumen visualization, colon segmentation, and polyp detection. Our initial results show that VC with the new bowel preparation and imaging protocol is capable of achieving accuracy comparable to conventional colonoscopy and our new algorithms for image analysis contribute to increased accuracy and efficiency in VC examinations.

  6. Implications of preoperative hypoalbuminemia in colorectal surgery

    PubMed Central

    Truong, Adam; Hanna, Mark H; Moghadamyeghaneh, Zhobin; Stamos, Michael J

    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 colorectal surgical patients, hypoalbuminemia significantly increases the length of hospital stay, rates of surgical site infections, enterocutaneous fistula risk, and deep vein thrombosis formation. The delay of surgical procedures to allow for preoperative correction of albumin levels in hypoalbuminemic patients has been shown to improve the morbidity and mortality in patients with severe nutritional risk. The importance of preoperative albumin levels and the patient’s chronic inflammatory state on the postoperative morbidity and mortality has led to the development of a variety of surgical scoring systems to predict outcomes efficiently. This review attempts to provide a systematic overview of albumin and its role and implications in colorectal surgery. PMID:27231513

  7. Implications of preoperative hypoalbuminemia in colorectal surgery.

    PubMed

    Truong, Adam; Hanna, Mark H; Moghadamyeghaneh, Zhobin; Stamos, Michael J

    2016-05-27

    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 colorectal surgical patients, hypoalbuminemia significantly increases the length of hospital stay, rates of surgical site infections, enterocutaneous fistula risk, and deep vein thrombosis formation. The delay of surgical procedures to allow for preoperative correction of albumin levels in hypoalbuminemic patients has been shown to improve the morbidity and mortality in patients with severe nutritional risk. The importance of preoperative albumin levels and the patient's chronic inflammatory state on the postoperative morbidity and mortality has led to the development of a variety of surgical scoring systems to predict outcomes efficiently. This review attempts to provide a systematic overview of albumin and its role and implications in colorectal surgery. PMID:27231513

  8. TNIK inhibition abrogates colorectal cancer stemness

    PubMed Central

    Masuda, Mari; Uno, Yuko; Ohbayashi, Naomi; Ohata, Hirokazu; Mimata, Ayako; Kukimoto-Niino, Mutsuko; Moriyama, Hideki; Kashimoto, Shigeki; Inoue, Tomoko; Goto, Naoko; Okamoto, Koji; Shirouzu, Mikako; Sawa, Masaaki; Yamada, Tesshi

    2016-01-01

    Canonical Wnt/β-catenin signalling is essential for maintaining intestinal stem cells, and its constitutive activation has been implicated in colorectal carcinogenesis. We and others have previously identified Traf2- and Nck-interacting kinase (TNIK) as an essential regulatory component of the T-cell factor-4 and β-catenin transcriptional complex. Consistent with this, Tnik-deficient mice are resistant to azoxymethane-induced colon tumorigenesis, and Tnik−/−/Apcmin/+ mutant mice develop significantly fewer intestinal tumours. Here we report the first orally available small-molecule TNIK inhibitor, NCB-0846, having anti-Wnt activity. X-ray co-crystal structure analysis reveals that NCB-0846 binds to TNIK in an inactive conformation, and this binding mode seems to be essential for Wnt inhibition. NCB-0846 suppresses Wnt-driven intestinal tumorigenesis in Apcmin/+ mice and the sphere- and tumour-forming activities of colorectal cancer cells. TNIK is required for the tumour-initiating function of colorectal cancer stem cells. Its inhibition is a promising therapeutic approach. PMID:27562646

  9. TNIK inhibition abrogates colorectal cancer stemness.

    PubMed

    Masuda, Mari; Uno, Yuko; Ohbayashi, Naomi; Ohata, Hirokazu; Mimata, Ayako; Kukimoto-Niino, Mutsuko; Moriyama, Hideki; Kashimoto, Shigeki; Inoue, Tomoko; Goto, Naoko; Okamoto, Koji; Shirouzu, Mikako; Sawa, Masaaki; Yamada, Tesshi

    2016-01-01

    Canonical Wnt/β-catenin signalling is essential for maintaining intestinal stem cells, and its constitutive activation has been implicated in colorectal carcinogenesis. We and others have previously identified Traf2- and Nck-interacting kinase (TNIK) as an essential regulatory component of the T-cell factor-4 and β-catenin transcriptional complex. Consistent with this, Tnik-deficient mice are resistant to azoxymethane-induced colon tumorigenesis, and Tnik(-/-)/Apc(min/+) mutant mice develop significantly fewer intestinal tumours. Here we report the first orally available small-molecule TNIK inhibitor, NCB-0846, having anti-Wnt activity. X-ray co-crystal structure analysis reveals that NCB-0846 binds to TNIK in an inactive conformation, and this binding mode seems to be essential for Wnt inhibition. NCB-0846 suppresses Wnt-driven intestinal tumorigenesis in Apc(min/+) mice and the sphere- and tumour-forming activities of colorectal cancer cells. TNIK is required for the tumour-initiating function of colorectal cancer stem cells. Its inhibition is a promising therapeutic approach. PMID:27562646

  10. Hyperplastic polyposis: association with colorectal cancer.

    PubMed

    Leggett, B A; Devereaux, B; Biden, K; Searle, J; Young, J; Jass, J

    2001-02-01

    Hyperplastic polyposis is a loosely defined syndrome initially thought not to confer a clinically important predisposition to colorectal cancer. The aim of the current study was to examine the clinical, histologic, and molecular features of a prospective series of cases meeting a strict definition of the condition. Twelve patients were identified, seven of whom had developed colorectal cancer. Most polyps were hyperplastic, but 11 patients also had polyps containing dysplasia as either serrated adenomas. mixed polyps, or traditional adenomas. The mean percentage of dysplastic polyps in patients with cancer was 35%, and in patients without cancer, 11% (p < 0.05). Microsatellite instability (MSI) was present in 3 of 47 hyperplastic polyps and two of eight serrated adenomas. Kras was mutated in 8 of 47 hyperplastic polyps and two of eight serrated adenomas. No polyps showed loss of heterozygosity of chromosomes 5q, 1p, or 18q. Two of seven cancers showed a high level of MSI. It is concluded that hyperplastic polyposis is associated with a high risk of colorectal cancer. Hyperplastic polyps are the dominant type of polyp, but most cases have some dysplastic epithelium. A higher proportion of dysplastic polyps is associated with increased cancer risk. Clonal genetic changes are observed in some hyperplastic polyps and serrated adenomas.

  11. Treatment of colorectal cancer in the elderly

    PubMed Central

    Millan, Monica; Merino, Sandra; Caro, Aleidis; Feliu, Francesc; Escuder, Jordi; Francesch, Tani

    2015-01-01

    Colorectal cancer has a high incidence, and approximately 60% of colorectal cancer patients are older than 70, with this incidence likely increasing in the near future. Elderly patients (> 70-75 years of age) are a very heterogeneous group, ranging from the very fit to the very frail. Traditionally, these patients have often been under-treated and recruited less frequently to clinical trials than younger patients, and thus are under-represented in publications about cancer treatment. Recent studies suggest that fit elderly patients can be treated in the same way as their younger counterparts, but the treatment of frail patients with comorbidities is still a matter of controversy. Many factors should be taken into account, including fitness for treatment, the wishes of the patient and family, and quality of life. This review will focus on the existing evidence for surgical, oncologic, and palliative treatment in patients over 70 years old with colorectal cancer. Careful patient assessment is necessary in order to individualize treatment approach, and this should rely on a multidisciplinary process. More well-designed controlled trials are needed in this patient population. PMID:26483875

  12. Therapeutic strategy in unresectable metastatic colorectal cancer

    PubMed Central

    Tournigand, Christophe; André, Thierry; de Gramont, Aimery

    2012-01-01

    While surgery is the cornerstone treatment for early-stage colorectal cancer, chemotherapy is the first treatment option for metastatic disease when tumor lesions are frequently not fully resectable at presentation. Mortality from colon cancer has decreased over the past 30 years, but there is still a huge heterogeneity in survival rates that can be mainly explained by patient and tumor characteristics, host response factors, and treatment modalities. The management of unresectable metastatic colorectal cancer is a global treatment strategy, which applies several lines of therapy, salvage surgery, maintenance, and treatment-free intervals. The individualization of cancer treatment is based on the evaluation of prognostic factors for survival (serum lactate dehydrogenase level, performance status), and predictive factors for treatment efficacy [Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation status]. The available treatment modalities for metastatic colorectal cancer are chemotherapy (fluoropyrimidine, oxaliplatin, irinotecan), anti-angiogenic agents (e.g. bevacizumab), and anti-epidermal growth factor agents (cetuximab, panitumumab). The increasing number of active compounds dictates the strategy of trials evaluating these treatments either in combination or sequentially. Alternative outcomes that can be measured earlier than overall survival are needed to shorten the duration and reduce the size and cost of clinical trials. PMID:22423266

  13. 75 FR 58016 - Consensus Standards, Standard Practice for Design, Alteration, and Certification of Airplane...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-23

    ... TRANSPORTATION Federal Aviation Administration Consensus Standards, Standard Practice for Design, Alteration, and...-07 Standard Practice for Design, Alteration, and Certification of Airplane Electrical Wiring Systems... design, alteration, and certification of electrical wiring systems for normal, utility, acrobatic,...

