Endoscopic detection rate of sessile serrated lesions in Lynch syndrome patients is comparable with an age- and gender-matched control population: case-control study with expert pathology review.

PubMed

Vleugels, Jasper L A; Sahin, Husna; Hazewinkel, Yark; Koens, Lianne; van den Berg, Jose G; van Leerdam, Monique E; Dekker, Evelien

2018-05-01

Carcinogenesis in Lynch syndrome involves fast progression of adenomas to colorectal cancer (CRC) because of microsatellite instability. The role of sessile serrated lesions (SSLs) and the serrated neoplasia pathway in these patients is unknown. The aim of this matched case-control study was to compare endoscopic detection rates and distribution of SSLs in Lynch syndrome patients with a matched control population. We collected data of Lynch syndrome patients with a proven germline mutation who underwent colonoscopy between January 2011 and April 2016 in 2 tertiary referral hospitals. Control subjects undergoing elective colonoscopy from 2011 and onward for symptoms or surveillance were selected from a prospectively collected database. Patients were matched 1:1 for age, gender, and index versus surveillance colonoscopy. An expert pathology review of serrated polyps was performed. The primary outcomes included the detection rates and distribution of SSLs. We identified 321 patients with Lynch syndrome who underwent at least 1 colonoscopy. Of these, 223 Lynch syndrome patients (mean age, 49.3; 59% women; index colonoscopy, 56%) were matched to 223 control subjects. SSLs were detected in 7.6% (95% confidence interval, 4.8-11.9) of colonoscopies performed in Lynch syndrome patients and in 6.7% (95% confidence interval, 4.1-10.8) of control subjects (P = .86). None of the detected SSLs in Lynch syndrome patients contained dysplasia. The detection rate of SSLs in Lynch syndrome patients undergoing colonoscopy is comparable with a matched population. These findings suggest that the role of the serrated neoplasia pathway in CRC development in Lynch syndrome seems to be comparable with that in the general population. Copyright © 2018 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.

Snaring large serrated polyps.

PubMed

Liang, Jennifer; Kalady, Matthew F; Church, James

2013-05-01

Serrated polyps of the large bowel are potentially premalignant, difficult to see, but important to remove. Few studies describe the technique or outcomes of serrated polypectomy. We sought to present outcomes of a series of polypectomies of large serrated polyps in comparison to a series of endoscopic resections of large adenomas. This retrospective, comparative, single endoscopist study was performed in an outpatient colonoscopy department of a tertiary referral medical center. Patients had outpatient colonoscopy where a large (≥2 cm) serrated polyp or adenoma was removed. Outcomes were completeness of excision and complications of polypectomy. A database of endoscopic polypectomies was reviewed. Polypectomy of large serrated polyps was compared with polypectomy of large adenomas. There were 132 large serrated polyps in 112 patients and 563 adenomas in 428 patients. More serrated polyps were right sided (120 of 130, 92.3 %, vs. 379 of 563, 67 %) (p < 0.0001). The serrated polyps were smaller than the adenomas (mean 25.5 ± 7.9 mm standard deviation) versus 36.8 ± 16.9 mm standard deviation (p < 0.001). There were four complications of serrated polypectomy in four patients (4 % of polyps, 5 % of patients): three postpolypectomy bleeds and one postpolypectomy syndrome. There were 33 complications of adenoma removal (31 postpolypectomy bleeding and two postpolypectomy syndrome) (6.9 % of polyps, p = 0.376, 8.4 % of patients, p = 0.371). On follow-up, 36 of 51 patients (71 %) with serrated polyps had metachronous lesions compared to 133 of 298 patients (45 %) with adenomas (p < 0.0001). There were fewer residual polyps in the serrated group (4 of 47 vs. 64 of 298, p = 0.001). Removal of large serrated colorectal polyps is no more complicated than polypectomy of similarly sized adenomas. However, large serrated polyps have a higher rate of metachronous polyps than similarly sized adenomas and surveillance should be adapted to reflect these findings.

Aberrant epithelial GREM1 expression initiates colonic tumorigenesis from cells outside of the crypt base stem cell niche

PubMed Central

Bansal, Mukesh; Rafferty, Hannah; Boitsova, Tatjana; Bardella, Chiara; Jaeger, Emma; Lewis, Annabelle; Freeman-Mills, Luke; Giner, Francesc Castro; Rodenas-Cuadrado, Pedro; Mallappa, Sreelakshmi; Clark, Susan; Thomas, Huw; Jeffery, Rosemary; Poulsom, Richard; Rodriguez-Justo, Manuel; Novelli, Marco; Chetty, Runjan; Silver, Andrew; Sansom, Owen James; Greten, Florian R; Wang, Lai Mun; East, James Edward; Tomlinson, Ian; Leedham, Simon John

2015-01-01

Hereditary mixed polyposis syndrome (HMPS) is characterised by the development of mixed morphology colorectal tumours and is caused by a 40 kb duplication that results in aberrant epithelial expression of the mesenchymal Bone Morphogenetic Protein antagonist, GREM1. Here we use HMPS tissue and a mouse model of the disease to show that epithelial GREM1 disrupts homeostatic intestinal morphogen gradients, altering cell-fate, that is normally determined by position along the vertical epithelial axis. This promotes the persistence and/or reacquisition of stem-cell properties in Lgr5 negative (non-expressing) progenitor cells that have exited the stem-cell niche. These cells form ectopic crypts, proliferate, accumulate somatic mutations and can initiate intestinal neoplasia, indicating that the crypt base stem-cell is not the sole cell-of-origin of colorectal cancer. Furthermore, we show that epithelial expression of GREM1 also occurs in traditional serrated adenomas, sporadic pre-malignant lesions with a hitherto unknown pathogenesis and these lesions can be considered the sporadic equivalents of HMPS polyps. PMID:25419707

BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt-beta-catenin signaling.

PubMed

He, Xi C; Zhang, Jiwang; Tong, Wei-Gang; Tawfik, Ossama; Ross, Jason; Scoville, David H; Tian, Qiang; Zeng, Xin; He, Xi; Wiedemann, Leanne M; Mishina, Yuji; Li, Linheng

2004-10-01

In humans, mutations in BMPR1A, SMAD4 and PTEN are responsible for juvenile polyposis syndrome, juvenile intestinal polyposis and Cowden disease, respectively. The development of polyposis is a common feature of these diseases, suggesting that there is an association between BMP and PTEN pathways. The mechanistic link between BMP and PTEN pathways and the related etiology of juvenile polyposis is unresolved. Here we show that conditional inactivation of Bmpr1a in mice disturbs homeostasis of intestinal epithelial regeneration with an expansion of the stem and progenitor cell populations, eventually leading to intestinal polyposis resembling human juvenile polyposis syndrome. We show that BMP signaling suppresses Wnt signaling to ensure a balanced control of stem cell self-renewal. Mechanistically, PTEN, through phosphatidylinosital-3 kinase-Akt, mediates the convergence of the BMP and Wnt pathways on control of beta-catenin. Thus, BMP signaling may control the duplication of intestinal stem cells, thereby preventing crypt fission and the subsequent increase in crypt number.

Peutz-Jeghers syndrome: data from the Singapore Polyposis Registry and a shifting paradigm in management.

PubMed

Tan, Veronique Km; Koh, Poh Koon; Loi, Carol Tt; Eu, Kong Weng; Tang, Choong Leong

2010-01-01

Peutz-Jeghers Syndrome (PJS) is an uncommon autosomal dominant hamartomatous polyposis syndrome. Morbidity arises from polyp-related complications and increased risks of malignancy. We report on PJS patients registered in the Singapore Polyposis Registry, identified principal causes of morbidity and appraised current management strategies. A followup protocol based on recent literature has been proposed. A search of a prospectively collected database in the Singapore Polyposis Registry was made. Only patients who fulfilled the diagnostic criteria of PJS were included. The clinical records were retrieved for review. Information on affected family members was obtained from the Registry's pedigree records. Seven unrelated patients fulfilled the criteria of having PJS. Principal causes of morbidity include recurrent bouts of abdominal colic, episodes of intestinal obstruction, gastrointestinal bleeding and the need for repeated laparotomies. Six out of 7 patients had initial presentation with acute intestinal obstruction requiring emergency laparotomy. Management was mostly problem-oriented and marked inter-surgeon variation with regard to cancer screening and genetic counselling was observed. Patients with PJS suffer gastrointestinal complications from polyposis and are at increased risks for developing cancers. A move towards surveillance and planned comprehensive care may reduce the morbidity of the condition. A protocol driven approach conducted in the setting of a Polyposis Registry is ideally suited to facilitate such care.

General Aspects of Colorectal Cancer

PubMed Central

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. PMID:23209942

Identification of Patients at Risk for Hereditary Colorectal Cancer

PubMed Central

Mishra, Nitin; Hall, Jason

2012-01-01

Diagnosis of hereditary colorectal cancer syndromes requires clinical suspicion and knowledge of such syndromes. Lynch syndrome is the most common cause of hereditary colorectal cancer. Other less common causes include familial adenomatous polyposis (FAP), Peutz-Jeghers syndrome (PJS), juvenile polyposis syndrome, and others. There have been a growing number of clinical and molecular tools used to screen and test at risk individuals. Screening tools include diagnostic clinical criteria, family history, genetic prediction models, and tumor testing. Patients who are high risk based on screening should be referred for genetic testing. PMID:23730221

Multidetector CT diagnosis of massive hemobilia due to gallbladder polyposis in a child with metachromatic leukodystrophy.

PubMed

Wanner, Matthew R; Karmazyn, Boaz; Fan, Rong

2015-12-01

Hemobilia secondary to gallbladder polyposis is rare in children but has been reported in a few children with metachromatic leukodystrophy. We present a case with preoperative multidetector computed tomography (MDCT) diagnosis of massive hemobilia caused by gallbladder polyposis in a patient with metachromatic leukodystrophy. Our report highlights the importance of both awareness of the association of gallbladder polyposis with other syndromes such as metachromatic leukodystrophy as well as the possibility of this entity presenting with life-threatening bleeding.

Appreciating the broad clinical features of SMAD4 mutation carriers: a multicenter chart review.

PubMed

Wain, Karen E; Ellingson, Marissa S; McDonald, Jamie; Gammon, Amanda; Roberts, Maegan; Pichurin, Pavel; Winship, Ingrid; Riegert-Johnson, Douglas L; Weitzel, Jeffrey N; Lindor, Noralane M

2014-08-01

Heterozygous loss-of-function SMAD4 mutations are associated with juvenile polyposis syndrome and hereditary hemorrhagic telangiectasia. Some carriers exhibit symptoms of both conditions, leading to juvenile polyposis-hereditary hemorrhagic telangiectasia syndrome. Three families have been reported with connective tissue abnormalities. To better understand the spectrum and extent of clinical findings in SMAD4 carriers, medical records of 34 patients (20 families) from five clinical practices were reviewed. Twenty-one percent of the patients (7/34) had features suggesting a connective tissue defect: enlarged aortic root (n = 3), aortic and mitral insufficiency (n = 2), aortic dissection (n = 1), retinal detachment (n = 1), brain aneurysms (n = 1), and lax skin and joints (n = 1). Juvenile polyposis-specific findings were almost uniformly present but variable. Ninety-seven percent of the patients had colon polyps that were generally pan-colonic and of variable histology and number. Forty-eight percent of the patients (15/31) had extensive gastric polyposis. Hereditary hemorrhagic telangiectasia features, including epistaxis (19/31, 61%), mucocutaneous telangiectases (15/31, 48%), liver arteriovenous malformation (6/16, 38%), brain arteriovenous malformation (1/26, 4%), pulmonary arteriovenous malformation (9/17, 53%), and intrapulmonary shunting (14/23, 61%), were documented in 76% of the patients. SMAD4 carriers should be managed for juvenile polyposis and hereditary hemorrhagic telangiectasia because symptoms of both conditions are likely yet unpredictable. Connective tissue abnormalities are an emerging component of juvenile polyposis-hereditary hemorrhagic telangiectasia syndrome, and larger studies are needed to understand these manifestations.

Gastric tumours in hereditary cancer syndromes: clinical features, molecular biology and strategies for prevention.

PubMed

Sereno, María; Aguayo, Cristina; Guillén Ponce, Carmen; Gómez-Raposo, César; Zambrana, Francisco; Gómez-López, Miriam; Casado, Enrique

2011-09-01

Gastric cancer is the major cause of cancer-related deaths worldwide. The majority of them are classified as sporadic, whereas the remaining 10% exhibit familial clustering. Hereditary diffuse gastric cancer (HDGC) syndrome is the most important condition that leads to hereditary gastric cancer. However, other hereditary cancer syndromes, such as hereditary non-polyposis colorectal cancer, familial adenomatous polyposis, Peutz-Jeghers syndrome, Li-Fraumeni syndrome and hereditary breast and ovarian cancer, entail a higher risk compared to the general population for developing this kind of neoplasia. In this review, we describe briefly the most important aspects related to clinical features, molecular biology and strategies for prevention in hereditary gastric associated to different cancer syndromes.

Cronkhite-Canada Syndrome (CCS)-A Rare Case Report.

PubMed

Chakrabarti, Subrata

2015-03-01

Cronkhite-Canada syndrome (CCS) is an extremely rare non-inherited condition characterized by gastrointestinal hamartomatous polyposis, alopecia, onychodystrophy, hyperpigmentation, weight loss and diarrhoea. The aetiology is probably autoimmune and diagnosis is based on history, physical examination, endoscopic findings of gastrointestinal polyposis, and histology. The disease is very rare; approximately 450 cases of CCS have been reported worldwide. The author reports a case of CCS in an elderly Indian male.

Perinatal detection of familial adenomatous polyposis.

PubMed

Birsner, Meredith L; Hoover-Fong, Julie; Bytyci Telegrafi, Aida; Hueppchen, Nancy A

2012-08-01

Hepatoblastoma is an uncommon fetal neoplasm that may represent an isolated malignancy or a component of a familial cancer or syndromic diagnosis. A large fetal liver mass was detected on routine ultrasound examination of a 23-year-old woman with thyroid nodules and hypertension. Inferior vena cava compression prompted delivery; postnatal biopsy revealed hepatoblastoma. Maternal thyroid biopsy revealed papillary carcinoma. Neonatal and maternal cytomolecular analysis revealed APC gene disruption at 5q22.2. Pedigree analysis exposed multigenerational colon cancer and thyroid cancer, which in conjunction with genetic testing is consistent with familial adenomatous polyposis. This is a novel means of familial adenomatous polyposis diagnosis. Obstetricians and perinatologists should be alert for familial cancer or syndromic diagnoses presenting as fetal neoplasms.

Attenuated familial adenomatous polyposis and Muir-Torre syndrome linked to compound biallelic constitutional MYH gene mutations.

PubMed

Ponti, G; Ponz de Leon, M; Maffei, S; Pedroni, M; Losi, L; Di Gregorio, C; Gismondi, V; Scarselli, A; Benatti, P; Roncari, B; Seidenari, S; Pellacani, G; Varotti, C; Prete, E; Varesco, L; Roncucci, L

2005-11-01

Attenuated familial adenomatous polyposis and Muir-Torre syndrome linked to compound biallelic constitutional MYH gene mutations.Peculiar dermatologic manifestations are present in several heritable gastrointestinal disorders. Muir-Torre syndrome (MTS) is a genodermatosis whose peculiar feature is the presence of sebaceous gland tumors associated with visceral malignancies. We describe one patient in whom multiple sebaceous gland tumors were associated with early onset colon and thyroid cancers and attenuated polyposis coli. Her family history was positive for colonic adenomas. She had a daughter presenting with yellow papules in the forehead region developed in the late infancy. Skin and visceral neoplasms were tested for microsatellite instability and immunohistochemical status of mismatch repair (MMR), APC and MYH proteins. The proband colon and skin tumors were microsatellite stable and showed normal expression of MMR proteins. Cytoplasmic expression of MYH protein was revealed in colonic cancer cells. Compound heterozygosity due to biallelic mutations in MYH, R168H and 379delC, was identified in the proband. The 11-year-old daughter was carrier of the monoallelic constitutional mutation 379delC in the MYH gene; in the sister, the R168H MYH gene mutation was detected. This report presents an interesting case of association between MYH-associated polyposis and sebaceous gland tumors. These findings suggest that patients with MTS phenotype that include colonic polyposis should be screened for MYH gene mutations.

Familial colorectal cancer.

PubMed

Lung, M S; Trainer, A H; Campbell, I; Lipton, L

2015-05-01

Identifying individuals with a genetic predisposition to developing familial colorectal cancer (CRC) is crucial to the management of the affected individual and their family. In order to do so, the physician requires an understanding of the different gene mutations and clinical manifestations of familial CRC. This review summarises the genetics, clinical manifestations and management of the known familial CRC syndromes, specifically Lynch syndrome, familial adenomatous polyposis, MUTYH-associated neoplasia, juvenile polyposis syndrome and Peutz-Jeghers syndrome. An individual suspected of having a familial CRC with an underlying genetic predisposition should be referred to a familial cancer centre to enable pre-test counselling and appropriate follow up. © 2015 Royal Australasian College of Physicians.

Single Incision Laparoscopic Surgery in Treating Patients With Colorectal Disease

ClinicalTrials.gov

2017-12-04

Adenomatous Polyp; Crohn Disease; Familial Adenomatous Polyposis; Hereditary Intestinal Polyposis Syndrome; Recurrent Colon Cancer; Stage I Colon Cancer; Stage IIA Colon Cancer; Stage IIB Colon Cancer; Stage IIC Colon Cancer; Stage IIIA Colon Cancer; Stage IIIB Colon Cancer; Stage IIIC Colon Cancer

Role of GALNT12 in the genetic predisposition to attenuated adenomatous polyposis syndrome

PubMed Central

Lorca, Víctor; Rueda, Daniel; Martín-Morales, Lorena; Poves, Carmen; Fernández-Aceñero, María Jesús; Ruiz-Ponte, Clara; Llovet, Patricia; Marrupe, David; García-Barberán, Vanesa; García-Paredes, Beatriz; Pérez-Segura, Pedro; de la Hoya, Miguel; Díaz-Rubio, Eduardo; Caldés, Trinidad

2017-01-01

The involvement of GALNT12 in colorectal carcinogenesis has been demonstrated but it is not clear to what extent it is implicated in familial CRC susceptibility. Partially inactivating variant, NM_024642.4:c.907G>A, p.(D303N), has been previously detected in familial CRC and proposed as the causative risk allele. Since phenotypes of the described carrier families showed not only CRC but also a polyp history, we hypothesized that GALNT12 could be involved in adenoma predisposition and consequently, in hereditary polyposis CRC syndromes. For that purpose, we have screened the GALNT12 gene in germline DNA from 183 unrelated attenuated polyposis patients. c.907G>A, p.(D303N) was detected in 4 cases (MAF = 1.1%) and no other candidate variants were found. After segregation studies, LOH analyses, glycosylation pattern tests and case-control studies, our results did not support the role of c.907G>A, p.(D303N) as a high-penetrance risk allele for polyposis CRC. PMID:29095867

[Consensus on clinical diagnosis, treatment and pedigree management of hereditary colorectal cancer in China].

PubMed

2018-01-23

Hereditary colorectal cancer can be divded into two categories based on the presence or absence of polyps. The first category is characterized by the development of polyposis, which includes familial adenomatous polyposis (FAP); The second category is nonpolyposis colorectal cancer, which is represented by Lynch syndrome. "Consensus on clinical diagnosis, treatment and pedigree management of hereditary colorectal cancer in China" developed by the Genetics Group of the Committee of Colorectal Cancer, Chinese Anti-cancer Association, is composed of three sections, including hereditary nonpolyposis syndrome, polyposis syndrome as well as genetic evaluation of hereditary colorectal cancer. The consensus aims to provide recommendations on management of the respective hereditary syndromes in terms of definition, clinical and pathological features, diagnostic standards, treatment, and follow-ups. In addition to describing diagnostic and treatment strategies, prophylactic treatment as well as genetic screening and pedigree monitoring is highly recommended. Through the establishment of this expert consensus, we hope to promote better understanding of hereditary colorectal cancer for clinicians and encourage standardized treatment through multidisciplinery approaches, eventually improving clinical treatment and pedigree management of hereditary colorectal cancer in China.

ColoSeq provides comprehensive lynch and polyposis syndrome mutational analysis using massively parallel sequencing.

PubMed

Pritchard, Colin C; Smith, Christina; Salipante, Stephen J; Lee, Ming K; Thornton, Anne M; Nord, Alex S; Gulden, Cassandra; Kupfer, Sonia S; Swisher, Elizabeth M; Bennett, Robin L; Novetsky, Akiva P; Jarvik, Gail P; Olopade, Olufunmilayo I; Goodfellow, Paul J; King, Mary-Claire; Tait, Jonathan F; Walsh, Tom

2012-07-01

Lynch syndrome (hereditary nonpolyposis colon cancer) and adenomatous polyposis syndromes frequently have overlapping clinical features. Current approaches for molecular genetic testing are often stepwise, taking a best-candidate gene approach with testing of additional genes if initial results are negative. We report a comprehensive assay called ColoSeq that detects all classes of mutations in Lynch and polyposis syndrome genes using targeted capture and massively parallel next-generation sequencing on the Illumina HiSeq2000 instrument. In blinded specimens and colon cancer cell lines with defined mutations, ColoSeq correctly identified 28/28 (100%) pathogenic mutations in MLH1, MSH2, MSH6, PMS2, EPCAM, APC, and MUTYH, including single nucleotide variants (SNVs), small insertions and deletions, and large copy number variants. There was 100% reproducibility of detection mutation between independent runs. The assay correctly identified 222 of 224 heterozygous SNVs (99.4%) in HapMap samples, demonstrating high sensitivity of calling all variants across each captured gene. Average coverage was greater than 320 reads per base pair when the maximum of 96 index samples with barcodes were pooled. In a specificity study of 19 control patients without cancer from different ethnic backgrounds, we did not find any pathogenic mutations but detected two variants of uncertain significance. ColoSeq offers a powerful, cost-effective means of genetic testing for Lynch and polyposis syndromes that eliminates the need for stepwise testing and multiple follow-up clinical visits. Copyright © 2012 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.

Constitutional MLH1 methylation presenting with colonic polyposis syndrome and not Lynch syndrome.

PubMed

Kidambi, Trilokesh D; Blanco, Amie; Van Ziffle, Jessica; Terdiman, Jonathan P

2016-04-01

At least one-third of patients meeting clinical criteria for Lynch syndrome will have no germline mutation and constitutional epimutations leading to promoter methylation of MLH1 have been identified in a subset of these patients. We report the first case of constitutional MLH1 promoter methylation associated with a colonic polyposis syndrome in a 39 year-old man with a family history of colorectal cancer (CRC) and a personal history of 21 polyps identified over 8 years as well as the development of two synchronous CRCs over 16 months who was evaluated for a hereditary cancer syndrome. Immunohistochemistry (IHC) of multiple tumors showed absent MLH1 and PMS2 expression, though germline testing with Sanger sequencing and multiplex ligation-dependent probe amplification of these mismatch repair genes (MMR) genes was negative. A next generation sequencing panel of 29 genes also failed to identify a pathogenic mutation. Hypermethylation was identified in MLH1 intron 1 in tumor specimens along with buccal cells and peripheral white blood cells, confirming the diagnosis of constitutional MLH1 promoter methylation. This case highlights that constitutional MLH1 methylation should be considered in the differential diagnosis for a polyposis syndrome if IHC staining shows absent MMR gene expression.

Cancer emerging from the recurrence of sessile serrated adenoma/polyp resected endoscopically 5 years ago.

PubMed

Chino, A; Nagayama, S; Ishikawa, H; Morishige, K; Kishihara, T; Arai, M; Sugiura, Y; Motoi, N; Yamamoto, N; Tamegai, Y; Igarashi, M

2016-01-01

Since the serrated neoplastic pathway has been regarded as an important pathway of colorectal carcinogenesis, few reports have been published on clinical cases of cancer derived from sessile serrated adenoma/polyp, especially on recurrence after resected sessile serrated adenoma/polyp. An elderly woman underwent endoscopic mucosal resection of a flat elevated lesion, 30 mm in diameter, in the ascending colon; the histopathological diagnosis at that time was a hyperplastic polyp, now known as sessile serrated adenoma/polyp. Five years later, cancer due to the malignant transformation of the sessile serrated adenoma/polyp was detected at the same site. The endoscopic diagnosis was a deep invasive carcinoma with a remnant sessile serrated adenoma/polyp component. The carcinoma was surgically removed, and the pathological diagnosis was an adenocarcinoma with sessile serrated adenoma/polyp, which invaded the muscularis propria. The surgically removed lesion did not have a B-RAF mutation in either the sessile serrated adenoma/polyp or the carcinoma; moreover, the initial endoscopically resected lesion also did not have a B-RAF mutation. Immunohistochemistry confirmed negative MLH1 protein expression in only the cancer cells. Lynch syndrome was not detected on genomic examination. The lesion was considered to be a cancer derived from sessile serrated adenoma/polyp recurrence after endoscopic resection, because both the surgically and endoscopically resected lesions were detected at the same location and had similar pathological characteristics, with a serrated structure and low-grade atypia. Furthermore, both lesions had a rare diagnosis of a sessile serrated adenoma/polyp without B-RAF mutation. This report highlights the need for the follow-up colonoscopy after endoscopic resection and rethinking our resection procedures to improve treatment. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Germline Mutations in BMPR1A/ALK3 Cause a Subset of Cases of Juvenile Polyposis Syndrome and of Cowden and Bannayan-Riley-Ruvalcaba Syndromes*

PubMed Central

Zhou, Xiao-Ping; Woodford-Richens, Kelly; Lehtonen, Rainer; Kurose, Keisuke; Aldred, Micheala; Hampel, Heather; Launonen, Virpi; Virta, Sanno; Pilarski, Robert; Salovaara, Reijo; Bodmer, Walter F.; Conrad, Beth A.; Dunlop, Malcolm; Hodgson, Shirley V.; Iwama, Takeo; Järvinen, Heikki; Kellokumpu, Ilmo; Kim, J. C.; Leggett, Barbara; Markie, David; Mecklin, Jukka-Pekka; Neale, Kay; Phillips, Robin; Piris, Juan; Rozen, Paul; Houlston, Richard S.; Aaltonen, Lauri A.; Tomlinson, Ian P. M.; Eng, Charis

2001-01-01

Juvenile polyposis syndrome (JPS) is an inherited hamartomatous-polyposis syndrome with a risk for colon cancer. JPS is a clinical diagnosis by exclusion, and, before susceptibility genes were identified, JPS could easily be confused with other inherited hamartoma syndromes, such as Bannayan-Riley-Ruvalcaba syndrome (BRRS) and Cowden syndrome (CS). Germline mutations of MADH4 (SMAD4) have been described in a variable number of probands with JPS. A series of familial and isolated European probands without MADH4 mutations were analyzed for germline mutations in BMPR1A, a member of the transforming growth-factor β–receptor superfamily, upstream from the SMAD pathway. Overall, 10 (38%) probands were found to have germline BMPR1A mutations, 8 of which resulted in truncated receptors and 2 of which resulted in missense alterations (C124R and C376Y). Almost all available component tumors from mutation-positive cases showed loss of heterozygosity (LOH) in the BMPR1A region, whereas those from mutation-negative cases did not. One proband with CS/CS-like phenotype was also found to have a germline BMPR1A missense mutation (A338D). Thus, germline BMPR1A mutations cause a significant proportion of cases of JPS and might define a small subset of cases of CS/BRRS with specific colonic phenotype. PMID:11536076

The gastrointestinal manifestation of constitutional mismatch repair deficiency syndrome: from a single adenoma to polyposis-like phenotype and early onset cancer.

PubMed

Levi, Z; Kariv, R; Barnes-Kedar, I; Goldberg, Y; Half, E; Morgentern, S; Eli, B; Baris, H N; Vilkin, A; Belfer, R G; Niv, Y; Elhasid, R; Dvir, R; Abu-Freha, N; Cohen, S

2015-11-01

Data on the clinical presentation of constitutional mismatch repair deficiency syndrome (CMMRD) is accumulating. However, as the extraintestinal manifestations are often fatal and occur at early age, data on the systematic evaluation of the gastrointestinal tract is scarce. Here we describe 11 subjects with verified biallelic carriage and who underwent colonoscopy, upper endoscopy and small bowel evaluation. Five subjects were symptomatic and in six subjects the findings were screen detected. Two subjects had colorectal cancer and few adenomatous polyps (19, 20 years), three subjects had polyposis-like phenotype (13, 14, 16 years), four subjects had few adenomatous polyps (8, 12-14 years) and two subjects had no polyps (both at age 6). Of the three subjects in the polyposis-like group, two subjects had already developed high-grade dysplasia or cancer and one subject had atypical juvenile polyps suggesting juvenile polyposis. Three out of the five subjects that underwent repeated exams had significant findings during short interval. The gastrointestinal manifestations of CMMRD are highly dependent upon age of examination and highly variable. The polyps may also resemble juvenile polyposis. Intensive surveillance according to current guidelines is mandatory. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Adenomas of the common bile duct in familial adenomatous polyposis

PubMed Central

Yan, Mao-Lin; Pan, Jun-Yong; Bai, Yan-Nan; Lai, Zhi-De; Chen, Zhong; Wang, Yao-Dong

2015-01-01

Familial adenomatous polyposis (FAP) or Gardner’s syndrome is often accompanied by adenomas of the stomach and duodenum. We experienced a case of adenomas of the common bile duct in a 40-year-old woman with FAP presenting with acute cholangitis. Only 8 cases of adenomas or adenocarcinoma of the common bile duct have been reported in the literature in patients with FAP or Gardner’s syndrome. Those patients presented with acute cholangitis or pancreatitis. Local excision or Whipple procedure may be the reasonable surgical option. PMID:25780319

Molecular approach to genetic and epigenetic pathogenesis of early-onset colorectal cancer

PubMed Central

Tezcan, Gulcin; Tunca, Berrin; Ak, Secil; Cecener, Gulsah; Egeli, Unal

2016-01-01

Colorectal cancer (CRC) is the third most frequent cancer type and the incidence of this disease is increasing gradually per year in individuals younger than 50 years old. The current knowledge is that early-onset CRC (EOCRC) cases are heterogeneous population that includes both hereditary and sporadic forms of the CRC. Although EOCRC cases have some distinguishing clinical and pathological features than elder age CRC, the molecular mechanism underlying the EOCRC is poorly clarified. Given the significance of CRC in the world of medicine, the present review will focus on the recent knowledge in the molecular basis of genetic and epigenetic mechanism of the hereditary forms of EOCRC, which includes Lynch syndrome, Familial CRC type X, Familial adenomatous polyposis, MutYH-associated polyposis, Juvenile polyposis syndrome, Peutz-Jeghers Syndrome and sporadic forms of EOCRC. Recent findings about molecular genetics and epigenetic basis of EOCRC gave rise to new alternative therapy protocols. Although exact diagnosis of these cases still remains complicated, the present review paves way for better predictions and contributes to more accurate diagnostic and therapeutic strategies into clinical approach. PMID:26798439

Clinical characterization and mutation spectrum in Hispanic families with adenomatous polyposis syndromes.

PubMed

Cruz-Correa, Marcia; Diaz-Algorri, Yaritza; Mendez, Vanessa; Vazquez, Pedro Juan; Lozada, Maria Eugenia; Freyre, Katerina; Lathroum, Liselle; Gonzalez-Pons, Maria; Hernandez-Marrero, Jessica; Giardiello, Francis; Rodriguez-Quilichini, Segundo

2013-09-01

Several genetically defined hereditary colorectal cancer (CRC) syndromes are associated with colonic polyposis including familial adenomatous polyposis (FAP) and MUTYH adenomatous polyposis (MAP). Limited data exists on the clinical characterization and genotypic spectrum of polyposis syndromes among Hispanics. To describe the phenotype and genotype of Puerto Rican Hispanic patients with FAP and MUTYH and compare with other ethnic and racial groups. Probands were identified from the Puerto Rico Familial Colorectal Cancer Registry (PURIFICAR). Recruited individuals completed risk factors, medical, and family history questionnaires and underwent genetic testing for genotype analysis. Frequency analysis, Chi square, Fisher's exact and Wilcoxon rank-sum tests were used for statistical analysis methods. A total of 31 FAP (from 19 families) and 13 MAP (from 13 families) Hispanic patients recruited from the PURIFICAR were evaluated. Among the FAP cases, mean age at diagnosis was 27.6 (range 9-71 years); 67.7 % cases had more than 100 polyps and 41.9 % had upper gastrointestinal polyps. Among the 19 FAP families, there were 77 affected FAP individuals and 26 colorectal cancer cases. Genetic mutations were available for 42.2 % of FAP families; all mutations identified were unique. Surgeries were reported in 31 cases; 14 (45.2 %) prophylactic surgeries and 6 (19.4 %) therapeutic surgeries for management of CRC. Among MAP cases, mean age at diagnosis was 53 (range 34-76 years). Genetic analysis revealed homozygous biallelic mutations (G382D) in 53.8 %, compound heterozygous mutations (G382/Y165C) in 23 %, and non-G382/Y165C monoallelic mutations in 23 %. Familial cancer registries should be promoted as vehicles for detection, education and follow up of families at-risk of acquiring familial cancers. PURIFICAR is the first and only familial cancer registry in Puerto Rico providing these services to families affected with familial cancer syndromes promoting education, testing and surveillance of at-risk family members, and focusing on cancer prevention efforts. The fact that only 40 % of FAP patients had access to genetic testing stresses the need to promote the establishment of policies supporting genetic testing coverage by medical insurance companies in order to provide patients with the highest standard of care to prevent cancer. Furthermore, our results suggest that Hispanics may have uncommon mutations in adenomatous polyposis related genes, which emphasize the need for full gene sequencing to establish genetic diagnosis.

Exclusion of the APC gene as the cause of a variant form of familial adenomatous polyposis (FAP)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stella, A.; Resta, N.; Susca, F.

Familial adenomatous polyposis (FAP) is a premalignant disease inherited as an autosomal dominant trait, characterized by hundreds to thousands of polyps in the colorectal tract. Recently, the syndrome has been shown to be caused by mutations in the APC (adenomatous polyposis coli) gene located on chromosome 5q21. The authors studied two families that both presented a phenotype different from that of the classical form of FAP. The most important findings observed in these two kindreds are (a) low and variable number of colonic polyps (from 5 to 100) and (b) a slower evolution of the disease, with colon cancer occurringmore » at a more advanced age than in FAP in spite of the early onset of intestinal manifestations. To determine whether mutations of the APC gene are also responsible for this variant syndrome, linkage studies were performed by using a series of markers both intragenic and tightly linked to the APC gene. The results provide evidence for exclusion of the APC gene as the cause of the variant form of polyposis present in the two families described. 30 refs., 1 fig., 1 tab.« less

Hereditary Mixed Polyposis Syndrome

MedlinePlus

... family. For most families with HMPS, a specific gene mutation causing the syndrome cannot be identified, although some ... Most, but not all, people with inherited GREM1 gene mutations are of Ashkenazi Jewish ancestry. How is HMPS ...

[Inherited colorectal cancer predisposition syndromes identified in the Instituto Nacional de Enfermedades Neoplasicas (INEN), Lima, Peru;].

PubMed

Castro-Mujica, María del Carmen; Sullcahuamán-Allende, Yasser; Barreda-Bolaños, Fernando; Taxa-Rojas, Luis

2014-04-01

Colorectal cancer (CRC) is the fourth most common cancer in the world and is classified according to their origin in sporadic CRC (~ 70%) and genetic CRC (~ 30%), this latter involves cases of familial aggregation and inherited síndromes that predispose to CRC. To describe inherited CRC predisposition syndromes, polyposic and non-polyposic, identified in the Oncogenetics Unit at National Institute of Cancer Disease (INEN). A descriptive observational record from the attentions of the Oncogenetics Unit at INEN during 2009 to 2013. We included patients with personal or familiar history of CRC and/or colonic polyposis who were referred for clinical assessment to the Oncogenetics Unitat INEN. 59.3 % were female, 40.7 % male, 69.8% under 50 years old, 60.5% had a single CRC, 23.2% had more than one CRC or CRC associated with other extracolonic neoplasia and 32.6% had a familiar history of cancer with autosomal dominant inheritance. According to the clinical genetic diagnosis, 93.1% of the included cases were inherited syndromes that predispose to CRC, with 33.8% of colonic polyposis syndromes, 23.3% of hereditary nonpolyposis CRC syndromes (HNPCC) and 36.0% of CCRHNP probable cases. Clinical genetic evaluation of patients with personal or familiar history of CRC and/or colonic polyposis can identify inherited colorectal cancer predisposition syndromes and provide an appropriategenetic counseling to patients and relatives at risk, establishing guidelines to follow-up and prevention strategies to prevent morbidity and mortality by cancer.

Café au lait macules and juvénile polyps.

PubMed

Pacheco, Theresa R; Scatena, Lisa S; Hoffenberg, Edward J; Gralla, Jane; Lee, Lela A

2007-01-01

Several hereditary and nonhereditary gastrointestinal tract polyposis syndromes exhibit extra-intestinal manifestations, including cutaneous findings. However, a lack of information exists regarding cutaneous features of juvenile polyposis. Our objective was to document the prevalence of cutaneous hyperpigmented lesions in children with juvenile polyposis coli or juvenile polyposis coli and their first degree relatives.Children seen in the gastroenterology practice at The Children's Hospital in Denver, Colorado with polyps (juvenile polyposis coli, sporadic juvenile polyps, and familial adenomatous polyposis coli) and their first degree relatives were invited to participate in the study. A comprehensive skin examination was performed on those who consented to participate. We found that 8 of 14 patients (eight with juvenile polyposis coli, four with juvenile polyposis, and two with familial adenomatous polyposis coli) had at least one café-au-lait macule, compared with three of 27 relatives (p=0.003).The prevalence of at least one café-au-lait macule in our patients (8/14 or 57.1%, CI: 28.9–82.3%) was significantly higher than the general population prevalence of 28.5% (p=0.023). However, if the two patients with familial adenomatous polyposis coli were excluded, the comparison with the general population prevalence did not reach statistical significance (p=0.095). The prevalence of multiple cafe´-au-lait macules in our patients (4/14 or 28.6%; CI:8.4–58.1%) was significantly higher than the general population prevalence of 5.2% (p ¼ 0.005). A notable finding was the presence of multiple café -au-lait macules in 4 of 12 juvenile polyposis coli/juvenile polyposis patients.Two patients with juvenile polyposis coli also had lentigines. In this selected case series, we observed single or multiple café-au-lait macules in a high proportion of children with the three types of polyps. Further studies are needed to assess a possible common pathway for hamartomatous polypsand café-au-lait macules.

Massive Gastric Juvenile Polyposis: A Clinicopathologic Study Using SMAD4 Immunohistochemistry.