  14. COLORECTAL CANCER SCREENING PRACTICES AMONG THREE AMERICAN INDIAN COMMUNITIES IN MINNESOTA.

    PubMed

    Filippi, Melissa K; Perdue, David G; Hester, Christina; Cully, Angelia; Cully, Lance; Greiner, K Allen; Daley, Christine M

    2016-01-01

    Colorectal cancer (CRC) is a leading cause of cancer morbidity and mortality. Effective prevention and early detection may be achieved through screening, but screening rates are low, especially in American Indian (AI) populations. We wanted to understand perceptions of CRC screening among AI located in the Great Lakes region. Focus groups were recorded and transcribed verbatim (N = 45). Data were analyzed using qualitative text analysis. Themes that deterred CRC screening were low CRC knowledge, fear of the procedure and results, cost and transportation issues, and a lack of quality and competent care. Suggestions for improvement included outreach efforts and culturally-tailored teaching materials.

  15. COLORECTAL CANCER SCREENING PRACTICES AMONG THREE AMERICAN INDIAN COMMUNITIES IN MINNESOTA.

    PubMed

    Filippi, Melissa K; Perdue, David G; Hester, Christina; Cully, Angelia; Cully, Lance; Greiner, K Allen; Daley, Christine M

    2016-01-01

    Colorectal cancer (CRC) is a leading cause of cancer morbidity and mortality. Effective prevention and early detection may be achieved through screening, but screening rates are low, especially in American Indian (AI) populations. We wanted to understand perceptions of CRC screening among AI located in the Great Lakes region. Focus groups were recorded and transcribed verbatim (N = 45). Data were analyzed using qualitative text analysis. Themes that deterred CRC screening were low CRC knowledge, fear of the procedure and results, cost and transportation issues, and a lack of quality and competent care. Suggestions for improvement included outreach efforts and culturally-tailored teaching materials. PMID:27188017

  16. Improving colorectal cancer screening: fact and fantasy

    NASA Astrophysics Data System (ADS)

    Van Dam, Jacques

    2008-02-01

    Premalignant diseases of the gastrointestinal tract, such as Barrett's esophagus, long-standing ulcerative colitis, and adenomatous polyps, have a significantly increased risk for development of adenocarcinoma, most often through an intermediate stage of dysplasia. Adenocarcinoma of the colon is the second most common cancer in the United States. Because patients with colorectal cancer often present with advanced disease, the outcomes are associated with significant morbidity and mortality. Effective methods of early detection are essential. As non-polypoid dysplasia is not visible using conventional endoscopy, surveillance of patients with Barrett's esophagus and ulcerative colitis is performed via a system in which multiple random biopsies are obtained at prescribed intervals. Sampling error and missed diagnoses occur frequently and render current screening methods inadequate. Also, the examination of a tissue biopsy is time consuming and costly, and significant intra- and inter-observer variation may occur. The newer methods discussed herein demonstrate the potential to solve these problems by early detection of disease with high sensitivity and specificity. Conventional endoscopy is based on the observation of white light reflected off the tissue surface. Subtle changes in color and shadow reveal structural changes. New developments in optical imaging go beyond white light, exploiting other properties of light. Several promising methods will be discussed at this meeting and shall be briefly discussed below. However, few such imaging modalities have arrived at our clinical practice. Some much more practical methods to improve colorectal cancer screening are currently being evaluated for their clinical impact. These methods seek to overcome limitations other than those of detecting dysplasia not visible under white light endoscopy. The current standard practice of colorectal cancer screening utilizes colonoscopy, an uncomfortable, sometimes difficult medical

  17. Gut Microbiota and Colorectal Surgery: Impact on Postoperative Complications.

    PubMed

    Russ, Andrew J; Casillas, Mark A

    2016-09-01

    Colorectal anastomotic leakage is a dreaded complication after colorectal surgery and causes high morbidity and mortality. The pathophysiology of anastomotic healing remains unclear despite numerous studies. In this article, our aim is to provide different perspectives on what is known about the role of the gastrointestinal tract microbiome and its relation to anastomotic integrity. PMID:27582651

  18. Colorectal cancer screening: The role of the noninvasive options.

    PubMed

    Dickerson, Lisa; Varcak, Susan Combs

    2016-09-01

    Recommended screening options for colorectal cancer are divided into noninvasive stool-based options, and invasive procedure-based options. Because multiple screening strategies are effective, efforts to reduce deaths from colorectal cancer should focus on maximizing the number of patients who are screened. This article reviews noninvasive stool-based screening options. PMID:27575898

  19. Is height a risk factor for colorectal adenoma?

    PubMed Central

    Pyo, Jeung Hui; Hong, Sung Noh; Min, Byung-Hoon; Chang, Dong Kyung; Son, Hee Jung; Rhee, Poong-Lyul; Kim, Jae J.; Kim, Young-Ho

    2016-01-01

    Background/Aims: Although it is generally known that the risk for all types of cancer increases with adult height, combined and for several common site-specific cancers (including colon and rectal), evidence is limited for adenomas, which are precursors to colorectal cancer. We evaluated the association between height and risk of colorectal adenoma at various stages of the adenoma-carcinoma pathway. Methods: We conducted a retrospective study using data from patients who had undergone a complete colonoscopy as part of a health examination at the Health Promotion Center of Samsung Medical Center between October 13, 2009 and December 31, 2011. A total of 1,347 male subjects were included in our study. Multivariate logistic regression analysis was used to evaluate the association between height and colorectal adenoma. Results: Each 5-cm increase in height was associated with 1.6% and 5.3% higher risks of advanced colorectal adenoma and high-risk colorectal adenoma, respectively, but associations were not significant after adjusting for age, body mass index, metabolic syndrome, alcohol intake, smoking, family history of colorectal cancer, and regular aspirin use (p = 0.840 and p = 0.472, respectively). Conclusions: No clear association was found between colorectal adenoma risk and height. Unlike other site-specific tumors reported to have a consistent relationship with height, the association between colorectal tumor and height remains controversial. PMID:26701232

  20. Endoscopic management of acute colorectal anastomotic complications with temporary stent.

    PubMed

    Abbas, Maher A

    2009-01-01

    Acute postoperative anastomotic complications following colorectal resection include leak and obstruction. Often an operation is necessary to treat these complications. The role of endoluminal procedures to treat these complications has been limited. This article illustrates that such an approach is technically feasible and can be used to treat some colorectal anastomotic complications.

  1. NIH study finds sigmoidoscopy reduces colorectal cancer rates

    Cancer.gov

    Study finds that flexible sigmoidoscopy is effective in reducing the rates of new cases and deaths due to colorectal cancer. Researchers found that overall colorectal cancer mortality was reduced by 26 percent and incidence was reduced by 21 percent as a

  2. HMGA1 drives metabolic reprogramming of intestinal epithelium during hyperproliferation, polyposis, and colorectal carcinogenesis.