PubMed

Lawless, Margaret E; Toweill, Daniel L; Jewell, Kim D; Jain, Dhanpat; Lamps, Laura; Krasinskas, Alyssa M; Swanson, Paul E; Upton, Melissa P; Yeh, Matthew M

2017-04-01

Juvenile polyps involving the stomach are uncommon. Massive gastric juvenile polyposis is even rarer. We describe the clinicopathologic features of nine cases of massive gastric juvenile polyposis. All patients had anemia; four had hypoalbuminemia. The polyps were composed predominantly of dilated crypts lined by columnar epithelium and abundant edematous stroma with mixed inflammatory infiltrates. One patient had a poorly differentiated adenocarcinoma, arising in juvenile polyp-associated intraepithelial neoplasia. A second patient had a well-differentiated intramucosal adenocarcinoma arising in a juvenile polyp with high-grade dysplasia. Three of our cases had polyposis restricted to the stomach. Six (66.6%) had loss of SMAD4 immunoreactivity, making them subject to severe bleeding and hypoproteinemia, as well as developing severe dysplasia or adenocarcinoma. SMAD4 immunohistochemstry is a helpful ancillary diagnostic test in cases of suspected juvenile polyposis syndrome involving the stomach. © American Society for Clinical Pathology, 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Colorectal adenomatous polyposis syndromes: Genetic determinism, clinical presentation and recommendations for care.

PubMed

Buecher, Bruno

2016-02-01

Colorectal adenomatous polyposis constitutes a diverse group of disorders with different modes of inheritance. Molecular diagnosis of this condition has become more complex. In fact, somatic mosaicism for APC mutations now appears to be more frequent than previously thought and rare germline alterations of this gene may be implicated in patients tested negative for "classical" APC mutations (point mutations and large genomic rearrangements). Moreover, the knowledge concerning several aspects of the MUTYH-associated polyposis has improved since its first description in 2002 and germline mutations in new genes have recently been implicated in some cases of unexplained adenomatous polyposis. Genetic testing in probands and their relatives should be conducted in the context of pre- and post-test genetic counseling. The recent advent of New Generation Sequencing (NGS) techniques affords the opportunity to rapidly screen patients for a comprehensive panel of colorectal cancer susceptibility genes in a cost-effective fashion. This type of approach will probably replace the classical sequential approach based on clinical presumptive diagnoses in the near future. The risk of colorectal cancer is very high in affected patients in the absence of appropriate care. Clinical management is complex and should be provided in centers with special expertise in these diseases. This review focuses on the various colorectal adenomatous polyposis syndromes with special attention to more innovative and important aspects. Copyright © 2015 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

Alopecia areata incognita in Cronkhite-Canada syndrome.

PubMed

Ong, S; Rodriguez-Garcia, C; Grabczynska, S; Carton, J; Osborn, M; Walters, J; Kubba, F; Stefanato, C M

2017-08-01

Cronkhite-Canada syndrome is an acquired inflammatory polyposis syndrome in which alopecia, onychomadesis and hyperpigmentation occur concurrently with gastrointestinal symptoms. The pathophysiology of alopecia in Cronkhite-Canada syndrome has not been definitively elucidated. We present evidence for alopecia areata incognita as a possible mechanism of hair loss. © 2016 British Association of Dermatologists.

[Turcot's syndrome confirmed by molecular biological tests].

PubMed

Jeannin, S; Lebrun, C; Van Den Bos, F; Olschwang, S; Bourg, V; Frenay, M

2006-06-01

Turcot's syndrome is characterized clinically by the concurrence of a primary brain tumor and a familial adenomatous polyposis or a hereditary nonpolyposis colorectal cancer. We report a case of a 45-year-old woman who underwent in 1995 neuro-oncological treatment for an anaplastic astrocytoma (grade III according to the World Health Organization classification). Treatment included complete surgery, radiotherapy, a first-line nitrosourea-based chemotherapy regimen and a second-line platinium salt-based regimen. It was then noted that the patient's brother had colorectal cancer. A genetic study detected a germ-line mutation on the hMSH2 gene specific of HNPCC syndrome (Human Non Polyposis Colorectal Cancer). Colonoscopy was normal. Eight years after the diagnosis, the patient developed a gliomatosis cerebri and died. Relevant personal and familial history can provide the clue to the diagnosis of Turcot's syndrome. Molecular diagnosis may contribute to appropriate care of affected patients.

Lynch syndrome and Lynch syndrome mimics: The growing complex landscape of hereditary colon cancer

PubMed Central

Carethers, John M; Stoffel, Elena M

2015-01-01

Hereditary non-polyposis colorectal cancer (HNPCC) was previously synonymous with Lynch syndrome; however, identification of the role of germline mutations in the DNA mismatch repair (MMR) genes has made it possible to differentiate Lynch syndrome from other conditions associated with familial colorectal cancer (CRC). Broadly, HNPCC may be dichotomized into conditions that demonstrate defective DNA MMR and microsatellite instability (MSI) vs those conditions that demonstrate intact DNA MMR. Conditions characterized by MMR deficient CRCs include Lynch syndrome (germline MMR mutation), Lynch-like syndrome (biallelic somatic MMR mutations), constitutional MMR deficiency syndrome (biallelic germline MMR mutations), and sporadic MSI CRC (somatic biallelic methylation of MLH1). HNPCC conditions with intact DNA MMR associated with familial CRC include polymerase proofreading associated polyposis and familial colorectal cancer type X. Although next generation sequencing technologies have elucidated the genetic cause for some HNPCC conditions, others remain genetically undefined. Differentiating between Lynch syndrome and the other HNPCC disorders has profound implications for cancer risk assessment and surveillance of affected patients and their at-risk relatives. Clinical suspicion coupled with molecular tumor analysis and testing for germline mutations can help differentiate the clinical mimicry within HNPCC and facilitate diagnosis and management. PMID:26309352

Lynch syndrome and Lynch syndrome mimics: The growing complex landscape of hereditary colon cancer.

PubMed

Carethers, John M; Stoffel, Elena M

2015-08-21

Hereditary non-polyposis colorectal cancer (HNPCC) was previously synonymous with Lynch syndrome; however, identification of the role of germline mutations in the DNA mismatch repair (MMR) genes has made it possible to differentiate Lynch syndrome from other conditions associated with familial colorectal cancer (CRC). Broadly, HNPCC may be dichotomized into conditions that demonstrate defective DNA MMR and microsatellite instability (MSI) vs those conditions that demonstrate intact DNA MMR. Conditions characterized by MMR deficient CRCs include Lynch syndrome (germline MMR mutation), Lynch-like syndrome (biallelic somatic MMR mutations), constitutional MMR deficiency syndrome (biallelic germline MMR mutations), and sporadic MSI CRC (somatic biallelic methylation of MLH1). HNPCC conditions with intact DNA MMR associated with familial CRC include polymerase proofreading associated polyposis and familial colorectal cancer type X. Although next generation sequencing technologies have elucidated the genetic cause for some HNPCC conditions, others remain genetically undefined. Differentiating between Lynch syndrome and the other HNPCC disorders has profound implications for cancer risk assessment and surveillance of affected patients and their at-risk relatives. Clinical suspicion coupled with molecular tumor analysis and testing for germline mutations can help differentiate the clinical mimicry within HNPCC and facilitate diagnosis and management.

Characteristics of MUTYH variants in Japanese colorectal polyposis patients.

PubMed

Takao, Misato; Yamaguchi, Tatsuro; Eguchi, Hidetaka; Tada, Yuhki; Kohda, Masakazu; Koizumi, Koichi; Horiguchi, Shin-Ichiro; Okazaki, Yasushi; Ishida, Hideyuki

2018-06-01

The base excision repair gene MUTYH is the causative gene of colorectal polyposis syndrome, which is an autosomal recessive disorder associated with a high risk of colorectal cancer. Since few studies have investigated the genotype-phenotype association in Japanese patients with MUTYH variants, the aim of this study was to clarify the clinicopathological findings in Japanese patients with MUTYH gene variants who were detected by screening causative genes associated with hereditary colorectal polyposis. After obtaining informed consent, genetic testing was performed using target enrichment sequencing of 26 genes, including MUTYH. Of the 31 Japanese patients with suspected hereditary colorectal polyposis, eight MUTYH variants were detected in five patients. MUTYH hotspot variants known for Caucasians, namely p.G396D and p.Y179D, were not among the detected variants.Of five patients, two with biallelic MUTYH variants were diagnosed with MUTYH-associated polyposis, while two others had monoallelic MUTYH variants. One patient had the p.P18L and p.G25D variants on the same allele; however, supportive data for considering these two variants 'pathogenic' were lacking. Two patients with biallelic MUTYH variants and two others with monoallelic MUTYH variants were identified among Japanese colorectal polyposis patients. Hotspot variants of the MUTYH gene for Caucasians were not hotspots for Japanese patients.

Hereditary mixed polyposis syndrome is caused by a 40-kb upstream duplication that leads to increased and ectopic expression of the BMP antagonist GREM1.

PubMed

Jaeger, Emma; Leedham, Simon; Lewis, Annabelle; Segditsas, Stefania; Becker, Martin; Cuadrado, Pedro Rodenas; Davis, Hayley; Kaur, Kulvinder; Heinimann, Karl; Howarth, Kimberley; East, James; Taylor, Jenny; Thomas, Huw; Tomlinson, Ian

2012-05-06

Hereditary mixed polyposis syndrome (HMPS) is characterized by apparent autosomal dominant inheritance of multiple types of colorectal polyp, with colorectal carcinoma occurring in a high proportion of affected individuals. Here, we use genetic mapping, copy-number analysis, exclusion of mutations by high-throughput sequencing, gene expression analysis and functional assays to show that HMPS is caused by a duplication spanning the 3' end of the SCG5 gene and a region upstream of the GREM1 locus. This unusual mutation is associated with increased allele-specific GREM1 expression. Whereas GREM1 is expressed in intestinal subepithelial myofibroblasts in controls, GREM1 is predominantly expressed in the epithelium of the large bowel in individuals with HMPS. The HMPS duplication contains predicted enhancer elements; some of these interact with the GREM1 promoter and can drive gene expression in vitro. Increased GREM1 expression is predicted to cause reduced bone morphogenetic protein (BMP) pathway activity, a mechanism that also underlies tumorigenesis in juvenile polyposis of the large bowel.

A novel germline POLE mutation causes an early onset cancer prone syndrome mimicking constitutional mismatch repair deficiency.

PubMed

Wimmer, Katharina; Beilken, Andreas; Nustede, Rainer; Ripperger, Tim; Lamottke, Britta; Ure, Benno; Steinmann, Diana; Reineke-Plaass, Tanja; Lehmann, Ulrich; Zschocke, Johannes; Valle, Laura; Fauth, Christine; Kratz, Christian P

2017-01-01

In a 14-year-old boy with polyposis and rectosigmoid carcinoma, we identified a novel POLE germline mutation, p.(Val411Leu), previously found as recurrent somatic mutation in 'ultramutated' sporadic cancers. This is the youngest reported cancer patient with polymerase proofreading-associated polyposis indicating that POLE mutation p.(Val411Leu) may confer a more severe phenotype than previously reported POLE and POLD1 germline mutations. The patient had multiple café-au-lait macules and a pilomatricoma mimicking the clinical phenotype of constitutional mismatch repair deficiency. We hypothesize that these skin features may be common to different types of constitutional DNA repair defects associated with polyposis and early-onset cancer.

POLE and POLD1 mutations in 529 kindred with familial colorectal cancer and/or polyposis: review of reported cases and recommendations for genetic testing and surveillance

PubMed Central

Bellido, Fernando; Pineda, Marta; Aiza, Gemma; Valdés-Mas, Rafael; Navarro, Matilde; Puente, Diana A.; Pons, Tirso; González, Sara; Iglesias, Silvia; Darder, Esther; Piñol, Virginia; Soto, José Luís; Valencia, Alfonso; Blanco, Ignacio; Urioste, Miguel; Brunet, Joan; Lázaro, Conxi; Capellá, Gabriel; Puente, Xose S.; Valle, Laura

2016-01-01

Purpose: Germ-line mutations in the exonuclease domains of POLE and POLD1 have been recently associated with polyposis and colorectal cancer (CRC) predisposition. Here, we aimed to gain a better understanding of the phenotypic characteristics of this syndrome to establish specific criteria for POLE and POLD1 mutation screening and to help define the clinical management of mutation carriers. Genet Med 18 4, 325–332. Methods: The exonuclease domains of POLE and POLD1 were studied in 529 kindred, 441 with familial nonpolyposis CRC and 88 with polyposis, by using pooled DNA amplification and massively parallel sequencing. Genet Med 18 4, 325–332. Results: Seven novel or rare genetic variants were identified. In addition to the POLE p.L424V recurrent mutation in a patient with polyposis, CRC and oligodendroglioma, six novel or rare POLD1 variants (four of them, p.D316H, p.D316G, p.R409W, and p.L474P, with strong evidence for pathogenicity) were identified in nonpolyposis CRC families. Phenotypic data from these and previously reported POLE/POLD1 carriers point to an associated phenotype characterized by attenuated or oligo-adenomatous colorectal polyposis, CRC, and probably brain tumors. In addition, POLD1 mutations predispose to endometrial and breast tumors. Genet Med 18 4, 325–332. Conclusion: Our results widen the phenotypic spectrum of the POLE/POLD1-associated syndrome and identify novel pathogenic variants. We propose guidelines for genetic testing and surveillance recommendations. Genet Med 18 4, 325–332. PMID:26133394

A distinct variant of papillary thyroid carcinoma indicating familial adenomatous polyposis (FAP): a case report and brief review.

PubMed

Liyanapathirana, Nishantha; Seneviratne, Sanjeewa Anuruddha; Samarasekera, Dharmabandhu Nandadeva

2015-12-17

Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited intestinal polyposis syndrome with an incidence of about 1/8300 births and accounts for about 1% of all colorectal cancers. It has a spectrum of extra-intestinal manifestations including thyroid carcinoma which occur in 1-2% of affected. The cribriform morular variant (CMV) is a rare but distinct histological subtype of papillary thyroid carcinoma (PTC) associated with FAP. Most of the reported cases describe the above entity in the background of well-established FAP. We report a case where both entities presenting simultaneously in a previously undiagnosed patient with FAP without a family history of polyposis. A 24 year old Asian female presented to the surgical clinic with a goitre of eight months duration and recent onset of altered bowel habits with features of anaemia. She was previously healthy and there was no family history of adenomatous polyposis, colorectal carcinoma or thyroid neoplasms. Colonoscopy revealed large bowel polyposis and fine needle aspiration of thyroid revealed a smear suspicious for malignancy. She underwent total thyroidectomy which revealed CMV PTC. Histology was characterized by a prominent cribriform pattern of growth with interspersed cell clusters arranged as morules along with papillary structures which are the key features of this subtype. Diagnosis of CMV warrants ruling out of underlying FAP, irrespective of family history or gastrointestinal symptoms.

A case report of desmoid tumour-a forgotten aspect of FAP?

PubMed

Xuereb, Sarah; Xuereb, Rachel; Buhagiar, Chiara; Gauci, Jonathan; Magri, Claude

2017-01-01

Desmoid tumours are locally aggressive tumours which are common in Familial Adenomatous Polyposis (FAP). A 20-year old Familial Adenomatous Polyposis (FAP) patient presented with abdominal pain and distention. Abdominal imaging showed small bowel obstruction and hydronephrosis due to a pelvic mass. This mass showed significant enlargement on repeat imaging, and a diagnostic biopsy confirmed desmoid tumour. The mass was deemed unresectable and he was initially started on sulindac and raloxifene. Repeat imaging however showed further enlargement of the tumour, and therefore vinblastine+methotrexate chemotherapy was commenced, with a good response. FAP is an autosomal dominant condition caused by a germline mutation in the adenomatous polyposis coli (APC) gene. Gardner's syndrome is also caused by a mutation in the APC gene, and is now considered a different phenotypic presentation of FAP. Desmoid tumours are initially kept under observation while their size remains stable. Treatment options for enlarging desmoids tumours include surgery (first-line), radiotherapy, and systemic therapy with non-cytotoxic and cytotoxic therapy. FAP patients should be examined regularly post-panprocotocolectomy, since desmoid tumours may arise. The presence of epidermal cysts in this FAP patient suggests a diagnosis of Gardner's syndrome. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

β-Catenin activation in fundic gland polyps, gastric cancer and colonic polyps in families afflicted by 'gastric adenocarcinoma and proximal polyposis of the stomach' (GAPPS).

PubMed

McDuffie, Lucas A; Sabesan, Arvind; Allgäeuer, Michael; Xin, Liqiang; Koh, Christopher; Heller, Theo; Davis, Jeremy L; Raffeld, Mark; Miettienen, Markku; Quezado, Martha; Rudloff, Udo

2016-09-01

To evaluate possible colon involvement in the 'gastric adenocarcinoma and proximal polyposis of the stomach' (GAPPS) gastrointestinal polyposis syndrome. Prospective clinicopathological evaluation of two GAPPS families and expression of nuclear β-catenin, p53 and Ki67 measured by immunohistochemistry on endoscopic and surgical specimens from patients with GAPPS. Patients with the GAPPS phenotype were more frequently affected by colonic polyps than patients at risk within the same families (p<0.01). Colonic polyps shared immunohistochemical features of fundic gland polyps and gastric cancers including increased expression of nuclear β-catenin, Ki67 and p53. Both gastric and colonic lesions harboured activating somatic variants of β-catenin signalling. Similarities in expression markers in fundic gland and colonic polyps, together with an enrichment of colonic adenomas in family members affected by GAPPS phenotype compared with family members at risk, support mild colonic involvement of this rare cancer syndrome. Colonoscopic screening might be warranted. #09-C-0079; Results. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Adenocarcinoma and polyposis of the colon in a 20-year-old patient with Trisomy 13: a case report.

PubMed

Thurtle, Danielle P; Huck, Michael B; Zeller, Kristen A; Jewett, Tamison

2018-03-04

Trisomy 13 is one of the most common autosomal trisomies, and although increasing in number, patients surviving past the neonatal period remain rare. The natural history and expected complications in these patients as they age remains unknown. Despite the rarity of this condition, unusual malignancies have been reported in the medical literature for decades. It is clear that providers should suspect unusual malignancies in these patients, particularly as they age. We report a 20-year-old Caucasian woman with Trisomy 13 who presented with colonic volvulus, found to have colonic polyposis and adenocarcinoma of the colon. Genetics of pathology specimens revealed 47(XX) + 13 without other mutations. She underwent prophylactic completion colectomy due to presumed risk of colorectal cancers given underlying adenomatous polyposis. She has recovered well without evidence of recurrence. The presence of colonic polyposis and colorectal cancer without family history or known mutations for polyposis syndrome suggests an intrinsic predisposition toward colorectal cancer in this patient with Trisomy 13. Recent research into colorectal cancer oncogenes supports that aneuploidy or increased copy number of certain genes on chromosome 13 may increase the risk of malignant transformation. This is an important correlation for researchers studying these topics and clinicians caring for patients with Trisomy 13 as they age.

Hereditary familial polyposis and Gardner's syndrome: contribution of the odonto-stomatology examination in its diagnosis and a case description.

PubMed

Chimenos-Küstner, Eduardo; Pascual, Montserrat; Blanco, Ignacio; Finestres, Fernando

2005-01-01

Familial Adenomatous Polyposis (FAP) and its phenotype variant, Gardner's syndrome, constitute a rare autosomal dominant inherited disorder. They are characterised by the development, generally during the second and third decades of life, of multiple adenomatous polyps in the colon and rectum. These polyps have a high risk of subsequently becoming malignant, which normally occurs in the third and fourth decades of life. The phenotypical features of FAP can be very variable. As well as colorectal polyps, these individuals can present with extra-colonic symptoms, among which are particularly: gastro-duodenal polyps, dermoid and epidermoid cysts, desmoid tumours, congenital hypertrophy of the retinal pigment epithelium, disorders of the maxillary and skeletal bones and dental anomalies. In this paper the most important aspects of this syndrome are reviewed, showing an example based on a well documented clinical case. The importance of odonto-stomatological examinations should be pointed out, among others, as a means of reaching a presumptive diagnosis, whose confirmation is vital to the patient.

Juvenile Polyposis Syndrome

MedlinePlus

... disease. This means that a parent with a gene mutation may pass along a copy of their normal ... a child when a prospective parent carries a gene mutation that increases the risk for this hereditary cancer ...

Translational Research in Familial Colorectal Cancer Syndromes.

PubMed

Ford, Molly M

2018-05-01

Growing knowledge of inherited colorectal cancer syndromes has led to better surveillance and better care of this subset of patients. The most well-known entities, including Lynch syndrome and familial adenomatous polyposis, are continually being studied and with the advent of more sophisticated genetic testing, additional genetic discoveries have been made in the field of inherited cancer. This article will summarize many of the updates to both the familiar and perhaps less familiar syndromes that can lead to inherited or early-onset colorectal cancer.

Cronkhite- Canada syndrome; a case report and review of the literature

PubMed Central

Safari, Mohammad Taghi; Shahrokh, Shabnam; Ebadi, Shahram; Sadeghi, Amir

2016-01-01

Cronkhite- Canada syndrome (CCS) considered as a rare and non-hereditary disorder. Gastrointestinal polyposis and diarrhea along with some extra signs and symptoms such as hypoproteinemia, and epidermal manifestations are recognized in this syndrome. The pathophysiology of this syndrome is not completely understood and it seems that inflammatory processes may be involved. We present a 50 year-old man with hamartomatous polyps throughout the colon and long-lasting diarrhea not responding to typical therapies during three years. PMID:26744616

Monoallelic mutation analysis (MAMA) for identifying germline mutations.

PubMed

Papadopoulos, N; Leach, F S; Kinzler, K W; Vogelstein, B

1995-09-01

Dissection of germline mutations in a sensitive and specific manner presents a continuing challenge. In dominantly inherited diseases, mutations occur in only one allele and are often masked by the normal allele. Here we report the development of a sensitive and specific diagnostic strategy based on somatic cell hybridization termed MAMA (monoallelic mutation analysis). We have demonstrated the utility of this strategy in two different hereditary colorectal cancer syndromes, one caused by a defective tumour suppressor gene on chromosome 5 (familial adenomatous polyposis, FAP) and the other caused by a defective mismatch repair gene on chromosome 2 (hereditary non-polyposis colorectal cancer, HNPCC).

MUTYH-associated colorectal cancer and adenomatous polyposis.

PubMed

Yamaguchi, Satoru; Ogata, Hideo; Katsumata, Daisuke; Nakajima, Masanobu; Fujii, Takaaki; Tsutsumi, Soichi; Asao, Takayuki; Sasaki, Kinro; Kuwano, Hiroyuki; Kato, Hiroyuki

2014-04-01

MUTYH-associated polyposis (MAP) was first described in 2002. MUTYH is a component of a base excision repair system that protects the genomic information from oxidative damage. When the MUTYH gene product is impaired by bi-allelic germline mutation, it leads to the mutation of cancer-related genes, such as the APC and/or the KRAS genes, via G to T transversion. MAP is a hereditary colorectal cancer syndrome inherited in an autosomal-recessive fashion. The clinical features of MAP include the presence of 10-100 adenomatous polyps in the colon, and early onset of colorectal cancer. Ethnic and geographical differences in the pattern of the MUTYH gene mutations have been suggested. In Caucasian patients, c.536A>G (Y179C) and c.1187G>A (G396D) mutations are frequently detected. In the Asian population, Y179C and G396D are uncommon, whereas other variants are suggested to be the major causes of MAP. We herein review the literature on MUTYH-associated colorectal cancer and adenomatous polyposis.

Genetics Home Reference: hereditary hemorrhagic telangiectasia

MedlinePlus

... Central OMIM: JUVENILE POLYPOSIS/HEREDITARY HEMORRHAGIC TELANGIECTASIA SYNDROME McDonald J, Bayrak-Toydemir P, Pyeritz RE. Hereditary hemorrhagic ... 10.1097/GIM.0b013e3182136d32. Review. Citation on PubMed McDonald J, Wooderchak-Donahue W, VanSant Webb C, Whitehead ...

Familial pancreatic cancer: Concept, management and issues.

PubMed

Matsubayashi, Hiroyuki; Takaori, Kyoichi; Morizane, Chigusa; Maguchi, Hiroyuki; Mizuma, Masamichi; Takahashi, Hideaki; Wada, Keita; Hosoi, Hiroko; Yachida, Shinichi; Suzuki, Masami; Usui, Risa; Furukawa, Toru; Furuse, Junji; Sato, Takamitsu; Ueno, Makoto; Kiyozumi, Yoshimi; Hijioka, Susumu; Mizuno, Nobumasa; Terashima, Takeshi; Mizumoto, Masaki; Kodama, Yuzo; Torishima, Masako; Kawaguchi, Takahisa; Ashida, Reiko; Kitano, Masayuki; Hanada, Keiji; Furukawa, Masayuki; Kawabe, Ken; Majima, Yoshiyuki; Shimosegawa, Toru

2017-02-14

Familial pancreatic cancer (FPC) is broadly defined as two first-degree-relatives with pancreatic cancer (PC) and accounts for 4%-10% of PC. Several genetic syndromes, including Peutz-Jeghers syndrome, hereditary pancreatitis, hereditary breast-ovarian cancer syndrome (HBOC), Lynch syndrome, and familial adenomatous polyposis (FAP), also have increased risks of PC, but the narrowest definition of FPC excludes these known syndromes. When compared with other familial tumors, proven genetic alterations are limited to a small proportion (< 20%) and the familial aggregation is usually modest. However, an ethnic deviation (Ashkenazi Jewish > Caucasian) and a younger onset are common also in FPC. In European countries, "anticipation" is reported in FPC families, as with other hereditary syndromes; a trend toward younger age and worse prognosis is recognized in the late years. The resected pancreases of FPC kindred often show multiple pancreatic intraepithelial neoplasia (PanIN) foci, with various K- ras mutations, similar to colorectal polyposis seen in the FAP patients. As with HBOC patients, a patient who is a BRCA mutation carrier with unresectable pancreatic cancer (accounting for 0%-19% of FPC patients) demonstrated better outcome following platinum and Poly (ADP-ribose) polymerase inhibitor treatment. Western countries have established FPC registries since the 1990s and several surveillance projects for high-risk individuals are now ongoing to detect early PCs. Improvement in lifestyle habits, including non-smoking, is recommended for individuals at risk. In Japan, the FPC study group was initiated in 2013 and the Japanese FPC registry was established in 2014 by the Japan Pancreas Society.

[Desmoid tumors in three patients].

PubMed

Mohos, E; Kovács, T; Brittig, F; Nagy, A

2001-12-01

Desmoids are rare tumors of the connective tissue. It develops about 1:1000 times more in patients with familial adenomatous polyposis (FAP, Gardner syndrome) compared to normal population. It has been shown in molecular genetic examinations, that different mutations of the APC gene are responsible for desmoid tumors in FAP. It means, that this disease is one of the extraintestinal manifestations of Gardner syndrome. This tumor has high recurrence rate and is growing rapidly, and as a result it is the second most common cause of death in FAP patients. That is why genetic examination for FAP patients is advised to decide if the patient has higher risk for desmoid formation. If the result of the genetic test is positive, it is advisable to try to slow the progression of polyposis with medical treatment, and so to delay the date of the colectomy because the surgical intervention--and connective tissue damage--can induce desmoid formation in these patients. At the same time it is reasonable to examine and regularly control patients with sporadic desmoid tumors searching for other manifestations of Gardner syndrome (colon, stomach and duodenum polyposis, tumor of papilla Vateri, retinopathy, etc.). Palliative surgery is not indicated in patients with inoperable intraabdominal desmoid tumors, because partial resections (R1, R2, debulking) result in further tumor progression. In these patients medical treatment (sulindac, tamoxifen), chemotherapy (doxorubicin, dacarbazin) and radiotherapy or combination of them can result tumor remission. We describe our three patients (an abdominal wall desmoid four years following Cesarean section; a desmoid tumor in the retroperitoneum and in the pelvis diagnosed three years after total colectomy; and a retroperitoneal and abdominal wall desmoid one year after total colectomy) and etiology, diagnosis and therapy of desmoid tumors are discussed.

Familial adenomatous polyposis

PubMed Central

Half, Elizabeth; Bercovich, Dani; Rozen, Paul

2009-01-01

Familial adenomatous polyposis (FAP) is characterized by the development of many tens to thousands of adenomas in the rectum and colon during the second decade of life. FAP has an incidence at birth of about 1/8,300, it manifests equally in both sexes, and accounts for less than 1% of colorectal cancer (CRC) cases. In the European Union, prevalence has been estimated at 1/11,300-37,600. Most patients are asymptomatic for years until the adenomas are large and numerous, and cause rectal bleeding or even anemia, or cancer develops. Generally, cancers start to develop a decade after the appearance of the polyps. Nonspecific symptoms may include constipation or diarrhea, abdominal pain, palpable abdominal masses and weight loss. FAP may present with some extraintestinal manifestations such as osteomas, dental abnormalities (unerupted teeth, congenital absence of one or more teeth, supernumerary teeth, dentigerous cysts and odontomas), congenital hypertrophy of the retinal pigment epithelium (CHRPE), desmoid tumors, and extracolonic cancers (thyroid, liver, bile ducts and central nervous system). A less aggressive variant of FAP, attenuated FAP (AFAP), is characterized by fewer colorectal adenomatous polyps (usually 10 to 100), later age of adenoma appearance and a lower cancer risk. Some lesions (skull and mandible osteomas, dental abnormalities, and fibromas on the scalp, shoulders, arms and back) are indicative of the Gardner variant of FAP. Classic FAP is inherited in an autosomal dominant manner and results from a germline mutation in the adenomatous polyposis (APC) gene. Most patients (~70%) have a family history of colorectal polyps and cancer. In a subset of individuals, a MUTYH mutation causes a recessively inherited polyposis condition, MUTYH-associated polyposis (MAP), which is characterized by a slightly increased risk of developing CRC and polyps/adenomas in both the upper and lower gastrointestinal tract. Diagnosis is based on a suggestive family history, clinical findings, and large bowel endoscopy or full colonoscopy. Whenever possible, the clinical diagnosis should be confirmed by genetic testing. When the APC mutation in the family has been identified, genetic testing of all first-degree relatives should be performed. Presymptomatic and prenatal (amniocentesis and chorionic villous sampling), and even preimplantation genetic testing is possible. Referral to a geneticist or genetic counselor is mandatory. Differential diagnoses include other disorders causing multiple polyps (such as Peutz-Jeghers syndrome, familial juvenile polyps or hyperplastic polyposis, hereditary mixed polyposis syndromes, and Lynch syndrome). Cancer prevention and maintaining a good quality of life are the main goals of management and regular and systematic follow-up and supportive care should be offered to all patients. By the late teens or early twenties, colorectal cancer prophylactic surgery is advocated. The recommended alternatives are total proctocolectomy and ileoanal pouch or ileorectal anastomosis for AFAP. Duodenal cancer and desmoids are the two main causes of mortality after total colectomy, they need to be identified early and treated. Upper endoscopy is necessary for surveillance to reduce the risk of ampullary and duodenal cancer. Patients with progressive tumors and unresectable disease may respond or stabilize with a combination of cytotoxic chemotherapy and surgery (when possible to perform). Adjunctive therapy with celecoxib has been approved by the US Food and Drug Administration and the European Medicines Agency in patients with FAP. Individuals with FAP carry a 100% risk of CRC; however, this risk is reduced significantly when patients enter a screening-treatment program. PMID:19822006

Molecular features of colorectal hyperplastic polyps and sessile serrated adenoma/polyps from Korea.

PubMed

Kim, Kyoung-Mee; Lee, Eui Jin; Ha, Sangyun; Kang, So Young; Jang, Kee-Taek; Park, Cheol Keun; Kim, Jin Yong; Kim, Young Ho; Chang, Dong Kyung; Odze, Robert Daniel

2011-09-01

Abundant recent data suggest that sessile serrated adenoma/polyp (SSA/P) is an early precursor lesion in the serrated pathway of carcinogenesis. It is believed that SSA/Ps develop cancer by an SSA/P-dysplasia-carcinoma sequence. Hyperplastic polyps (HPs) share some histologic and molecular characteristics with SSA/P, but it is unclear whether SSA/Ps are derived from HPs or whether they develop by a different pathogenetic pathway. Previous studies have shown that serrated polyps from Korean patients show different prevalence rates of certain molecular abnormalities compared with similar lesions from American patients, and this suggests that lifestyle and dietary factors may influence the serrated neoplasia pathway. The purpose of this study was to evaluate the molecular features of HPs and SSA/Ps, the latter both with and without dysplasia, from Korean patients and to compare the findings with similar lesions from American patients. One hundred and eleven serrated polyps, consisting of 45 HPs (30 microvesicular, 11 goblet cell, 4 mucin depleted) and 56 SSA/Ps (36 with dysplasia, 20 without dysplasia), were retrieved from the pathology files of a large medical center in Korea and 38 SSA/P from American patients were evaluated for BRAF and KRAS mutations, microsatellite instability, and hypermethylation of O6-methylguanine-DNA methyltransferase (MGMT), hMLH1, adenomatous polyposis coli (APC), p16, methylated in tumor-1 (MINT-1), MINT2, and MINT31. Methylation of hMLH1 was performed using 2 different sets of primers. Twenty-three conventional adenomas from Korean patients were included as controls. The data were compared between polyp subtypes and between polyps in the right versus the left colon. With regard to HP, KRAS mutations were present in 31.1% of polyps and BRAF mutations in 46.7% of polyps. KRAS mutations were significantly more common in goblet cell HP and BRAF in microvesicular HP (MVHP). Methylation of MGMT, hMLH1, APC, p16, MINT1, MINT2, and MINT31 were present in 42.2%, 64.4% (and 24.4%), 37.8%, 60%, 68.9%, 51.1%, and 60% of HPs. CpG island methylator phenotype high was noted in 60% of HPs. Methylation of hMLH1, p16, MINT2, and MINT31 were more frequent in MVHPs compared with other types of HPs. In contrast, SSA/Ps showed KRAS and BRAF mutations in 12.5% and 60.7% of cases, respectively. Methylation of all tumor-related genes, except hMLH1 (23.2% using 1 type of primers) and APC (37.5%), occurred in >50% of lesions, and CpG island methylator phenotype (CIMP) high was noted in 76.8% of cases. None of the molecular findings were significantly more common in SSA/P with, versus those without, dysplasia, but only 2 of the 36 polyps with dysplasia were of the conventional adenomatous type; the remainder (34 of 36) was of the serrated type. Nevertheless, both SSA/P with conventional adenomatous dysplasia showed methylation of MGMT, APC, MINT1, and MINT31 and were CIMP high. BRAF mutations, methylation of most tumor related genes, and CIMP high occurred more frequently in HPs and SSA/Ps in the right colon, compared with the left colon. In fact, no significant differences were observed between HPs and SSPs of the right colon and HPs and SSA/Ps from the left colon. Furthermore, compared with American patients, Korean male individuals were affected more frequently than female individuals, and both BRAF mutations and hMLH1 methylation were less frequent in the latter compared with the former. We conclude that HPs and SSA/Ps in Korean patients share some, but not all, clinical and molecular characteristics to those that occur in Americans. The data support the theory that the right and left colon are biologically different with regard to susceptibility to serrated cancer, and that anatomic location (right vs. left) may be a more significant risk factor of progression than the histologic type of polyp. Our data also support the theory that right-sided MVHPs may be a precursor to SSA/P.

MLH1-deficient Colorectal Carcinoma With Wild-type BRAF and MLH1 Promoter Hypermethylation Harbor KRAS Mutations and Arise From Conventional Adenomas.

PubMed

Farchoukh, Lama; Kuan, Shih-Fan; Dudley, Beth; Brand, Randall; Nikiforova, Marina; Pai, Reetesh K

2016-10-01

Between 10% and 15% of colorectal carcinomas demonstrate sporadic DNA mismatch-repair protein deficiency as a result of MLH1 promoter methylation and are thought to arise from sessile serrated adenomas, termed the serrated neoplasia pathway. Although the presence of the BRAF V600E mutation is indicative of a sporadic cancer, up to 30% to 50% of colorectal carcinomas with MLH1 promoter hypermethylation will lack a BRAF mutation. We report the clinicopathologic and molecular features of MLH1-deficient colorectal carcinoma with wild-type BRAF and MLH1 promoter hypermethylation (referred to as MLH1-hypermethylated BRAF wild-type colorectal carcinoma, n=36) in comparison with MLH1-deficient BRAF-mutated colorectal carcinoma (n=113) and Lynch syndrome-associated colorectal carcinoma (n=36). KRAS mutations were identified in 31% of MLH1-hypermethylated BRAF wild-type colorectal carcinomas compared with 0% of MLH1-deficient BRAF-mutated colorectal carcinomas and 37% of Lynch syndrome-associated colorectal carcinomas. When a precursor polyp was identified, MLH1-hypermethylated BRAF wild-type colorectal carcinomas arose from precursor polyps resembling conventional tubular/tubulovillous adenomas in contrast to MLH1-deficient BRAF-mutated colorectal carcinomas, which arose from precursor sessile serrated adenomas (P<0.001). Both MLH1-hypermethylated BRAF wild-type colorectal carcinoma and MLH1-deficient BRAF-mutated colorectal carcinoma had a predilection for the right colon compared with Lynch syndrome-associated colorectal carcinoma (86% vs. 92% vs. 49%, P<0.001). There was no significant difference in mucinous differentiation, tumor-infiltrating lymphocytes, Crohn-like reaction, and medullary differentiation between the 3 tumor groups. Using Kaplan-Meier survival functions, there was no significant difference in disease-specific survival between the 3 patient groups (P>0.05). In conclusion, our results indicate that MLH1-hypermethylated BRAF wild-type colorectal carcinomas can harbor KRAS mutations and arise from precursor polyps resembling conventional tubular/tubulovillous adenomas.

Familial pancreatic cancer: Concept, management and issues

PubMed Central

Matsubayashi, Hiroyuki; Takaori, Kyoichi; Morizane, Chigusa; Maguchi, Hiroyuki; Mizuma, Masamichi; Takahashi, Hideaki; Wada, Keita; Hosoi, Hiroko; Yachida, Shinichi; Suzuki, Masami; Usui, Risa; Furukawa, Toru; Furuse, Junji; Sato, Takamitsu; Ueno, Makoto; Kiyozumi, Yoshimi; Hijioka, Susumu; Mizuno, Nobumasa; Terashima, Takeshi; Mizumoto, Masaki; Kodama, Yuzo; Torishima, Masako; Kawaguchi, Takahisa; Ashida, Reiko; Kitano, Masayuki; Hanada, Keiji; Furukawa, Masayuki; Kawabe, Ken; Majima, Yoshiyuki; Shimosegawa, Toru

2017-01-01

Familial pancreatic cancer (FPC) is broadly defined as two first-degree-relatives with pancreatic cancer (PC) and accounts for 4%-10% of PC. Several genetic syndromes, including Peutz-Jeghers syndrome, hereditary pancreatitis, hereditary breast-ovarian cancer syndrome (HBOC), Lynch syndrome, and familial adenomatous polyposis (FAP), also have increased risks of PC, but the narrowest definition of FPC excludes these known syndromes. When compared with other familial tumors, proven genetic alterations are limited to a small proportion (< 20%) and the familial aggregation is usually modest. However, an ethnic deviation (Ashkenazi Jewish > Caucasian) and a younger onset are common also in FPC. In European countries, “anticipation” is reported in FPC families, as with other hereditary syndromes; a trend toward younger age and worse prognosis is recognized in the late years. The resected pancreases of FPC kindred often show multiple pancreatic intraepithelial neoplasia (PanIN) foci, with various K-ras mutations, similar to colorectal polyposis seen in the FAP patients. As with HBOC patients, a patient who is a BRCA mutation carrier with unresectable pancreatic cancer (accounting for 0%-19% of FPC patients) demonstrated better outcome following platinum and Poly (ADP-ribose) polymerase inhibitor treatment. Western countries have established FPC registries since the 1990s and several surveillance projects for high-risk individuals are now ongoing to detect early PCs. Improvement in lifestyle habits, including non-smoking, is recommended for individuals at risk. In Japan, the FPC study group was initiated in 2013 and the Japanese FPC registry was established in 2014 by the Japan Pancreas Society. PMID:28246467

Familial adenomatous polyposis: clinical presentation, detection and surveillance.