    PubMed

    Williams, Michael D; Zhang, Xing; Belton, Amy S; Xian, Lingling; Huso, Tait; Park, Jeong-Jin; Siems, William F; Gang, David R; Resar, Linda M S; Reeves, Raymond; Hill, Herbert H

    2015-03-01

    Although significant progress has been made in the diagnosis and treatment of colorectal cancer (CRC), it remains a leading cause of cancer death worldwide. Early identification and removal of polyps that may progress to overt CRC is the cornerstone of CRC prevention. Expression of the High Mobility Group A1 (HMGA1) gene is significantly elevated in CRCs as compared with adjacent, nonmalignant tissues. We investigated metabolic aberrations induced by HMGA1 overexpression in small intestinal and colonic epithelium using traveling wave ion mobility mass spectrometry (TWIMMS) in a transgenic model in which murine Hmga1 was misexpressed in colonic epithelium. To determine if these Hmga1-induced metabolic alterations in mice were relevant to human colorectal carcinogenesis, we also investigated tumors from patients with CRC and matched, adjacent, nonmalignant tissues. Multivariate statistical methods and manual comparisons were used to identify metabolites specific to Hmga1 and CRC. Statistical modeling of data revealed distinct metabolic patterns in Hmga1 transgenics and human CRC samples as compared with the control tissues. We discovered that 13 metabolites were specific for Hmga1 in murine intestinal epithelium and also found in human CRC. Several of these metabolites function in fatty acid metabolism and membrane composition. Although further validation is needed, our results suggest that high levels of HMGA1 protein drive metabolic alterations that contribute to CRC pathogenesis through fatty acid synthesis. These metabolites could serve as potential biomarkers or therapeutic targets.

  3. Protein expression and gene polymorphism of CXCL10 in patients with colorectal cancer.

    PubMed

    Dimberg, Jan; Skarstedt, Marita; Löfgren, Sture; Zar, Niklas; Matussek, Andreas

    2014-05-01

    Chemokines (chemotactic cytokines) promote leukocyte attraction to sites of inflammation and cancer. Certain chemokines promote and regulate neoplastic progression, including metastasis and angiogenesis. One such chemokine, CXCL10, was found to be expressed in colorectal cancer (CRC) tissue. To gain insight into the prognostic significance of CXCL10, we investigated whether the levels of this chemokine were altered in the colorectal tissue or plasma of CRC patients. Using Luminex technology for protein analyses, we observed a significantly higher CXCL10 protein level in cancer tissue compared to that in paired normal tissue. Moreover, significantly higher plasma levels of CXCL10 were detected in patients compared to those in control subjects and the plasma levels of CXCL10 in disseminated disease were found to be significantly higher compared to those in localized disease. The single-nucleotide polymorphism rs8878, which has been described in exon 4 in the 3'-untranslated region of the CXCL10 gene, was investigated using a TaqMan system. There were significant differences in genotype distribution and allelic frequencies between CRC patients and control subjects. In conclusion, altered CXCL10 protein concentrations in CRC tissues or plasma and the rs8878 genotype variant of CXCL10 may contribute to the prediction of clinical outcome.

  4. Augmented pentose phosphate pathway plays critical roles in colorectal carcinomas.

    PubMed

    Shibuya, Norisuke; Inoue, Ken-ichi; Tanaka, Genki; Akimoto, Kazumi; Kubota, Keiichi

    2015-01-01

    Glycolysis and the pentose phosphate pathway (PPP) are preferentially activated in cancer cells. Accumulating evidence indicated the significance of the altered glucose metabolism in cancer, but the implication for oncotherapy remains unclear. Here we report that the synthesis of glycolytic and PPP enzymes is almost ubiquitously augmented in colorectal carcinoma (CRC) specimens. The mammalian target of rapamycin (mTOR) inhibitor INK128 (300 nM) and phytochemical Avemar (1 mg/ml) inhibited the synthesis of PPP enzymes in CRC cell lines. INK128 (150-600 nM) and resveratrol (75-300 μM) inhibited aerobic glycolysis in the cell lines. INK128 (300 nM) and Avemar (1 mg/ml) decreased the NADPH/NADP(+) ratio as well as the GSH/GSSG ratio in the cell lines. Finally, per os administration of INK128 (0.8 mg/kg) or Avemar (1 g/kg) suppressed tumor growth and delayed tumor formation by transplantable CRC specimens derived from patients. Taken together, pharmacological inhibition of the mTOR-PPP axis is a promising therapeutic strategy against CRCs.

  5. Clinical and molecular features of young-onset colorectal cancer

    PubMed Central

    Ballester, Veroushka; Rashtak, Shahrooz; Boardman, Lisa

    2016-01-01

    Colorectal cancer (CRC) is one of the leading causes of cancer related mortality worldwide. Although young-onset CRC raises the possibility of a hereditary component, hereditary CRC syndromes only explain a minority of young-onset CRC cases. There is evidence to suggest that young-onset CRC have a different molecular profile than late-onset CRC. While the pathogenesis of young-onset CRC is well characterized in individuals with an inherited CRC syndrome, knowledge regarding the molecular features of sporadic young-onset CRC is limited. Understanding the molecular mechanisms of young-onset CRC can help us tailor specific screening and management strategies. While the incidence of late-onset CRC has been decreasing, mainly attributed to an increase in CRC screening, the incidence of young-onset CRC is increasing. Differences in the molecular biology of these tumors and low suspicion of CRC in young symptomatic individuals, may be possible explanations. Currently there is no evidence that supports that screening of average risk individuals less than 50 years of age will translate into early detection or increased survival. However, increasing understanding of the underlying molecular mechanisms of young-onset CRC could help us tailor specific screening and management strategies. The purpose of this review is to evaluate the current knowledge about young-onset CRC, its clinicopathologic features, and the newly recognized molecular alterations involved in tumor progression. PMID:26855533

  6. Dietary fibres as "prebiotics": implications for colorectal cancer.

    PubMed

    Lim, Chiara C; Ferguson, Lynnette R; Tannock, Gerald W

    2005-06-01

    A "prebiotic" is a nondigestible food ingredient whose beneficial effects on the host result from the selective stimulation of growth and/or activity of members of the bacterial community that inhabits the human bowel (the gut microbiota). Although much of the prebiotic literature focuses on nondigestible oligosaccharides, such as oligofructose, most dietary fibres that are fermentable carbohydrates could be considered as prebiotics. Early studies suggested that colonic bacteria were risk factors for colon cancer. However, altering the composition or metabolic activity of the bowel microbiota through the use of dietary fibre might be important in reducing the prevalence of colorectal cancer. Mechanisms for beneficial effects of prebiotics might include changing the activity of exogenous carcinogens through modulating metabolic activation and/or detoxification, or stimulating the production of the short-chain fatty acid, butyrate. However, modern analytical techniques suggest that an important consequence of a modified bacterial community could be a change in the expression not only of a range of different bacterial genes in bowel contents, but also in the bowel mucosa of the host. Analogous with observations with probiotics, the stimulation of cytokines and modification of immune responses could be important in producing beneficial effects. Compared with transitory effects of probiotics, the prebiotic action of fermentable carbohydrates potentially provide the opportunity for sustainable modulation of activity of the gut microbiota. However, their mechanisms of action in humans are speculative, and research aimed at providing an integrated view of the gut microbiota and dietary fibre nutrition of humans needs to be developed.

  7. Immune escape mechanisms in colorectal cancer pathogenesis and liver metastasis.

    PubMed

    Pancione, Massimo; Giordano, Guido; Remo, Andrea; Febbraro, Antonio; Sabatino, Lina; Manfrin, Erminia; Ceccarelli, Michele; Colantuoni, Vittorio

    2014-01-01

    Over the past decade, growing evidence indicates that the tumor microenvironment (TME) contributes with genomic/epigenomic aberrations of malignant cells to enhance cancer cells survival, invasion, and dissemination. Many factors, produced or de novo synthesized by immune, stromal, or malignant cells, acting in a paracrine and autocrine fashion, remodel TME and the adaptive immune response culminating in metastasis. Taking into account the recent accomplishments in the field of immune oncology and using metastatic colorectal cancer (mCRC) as a model, we propose that the evasion of the immune surveillance and metastatic spread can be achieved through a number of mechanisms that include (a) intrinsic plasticity and adaptability of immune and malignant cells to paracrine and autocrine stimuli or genotoxic stresses; (b) alteration of positional schemes of myeloid-lineage cells, produced by factors controlling the balance between tumour-suppressing and tumour-promoting activities; (c) acquisition by cancer cells of aberrant immune-phenotypic traits (NT5E/CD73, CD68, and CD163) that enhance the interactions among TME components through the production of immune-suppressive mediators. These properties may represent the driving force of metastatic progression and thus clinically exploitable for cancer prevention and therapy. In this review we summarize results and suggest new hypotheses that favour the growing impact of tumor-infiltrating immune cells on tumour progression, metastasis, and therapy resistance.

  8. Patients with genetically heterogeneous synchronous colorectal cancer carry rare damaging germline mutations in immune-related genes.