PubMed

Laurent, S; Franchimont, D; Coppens, J P; Leunen, K; Macken, L; Peeters, M; Plomteux, O; Polus, M; Poppe, B; Sempoux, C; Tejpar, S; Van Den Eynde, M; Van Gossum, A; Vannoote, J; Kartheuser, A; Van Cutsem, E

2011-09-01

Colorectal cancer (CRC) is a leading cause of cancer related death in the western countries. It remains an important health problem, often under-diagnosed. The symptoms can appear very late and about 25% of the patients are diagnosed at metastatic stage. Familial adenomatous polyposis (FAP) is an inherited colorectal cancer syndrome, characterized by the early onset of hundred to thousands of adenomatous polyps in the colon and rectum. Left untreated, there is a nearly 100% cumulative risk of progression to CRC by the age of 35-40 years, as well as an increased risk of various other malignancies. CRC can be prevented by the identification of the high risk population and by the timely implementation of rigid screening programs which will lead to special medico-surgical interventions.

Shark teeth as edged weapons: serrated teeth of three species of selachians.

PubMed

Moyer, Joshua K; Bemis, William E

2017-02-01

Prior to European contact, South Pacific islanders used serrated shark teeth as components of tools and weapons. They did this because serrated shark teeth are remarkably effective at slicing through soft tissues. To understand more about the forms and functions of serrated shark teeth, we examined the morphology and histology of tooth serrations in three species: the Tiger Shark (Galeocerdo cuvier), Blue Shark (Prionace glauca), and White Shark (Carcharodon carcharias). We show that there are two basic types of serrations. A primary serration consists of three layers of enameloid with underlying dentine filling the serration's base. All three species studied have primary serrations, although the dentine component differs (orthodentine in Tiger and Blue Sharks; osteodentine in the White Shark). Smaller secondary serrations are found in the Tiger Shark, formed solely by enameloid with no contribution from underlying dentine. Secondary serrations are effectively "serrations within serrations" that allow teeth to cut at different scales. We propose that the cutting edges of Tiger Shark teeth, equipped with serrations at different scales, are linked to a diet that includes large, hard-shelled prey (e.g., sea turtles) as well as smaller, softer prey such as fishes. We discuss other aspects of serration form and function by making analogies to man-made cutting implements, such as knives and saws. Copyright © 2016 Elsevier GmbH. All rights reserved.

Morphological Variations of Leading-Edge Serrations in Owls (Strigiformes).

PubMed

Weger, Matthias; Wagner, Hermann

2016-01-01

Owls have developed serrations, comb-like structures, along the leading edge of their wings. Serrations were investigated from a morphological and a mechanical point of view, but were not yet quantitatively compared for different species. Such a comparative investigation of serrations from species of different sizes and activity patterns may provide new information about the function of the serrations. Serrations on complete wings and on tenth primary remiges of seven owl species were investigated. Small, middle-sized, and large owl species were investigated as well as species being more active during the day and owls being more active during the night. Serrations occurred at the outer parts of the wings, predominantly at tenth primary remiges, but also on further wing feathers in most species. Serration tips were oriented away from the feather rachis so that they faced into the air stream during flight. The serrations of nocturnal owl species were higher developed as demonstrated by a larger inclination angle (the angle between the base of the barb and the rachis), a larger tip displacement angle (the angle between the tip of the serration and the base of the serration) and a longer length. Putting the measured data into a clustering algorithm yielded dendrograms that suggested a strong influence of activity pattern, but only a weak influence of size on the development of the serrations. Serrations are supposed to be involved in noise reduction during flight and also depend on the aerodynamic properties that in turn depend on body size. Since especially nocturnal owls have to rely on hearing during prey capture, the more pronounced serrations of nocturnal species lend further support to the notion that serrations have an important function in noise reduction. The differences in shape of the serrations investigated indicate that a silent flight requires well-developed serrations.

Diagnosing lynch syndrome in absence of colorectal cancer.

PubMed

Lynch, Henry T; Knezetic, Joseph; Lanspa, Stephen

2012-11-01

There are many ways in which a diagnosis of Lynch syndrome can be made, most prominent of which is family history, presence of cancer, high microsatellite instability, immunohistochemistry, and a mismatch repair germline mutation. There are at least four molecular pathways for colorectal cancer carcinogenesis: 1) adenoma-carcinoma sequence; 2) hereditary microsatellite instability; 3) serrated pathway; 4) epidermal growth factor receptor. The answer to diagnosing Lynch syndrome in the absence of colorectal cancer may be partially based upon the phenotypic characteristics of the colonic polyps should they be identified at colonoscopy, specifically their phenotypic characteristics of location, size, histology, number, and age of polyp onset.

Tool mark striations in pig skin produced by stabs from a serrated blade.

PubMed

Pounder, Derrick J; Bhatt, Shivani; Cormack, Lesley; Hunt, Bill A C

2011-03-01

Stab wounds produced by serrated blades are generally indistinguishable from stab wounds produced by non-serrated blades, except when visible tool mark striations are left on severed cartilage. Using a pig-skin experimental model, we explored the possibility that similar striations may be left in skin. Stabs into pig skin were made using a straight spine coarsely serrated blade (121), a drop point finely serrated blade (20), a clip point irregular coarsely serrated blade (20), a drop point coarsely serrated blade (15), and as controls 2 non-serrated blades (40). Tool mark striations could be seen on the skin wall of the stab canal in all stabs made using serrated blades but in none with non-serrated blades.The striation pattern, reflecting the class characteristics of the serrated blade, was the same as that described in cartilage but less well defined. Fixation of the specimen with Carnoy's solution best preserved visible striations, and fixation with formaldehyde after staining with 5% Neutral Red was also satisfactory. Casting with vinyl polysiloxane dental impression material greatly facilitated photo-documentation. Applying the technique to homicidal stabbings may help identify stab wounds produced with serrated blades.

Morphological Variations of Leading-Edge Serrations in Owls (Strigiformes)

PubMed Central

Weger, Matthias; Wagner, Hermann

2016-01-01

Background Owls have developed serrations, comb-like structures, along the leading edge of their wings. Serrations were investigated from a morphological and a mechanical point of view, but were not yet quantitatively compared for different species. Such a comparative investigation of serrations from species of different sizes and activity patterns may provide new information about the function of the serrations. Results Serrations on complete wings and on tenth primary remiges of seven owl species were investigated. Small, middle-sized, and large owl species were investigated as well as species being more active during the day and owls being more active during the night. Serrations occurred at the outer parts of the wings, predominantly at tenth primary remiges, but also on further wing feathers in most species. Serration tips were oriented away from the feather rachis so that they faced into the air stream during flight. The serrations of nocturnal owl species were higher developed as demonstrated by a larger inclination angle (the angle between the base of the barb and the rachis), a larger tip displacement angle (the angle between the tip of the serration and the base of the serration) and a longer length. Putting the measured data into a clustering algorithm yielded dendrograms that suggested a strong influence of activity pattern, but only a weak influence of size on the development of the serrations. Conclusions Serrations are supposed to be involved in noise reduction during flight and also depend on the aerodynamic properties that in turn depend on body size. Since especially nocturnal owls have to rely on hearing during prey capture, the more pronounced serrations of nocturnal species lend further support to the notion that serrations have an important function in noise reduction. The differences in shape of the serrations investigated indicate that a silent flight requires well-developed serrations. PMID:26934104

Urinary tract cancer in patients with hereditary non-polyposis colorectal cancer.

PubMed

Zachhau, Peter; Walter, Steen

2012-02-01

Hereditary non-polyposis colorectal cancer (HNPCC), or Lynch syndrome, is characterized as a hereditary colorectal cancer with an increased risk of cancer elsewhere in the body. In the Department of Urology at Odense University Hospital, screening for cancer in the urinary tract has been carried out on 20 patients with HNPCC since November 2001. Clinical records and pathology results were reviewed for all patients during the screening period. During screening two patients without urological symptoms were found to have cancer in the ureter. HNPCC patients with increased risk of urinary tract cancer should be referred for screening of the urinary tract. It is also important to discuss a rational strategy towards the screening of HNPCC patients for urinary tract cancer, and to initiate further investigation into this screening.

Multiple pilomatrixomas in a survivor of WNT-activated medulloblastoma leading to the discovery of a germline APC mutation and the diagnosis of familial adenomatous polyposis.

PubMed

Bendelsmith, Charles R; Skrypek, Mary M; Patel, Sachin R; Pond, Dinel A; Linabery, Amy M; Bendel, Anne E

2018-01-01

Because children diagnosed with WNT-activated medulloblastoma have a 10-year overall survival rate of 95%, active long-term follow-up is critically important in reducing mortality from other causes. Here, we describe an 11-year-old adopted female who developed multiple pilomatrixomas 3 years after diagnosis of WNT-activated medulloblastoma, an unusual finding that prompted deeper clinical investigation. A heterozygous germline APC gene mutation was discovered, consistent with familial adenomatous polyposis. Screening endoscopy revealed numerous precancerous polyps that were excised. This case highlights the importance of long-term follow-up of pediatric cancer survivors, including attention to unexpected symptoms, which might unveil an underlying cancer predisposition syndrome. © 2017 Wiley Periodicals, Inc.

Dento-osseous anomalies associated to familial adenomatous polyposis mimicking florid cemento-osseous dysplasia.

PubMed

Almeida, Fabiana Tolentino; Leite, André Ferreira; de Souza Figueiredo, Paulo Tadeu; Melo, Nilce Santos; Sousa, João Batista; Almeida, Rômulo; Acevedo, Ana Carolina; Silva Guerra, Eliete Neves

2012-12-01

Familial adenomatous polyposis (FAP) is a colorectal cancer syndrome characterized by the development of multiple polyps of the colon and rectum with high risk of malignant transformation. The extraintestinal manifestations such as dento-osseous changes are associated with FAP. This is a case report of a 36-year-old female patient who was referred for dental treatment with the initial diagnosis of florid cemento-osseous dysplasia (FCOD). However, the association of the imaging dento-osseous findings with the medical history confirmed the diagnosis of FAP. The paper illustrates the clinical characteristics and imaging findings associated with FAP, and also discusses misdiagnosis based exclusively on imaging features. Copyright © 2012 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.

The three-dimensional shape of serrations at barn owl wings: towards a typical natural serration as a role model for biomimetic applications

PubMed Central

Bachmann, Thomas; Wagner, Hermann

2011-01-01

Barn owl feathers at the leading edge of the wing are equipped with comb-like structures termed serrations on their outer vanes. Each serration is formed by one barb ending that separates and bends upwards. This structure is considered to play a role in air-flow control and noise reduction during flight. Hence, it has considerable potential for engineering applications, particularly in the aviation industry. Several publications have reported possible functions of serrations at artificial airfoils. However, only crude approximations of natural serrations have so far been investigated. We refer to these attempts as zero-order approximations of serrations. It was the goal of this study to present a quantitative three-dimensional characterization of natural serrations as first-order approximations (mean values) and second-order approximations (listed differences depending on the position of the serration along the leading edge). Confocal laser scanning microscopy was used for a three-dimensional reconstruction and investigation with high spatial resolution. Each serration was defined by its length, profile geometry and curvature. Furthermore, the orientation of the serrations at the leading edge was characterized by the inclination angle, the tilt angle and the separation distance of neighboring serrations. These data are discussed with respect to possible applications of serration-like structures for noise suppression and air-flow control. PMID:21507001

Serrated Colon Polyps as Precursors to Colorectal Cancer

PubMed Central

Sweetser, Seth; Smyrk, Thomas C.; Sinicrope, Frank A.

2013-01-01

Identification of the serrated neoplasia pathway has improved our understanding of the pathogenesis of colorectal cancer (CRC). Insights have included an increased recognition of the malignant potential of different types of serrated polyps, such as sessile and traditional serrated adenomas. Sessile serrated adenomas share molecular features with colon tumors, such as microsatellite instability and a methylator phenotype, indicating that these lesions are precursors that progress via the serrated neoplasia pathway. There is evidence that the serrated pathway contributes to interval or missed cancers. These data have important implications for clinical practice and CRC prevention, since hyperplastic polyps were previously regarded as having no malignant potential. Endoscopic detection of serrated polyps is a challenge because they are often inconspicuous with indistinct margins, and are frequently covered by adherent mucus. It is important for gastroenterologists to recognize the subtle endoscopic features of serrated polyps, which would facilitate their detection and removal, to ensure a high-quality colonoscopy examination. Recognition of the role of serrated polyps in colon carcinogenesis has led to the inclusion of these lesions in post-polypectomy surveillance guidelines. However, an enhanced effort is needed to identify and completely remove serrated adenomas, with the goal of increasing the effectiveness of colonoscopy to reduce CRC incidence. PMID:23267866

Benefits of curved serrations on broadband trailing-edge noise reduction

NASA Astrophysics Data System (ADS)

Avallone, F.; van der Velden, W. C. P.; Ragni, D.

2017-07-01

Far-field noise and flow field over a novel curved trailing-edge serration (named as iron-shaped serration) are investigated. Spectra of the far-field broadband noise, directivity plots and the flow-field over the iron-shaped serration are obtained from numerical computations performed using a compressible Lattice-Boltzmann solver. The new design is compared to a conventional trailing-edge serration with a triangular geometry. Both serration geometries were retrofitted to a NACA 0018 airfoil at zero degree angle of attack. The iron-shaped geometry is found to reduce far-field broadband noise of approximately 2 dB more than the conventional sawtooth serration for chord-based Strouhal numbers Stc<15. At higher frequencies, the far-field broadband noise for the two serration geometries has comparable intensity. Near-wall velocity distribution and surface pressure fluctuations show that their intensity and spectra are independent on the serration geometry, but a function of the streamwise location. It is found that the larger noise reduction achieved by the iron-shaped trailing-edge serration is due to the mitigation of the scattered noise at the root. This effect is obtained by mitigating the interaction between the two sides of the serration, by delaying toward the tip both the outward (i.e., the tendency of the flow to deviate from the centerline to the edge of the serration) and the downward (i.e., the tendency of the flow to merge between the upper and bottom side of the serration) flow motions present at the root of the sawtooth.

Deep sequencing with intronic capture enables identification of an APC exon 10 inversion in a patient with polyposis.

PubMed

Shirts, Brian H; Salipante, Stephen J; Casadei, Silvia; Ryan, Shawnia; Martin, Judith; Jacobson, Angela; Vlaskin, Tatyana; Koehler, Karen; Livingston, Robert J; King, Mary-Claire; Walsh, Tom; Pritchard, Colin C

2014-10-01

Single-exon inversions have rarely been described in clinical syndromes and are challenging to detect using Sanger sequencing. We report the case of a 40-year-old woman with adenomatous colon polyps too numerous to count and who had a complex inversion spanning the entire exon 10 in APC (the gene encoding for adenomatous polyposis coli), causing exon skipping and resulting in a frameshift and premature protein truncation. In this study, we employed complete APC gene sequencing using high-coverage next-generation sequencing by ColoSeq, analysis with BreakDancer and SLOPE software, and confirmatory transcript analysis. ColoSeq identified a complex small genomic rearrangement consisting of an inversion that results in translational skipping of exon 10 in the APC gene. This mutation would not have been detected by traditional sequencing or gene-dosage methods. We report a case of adenomatous polyposis resulting from a complex single-exon inversion. Our report highlights the benefits of large-scale sequencing methods that capture intronic sequences with high enough depth of coverage-as well as the use of informatics tools-to enable detection of small pathogenic structural rearrangements.

Germline mutations in the spindle assembly checkpoint genes BUB1 and BUB3 are infrequent in familial colorectal cancer and polyposis.

PubMed

Mur, Pilar; De Voer, Richarda M; Olivera-Salguero, Rubén; Rodríguez-Perales, Sandra; Pons, Tirso; Setién, Fernando; Aiza, Gemma; Valdés-Mas, Rafael; Bertini, Angelo; Pineda, Marta; Vreede, Lilian; Navarro, Matilde; Iglesias, Silvia; González, Sara; Brunet, Joan; Valencia, Alfonso; Esteller, Manel; Lázaro, Conxi; Kops, Geert J P L; Urioste, Miguel; Puente, Xose S; Capellá, Gabriel; Valle, Laura

2018-02-15

Germline mutations in BUB1 and BUB3 have been reported to increase the risk of developing colorectal cancer (CRC) at young age, in presence of variegated aneuploidy and reminiscent dysmorphic traits of mosaic variegated aneuploidy syndrome. We performed a mutational analysis of BUB1 and BUB3 in 456 uncharacterized mismatch repair-proficient hereditary non-polyposis CRC families and 88 polyposis cases. Four novel or rare germline variants, one splice-site and three missense, were identified in four families. Neither variegated aneuploidy nor dysmorphic traits were observed in carriers. Evident functional effects in the heterozygous form were observed for c.1965-1G>A, but not for c.2296G>A (p.E766K), in spite of the positive co-segregation in the family. BUB1 c.2473C>T (p.P825S) and BUB3 c.77C>T (p.T26I) remained as variants of uncertain significance. As of today, the rarity of functionally relevant mutations identified in familial and/or early onset series does not support the inclusion of BUB1 and BUB3 testing in routine genetic diagnostics of familial CRC.

APC promoter 1B deletion in seven American families with familial adenomatous polyposis.

PubMed

Snow, A K; Tuohy, T M F; Sargent, N R; Smith, L J; Burt, R W; Neklason, D W

2015-10-01

Familial adenomatous polyposis (FAP) is a colorectal cancer predisposition syndrome caused by mutations in the adenomatous polyposis coli (APC) gene. Clinical genetic testing fails to identify disease causing mutations in up to 20% of clinically apparent FAP cases. Following the inclusion of multiplex ligation-dependent probe amplification (MLPA) probes specific for APC promoter 1B, seven probands were identified with a deletion of promoter 1B. Using haplotype analysis spanning the APC locus, the seven families appear to be identical by descent from a common founder. The clinical phenotype of 19 mutation carriers is classical FAP with colectomy at an average age of 24. The majority of cases had a large number of duodenal and gastric polyps. Measurements of allele-specific expression of APC mRNA using TaqMan assay confirmed that relative expression in the allele containing the promoter 1B deletion was reduced 42-98%, depending on tissue type. This study confirms the importance of APC promoter deletions as a cause of FAP and identifies a founder mutation in FAP patients from the United States. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Familial Adenomatous Polyposis (FAP)-A Case Study and Review of Literature.

PubMed

Dalavi, Santosh Bhimrao; Vedpalsingh, Tanwar Harshwardhan; Bankar, Sanket Subhash; Ahmed, Mohd Hamid Shafique; Bhosale, Dattatray Nivrutti

2015-03-01

Familial adenomatous polyposis (FAP) is a syndrome characteristically having numerous (hundreds to thousands) polyps in the epithelium of the large intestines with an autosomal dominant inheritance caused by germ line mutations in adenomatous polyposis coli (APC) gene in chromosome 5q21. Most FAP patients have a family history of colorectal polyps and cancer but 25-30% of them are "de novo", without any clinical or genetic evidence of FAP in family members. Prophylactic proctocolectomy is required in almost all patients since all affected patients inevitably develop cancer. We report a case of a 32-year-old man who presented with vague abdominal complaints without any family history, which on evaluation as found to have multiple colorectal polyps and underwent a prophylactic proctocolectomy with end continent ileostomy. Two of his children were evaluated and found to have multiple colorectal polyps on colonoscopy and have been advised regular follow up annually. In conclusion, patients with FAP may present with vague abdominal complaints and without any family history, hence need to be carefully evaluated. Good patient compliance is of prime importance in deciding the treatment and surveillance modality subsequently determining the prognosis of patients with FAP.

Upper gastrointestinal tumours in Japanese familial adenomatous polyposis patients

PubMed Central

Yamaguchi, Tatsuro; Ishida, Hideyuki; Ueno, Hideki; Kobayashi, Hirotoshi; Hinoi, Takao; Inoue, Yasuhiro; Ishida, Fumio; Kanemitsu, Yukihide; Konishi, Tsuyoshi; Tomita, Naohiro; Matsubara, Nagahide; Watanabe, Toshiaki; Sugihara, Kenichi

2016-01-01

Objective The upper gastrointestinal characteristics in Japanese familial adenomatous polyposis patients have not yet been clarified. The aim of the present study was to elucidate these characteristics in Japanese familial adenomatous polyposis patients. Methods This study was conducted by the study group for familial adenomatous polyposis in the Japanese Society for Cancer of the Colon and Rectum. Familial adenomatous polyposis patients who underwent surgical resection from 2000 to 2012 were included in the study. Results In total, 303 familial adenomatous polyposis patients were enrolled, with 265 cases of classical familial adenomatous polyposis (≥100 adenomas) and 38 cases of attenuated familial adenomatous polyposis (<100 adenomas). Fundic gland polyps were significantly more common in classical familial adenomatous polyposis than in attenuated familial adenomatous polyposis; however, gastric cancer was significantly less common in classical familial adenomatous polyposis than in attenuated familial adenomatous polyposis. Gastric cancer and duodenal adenoma were significantly more common in familial adenomatous polyposis patients with gastric adenoma than in those without gastric adenoma. Duodenal cancer was detected in 7 of 72 familial adenomatous polyposis patients with duodenal adenoma. The median tumour risk in 50-year-old familial adenomatous polyposis patients was 55.3, 21.8, 3.8, 39.2 and 7.7% for fundic gland polyp, gastric adenoma, gastric cancer, duodenal adenoma and duodenal cancer, respectively. Conclusions Upper gastrointestinal tumours/polyps were frequently found in familial adenomatous polyposis patients, and their incidences were correlated; however, the frequency of gastric cancer in Japanese familial adenomatous polyposis patients was similar to that in the general population. PMID:26819281

Serrated pathway in colorectal carcinogenesis

PubMed Central

Yamane, Letícia; Scapulatempo-Neto, Cristovam; Reis, Rui Manuel; Guimarães, Denise Peixoto

2014-01-01

Serrated adenocarcinoma is a recently described subset of colorectal cancer (CRC), which account for about 10% of all CRCs and follows an alternative pathway in which serrated polyps replace the traditional adenoma as the precursor lesion to CRC. Serrated polyps form a heterogeneous group of colorectal lesions that includes hyperplastic polyps (HPs), sessile serrated adenoma (SSA), traditional serrated adenoma (TSA) and mixed polyps. HPs are the most common serrated polyp followed by SSA and TSA. This distinct histogenesis is believed to have a major influence in prevention strategies, patient prognosis and therapeutic impact. Genetically, serrated polyps exhibited also a distinct pattern, with KRAS and BRAF having an important contribution to its development. Two other molecular changes that have been implicated in the serrated pathway include microsatellite instability and the CpG island methylator phenotype. In the present review we will address the current knowledge of serrated polyps, clinical pathological features and will update the most recent findings of its molecular pathways. The understanding of their biology and malignancy potential is imperative to implement a surveillance approach in order to prevent colorectal cancer development. PMID:24627599

Appreciating the broad clinical features of SMAD4 mutation carriers: a multi-center chart review

PubMed Central

Wain, K.E.; Ellingson, M.S.; McDonald, J.; Gammon, A.; Roberts, M.; Pichurin, P.; Winship, I.; Riegert-Johnson, D.; Weitzel, J. N.; Lindor, N.M.

2014-01-01

Heterozygous loss-of-function (LOF) SMAD4 mutations are associated with juvenile polyposis syndrome (JP) and hereditary hemorrhagic telangiectasia (HHT). Some carriers exhibit symptoms of both conditions, leading to the name JP-HHT syndrome. Three families have been reported with connective tissue abnormalities. In order to better understand the spectrum and extent of clinical findings in SMAD4 carriers, medical records of 34 patients (20 families) from five clinical practices were reviewed. Twenty-one percent (7/34) had features suggesting a connective tissue defect: enlarged aortic root (n=3), aortic and mitral insufficiency (n=2), aortic dissection (n=1), retinal detachment (n=1), brain aneurysms (n=1), lax skin and joints (n=1). JP-specific findings were almost uniformly present but variable. Ninety-seven percent had colon polyps that were generally pan-colonic and of variable histology and number. Forty-eight percent (15/31) had extensive gastric polyposis. HHT features were documented in 76% including epistaxis (19/31, 61%), mucocutaneous telangiectases (15/31, 48%), liver arteriovenous malformation (AVM) (6/16, 38%), brain AVM (1/26, 4%), pulmonary AVM (9/17, 53%), and intrapulmonary shunting (14/23, 61%). SMAD4 carriers should be managed for JP and HHT, since symptoms of both are likely yet unpredictable. Connective tissue abnormalities are an emerging component of JP-HHT syndrome, and larger studies are needed to understand these manifestations. PMID:24525918

Singapore Cancer Network (SCAN) Guidelines for Referral for Genetic Evaluation of Common Hereditary Cancer Syndromes.

PubMed

2015-10-01

The SCAN cancer genetics workgroup aimed to develop Singapore Cancer Network (SCAN) clinical practice guidelines for referral for genetic evaluation of common hereditary cancer syndromes. The workgroup utilised a modified ADAPTE process to calibrate high quality international evidence-based clinical practice guidelines to our local setting. To formulate referral guidelines for the 3 most commonly encountered hereditary cancer syndromes to guide healthcare providers in Singapore who care for cancer patients and/or their family members, 7, 5, and 3 sets of international guidelines respectively for hereditary breast and ovarian cancer (HBOC) syndrome, Lynch syndrome (LS), and familial adenomatous polyposis (FAP) were evaluated. For each syndrome, the most applicable one was selected, with modifications made such that they would be appropriate to the local context. These adapted guidelines form the SCAN Guidelines 2015 for referral for genetic evaluation of common hereditary cancer syndromes.

New genes emerging for colorectal cancer predisposition.

PubMed

Esteban-Jurado, Clara; Garre, Pilar; Vila, Maria; Lozano, Juan José; Pristoupilova, Anna; Beltrán, Sergi; Abulí, Anna; Muñoz, Jenifer; Balaguer, Francesc; Ocaña, Teresa; Castells, Antoni; Piqué, Josep M; Carracedo, Angel; Ruiz-Ponte, Clara; Bessa, Xavier; Andreu, Montserrat; Bujanda, Luis; Caldés, Trinidad; Castellví-Bel, Sergi

2014-02-28

Colorectal cancer (CRC) is one of the most frequent neoplasms and an important cause of mortality in the developed world. This cancer is caused by both genetic and environmental factors although 35% of the variation in CRC susceptibility involves inherited genetic differences. Mendelian syndromes account for about 5% of the total burden of CRC, with Lynch syndrome and familial adenomatous polyposis the most common forms. Excluding hereditary forms, there is an important fraction of CRC cases that present familial aggregation for the disease with an unknown germline genetic cause. CRC can be also considered as a complex disease taking into account the common disease-commom variant hypothesis with a polygenic model of inheritance where the genetic components of common complex diseases correspond mostly to variants of low/moderate effect. So far, 30 common, low-penetrance susceptibility variants have been identified for CRC. Recently, new sequencing technologies including exome- and whole-genome sequencing have permitted to add a new approach to facilitate the identification of new genes responsible for human disease predisposition. By using whole-genome sequencing, germline mutations in the POLE and POLD1 genes have been found to be responsible for a new form of CRC genetic predisposition called polymerase proofreading-associated polyposis.

Cancer in an unexpected site post pouch surgery for familial adenomatous polyposis (FAP).

PubMed

Alwahbi, Omar A; Abduljabbar, Alaa S; Anwer, Lucman A

2018-01-01

Familial Adenomatous Polyposis (FAP) is a hereditary condition characterized by multiple colorectal adenomatous polyps. FAP is the most common adenomatous polyposis syndrome. Restorative proctocolectomy is the most commonly performed surgical procedure performed for patients suffering from FAP with different options for anastomosis, namely ileorectal anastomosis (IRA) or ileal pouch anal anastomosis (IPAA). The occurrence of adenomas is a common finding during follow up and surveillance post surgery for these patients. Although there are a few cases of carcinoma that were namely at the anal transitional zone (ATZ), there are only a few cases of ileal pouch related adenocarcinoma reported. This work has been reported in line with the SCARE criteria (Agha et al., 2016) [1]. We report a case of a 34-year-old man diagnosed with FAP who underwent proctocolectomy with IPAA, and subsequently referred to our center, who, despite appropriate measures and surveillance, developed adenocarcinoma in the ileal pouch. Restorative proctocolectomy for Familial Adenomatous Polyposis (FAP) is the mainstay of treatment. There are different surgical options, each with its own set of advantages and disadvantages. The most favored option is proctocolectomy with ileal pouch anal anastomosis (IPAA) due to because it involves resection of the rectum. Despite these interventions, adenomas and/or carcinomas have been reported on follow up post surgery. Although the risk of developing adenomas or carcinomas in the ileal pouch post proctocolectomy with IPAA is low it should not be neglected as cancer occurrence or recurrence is unpredictable even with appropriate measures. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

[Hereditary gastric and pancreatic cancer predisposition syndromes].

PubMed

Leoz, María Liz; Sánchez, Ariadna; Carballal, Sabela; Ruano, Lucía; Ocaña, Teresa; Pellisé, María; Castells, Antoni; Balaguer, Francesc; Moreira, Leticia

2016-01-01

The most common hereditary gastrointestinal cancers are colorectal, mainly hereditary nonpolyposis colorectal cancer (Lynch syndrome) and familial adenomatous polyposis. Other extracolonic neoplasms, including the gastric and pancreatic adenocarcinomas, are less well known and studied because they account for a relatively small percentage of hereditary gastrointestinal cancers. Nonetheless, they merit special attention because of the high associated morbidity and mortality rates. We review the hereditary and familial syndromes associated with gastric and pancreatic cancers with a view to improving knowledge and understanding of these diseases, in order to heighten diagnostic suspicion and thus implement appropriate diagnostic strategies, screening, surveillance and treatment. Copyright © 2016 Elsevier España, S.L.U. y AEEH y AEG. All rights reserved.

Hyper-Methylated Loci Persisting from Sessile Serrated Polyps to Serrated Cancers.

PubMed

Andrew, Angeline S; Baron, John A; Butterly, Lynn F; Suriawinata, Arief A; Tsongalis, Gregory J; Robinson, Christina M; Amos, Christopher I

2017-03-02

Although serrated polyps were historically considered to pose little risk, it is now understood that progression down the serrated pathway could account for as many as 15%-35% of colorectal cancers. The sessile serrated adenoma/polyp (SSA/P) is the most prevalent pre-invasive serrated lesion. Our objective was to identify the CpG loci that are persistently hyper-methylated during serrated carcinogenesis, from the early SSA/P lesion through the later cancer phases of neoplasia development. We queried the loci hyper-methylated in serrated cancers within our rightsided SSA/Ps from the New Hampshire Colonoscopy Registry, using the Illumina Infinium Human Methylation 450 k panel to comprehensively assess the DNA methylation status. We identified CpG loci and regions consistently hyper-methylated throughout the serrated carcinogenesis spectrum, in both our SSA/P specimens and in serrated cancers. Hyper-methylated CpG loci included the known the tumor suppressor gene RET (p = 5.72 x 10-10), as well as loci in differentially methylated regions for GSG1L, MIR4493, NTNG1, MCIDAS, ZNF568, and RERG. The hyper-methylated loci that we identified help characterize the biology of SSA/P development, and could be useful as therapeutic targets, or for future identification of patients who may benefit from shorter surveillance intervals.

Pathogenesis and Management of Serrated Polyps: Current Status and Future Directions

PubMed Central

Anderson, Joseph C.

2014-01-01

Hyperplastic or serrated polyps were once believed to have little to no clinical significance. A subset of these polyps are now considered to be precursors to colorectal cancers (CRC) in the serrated pathway that may account for at least 15% of all tumors. The serrated pathway is distinct from the two other CRC pathways and involves an epigenetic hypermethylation mechanism of CpG islands within promoter regions of tumor suppressor genes. This process results in the formation of CpG island methylator phenotype tumors. Serrated polyps are divided into hyperplastic polyps, sessile serrated adenomas/polyps (SSA/Ps), and traditional serrated adenomas (TSAs). The SSA/P and the TSA have the potential for dysplasia and subsequent malignant transformation. The SSA/Ps are more common and are more likely to be flat than TSAs. Their flat morphology may make them difficult to detect and thus explain the variation in detection rates among endoscopists. Challenges for endoscopists also include the difficulty in pathological interpretation as well surveillance of these lesions. Furthermore, serrated polyps may be inadequately resected by endoscopists. Thus, it is not surprising that the serrated pathway has been linked with interval cancers. This review will provide the physician or clinician with the knowledge to manage patients with serrated polyps. PMID:25368744

The role of APC in WNT pathway activation in serrated neoplasia.

PubMed

Borowsky, Jennifer; Dumenil, Troy; Bettington, Mark; Pearson, Sally-Ann; Bond, Catherine; Fennell, Lochlan; Liu, Cheng; McKeone, Diane; Rosty, Christophe; Brown, Ian; Walker, Neal; Leggett, Barbara; Whitehall, Vicki

2018-03-01

Conventional adenomas are initiated by APC gene mutation that activates the WNT signal. Serrated neoplasia is commonly initiated by BRAF or KRAS mutation. WNT pathway activation may also occur, however, to what extent this is owing to APC mutation is unknown. We examined aberrant nuclear β-catenin immunolocalization as a surrogate for WNT pathway activation and analyzed the entire APC gene coding sequence in serrated and conventional pathway polyps and cancers. WNT pathway activation was a common event in conventional pathway lesions with aberrant nuclear immunolocalization of β-catenin and truncating APC mutations in 90% and 89% of conventional adenomas and 82% and 70% of BRAF wild-type cancers, respectively. WNT pathway activation was seen to a lesser extent in serrated pathway lesions. It occurred at the transition to dysplasia in serrated polyps with a significant increase in nuclear β-catenin labeling from sessile serrated adenomas (10%) to sessile serrated adenomas with dysplasia (55%) and traditional serrated adenomas (9%) to traditional serrated adenomas with dysplasia (39%) (P=0.0001). However, unlike the conventional pathway, truncating APC mutations were rare in the serrated pathway lesions especially sessile serrated adenomas even when dysplastic (15%) and in the BRAF mutant cancers with microsatellite instability that arise from them (8%). In contrast, APC missense mutations that were rare in conventional pathway adenomas and cancers (3% in BRAF wild-type cancers) were more frequent in BRAF mutant cancers with microsatellite instability (32%). We conclude that increased WNT signaling is important in the transition to malignancy in the serrated pathway but that APC mutation is less common and the spectrum of mutations is different than in conventional colorectal carcinogenesis. Moderate impact APC mutations and non-APC-related causes of increased WNT signaling may have a more important role in serrated neoplasia than the truncating APC mutations common in conventional adenomas.

Genetic Counselor Practices Involving Pediatric Patients with FAP: an Investigation of their Self-Reported Strategies for Genetic Testing and Hepatoblastoma Screening.

PubMed

Lawson, Caitlin E; Attard, Thomas M; Dai, Hongying; Septer, Seth

2017-06-01

Familial adenomatous polyposis (FAP) is a cancer predisposition syndrome that causes early-onset polyposis and is associated with an increased risk for hepatoblastoma. There is currently a lack of consensus on when to order APC (adenomatous polyposis coli) gene testing or implement surveillance for hepatoblastoma. An online questionnaire was completed by 62 genetic counselors to capture their current practices regarding these questions. Extracolonic findings associated with FAP that were most likely to prompt APC testing in an otherwise asymptomatic 10 year-old child with a negative family history were multiple desmoid tumors, congenital hypertrophy of the retinal pigment epithelium (CHRPE), jaw osteomas, and hepatoblastoma. For hepatoblastoma screening, the majority did recommend this in children less than age five years with known APC mutations. An interval of every 3-6 months was most commonly suggested; however, responses extended to screening on a less than annual basis. These results highlight the need for further investigation into why some genetic counselors do not recommend APC testing in young at-risk children and what factors influence views about the ideal age and indication for APC testing. Studies of these issues would help to define the best clinical practice model for genetic testing and hepatoblastoma screening in pediatric patients with FAP.

[Premalignant conditions of the small bowel].

PubMed

Drastich, P

2013-01-01

Small intestinal dysplastic lesions are rare and difficult to detect before they progress to cancer. New investigative modalities, such as capsule endoscopy and doubleballoon enteroscopy, are very promising in search for premalignant lesions. Screening patients at high-risk for small bowel neoplasia is the only sensible approach. Duodenal adenoma represents the most easily accessible tumors with the possibility of curative endoscopic resection. Due to the strong association of the small bowel and colonic adenomas, it is always necessary to perform colonoscopy. In young patients, the exclusion of familial polyposis by genetic testing is always mandatory. Patients with celiac disease are especially at risk of developing nonHodgkins lymphomas and adenocarcinomas. There is a high-risk of ampuloma and other adenomas in patients with familial adenomatous polyposis. Patients with prolonged and complicated course of Crohns disease, Peutz Jeghers syndrome and patients with ileoanal pouch have higher risk of adenocarcinoma of the small intestine.

The serrated neoplasia pathway of colorectal tumors: Identification of MUC5AC hypomethylation as an early marker of polyps with malignant potential.

PubMed

Renaud, Florence; Mariette, Christophe; Vincent, Audrey; Wacrenier, Agnès; Maunoury, Vincent; Leclerc, Julie; Coppin, Lucie; Crépin, Michel; Van Seuningen, Isabelle; Leteurtre, Emmanuelle; Buisine, Marie-Pierre

2016-03-15

The serrated neoplasia pathway accounts for 20-30% of colorectal cancers (CRC), which are characterized by extensive methylation (CpG island methylation phenotype, CIMP), frequent BRAF mutation and high microsatellite instability (MSI). We recently identified MUC5AC mucin gene hypomethylation as a specific marker of MSI CRC. The early identification of preneoplastic lesions among serrated polyps is currently challenging. Here, we performed a detailed pathological and molecular analysis of a large series of colorectal serrated polyps and evaluated the usefulness of mucin genes MUC2 and MUC5AC to differentiate serrated polyps and to identify lesions with malignant potential. A series of 330 colorectal polyps including 218 serrated polyps [42 goblet cell-rich hyperplastic polyps (GCHP), 68 microvesicular hyperplastic polyps (MVHP), 100 sessile serrated adenoma (SSA) and eight traditional serrated adenoma (TSA)] and 112 conventional adenomas was analyzed for BRAF/KRAS mutations, MSI, CIMP, MLH1 and MGMT methylation, and MUC2 and MUC5AC expression and methylation. We show that MUC5AC hypomethylation is an early event in the serrated neoplasia pathway, and specifically detects MVHP and SSA, arguing for a filiation between MVHP, SSA and CIMP-H/MSI CRC, whereas GCHP and TSA arise from a distinct pathway. Moreover, MUC5AC hypomethylation specifically identified serrated lesions with BRAF mutation, CIMP-H or MSI, suggesting that it may be useful to identify serrated neoplasia pathway-related precursor lesions. Our data suggest that MVHP should be recognized among HP and require particular attention. © 2015 UICC.