    PubMed

    Cereda, Matteo; Gambardella, Gennaro; Benedetti, Lorena; Iannelli, Fabio; Patel, Dominic; Basso, Gianluca; Guerra, Rosalinda F; Mourikis, Thanos P; Puccio, Ignazio; Sinha, Shruti; Laghi, Luigi; Spencer, Jo; Rodriguez-Justo, Manuel; Ciccarelli, Francesca D

    2016-01-01

    Synchronous colorectal cancers (syCRCs) are physically separated tumours that develop simultaneously. To understand how the genetic and environmental background influences the development of multiple tumours, here we conduct a comparative analysis of 20 syCRCs from 10 patients. We show that syCRCs have independent genetic origins, acquire dissimilar somatic alterations, and have different clone composition. This inter- and intratumour heterogeneity must be considered in the selection of therapy and in the monitoring of resistance. SyCRC patients show a higher occurrence of inherited damaging mutations in immune-related genes compared to patients with solitary colorectal cancer and to healthy individuals from the 1,000 Genomes Project. Moreover, they have a different composition of immune cell populations in tumour and normal mucosa, and transcriptional differences in immune-related biological processes. This suggests an environmental field effect that promotes multiple tumours likely in the background of inflammation. PMID:27377421

  9. Patients with genetically heterogeneous synchronous colorectal cancer carry rare damaging germline mutations in immune-related genes

    PubMed Central

    Cereda, Matteo; Gambardella, Gennaro; Benedetti, Lorena; Iannelli, Fabio; Patel, Dominic; Basso, Gianluca; Guerra, Rosalinda F.; Mourikis, Thanos P.; Puccio, Ignazio; Sinha, Shruti; Laghi, Luigi; Spencer, Jo; Rodriguez-Justo, Manuel; Ciccarelli, Francesca D.

    2016-01-01

    Synchronous colorectal cancers (syCRCs) are physically separated tumours that develop simultaneously. To understand how the genetic and environmental background influences the development of multiple tumours, here we conduct a comparative analysis of 20 syCRCs from 10 patients. We show that syCRCs have independent genetic origins, acquire dissimilar somatic alterations, and have different clone composition. This inter- and intratumour heterogeneity must be considered in the selection of therapy and in the monitoring of resistance. SyCRC patients show a higher occurrence of inherited damaging mutations in immune-related genes compared to patients with solitary colorectal cancer and to healthy individuals from the 1,000 Genomes Project. Moreover, they have a different composition of immune cell populations in tumour and normal mucosa, and transcriptional differences in immune-related biological processes. This suggests an environmental field effect that promotes multiple tumours likely in the background of inflammation. PMID:27377421

  10. Nomenclature, molecular genetics and clinical significance of the precursor lesions in the serrated polyp pathway of colorectal carcinoma.

    PubMed

    Liang, John J; Alrawi, Sadir; Tan, Dongfeng

    2008-01-01

    Serrated adenomas (SAs) are part of the distinct serrated polyp pathway of colorectal carcinogenesis characterized by microsatellite instability and deficiency in DNA mismatch repair. Sessile SA is a recently recognized lesion that typically presents as a large sessile polyp, but lacks the conventional dysplasia. It is more frequently found on the right side than on the left side of the colon, and is thought to represent an intermediate form in the hyperplastic polyp to sessile SA, traditional SA, and colon cancer sequence. Many terms have been used and are still in use in the literature to describe this lesion, such as "hyperplastic polyposis", "giant hyperplastic polyposis," "large hyperplastic polyps," "hyperplastic-adenomatous polyposis syndrome," "giant hyperplastic polyp," and "mixed epithelial polyp." The purpose of this paper is to review and clarify the confusing nomenclature, and to provide a framework for understanding the genetic alterations and clinical significance of these precursor lesions in the serrated polyp pathway of colorectal caner.

  11. Fusobacterium nucleatum: an emerging bug in colorectal tumorigenesis.

    PubMed

    Bashir, Arif; Miskeen, Abid Y; Bhat, Ashaqullah; Fazili, Khalid M; Ganai, Bashir A

    2015-09-01

    The human intestinal microbiota is a plethora of diverse microbial species, wherein certain bacteria considered as driver bacteria with procarcinogenic features contribute directly toward colonic epithelium cell damage to initiate colorectal carcinogenesis. However, some bacteria, in particular Fusobacterium nucleatum, which is otherwise a normal resident of the oral microflora and a relatively poor colonizer of the healthy gut, have also been considered to play a role in the development of colorectal cancer. Many studies have reported that F. nucleatum is associated with colorectal adenomas and advanced-stage colorectal cancer, but its precise role in the early stages of colorectal tumorigenesis is poorly understood. Here, we review some of the important features of F. nucleatum, its association with inflammatory bowel disease, modulation of the tumor-immune microenvironment, and E-cadherin/β-catenin signaling.

  12. Aflibercept in the Treatment of Metastatic Colorectal Cancer

    PubMed Central

    Wang, Tzu-Fei; Lockhart, Albert Craig

    2012-01-01

    Colorectal cancer is the third most common cancer in the US. In recent decades, an improved understanding of the role of the angiogenesis pathway in colorectal cancer has led to advancements in treatment. Bevacizumab has been shown to improve the progression-free survival and overall survival when combined with cytotoxic chemotherapy in patients with metastatic colorectal cancer, and at present is the only antiangiogenesis agent approved for the treatment of this cancer. Aflibercept is a novel angiogenesis-targeting agent, and has demonstrated efficacy in treating metastatic colorectal cancer in a recent randomized Phase III trial. Here we review the role of angiogenesis in the tumorigenesis of colorectal cancer, strategies for targeting angiogenesis, and the clinical development of aflibercept. PMID:22253552

  13. Microsatellite instability in tumor and nonneoplastic colorectal cells from hereditary non-polyposis colorectal cancer and sporadic high microsatellite-instable tumor patients.

    PubMed

    Dietmaier, W; Gänsbauer, S; Beyser, K; Renke, B; Hartmann, A; Rümmele, P; Jauch, K W; Hofstädter, F; Rüschoff, J

    2000-01-01

    Genetic alterations such as loss of heterozygosity (LOH) and microsatellite instability (MSI) have been frequently studied in various tumor types. Genetic heterogeneity of nonneoplastic cells has not yet been sufficiently investigated. However, genomic instability in normal cells could be a potentially important issue, in particular when these cells are used as reference in LOH and MSI analyses of tumor samples. In order to investigate possible genetic abnormalities in normal colorectal cells of tumor patients, MSI analyses of normal colonic mucosa were performed. Up to 15 different laser-microdissected normal regions containing 50-150 cells were investigated in each of 15 individual microsatellite-stable, sporadic high microsatellite-instable (MSI-H) and hereditary non-polyposis coli cancer (HNPCC) colorectal cancer patients. Frequent MSI and heterogeneity in the MSI pattern were found both in normal and tumor cells from 10 HNPCC and sporadic MSI-H tumor patients whose tumors had defect mismatch repair protein expressions. This observation shows that MSI can also occur in nonneoplastic cells which has to be considered in MSI analyses for molecular HNPCC screening. In addition, considerable genetic heterogeneity was detected in all MSI-H (sporadic and HNPCC) tumors when analyzing five different regions with less than 150 cells, respectively. These differences were not detectable in larger tumor regions containing about 10,000 cells. Thus, heterogeneity of the MSI pattern (e.g. intratumoral MSI) is an important feature of tumors with the MSI-H phenotype.

  14. Biological Mechanisms Underlying Structural Changes Induced by Colorectal Field Carcinogenesis Measured with Low-Coherence Enhanced Backscattering (LEBS) Spectroscopy

    PubMed Central

    Mutyal, Nikhil N.; Radosevich, Andrew; Tiwari, Ashish K.; Stypula, Yolanda; Wali, Ramesh; Kunte, Dhananjay; Roy, Hemant K.; Backman, Vadim

    2013-01-01

    We previously reported the utility of Low-Coherence Enhanced Backscattering (LEBS) Spectroscopy in detecting optical changes in uninvolved rectal mucosa, changes that are indicative of the presence of advanced colorectal adenomas elsewhere in the colon (field carcinogenesis). We hypothesized that the alterations in optical signatures are due to structural changes in colonocytes. To elucidate those colonocyte changes, we used LEBS and an early time point in an animal model of colorectal field carcinogenesis – rats treated with azoxymethane (AOM). Changes in LEBS markers in intact mucosa from AOM-treated rats could be at least partially attributed to changes in colonocytes. To investigate the molecular mechanisms underlying the colonocyte abnormalities in premalignant colon, we took a candidate approach. We compared expression profiles of genes implicated directly or indirectly in cytoskeletal dysregulation in colorectal tissues from saline-treated versus AOM-treated rats. Our data suggest that a number of genes known to affect colon tumorigenesis are up-regulated in colonocytes, and genes previously reported to be tumor suppressors in metastatic cancer are down-regulated in colonocytes, despite the colonocytes being histologically normal. To further understand the role of the cytoskeleton in generating changes in optical markers of cells, we used pharmacological disruption (using colchicine) of the cytoskeleton. We found that differences in optical markers (between AOM- and control-treated rats) were negated by the disruption, suggesting cytoskeletal involvement in the optical changes. These studies provide significant insights into the micro-architectural alterations in early colon carcinogenesis, and may enable optimization of both bio-photonic and molecular risk stratification techniques to personalize colorectal cancer screening. PMID:23431406

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

    PubMed Central

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

    1993-01-01

    The perceived or self-reported degree of 'religiousness' was obtained by interview from 715 colorectal cancer patients and 727 age/sex matched community controls, as part of a large, comprehensive population-based study of colorectal cancer incidence, aetiology and survival (The Melbourne Colorectal Cancer Study) conducted in Melbourne, Australia. Self-reported or perceived 'religiousness', as defined in the study, was a statistically significant protective factor [relative risk (RR) = 0.70, 95% confidence interval (CI) = 0.6-0.9, P = 0.002]. This statistically significant protection remained after the previously determined major risk factors found in the study, namely a family history of colorectal cancer, dietary risk factors, beer consumption, number of children and age at birth of the first child, were statistically corrected for (P = 0.004). There was no association between Dukes' staging of the cancer and perceived degree of 'religiousness' (P = 0.42). Although self-reported or perceived 'religiousness' was associated with a median survival time of 62 months compared with 52 months in those self-reporting as being 'non-religious', this difference was not statistically significant (P = 0.64). PMID:8258800

  16. [Clinicopathological characteristics of colorectal carcinoma in the elderly].

    PubMed

    Tao, Kaixiong; Gao, Jinbo; Wang, Guobin

    2016-05-01

    Elderly patients with colorectal cancer have different clincopathological characteristics from younger patients. Colorectal cancers tend to localize in the proximal colon, from cecum to the splenic flexure in the elderly patients. Changes in the stools, rectal bleeding or black stool, abdominal pain, fatigue, weight loss and anemia are the common symptoms. Analysis showed that age is one of independent risk factors for lower completion rates of colonoscopy. Therefore, the choice of diagnosis methods in elderly patients should be careful. Achieving a clear diagnosis and avoiding complications should be considered at the same time. Most colorectal cancers in elderly are highly and moderately differentiated adenocarcinomas and locally advanced, and have less lymphatic and blood metastasis. The proportion of poorly differentiated adenocarcinoma increases with the increase of age, which should be concerned. Multiple colorectal cancers and colorectal cancer with extra-colorectal malignancy are not rare in the elderly patients. The common extra-colorectal tumors consist of gastric cancer, lung cancer, biliary carcinoma, pancreas cancer and malignancy from blood system. Molecular events, such as mutations of KARS, BRAF, TP53 and deficiency of DNA mismatch repair, are more frequent in elderly colorectal cancer patients. Many factors have impact on treatment decision in elderly patients with colorectal cancer, including age, comorbidities, physiological functions of organs and willingness of patients and their relatives. Although surgery is still the main treatment, the proportion of radical surgery is lower and emergency surgery is higher as compared to younger patients. With the development of minimally invasive surgical techniques and advances in anesthesia and perioperative management, laparoscopic surgery has become widespread in elderly patients with colorectal cancer. In addition, more attention should be paid to adjuvant therapy. Comprehensive individualized

  17. [Clinicopathological characteristics of colorectal carcinoma in the elderly].

    PubMed

    Tao, Kaixiong; Gao, Jinbo; Wang, Guobin

    2016-05-01

    Elderly patients with colorectal cancer have different clincopathological characteristics from younger patients. Colorectal cancers tend to localize in the proximal colon, from cecum to the splenic flexure in the elderly patients. Changes in the stools, rectal bleeding or black stool, abdominal pain, fatigue, weight loss and anemia are the common symptoms. Analysis showed that age is one of independent risk factors for lower completion rates of colonoscopy. Therefore, the choice of diagnosis methods in elderly patients should be careful. Achieving a clear diagnosis and avoiding complications should be considered at the same time. Most colorectal cancers in elderly are highly and moderately differentiated adenocarcinomas and locally advanced, and have less lymphatic and blood metastasis. The proportion of poorly differentiated adenocarcinoma increases with the increase of age, which should be concerned. Multiple colorectal cancers and colorectal cancer with extra-colorectal malignancy are not rare in the elderly patients. The common extra-colorectal tumors consist of gastric cancer, lung cancer, biliary carcinoma, pancreas cancer and malignancy from blood system. Molecular events, such as mutations of KARS, BRAF, TP53 and deficiency of DNA mismatch repair, are more frequent in elderly colorectal cancer patients. Many factors have impact on treatment decision in elderly patients with colorectal cancer, including age, comorbidities, physiological functions of organs and willingness of patients and their relatives. Although surgery is still the main treatment, the proportion of radical surgery is lower and emergency surgery is higher as compared to younger patients. With the development of minimally invasive surgical techniques and advances in anesthesia and perioperative management, laparoscopic surgery has become widespread in elderly patients with colorectal cancer. In addition, more attention should be paid to adjuvant therapy. Comprehensive individualized

  18. Allele-specific expression of mutated in colorectal cancer (MCC) gene and alternative susceptibility to colorectal cancer in schizophrenia.

    PubMed

    Wang, Yang; Cao, Yanfei; Huang, Xiaoye; Yu, Tao; Wei, Zhiyun; McGrath, John; Xu, Fei; Bi, Yan; Li, Xingwang; Yang, Fengping; Li, Weidong; Zou, Xia; Peng, Zhihai; Xiao, Yanzeng; Zhang, Yan; He, Lin; He, Guang

    2016-01-01

    Evidence has indicated that the incidence of colorectal cancer (CRC) among schizophrenia is lower than normal. To explore this potential protective effect, we employed an innovative strategy combining association study with allele-specific expression (ASE) analysis in MCC gene. We first genotyped four polymorphisms within MCC in 312 CRC patients, 270 schizophrenia patients and 270 controls. Using the MassArray technique, we performed ASE measurements in a second sample series consisting of 50 sporadic CRC patients, 50 schizophrenia patients and 52 controls. Rs2227947 showed significant differences between schizophrenia cases and controls, and haplotype analysis reported some significant discrepancies among these three subject groups. ASE values of rs2227948 and rs2227947 presented consistently differences between CRC (or schizophrenia) patients and controls. Of the three groups, highest frequencies of ASE in MCC were concordantly found in CRC group, whereas lowest frequencies of ASE were observed in schizophrenia group. Similar trends were confirmed in both haplotype frequencies and ASE frequencies (i.e. CRC > control > schizophrenia). We provide a first indication that MCC might confer alterative genetic susceptibility to CRC in individuals with schizophrenia promising to shed more light on the relationship between schizophrenia and cancer progression. PMID:27226254

  19. Molecular Pathologic Epidemiology of Colorectal Neoplasia: An Emerging Transdisciplinary and Interdisciplinary Field

    PubMed Central

    Ogino, Shuji; Chan, Andrew T.; Fuchs, Charles S.; Giovannucci, Edward

    2011-01-01

    Colorectal cancer is a complex disease resulting from somatic genetic and epigenetic alterations, including locus-specific CpG island methylation and global DNA or LINE-1 hypomethylation. Global molecular characteristics such as microsatellite instability (MSI), CpG island methylator phenotype (CIMP), global DNA hypomethylation, and chromosomal instability cause alterations of gene function in a genome-wide scale. Activation of oncogenes including KRAS, BRAF and PIK3CA affects intracellular signaling pathways and has been associated with CIMP and MSI. Traditional epidemiology research has investigated various factors in relation to an overall risk of colon and/or rectal cancer. However, colorectal cancers comprise a heterogeneous group of diseases with different sets of genetic and epigenetic alterations. To better understand how a particular exposure influences the carcinogenic process, somatic molecular changes and tumor biomarkers have been studied in relation to the exposure of interest. Moreover, an investigation of interactive effects of tumor molecular changes and the exposures of interest on tumor behavior (prognosis or clinical outcome) can lead to a better understanding of tumor molecular changes, which may be prognostic or predictive tissue biomarkers. These new research efforts represent “Molecular Pathologic Epidemiology”, which is a multidisciplinary field of investigations of the interrelationship between exogenous and endogenous (e.g., genetic) factors, tumoral molecular signatures and tumor progression. Furthermore, integrating genome-wide association studies (GWAS) with molecular pathologic investigation is a promising area. Examining the relationship between susceptibility alleles identified by GWAS and specific molecular alterations can help elucidate the function of these alleles and provide insights into whether susceptibility alleles are truly causal. Although there are challenges, molecular pathologic epidemiology has unique strengths

  20. 49 CFR 179.6 - Repairs and alterations.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 2 2010-10-01 2010-10-01 false Repairs and alterations. 179.6 Section 179.6... Introduction, Approvals and Reports § 179.6 Repairs and alterations. For procedure to be followed in making repairs or alterations, see appendix R of the AAR Specifications for Tank Cars (IBR, see § 171.7 of...