[Clinical and endoscopic features of a selected population with serrated colorectal adenomas in a private clinic in Lima - Peru].

PubMed

Castillo, Ofelia; Barreda, Carlos; Recavarren, Sixto; Barriga, José A; Salazar M, Fernando; Yriberry, Simón; Barriga, Eduardo; Salazar C, Fernando

2013-01-01

To describe the clinical and endoscopic caracteristics of a population that has only serrated polyps of colon (mainly sessile serrated adenomas) in a private clinic in Lima, Perú, from 2009-2011. Retrospective study conducted at the endoscopy center of Clinic Ricardo Palma, Lima, Peru. Olympus colonoscope was used with high definition, including NBI (narrow band imaging) and electronic magnification. Patients had pathologic diagnosis of “polyps and / or colorectal serrated adenomas” and excluded those with synchronous tubular or villous adenomas. Images were evaluated by two endoscopists and then by a third gastroenterologist. We found 201 serrated polyps in 108 patients. Women were 60.2% and overweight predominated. Eighty (74.1%) had only one serrated adenoma and 23 (21.3%) with at least one synchronous hyperplastic polyp. The average size of sessile serrated adenomas was 5.12 mm (± 3.87 DS) and the flat type was 91 (58.7%). There were significant differences in the diameter of sessile serrated adenomas between the distal and proximal colon (4.47 mm ± 2.23 vs. 6.90 mm ± 6.25; p<0.000). The common features of sessile serrated adenomas were: White (31/36, 86.1%), smooth (28/36, 77.8%) and regular margins (26/36, 72.2%). There was a relationship between vascular pattern according NBI and serrated polyp histology (p=0.024). The endoscopic features of sessile serrated adenomas can evade detection to white light. NBI is a useful tool to define some features of these lesions.

Clinical outcomes of gastric polyps and neoplasms in patients with familial adenomatous polyposis

PubMed Central

Nakamura, Keiko; Nonaka, Satoru; Nakajima, Takeshi; Yachida, Tatsuo; Abe, Seiichiro; Sakamoto, Taku; Suzuki, Haruhisa; Yoshinaga, Shigetaka; Oda, Ichiro; Matsuda, Takahisa; Sekine, Shigeki; Kanemitsu, Yukihide; Katai, Hitoshi; Saito, Yutaka; Hirota, Seiichi

2017-01-01

Background and study aims Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome caused by a germline mutation in the adenomatous polyposis coli (APC) gene, characterized by the presence of more than 100 adenomatous polyps in the colorectum. The upper gastrointestinal tract is an extracolonic site for malignancy in patients with FAP. The frequency of death in Japanese patients with FAP because of gastric cancer is 2.8 % and that because of colon cancer is 60.6 %. Few studies have reported upper gastrointestinal diseases in patients with FAP. In the present study, we investigated the clinical outcomes of patients with FAP diagnosed with gastric neoplasms. Patients and methods We enrolled 80 patients with FAP who underwent esophagogastroduodenoscopy from October 1997 to December 2011. We investigated patient characteristics, endoscopic findings of gastric lesions, treatment outcomes, and long-term courses. Results Fundic gland polyposis was observed in 51 patients (64 %) and gastric neoplasms in 22 patients (28 %), including 20 with non-invasive and 2 with invasive neoplasm. Of the 26 neoplasms, 11 were treated by endoscopic resection (ER) and 4 by surgical resection. Metachronous gastric neoplasms were observed in 7 patients (15 lesions) and treated by ER, except for in 1 patient. No patients died of gastric lesions during a median follow-up period of 6.5 years (range, 0 – 14). Conclusion Because gastric lesions including gastric cancers in patients with FAP did not cause any deaths, they can be considered to have favorable prognoses. Early detection of gastric neoplasms through an appropriate follow-up interval may have contributed to these good outcomes. PMID:28271094

Colorectal cancer risk variants at 8q23.3 and 11q23.1 are associated with disease phenotype in APC mutation carriers.

PubMed

Ghorbanoghli, Z; Nieuwenhuis, M H; Houwing-Duistermaat, J J; Jagmohan-Changur, S; Hes, F J; Tops, C M; Wagner, A; Aalfs, C M; Verhoef, S; Gómez García, E B; Sijmons, R H; Menko, F H; Letteboer, T G; Hoogerbrugge, N; van Wezel, T; Vasen, H F A; Wijnen, J T

2016-10-01

Familial adenomatous polyposis (FAP) is a dominantly inherited syndrome caused by germline mutations in the APC gene and characterized by the development of multiple colorectal adenomas and a high risk of developing colorectal cancer (CRC). The severity of polyposis is correlated with the site of the APC mutation. However, there is also phenotypic variability within families with the same underlying APC mutation, suggesting that additional factors influence the severity of polyposis. Genome-wide association studies identified several single nucleotide polymorphisms (SNPs) that are associated with CRC. We assessed whether these SNPs are associated with polyp multiplicity in proven APC mutation carriers. Sixteen CRC-associated SNPs were analysed in a cohort of 419 APC germline mutation carriers from 182 families. Clinical data were retrieved from the Dutch Polyposis Registry. Allele frequencies of the SNPs were compared for patients with <100 colorectal adenomas versus patients with ≥100 adenomas, using generalized estimating equations with the APC genotype as a covariate. We found a trend of association of two of the tested SNPs with the ≥100 adenoma phenotype: the C alleles of rs16892766 at 8q23.3 (OR 1.71, 95 % CI 1.05-2.76, p = 0.03, dominant model) and rs3802842 at 11q23.1 (OR 1.51, 95 % CI 1.03-2.22, p = 0.04, dominant model). We identified two risk variants that are associated with a more severe phenotype in APC mutation carriers. These risk variants may partly explain the phenotypic variability in families with the same APC gene defect. Further studies with a larger sample size are recommended to evaluate and confirm the phenotypic effect of these SNPs in FAP.

Contribution of APC and MUTYH mutations to familial adenomatous polyposis susceptibility in Hungary.

PubMed

Papp, Janos; Kovacs, Marietta Eva; Matrai, Zoltan; Orosz, Enikő; Kásler, Miklós; Børresen-Dale, Anne-Lise; Olah, Edith

2016-01-01

Familial adenomatous polyposis (FAP) is a colorectal cancer predisposition syndrome with considerable genetic and phenotypic heterogeneity, defined by the development of multiple adenomas throughout the colorectum. FAP is caused either by monoallelic mutations in the adenomatous polyposis coli gene APC, or by biallelic germline mutations of MUTYH, this latter usually presenting with milder phenotype. The aim of the present study was to characterize the genotype and phenotype of Hungarian FAP patients. Mutation screening of 87 unrelated probands from FAP families (21 of them presented as the attenuated variant of the disease, showing <100 polyps) was performed using DNA sequencing and multiplex ligation-dependent probe amplification. Twenty-four different pathogenic mutations in APC were identified in 65 patients (75 %), including nine cases (37.5 %) with large genomic alterations. Twelve of the point mutations were novel. In addition, APC-negative samples were also tested for MUTYH mutations and we were able to identify biallelic pathogenic mutations in 23 % of these cases (5/22). Correlations between the localization of APC mutations and the clinical manifestations of the disease were observed, cases with a mutation in the codon 1200-1400 region showing earlier age of disease onset (p < 0.003). There were only a few, but definitive dissimilarities between APC- and MUTYH-associated FAP in our cohort: the age at onset of polyposis was significantly delayed for biallelic MUTYH mutation carriers as compared to patients with an APC mutation. Our data represent the first comprehensive study delineating the mutation spectra of both APC and MUTYH in Hungarian FAP families, and underscore the overlap between the clinical characteristics of APC- and MUTYH-associated phenotypes, necessitating a more appropriate clinical characterization of FAP families.

Common colorectal cancer risk alleles contribute to the multiple colorectal adenoma phenotype, but do not influence colonic polyposis in FAP.

PubMed

Cheng, Timothy H T; Gorman, Maggie; Martin, Lynn; Barclay, Ella; Casey, Graham; Saunders, Brian; Thomas, Huw; Clark, Sue; Tomlinson, Ian

2015-02-01

The presence of multiple (5-100) colorectal adenomas suggests an inherited predisposition, but the genetic aetiology of this phenotype is undetermined if patients test negative for Mendelian polyposis syndromes such as familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). We investigated whether 18 common colorectal cancer (CRC) predisposition single-nucleotide polymorphisms (SNPs) could help to explain some cases with multiple adenomas who phenocopied FAP or MAP, but had no pathogenic APC or MUTYH variant. No multiple adenoma case had an outlying number of CRC SNP risk alleles, but multiple adenoma patients did have a significantly higher number of risk alleles than population controls (P=5.7 × 10(-7)). The association was stronger in those with ≥10 adenomas. The CRC SNPs accounted for 4.3% of the variation in multiple adenoma risk, with three SNPs (rs6983267, rs10795668, rs3802842) explaining 3.0% of the variation. In FAP patients, the CRC risk score did not differ significantly from the controls, as we expected given the overwhelming effect of pathogenic germline APC variants on the phenotype of these cases. More unexpectedly, we found no evidence that the CRC SNPs act as modifier genes for the number of colorectal adenomas in FAP patients. In conclusion, common colorectal tumour risk alleles contribute to the development of multiple adenomas in patients without pathogenic germline APC or MUTYH variants. This phenotype may have 'polygenic' or monogenic origins. The risk of CRC in relatives of multiple adenoma cases is probably much lower for cases with polygenic disease, and this should be taken into account when counselling such patients.

A role for the epidermal growth factor receptor signaling in development of intestinal serrated polyps in mice and humans.

PubMed

Bongers, Gerold; Muniz, Luciana R; Pacer, Michelle E; Iuga, Alina C; Thirunarayanan, Nanthakumar; Slinger, Erik; Smit, Martine J; Reddy, E Premkumar; Mayer, Lloyd; Furtado, Glaucia C; Harpaz, Noam; Lira, Sergio A

2012-09-01

Epithelial cancers can be initiated by activating mutations in components of the mitogen-activated protein kinase signaling pathway such as v-raf murine sarcoma viral oncogene homolog B1 (BRAF), v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), or epidermal growth factor receptor (EGFR). Human intestinal serrated polyps are a heterogeneous group of benign lesions, but some progress to colorectal cancer. Tumors that arise from these polyps frequently contain activating mutations in BRAF or KRAS, but little is known about the role of EGFR activation in their development. Polyp samples were obtained from adults during screening colonoscopies at Mount Sinai Hospital in New York. We measured levels of EGFR protein and phosphorylation in human serrated polyps by immunohistochemical and immunoblot analyses. We generated transgenic mice that express the ligand for EGFR, Heparin-binding EGF-like growth factor (HB-EGF), in the intestine. EGFR and the extracellular-regulated kinases (ERK)1/2 were phosphorylated in serrated areas of human hyperplastic polyps (HPPs), sessile serrated adenomas, and traditional serrated adenomas. EGFR and ERK1/2 were phosphorylated in the absence of KRAS or BRAF activating mutations in a subset of HPP. Transgenic expression of the EGFR ligand HB-EGF in the intestines of mice promoted development of small cecal serrated polyps. Mice that expressed a combination of HB-EGF and US28 (a constitutively active, G-protein-coupled receptor that increases processing of HB-EGF from the membrane) rapidly developed large cecal serrated polyps. These polyps were similar to HPPs and had increased phosphorylation of EGFR and ERK1/2 within the serrated epithelium. Administration of pharmacologic inhibitors of EGFR or MAPK to these transgenic mice significantly reduced polyp development. Activation of EGFR signaling in the intestine of mice promotes development of serrated polyps. EGFR signaling also is activated in human HPPs, sessile serrated adenomas, and traditional serrated adenomas. Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.

Overlapping spectra of SMAD4 mutations in juvenile polyposis (JP) and JP-HHT syndrome.

PubMed

Gallione, Carol; Aylsworth, Arthur S; Beis, Jill; Berk, Terri; Bernhardt, Barbara; Clark, Robin D; Clericuzio, Carol; Danesino, Cesare; Drautz, Joanne; Fahl, Jeffrey; Fan, Zheng; Faughnan, Marie E; Ganguly, Arupa; Garvie, John; Henderson, Katharine; Kini, Usha; Leedom, Tracey; Ludman, Mark; Lux, Andreas; Maisenbacher, Melissa; Mazzucco, Sara; Olivieri, Carla; Ploos van Amstel, Johannes K; Prigoda-Lee, Nadia; Pyeritz, Reed E; Reardon, Willie; Vandezande, Kirk; Waldman, J Deane; White, Robert I; Williams, Charles A; Marchuk, Douglas A

2010-02-01

Juvenile polyposis (JP) and hereditary hemorrhagic telangiectasia (HHT) are clinically distinct diseases caused by mutations in SMAD4 and BMPR1A (for JP) and endoglin and ALK1 (for HHT). Recently, a combined syndrome of JP-HHT was described that is also caused by mutations in SMAD4. Although both JP and JP-HHT are caused by SMAD4 mutations, a possible genotype:phenotype correlation was noted as all of the SMAD4 mutations in the JP-HHT patients were clustered in the COOH-terminal MH2 domain of the protein. If valid, this correlation would provide a molecular explanation for the phenotypic differences, as well as a pre-symptomatic diagnostic test to distinguish patients at risk for the overlapping but different clinical features of the disorders. In this study, we collected 19 new JP-HHT patients from which we identified 15 additional SMAD4 mutations. We also reviewed the literature for other reports of JP patients with HHT symptoms with confirmed SMAD4 mutations. Our combined results show that although the SMAD4 mutations in JP-HHT patients do show a tendency to cluster in the MH2 domain, mutations in other parts of the gene also cause the combined syndrome. Thus, any mutation in SMAD4 can cause JP-HHT. Any JP patient with a SMAD4 mutation is, therefore, at risk for the visceral manifestations of HHT and any HHT patient with SMAD4 mutation is at risk for early onset gastrointestinal cancer. In conclusion, a patient who tests positive for any SMAD4 mutation must be considered at risk for the combined syndrome of JP-HHT and monitored accordingly. Copyright 2010 Wiley-Liss, Inc.

Germline truncating-mutations in BRCA1 and MSH6 in a patient with early onset endometrial cancer.

PubMed

Kast, Karin; Neuhann, Teresa M; Görgens, Heike; Becker, Kerstin; Keller, Katja; Klink, Barbara; Aust, Daniela; Distler, Wolfgang; Schröck, Evelin; Schackert, Hans K

2012-11-20

Hereditary Breast and Ovarian Cancer Syndrome (HBOCS) and Hereditary Non-Polyposis Colorectal Cancer Syndrome (HNPCC, Lynch Syndrome) are two tumor predisposition syndromes responsible for the majority of hereditary breast and colorectal cancers. Carriers of both germline mutations in breast cancer genes BRCA1 or BRCA2 and in mismatch repair (MMR) genes MLH1, MSH2, MSH6 or PMS2 are very rare. We identified germline mutations in BRCA1 and in MSH6 in a patient with increased risk for HBOC diagnosed with endometrial cancer at the age of 46 years. Although carriers of mutations in both MMR and BRCA genes are rare in Caucasian populations and anamnestical and histopathological findings may guide clinicians to identify these families, both syndromes can only be diagnosed through a complete gene analysis of the respective genes.

Gardner's Syndrome: Report of a Family

PubMed Central

Koren, E.; Lazarovitch, A.; Baratz, M.; Loewenthal, M.; Solowiejczyk, M.

1974-01-01

Two cases of Gardner's syndrome in one family are presented. The father presented all three stigmas of the syndrome, while in the daughter no osseous manifestations were found. In the first patient, the diagnosis was made only after the second abdominal operation, when a mesenteric fibrous mass was seen. In the second case, the intestinal polyposis was clinically suspected, considering the hereditary aspects of this syndrome, and the episode of bloody diarrhea presented by this patient. Both patients were treated by subtotal colectomy with ileo-rectal anastomosis. Both of them presented fibrous tumors after the abdominal operation (the father after six years and the daughter after one year). The authors stress the importance of postoperative followup for the detection of fibrous masses that may appear due to the surgical stimulus. The literature on Gardner's syndrome is reviewed and summarized. ImagesFig. 1.Fig. 2.Fig. 3.Fig. 4. PMID:4842981

[Parotid involvement in Churg-Strauss syndrome].

PubMed

Bonnet, R; Bertin, H; Delemazure, A S; Clairand, R; Mercier, J; Corre, P

2014-06-01

Churg-Strauss syndrome is a rare systemic vascularitis. This disease causes eosinophilic tissue infiltration. The most frequent manifestations are cortico-dependent asthma, mono- or polyneuropathy, paranasal sinus polyposis, and digestive and renal dysfunction. Salivary glands are very rarely involved. We describe a case of CSS in a patient presenting with bilateral parotid swelling. The morphological study of salivary glands revealed an unusual thickening of the salivary duct walls. Salivary gland involvement in Churg and Strauss syndrome can be difficult to demonstrate histologically; it does not usually present in the clinical foreground of the disease, and can be a source of misdiagnosis. The biopsy should be performed in the symptomatic gland, away from any previous corticoid treatment. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Serration Behavior of a Zr-Based Metallic Glass Under Different Constrained Loading Conditions

NASA Astrophysics Data System (ADS)

Yang, G. N.; Gu, J. L.; Chen, S. Q.; Shao, Y.; Wang, H.; Yao, K. F.

2016-11-01

To understand the plastic behavior and shear band dynamics of metallic glasses (MGs) being tuned by the external constraint, uniaxial compression tests were performed on Zr41.2Ti13.8Cu12.5Ni10.0Be22.5 MG samples with aspect ratios of 0.5:1, 1:1, 1.5:1, 2:1, 2.5:1, and 3:1. Better plasticity was observed for the samples with smaller aspect ratio (under higher constraint degree). In the beginning of yielding, increasing serration (jerky stress drop) size on the loading curves was noticed for all samples. Statistical analysis of the serration patterns indicated that the small stress-drop serrations and large stress-drop serrations follow self-organized critical and chaotic dynamics, respectively. Under constrained loading, the large stress-drop serrations are depressed, while the small stress-drop serrations are less affected. When changing the external constraint level by varying the sample aspect ratio, the serration pattern, shear band dynamics, and plastic behavior will change accordingly. This study provides a perspective from tuning shear band dynamics to understand the plastic behavior of MGs under different external constraint.

Serrated adenoma of the gallbladder: a case report.

PubMed

Rubio, Carlos A

2015-06-01

A case of serrated adenomatous polyp found in a cholecystectomy specimen is reported. The adenoma was built with mucosal crypts exhibiting unlocked serrations lined with up to high-grade dysplastic cells. A desmoplastic sclerotic tissue having multiple stromal hubs with branched thin spokes replaced the subjacent lamina propia, muscularis mucosae, and submucosa. The generous serrated configurations covering a multi-branched sclerotic stroma, gave the adenoma a papillary appearance. Review of the literature indicates that this appears to be the first reported case of serrated adenoma of the gallbladder. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Churg-Strauss syndrome associated with antiphospholipid antibodies in a patient with retinal vasculitis.

PubMed

Sánchez-Vicente, J L; Gálvez-Carvajal, S; Medina-Tapia, A; Rueda, T; González-García, L; Szewc, M; Muñoz-Morales, A

2016-11-01

We present the case of a 69-year-old woman with unilateral retinal vasculitis. Investigations showed asthma, rhinosinusitis, nasal polyposis, peripheral blood eosinophilia, increased sedimentation rate, proteinuria, and antiphospholipid antibodies. Anti-neutrophil cytoplasmic antibodies (ANCA) were negative. Although her anti-neutrophil cytoplasmatic antibody (ANCA) status was negative, taking into account the other clinical and laboratory features, retinal vasculitis was thought to be an ocular manifestation of Churg-Strauss syndrome. Treatment was started with high-dose corticosteroids and anticoagulant therapy. Copyright © 2016 Sociedad Española de Oftalmología. Publicado por Elsevier España, S.L.U. All rights reserved.