  1. Outcome of Colorectal Surgery in Elderly Populations

    PubMed Central

    Di Lorenzo, Nicola; Franceschilli, Luana; Perrone, Federico; Angelucci, Giulio P.; Quareisma, Silvia; Gaspari, Achille L.; Sileri, Pierpaolo

    2016-01-01

    Purpose The aim of this study is to investigate the impact of age on short-term outcomes after colorectal surgery in terms of the 30-day postoperative morbidity and mortality rates. Methods The subjects for the study were patients who had undergone colorectal surgery. Patients were divided into 2 groups according to age; groups A and B patients were ≥80 and <80 years old of age, respectively. Both groups were manually matched for body mass index, American Society of Anesthesiologists score, Charlson Comorbidity Index and procedure performed. Results A total of 200 patients, 91 men (45.5%) and 109 women (54.5%), were included in this retrospective study. These patients were equally divided into 2 groups. The mean ages were 85 years in group A (range, 80 to 104 years) and 55.3 years in group B (range, 13 to 79 years). The overall 30-day postoperative mortality rate was 1% of total 200 patients; both of these 2 patients were in group A. However, this observation had no statistical significance. No intraoperative complications were encountered in either group. The overall 30-day postoperative morbidity rate was 27% (54 of 200) for both groups. The 30-day postoperative morbidity rates in groups A and B were 28% (28 of 100) and 26% (26 of 100), respectively. However, these differences between the groups had no statistical significance importance. Conclusion Age alone should not be considered to be more of a contraindication or a worse predictor than other factors for the outcome after colorectal surgery on elderly patients.

  2. Outcome of Colorectal Surgery in Elderly Populations

    PubMed Central

    Di Lorenzo, Nicola; Franceschilli, Luana; Perrone, Federico; Angelucci, Giulio P.; Quareisma, Silvia; Gaspari, Achille L.; Sileri, Pierpaolo

    2016-01-01

    Purpose The aim of this study is to investigate the impact of age on short-term outcomes after colorectal surgery in terms of the 30-day postoperative morbidity and mortality rates. Methods The subjects for the study were patients who had undergone colorectal surgery. Patients were divided into 2 groups according to age; groups A and B patients were ≥80 and <80 years old of age, respectively. Both groups were manually matched for body mass index, American Society of Anesthesiologists score, Charlson Comorbidity Index and procedure performed. Results A total of 200 patients, 91 men (45.5%) and 109 women (54.5%), were included in this retrospective study. These patients were equally divided into 2 groups. The mean ages were 85 years in group A (range, 80 to 104 years) and 55.3 years in group B (range, 13 to 79 years). The overall 30-day postoperative mortality rate was 1% of total 200 patients; both of these 2 patients were in group A. However, this observation had no statistical significance. No intraoperative complications were encountered in either group. The overall 30-day postoperative morbidity rate was 27% (54 of 200) for both groups. The 30-day postoperative morbidity rates in groups A and B were 28% (28 of 100) and 26% (26 of 100), respectively. However, these differences between the groups had no statistical significance importance. Conclusion Age alone should not be considered to be more of a contraindication or a worse predictor than other factors for the outcome after colorectal surgery on elderly patients. PMID:27626024

  3. Repeat hepatectomy for colorectal liver metastases.

    PubMed Central

    Adam, R; Bismuth, H; Castaing, D; Waechter, F; Navarro, F; Abascal, A; Majno, P; Engerran, L

    1997-01-01

    OBJECTIVE: The authors assess the long-term results of repeat hepatectomies for recurrent metastases of colorectal cancer and determine the factors that can predict survival. SUMMARY BACKGROUND DATA: Safer techniques of hepatic resection have allowed surgeons to consider repeat hepatectomy for colorectal metastases in an increasing number of patients. However, higher operative bleeding and increased morbidity have been reported after repeat hepatectomies, and the long-term benefit of these procedures needs to be evaluated. STUDY POPULATION: Sixty-four patients from a group of 243 patients resected for colorectal liver metastases were submitted to 83 repeat hepatectomies (64 second, 15 third, and 4 fourth hepatectomies). Combined extrahepatic surgery was performed in 21 (25%) of these 83 repeat hepatectomies. RESULTS: There was no intraoperative or postoperative mortality. Operative bleeding was not significantly increased in repeat hepatectomies as compared to first resections. Morbidity and duration of hospital stay were comparable to first hepatectomies. Overall and disease-free survival after a second hepatectomy were 60% and 42%, respectively, at 3 years and 41% and 26%, respectively, at 5 years. Factors of prognostic value on univariate analysis included the curative nature of first and second hepatectomies (p = 0.04 and p = 0.002, respectively), an interval between the two procedures of more than 1 year (p = 0.003), the number of recurrent tumors (p = 0.002), serum carcinoembryonic antigen levels (p = 0.03), and the presence of extrahepatic disease (p = 0.03). Only the curative nature of the second hepatectomy and an interval of more than 1 year between the two procedures were independently related to survival on multivariate analysis. CONCLUSIONS: Repeat hepatectomies can provide long-term survival rates similar to those of first hepatectomies, with no mortality and comparable morbidity. Combined extrahepatic surgery can be required to achieve tumor

  4. Virtual colonoscopy in stenosing colorectal cancer

    PubMed Central

    Coccetta, Marco; Migliaccio, Carla; La Mura, Francesco; Farinella, Eriberto; Galanou, Ioanna; Delmonaco, Pamela; Spizzirri, Alessandro; Napolitano, Vincenzo; Cattorini, Lorenzo; Milani, Diego; Cirocchi, Roberto; Sciannameo, Francesco

    2009-01-01

    Background Between 5 and 10% of the patients undergoing a colonoscopy cannot have a complete procedure mainly due to stenosing neoplastic lesion of rectum or distal colon. Nevertheless the elective surgical treatment concerning the stenosis is to be performed after the pre-operative assessment of the colonic segments upstream the cancer. The aim of this study is to illustrate our experience with the Computed Tomographic Colonography (CTC) for the pre-operative assessment of the entire colon in the patients with stenosing colorectal cancers. Methods From January 2005 till March 2009, we observed and treated surgically 43 patients with stenosing colorectal neoplastic lesions. All patients did not tolerate the pre-operative colonoscopy. For this reason they underwent a pre-operative CTC in order to have a complete assessment of the entire colon. All patients underwent a follow-up colonoscopy 3 months after the surgical treatment. The CTC results were compared with both macroscopic examination of the specimen and the follow-up coloscopy. Results The pre-operative CTC showed four synchronous lesions in four patients (9.3% of the cases). The macroscopic examination of the specimen revealed three small sessile polyps (3 - 4 mm in diameter) missed in the pre-operative assessment near the stenosing colorectal cancer. The follow-up colonoscopy showed four additional sessile polyps with a diameter between 3 - 11 mm in three patients. Our experience shows that CTC has a sensitivity of 83,7%. Conclusion In patients with stenosing colonic lesions, CTC allows to assess the entire colon pre-operatively avoiding the need of an intraoperative colonoscopy. More synchronous lesions are detected and treated at the time of the elective surgery for the stenosing cancer avoiding further surgery later on. PMID:19900286

  5. Biomechanical investigation of colorectal cancer cells

    NASA Astrophysics Data System (ADS)

    Palmieri, Valentina; Lucchetti, Donatella; Maiorana, Alessandro; Papi, Massimiliano; Maulucci, Giuseppe; Ciasca, Gabriele; Svelto, Maria; De Spirito, Marco; Sgambato, Alessandro

    2014-09-01

    The nanomechanical properties of SW480 colon cancer cells were investigated using Atomic Force Microscopy. SW480 cells are composed of two sub-populations with different shape and invasiveness. These two cells populations showed similar adhesion properties while appeared significantly different in term of cells stiffness. Since cell stiffness is related to invasiveness and growth, we suggest elasticity as a useful parameter to distinguish invasive cells inside the colorectal tumor bulk and the high-resolution mechanical mapping as a promising diagnostic tool for the identification of malignant cells.

  6. Management of Colorectal Cancer in Older Adults.

    PubMed

    Hubbard, Joleen M

    2016-02-01

    Treatment for colorectal cancer should not be based on age alone. Pooled analyses from clinical trials show that fit older adults are able to tolerate treatment well with similar efficacy as younger adults. When an older adult is considered for treatment, the clinical encounter must evaluate for deficits in physical and cognitive function, and assess comorbidities, medications, and the degree of social support, all which have may affect tolerance of treatment. Based on the degree of fitness of the patient, multiple alternatives to aggressive treatment regimens and strategies exist to minimize toxicity and preserve quality of life during treatment.

  7. Modelling multiscale aspects of colorectal cancer

    NASA Astrophysics Data System (ADS)

    van Leeuwen, Ingeborg M. M.; Byrne, Helen M.; Johnston, Matthew D.; Edwards, Carina M.; Chapman, S. Jonathan; Bodmer, Walter F.; Maini, Philip K.

    2008-01-01

    Colorectal cancer (CRC) is responsible for nearly half a million deaths annually world-wide [11]. We present a series of mathematical models describing the dynamics of the intestinal epithelium and the kinetics of the molecular pathway most commonly mutated in CRC, the Wnt signalling network. We also discuss how we are coupling such models to build a multiscale model of normal and aberrant guts. This will enable us to combine disparate experimental and clinical data, to investigate interactions between phenomena taking place at different levels of organisation and, eventually, to test the efficacy of new drugs on the system as a whole.

  8. Pharmacogenomics of cetuximab in metastatic colorectal carcinoma.

    PubMed

    Silvestris, Nicola; Vincenzi, Bruno; Brunetti, Anna Elisabetta; Loupakis, Fotious; Dell'Aquila, Emanuela; Russo, Antonio; Scartozzi, Mario; Giampieri, Riccardo; Cascinu, Stefano; Lorusso, Vito; Tonini, Giuseppe; Falcone, Alfredo; Santini, Daniele

    2014-09-01

    Cetuximab is a chimeric monoclonal antibody that has revolutionized the treatment of metastatic colorectal cancer. Knowledge of the mechanisms that underlie its effectiveness, as well as the primary and secondary resistance mechanisms, have led to important developments in the understanding of cetuximab biology. In light of knowledge gained from recent trials, the efficacy of cetuximab has been clearly demonstrated to depend upon RAS mutational status, moreover cetuximab should only be used in a subset of patients who may benefit. In this article, we critically review clinical and pharmacogenetic issues of cetuximab, focusing on the cost-effectiveness involved with the use of the drug.

  9. Immune cell interplay in colorectal cancer prognosis

    PubMed Central

    Norton, Samuel E; Ward-Hartstonge, Kirsten A; Taylor, Edward S; Kemp, Roslyn A

    2015-01-01

    The immune response to colorectal cancer has proven to be a reliable measure of patient outcome in several studies. However, the complexity of the immune response in this disease is not well understood, particularly the interactions between tumour-associated cells and cells of the innate and adaptive immune system. This review will discuss the relationship between cancer associated fibroblasts and macrophages, as well as between macrophages and T cells, and demonstrate how each population may support or prevent tumour growth in a different immune environment. PMID:26483876

  10. Hereditary Colorectal Cancer: Genetics and Screening.

    PubMed

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

    2015-10-01

    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. In addition, serrated polyposis is a clinically defined syndrome with multiple serrated polyps in the colorectum and an increased CRC risk for which the genetics are unknown. This article focuses on genetic and clinical aspects of Lynch syndrome, familial adenomatous polyposis, and MUTYH-associated polyposis.

  11. Primary and recurrent colorectal cancer masquerading as gynaecological malignancy.

    PubMed

    Brand, A; Scurry, J; Planner, R; Leung, S

    1996-05-01

    To make clinicians more aware of the phenomenon of primary and recurrent colorectal and anal carcinoma masquerading as primary gynaecological malignancy, we reviewed the records of 8 women referred to our gynaecological oncology unit with primary colorectal cancer (1), recurrent colorectal cancer (6) and primary anal cancer (1). Seven of these patients presented with abnormal vaginal bleeding or discharge. All patients had Papanicolaou smears performed; 7 were abnormal and 1 unsuitable for cytological assessment. None of the 6 patients with recurrent carcinoma had been previously treated with more than standard anterior or abdominoperineal resection; no radiotherapy had been given, and only 1 patient had received chemotherapy. These patients were treated in our gynaecological oncology unit for their recurrence by surgery and/or chemotherapy and/or irradiation. All 6 had further recurrences in the pelvis despite this aggressive therapy. Follow-up of colorectal cancer in women should involve gynaecological history, pelvirectal examination and Pap smear at each visit. Correct diagnosis of the colorectal origin of a genital tract tumour is made on careful history, examination and biopsy. An abnormal Pap smear may be the first indication of recurrent colorectal cancer in the cervix and vagina, although most patients ultimately present with abnormal vaginal bleeding. The presence of a tumour invading both cervix and posterior vaginal wall is suggestive of spread from a colorectal tumour compared to the more common lateral spread of a cervical primary.

  12. Primary prevention of colorectal cancer: lifestyle, nutrition, exercise.

    PubMed

    Martínez, María Elena

    2005-01-01

    The past two decades have provided a vast amount of literature related to the primary prevention of colorectal cancer. Large international variation in colorectal cancer incidence and mortality rates and the prominent increases in the incidence of colorectal cancer in groups that migrated from low- to high-incidence areas provided important evidence that lifestyle factors influence the development of this malignancy. Moreover, there is convincing evidence from epidemiological and experimental studies that dietary intake is an important etiological factor in colorectal neoplasia. Although the precise mechanisms have not been clarified, several lifestyle factors are likely to have a major impact on colorectal cancer development. Physical inactivity and to a lesser extent, excess body weight, are consistent risk factors for colon cancer. Exposure to tobacco products early in life is associated with a higher risk of developing colorectal neoplasia. Diet and nutritional factors are also clearly important. Diets high in red and processed meat increase risk. Excess alcohol consumption, probably in combination with a diet low in some micronutrients such as folate and methionine, appear to increase risk. There is also recent evidence supporting a protective effect of calcium and vitamin D in the etiology of colorectal neoplasia. The relationship between intake of dietary fiber and risk of colon cancer has been studied for three decades but the results are still inconclusive. However, some micronutrients or phytochemicals in fiber-rich foods may be important; folic acid is one such micronutrient that has been shown to protect against the development of colorectal neoplasia and is currently being studied in intervention trials of adenoma recurrence. The overwhelming evidence indicates that primary prevention of colon cancer is feasible. Continued focus on primary prevention of colorectal cancer, in combination with efforts aimed at screening and surveillance, will be vital in

  13. Role of physical activity and diet after colorectal cancer diagnosis.

    PubMed

    Van Blarigan, Erin L; Meyerhardt, Jeffrey A

    2015-06-01

    This review summarizes the evidence regarding physical activity and diet after colorectal cancer diagnosis in relation to quality of life, disease recurrence, and survival. There have been extensive reports on adiposity, inactivity, and certain diets, particularly those high in red and processed meats, and increased risk of colorectal cancer. Only in the past decade have data emerged on how such lifestyle factors are associated with outcomes in colorectal cancer survivors. Prospective observational studies have consistently reported that physical activity after colorectal cancer diagnosis reduces mortality. A meta-analysis estimated that each 15 metabolic equivalent task-hour per week increase in physical activity after colorectal cancer diagnosis was associated with a 38% lower risk of mortality. No randomized controlled trials have been completed to confirm that physical activity lowers risk of mortality among colorectal cancer survivors; however, trials have shown that physical activity, including structured exercise, is safe for colorectal cancer survivors (localized to metastatic stage, during and after treatment) and improves cardiorespiratory fitness and physical function. In addition, prospective observational studies have suggested that a Western dietary pattern, high carbohydrate intake, and consuming sugar-sweetened beverages after diagnosis may increase risk of colorectal cancer recurrence and mortality, but these data are limited to single analyses from one of two US cohorts. Additional data from prospective studies and randomized controlled trials are needed. Nonetheless, on the basis of the available evidence, it is reasonable to counsel colorectal cancer survivors to engage in regular physical activity and limit consumption of refined carbohydrates, red and processed meats, and sugar-sweetened beverages.

  14. Role of Physical Activity and Diet After Colorectal Cancer Diagnosis

    PubMed Central

    Van Blarigan, Erin L.; Meyerhardt, Jeffrey A.

    2015-01-01

    This review summarizes the evidence regarding physical activity and diet after colorectal cancer diagnosis in relation to quality of life, disease recurrence, and survival. There have been extensive reports on adiposity, inactivity, and certain diets, particularly those high in red and processed meats, and increased risk of colorectal cancer. Only in the past decade have data emerged on how such lifestyle factors are associated with outcomes in colorectal cancer survivors. Prospective observational studies have consistently reported that physical activity after colorectal cancer diagnosis reduces mortality. A meta-analysis estimated that each 15 metabolic equivalent task-hour per week increase in physical activity after colorectal cancer diagnosis was associated with a 38% lower risk of mortality. No randomized controlled trials have been completed to confirm that physical activity lowers risk of mortality among colorectal cancer survivors; however, trials have shown that physical activity, including structured exercise, is safe for colorectal cancer survivors (localized to metastatic stage, during and after treatment) and improves cardiorespiratory fitness and physical function. In addition, prospective observational studies have suggested that a Western dietary pattern, high carbohydrate intake, and consuming sugar-sweetened beverages after diagnosis may increase risk of colorectal cancer recurrence and mortality, but these data are limited to single analyses from one of two US cohorts. Additional data from prospective studies and randomized controlled trials are needed. Nonetheless, on the basis of the available evidence, it is reasonable to counsel colorectal cancer survivors to engage in regular physical activity and limit consumption of refined carbohydrates, red and processed meats, and sugar-sweetened beverages. PMID:25918293

  15. Circulating levels of inflammatory cytokines and risk of colorectal adenomas

    PubMed Central

    Kim, Sangmi; Keku, Temitope O.; Martin, Christopher; Galanko, Joseph; Woosley, John T.; Schroeder, Jane C.; Satia, Jessie A.; Halabi, Susan; Sandler, Robert S.

    2009-01-01

    The association between obesity and colorectal neoplasia may be mediated by inflammation. Circulating levels of C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) are elevated in the obese. Adipose tissue can produce and release the inflammatory cytokines that are potentially procarcinogenic. We examined circulating levels of CRP, IL-6, and TNF-α in relation to risk factors and the prevalence of colorectal adenomas. Plasma levels of CRP, IL-6, and TNF-α were quantified in 873 participants (242 colorectal adenoma cases and 631 controls) in a colonoscopy-based cross-sectional study conducted between 1998 and 2002. Multivariable logistic regression was used to estimate associations between levels of inflammatory cytokines, colorectal adenomas, and known risk factors. Several known risk factors for colorectal neoplasia were associated with higher levels of inflammatory cytokines such as older age, current smoking, and increasing adiposity. The prevalence of colorectal adenomas was associated with higher concentrations of IL-6 and TNF-α, and to a lesser degree, with CRP. For IL-6, adjusted odds ratios for colorectal adenomas were 1.78 (95% confidence interval [CI]: 1.18–2.68) for the second highest plasma level, and 1.84 (95% CI: 1.24– 2.74) for the highest level compared with the reference level. A similar association was found with TNF-α, with adjusted odds ratios of 1.54 (95% CI: 1.02–2.33) and 1.65 (95% CI: 1.09–2.50), respectively. Our findings indicate that inflammation might be involved in the early development of colorectal neoplasia, and suggest that systemic inflammatory cytokines might be an indicator of obesity and other risk factors for colorectal neoplasia. PMID:18172326

  16. Effects of autophagy regulation of tumor-associated macrophages on radiosensitivity of colorectal cancer cells.

    PubMed

    Shao, Le-Ning; Zhu, Bao-Song; Xing, Chun-Gen; Yang, Xiao-Dong; Young, Wu; Cao, Jian-Ping

    2016-03-01

    Tumor‑associated macrophages (TAMs), a major component of the tumor microenvironment, are crucial to the processes of tumor growth, infiltration and metastasis, and contribute to drug resistance. The importance of TAMs in radiation resistance of colorectal cancer remains unclear. To investigate the effects of autophagy regulation of TAMs on the radiosensitivity of colorectal cancer cells, the current study induced TAM formation from THP‑1 monocyte cells. Sequential treatment of THP‑1 cells with PMA for 72 h and human recombinant interleukin‑4 for 24 h was used to stimulate THP‑1 differentiation to TAMs. Expression of the cell surface markers CD68, CD204 and CD206, and changes to cell morphology were used to confirm successful differentiation. The TAMs were stimulated to promote or inhibit autophagy during co‑culture with LoVo colorectal adenocarcinoma cells. The cells were irradiated, with subsequent measurement of LoVo colony formation and apoptosis. Additionally, the expression of p53, Bcl‑2, survivin and Smac proteins was assessed by western blotting. Monodansylcadaverin staining was used to analyze the presence of autophagic vacuoles in TAM, and western blot analysis was used to assess the expression of Beclin‑1, LC3B I and II, ATG‑3, ‑5 and ‑7. The results demonstrated TAM autophagy to be markedly altered by rapamycin and bafilomycin A1 treatment. Following co‑culture with TAMs, the colony formation rate and survival fraction of LoVo cells were significantly higher than those in the control group (P<0.05). It was further demonstrated that the regulation of autophagy in TAMs was able to inhibit the colony formation of LoVo colorectal cancer cells. Upregulation of TAM autophagy using rapamycin exhibited more effective inhibition of LoVo colony formation than autophagy downregulation. Notably, apoptosis was significantly increased in LoVo cells when co‑cultured with TAMs only, or with rapamycin‑mediated autophagy upregulated TAMs

  17. International collaboration for the prevention of colorectal cancer.

    PubMed Central

    Winawer, S. J.

    1990-01-01

    This brief paper describes the involvement of the World Health Organization in promoting international collaboration for the prevention of colorectal cancer, more than half a million cases of which are diagnosed every year. A WHO Collaborating Centre was designated in 1985 in the USA and the activities of this Centre have included the preparation of a series of six articles for publication in the Bulletin of the World Health Organization. These articles deal with primary prevention, risk and screening of average-risk individuals, as well as risk and surveillance of individuals with chronic ulcerative colitis, colorectal polyps, and heritable factors for colorectal cancer. PMID:2393985

  18. [Streamlined treatment pathway for a colorectal cancer patient].

    PubMed

    Rantala, Arto; Ristamäki, Raija; Keränen, Ulla

    2016-01-01

    The organization of colorectal cancer patient treatment, the pathway, is an important component of the quality of care of a large patient group as nearly 3000 colorectal cancer patients are diagnosed and treated annually in Finland. By designing and describing the whole pathway, the more streamlined approach can be made and thus improve patient care. Multidisciplinary team work between colorectal surgeons, oncologists, pathologists and radiologists is flexible team work, having been proven to improve overall treatment results. This method of working together is also a good tool for the development of the pathway to a better organized treatment. PMID:27483633

  19. Unsuspected colorectal carcinoma on routine abdominopelvic computed tomography.

    PubMed

    Lee, Su Ann; Poh, Angeline

    2015-05-01

    Colorectal carcinoma is a common lethal disease with signs and symptoms that may be nonspecific. Computed tomography (CT) of the abdomen and pelvis with or without contrast is frequently performed for various general abdominal complaints, but unlike CT colonography, the large bowel may not be optimally prepared for evaluation. As such, careful and diligent assessment of the non-prepared colon in all CT images of the abdomen and pelvis is important, as it ensures that incidental colorectal malignancy is not missed, especially in older patients. This article gives an overview of multidetector CT imaging signs and subtle clues to aid in the diagnosis of colorectal carcinoma, as well as their pitfalls.

  20. [Overview of current modalities of colorectal cancer screening].

    PubMed

    Kajzrlíková, Ivana Mikoviny; Vítek, Petr

    2016-04-01

    There are one-step and two-steps programs for colorectal cancer screening. The aim of all screening examinations is to detect early stage of the disease in asymptomatic patient. The aim of this article is actual review of current screening modalities such as fecal occult blood test, flexible sigmoideoscopy, colonoscopy, CT colonography, capsule endoscopy, blood-based tests and stool DNA tests. Colonoscopy still remains the gold standard for detection of colorectal neoplasias. In majority of countries worldwide programs for colorectal cancer screening are based on immunochemical fecal occult blood test followed by colonoscopy when positive.