Synthesis, Properties and Applications of Gallium Nitride Nanowires

NASA Astrophysics Data System (ADS)

Ma, Zheng

This main focus of the work is on controlling the growth morphology in GaN and related nanowires. Two key results are presented: (1) demonstration of GaN nanowire growth in a newly discovered `serrated' morphology and (2) demonstration of Mn-doped, GaMnN nanowires by a new method. In (1) it is shown that simply by controlling the type of catalyst, size of the catalyst and the initial ratio of the precursor materials, GaN nanowire growth in a highly periodic serrated morphology can be obtained. Unlike regular non-serrated wires which grow in the non-polar [1010] direction, growth of the serrated wires is in the polar [0001] direction. The serrated faces are oriented in the semi-polar directions. Wires with serrated faces in both [1011] and [1122] semi-polar directions have been obtained. In (2) it has been shown that by using Au-Mn alloy catalyst method, GaMnN wire growth can be obtained. This is a significant result since this may be the first demonstration wherein Mn doping is achieved by introducing Mn as a catalyst rather than as a source material. The growth direction of these GaMnN wires is in the non-polar direction as in the case of non-serrated wires. Interestingly, unlike the non-serrated GaN wires, in this case the growth direction is [1120]. A second focus of the work is on the investigation of transport properties of serrated GaN nanowires and comparison with the non-serrated GaN nanowires. For the serrated nanowires our results indicate significant influence of surface effects on the electronic transport resulting in much higher electrical resistivity. A third focus of the work is on the investigation of magnetic properties of the GaMnN nanowires which indicates potential weak ferromagnetic behavior. This is consistent with low hole concentration and low Mn doping concentration (~0.5%) in these nanowires.

MicroRNA-31 expression in relation to BRAF mutation, CpG island methylation and colorectal continuum in serrated lesions.

PubMed

Ito, Miki; Mitsuhashi, Kei; Igarashi, Hisayoshi; Nosho, Katsuhiko; Naito, Takafumi; Yoshii, Shinji; Takahashi, Hiroaki; Fujita, Masahiro; Sukawa, Yasutaka; Yamamoto, Eiichiro; Takahashi, Taiga; Adachi, Yasushi; Nojima, Masanori; Sasaki, Yasushi; Tokino, Takashi; Baba, Yoshifumi; Maruyama, Reo; Suzuki, Hiromu; Imai, Kohzoh; Yamamoto, Hiroyuki; Shinomura, Yasuhisa

2014-12-01

The CpG island methylator phenotype (CIMP) is a distinct form of epigenomic instability. Many CIMP-high colorectal cancers (CRCs) with BRAF mutation are considered to arise from serrated pathway. We recently reported that microRNA-31 (miR-31) is associated with BRAF mutation in colorectal tumors. Emerging new approaches have revealed gradual changes in BRAF mutation and CIMP-high throughout the colorectum in CRCs. Here, we attempted to identify a possible association between miR-31 and epigenetic features in serrated pathway, and hypothesized that miR-31 supports the "colorectal continuum" concept. We evaluated miR-31 expression, BRAF mutation and epigenetic features including CIMP status in 381 serrated lesions and 222 non-serrated adenomas and examined associations between them and tumor location (rectum; sigmoid, descending, transverse and ascending colon and cecum). A significant association was observed between high miR-31 expression and CIMP-high status in serrated lesions with BRAF mutation (p = 0.0001). In contrast, miR-31 was slightly but insignificantly associated with CIMP status in the cases with wild-type BRAF. miR-31 expression in sessile serrated adenomas (SSAs) with cytological dysplasia was higher than that in SSAs, whereas, no significant difference was observed between traditional serrated adenomas (TSAs) and TSAs with high-grade dysplasia. The frequency of miR-31, BRAF mutation CIMP-high and MLH1 methylation increased gradually from the rectum to cecum in serrated lesions. In conclusion, miR-31 expression was associated with CIMP-high status in serrated lesions with BRAF mutation. Our data also suggested that miR-31 plays an important role in SSA evolution and may be a molecule supporting the colorectal continuum. © 2014 UICC.

Constitutional mismatch repair-deficiency syndrome: have we so far seen only the tip of an iceberg?

PubMed

Wimmer, Katharina; Etzler, Julia

2008-09-01

Heterozygous mutations in one of the mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2 cause the dominant adult cancer syndrome termed Lynch syndrome or hereditary non-polyposis colorectal cancer. During the past 10 years, some 35 reports have delineated the phenotype of patients with biallelic inheritance of mutations in one of these MMR genes. The patients suffer from a condition that is characterised by the development of childhood cancers, mainly haematological malignancies and/or brain tumours, as well as early-onset colorectal cancers. Almost all patients also show signs reminiscent of neurofibromatosis type 1, mainly café au lait spots. Alluding to the underlying mechanism, this condition may be termed as "constitutional mismatch repair-deficiency (CMMR-D) syndrome". To give an overview of the current knowledge and its implications of this recessively inherited cancer syndrome we summarise here the genetic, clinical and pathological findings of the so far 78 reported patients of 46 families suffering from this syndrome.

Synchronous Hepatoblastoma, Neuroblastoma, and Cutaneous Capillary Hemangiomas: A Case Report.

PubMed

Ozawa, Michael G; Cooney, Tabitha; Rangaswami, Arun; Hazard, Florette K

2016-01-01

Multiple synchronous tumors presenting in infancy raise concern for inherited or sporadic cancer predisposition syndromes, which include Beckwith-Wiedemann syndrome, familial adenomatous polyposis syndrome, and Li-Fraumeni syndrome. We report a case of a 7-month-old previously healthy male born following an in vitro fertilization-assisted twin pregnancy who presented with new-onset refractory shock, severe acidosis, and rapid decline over several hours. An autopsy revealed a ruptured liver involved by hepatoblastoma, an adrenal gland involved by neuroblastoma, and multiple cutaneous capillary hemangiomas. Standard genetic testing demonstrated that both twins were Gaucher disease (GD) carriers without evidence of other known cancer predisposition syndromes. This report describes a unique association of multiple synchronous tumors, which underscores the utility and importance of the pediatric autopsy. Moreover, given that the reported child was a GD carrier, the possibility the tumors were the result of a GD-mediated cancer-associated phenotype or an unrecognized sporadic clinical syndrome remains an unanswered, but intriguing, question worthy of further investigation.

Comparative effectiveness of next generation genomic sequencing for disease diagnosis: design of a randomized controlled trial in patients with colorectal cancer/polyposis syndromes.

PubMed

Gallego, Carlos J; Bennette, Caroline S; Heagerty, Patrick; Comstock, Bryan; Horike-Pyne, Martha; Hisama, Fuki; Amendola, Laura M; Bennett, Robin L; Dorschner, Michael O; Tarczy-Hornoch, Peter; Grady, William M; Fullerton, S Malia; Trinidad, Susan B; Regier, Dean A; Nickerson, Deborah A; Burke, Wylie; Patrick, Donald L; Jarvik, Gail P; Veenstra, David L

2014-09-01

Whole exome and whole genome sequencing are applications of next generation sequencing transforming clinical care, but there is little evidence whether these tests improve patient outcomes or if they are cost effective compared to current standard of care. These gaps in knowledge can be addressed by comparative effectiveness and patient-centered outcomes research. We designed a randomized controlled trial that incorporates these research methods to evaluate whole exome sequencing compared to usual care in patients being evaluated for hereditary colorectal cancer and polyposis syndromes. Approximately 220 patients will be randomized and followed for 12 months after return of genomic findings. Patients will receive findings associated with colorectal cancer in a first return of results visit, and findings not associated with colorectal cancer (incidental findings) during a second return of results visit. The primary outcome is efficacy to detect mutations associated with these syndromes; secondary outcomes include psychosocial impact, cost-effectiveness and comparative costs. The secondary outcomes will be obtained via surveys before and after each return visit. The expected challenges in conducting this randomized controlled trial include the relatively low prevalence of genetic disease, difficult interpretation of some genetic variants, and uncertainty about which incidental findings should be returned to patients. The approaches utilized in this study may help guide other investigators in clinical genomics to identify useful outcome measures and strategies to address comparative effectiveness questions about the clinical implementation of genomic sequencing in clinical care. Copyright © 2014 Elsevier Inc. All rights reserved.

UK guidance for the pathological reporting of serrated lesions of the colorectum.

PubMed

Bateman, Adrian C; Shepherd, Neil A

2015-08-01

Bowel cancer screening programmes have highlighted to endoscopists and clinicians the spectrum of serrated colorectal lesions. One of the most significant developments has been the recognition that sessile serrated lesions (SSLs), while bearing histological resemblance to hyperplastic polyps (HPs), may be associated with the enhanced development of epithelial dysplasia and colorectal adenocarcinoma. Different minimum criteria exist for the diagnosis of SSLs and their differentiation from HPs. Furthermore, the spectrum of terminology used to describe the entire range of serrated lesions is wide. This variability has impaired interobserver agreement during their histopathological assessment. Here, we provide guidance for the histopathological reporting of serrated lesions, including a simplified nomenclature system. Essentially, we recommend use of the following terms: HP, SSL, SSL with dysplasia, traditional serrated adenoma (TSA) and mixed polyp. It is hoped that this standardisation of nomenclature will facilitate studies of the biological significance of serrated lesions in terms of the relative risk of disease progression. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Porous Anodic Aluminum Oxide with Serrated Nanochannels

NASA Astrophysics Data System (ADS)

Li, Dongdong; Zhao, Liang; Lu, Jia G.

2010-03-01

Self-assembled nanoporous anodic aluminum oxide (AAO) membrane with straight channels has long been an important tool in synthesizing highly ordered and vertically aligned quasi-1D nanostructures for various applications. Recently shape-selective nanomaterials have been achieved using AAO as a template. It is envisioned that nanowires with multi-branches will significantly increase the active functional sites for applications as sensors, catalysts, chemical cells, etc. Here AAO membranes with serrated nanochannels have been successfully fabricated via a two-step annodization method. The serrated channels with periodic intervals are aligned at an angle of ˜25^circ along the stem channels. The formation of the serrated channels is attributed to the evolution of oxygen gas bubbles and the resulted plastic deformation in oxide membrane. In order to reveal the inside channel structure, Platinum are electrodeposited into the AAO template. The as-synthesized serrated Pt nanowires demonstrate a superior electrocatalytic activity. This is attributed to the enhanced electric field strength around serrated tips as shown in the electric field simulation by COMOSL. Moreover, hierarchical serrated/straight hybrid structures can be constructed using this simple and novel self assembly technique.

CpG Island Methylator Phenotype-High Colorectal Cancers and Their Prognostic Implications and Relationships with the Serrated Neoplasia Pathway.

PubMed

Rhee, Ye-Young; Kim, Kyung-Ju; Kang, Gyeong Hoon

2017-01-15

The concept of a CpG island methylator phenotype (CIMP) was first introduced by Toyota and Issa to describe a subset of colorectal cancers (CRCs) with concurrent hypermethylation of multiple CpG island loci. The concept of CIMP as a molecular carcinogenesis mechanism was consolidated by the identification of the serrated neoplasia pathway, in which CIMP participates in the initiation and progression of serrated adenomas. Distinct clinicopathological and molecular features of CIMP-high (CIMP-H) CRCs have been characterized, including proximal colon location, older age of onset, female preponderance, and frequent associations of high-level microsatellite instability and BRAF mutations. CIMP-H CRCs arise in sessile or traditional serrated adenomas and thus tend to display the morphological characteristics of serrated adenomas, including epithelial serration, vesicular nuclei, and abundant cytoplasm. Both the frequent association of CIMP and poor prognosis and different responses of CRCs to adjuvant therapy depending on CIMP status indicate clinical implications. In this review, we present an overview of the literature documenting the relevant findings of CIMP-H CRCs and their relationships with the serrated neoplasia pathway.

An analytically-based method for predicting the noise generated by the interaction between turbulence and a serrated leading edge

NASA Astrophysics Data System (ADS)

Mathews, J. R.; Peake, N.

2018-05-01

This paper considers the interaction of turbulence with a serrated leading edge. We investigate the noise produced by an aerofoil moving through a turbulent perturbation to uniform flow by considering the scattered pressure from the leading edge. We model the aerofoil as an infinite half plane with a leading edge serration, and develop an analytical model using a Green's function based upon the work of Howe. This allows us to consider both deterministic eddies and synthetic turbulence interacting with the leading edge. We show that it is possible to reduce the noise by using a serrated leading edge compared with a straight edge, but the optimal noise-reducing choice of serration is hard to predict due to the complex interaction. We also consider the effect of angle of attack, and find that in general the serrations are less effective at higher angles of attack.

Clinics in diagnostic imaging. 159. Jejunal intussusception due to Peutz-Jeghers syndrome.

PubMed

Krishnan, Vijay; Chawla, Ashish; Wee, Eric; Peh, Wilfred C G

2015-02-01

A 21-year-old woman presented with acute onset of upper abdominal pain. A diagnosis of Peutz-Jeghers syndrome (PJS) was made based on the clinical picture of perioral pigmentation with imaging findings of transient jejunojejunal intussusceptions and small bowel polyps, and confirmed by characteristic histopathological appearances of Peutz-Jeghers polyps. PJS is a rare hereditary condition characterised by unique hamartomatous polyps, perioral mucocutaneous pigmentations, and increased susceptibility to gastrointestinal and extraintestinal neoplasms. Patients usually present with recurrent abdominal pain due to intussusception caused by polyps. Other modes of presentations include rectal bleeding and melaena. We describe the imaging findings of PJS and provide a brief review of bowel polyposis syndromes. The latter are relatively rare disorders characterised by multiple polyps in the large or small intestine, with associated risk of malignancies and other extraintestinal manifestations. Awareness of the manifestations and early diagnosis of these syndromes is crucial to prevent further complications.

β-Catenin destruction complex-independent regulation of Hippo–YAP signaling by APC in intestinal tumorigenesis

PubMed Central

Cai, Jing; Maitra, Anirban; Anders, Robert A.; Taketo, Makoto M.; Pan, Duojia

2015-01-01

Mutations in Adenomatous polyposis coli (APC) underlie familial adenomatous polyposis (FAP), an inherited cancer syndrome characterized by the widespread development of colorectal polyps. APC is best known as a scaffold protein in the β-catenin destruction complex, whose activity is antagonized by canonical Wnt signaling. Whether other effector pathways mediate APC's tumor suppressor function is less clear. Here we report that activation of YAP, the downstream effector of the Hippo signaling pathway, is a general hallmark of tubular adenomas from FAP patients. We show that APC functions as a scaffold protein that facilitates the Hippo kinase cascade by interacting with Sav1 and Lats1. Consistent with the molecular link between APC and the Hippo signaling pathway, genetic analysis reveals that YAP is absolutely required for the development of APC-deficient adenomas. These findings establish Hippo–YAP signaling as a critical effector pathway downstream from APC, independent from its involvement in the β-catenin destruction complex. PMID:26193883

Striation patterns in serrated blade stabs to cartilage.

PubMed

Pounder, Derrick J; Reeder, Francesca D

2011-05-20

Stab wounds were made in porcine cartilage with 13 serrated knives, amongst which 4 were drop-point and 9 straight-spine; 9 coarsely serrated, 3 finely serrated and 1 with mixed pattern serrations. The walls of the stab tracks were cast with dental impression material, and the casts photographed together with the knife blades for comparison. All 13 serrated blades produced an "irregularly regular" pattern of striations on cartilage in all stabbings. Unusual and distinctive blade serration patterns produced equally distinctive wound striation patterns. A reference collection of striation patterns and corresponding blades might prove useful for striation pattern analysis. Drop-point blades produced similar striations to straight-spine blades except that the striations were not parallel but rather fan-shaped, converging towards the wound exit. The fan-shaped striation pattern characteristic of drop-point blades is explained by the initial lateral movement of the blade through the cartilage imposed by the presence of the drop point shape. It appears that the greater the overall angle of the drop point, the shorter the blade length over which the drop point occurs, and the closer the first serration is to the knife tip, the more obvious is the fan-shaped pattern. We anticipate that micro-irregularities producing individualising characteristics in non-serrated drop point blades, provided they were located at the tip opposite the drop point, should also show a fan-shaped pattern indicative of a drop point blade. The examination of the walls of stab wounds to cartilage represents an under-utilised source of forensic information to assist in knife identification. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Aerodynamic robustness in owl-inspired leading-edge serrations: a computational wind-gust model.

PubMed

Rao, Chen; Liu, Hao

2018-06-08

Owls are a master to achieve silent flight in gliding and flapping flights under natural turbulent environments owing to their unique wing morphologies. While the leading-edge serrations are recently revealed, as a passive flow control micro-device, to play a crucial role in aerodynamic force production and sound suppression [25], the characteristics of wind-gust rejection associated with leading-edge serrations remain unclear. Here we address a large-eddy simulation (LES)-based study of aerodynamic robustness in owl-inspired leading-edge serrations, which is conducted with clean and serrated wing models through mimicking wind-gusts under a longitudinal fluctuation in free-stream inflow and a lateral fluctuation in pitch angle over a broad range of angles of attack (AoAs) over 0° ≤ Φ ≤ 20°. Our results show that the leading-edge serration-based passive flow control mechanisms associated with laminar-turbulent transition work effectively under fluctuated inflow and wing pitch, indicating that the leading-edge serrations are of potential gust fluctuation rejection or robustness in aerodynamic performance. Moreover, it is revealed that the tradeoff between turbulent flow control (i.e., aero-acoustic suppression) and force production in the serrated model holds independently to the wind-gust environments: poor at lower AoAs but capable of achieving equivalent aerodynamic performance at higher AoAs > 15o compared to the clean model. Our results reveal that the owl-inspired leading-edge serrations can be a robust micro-device for aero-acoustic control coping with unsteady and complex wind environments in biomimetic rotor designs for various fluid machineries. © 2018 IOP Publishing Ltd.

Aberrant gene promoter methylation associated with sporadic multiple colorectal cancer.

PubMed

Gonzalo, Victoria; Lozano, Juan José; Muñoz, Jenifer; Balaguer, Francesc; Pellisé, Maria; Rodríguez de Miguel, Cristina; Andreu, Montserrat; Jover, Rodrigo; Llor, Xavier; Giráldez, M Dolores; Ocaña, Teresa; Serradesanferm, Anna; Alonso-Espinaco, Virginia; Jimeno, Mireya; Cuatrecasas, Miriam; Sendino, Oriol; Castellví-Bel, Sergi; Castells, Antoni

2010-01-19

Colorectal cancer (CRC) multiplicity has been mainly related to polyposis and non-polyposis hereditary syndromes. In sporadic CRC, aberrant gene promoter methylation has been shown to play a key role in carcinogenesis, although little is known about its involvement in multiplicity. To assess the effect of methylation in tumor multiplicity in sporadic CRC, hypermethylation of key tumor suppressor genes was evaluated in patients with both multiple and solitary tumors, as a proof-of-concept of an underlying epigenetic defect. We examined a total of 47 synchronous/metachronous primary CRC from 41 patients, and 41 gender, age (5-year intervals) and tumor location-paired patients with solitary tumors. Exclusion criteria were polyposis syndromes, Lynch syndrome and inflammatory bowel disease. DNA methylation at the promoter region of the MGMT, CDKN2A, SFRP1, TMEFF2, HS3ST2 (3OST2), RASSF1A and GATA4 genes was evaluated by quantitative methylation specific PCR in both tumor and corresponding normal appearing colorectal mucosa samples. Overall, patients with multiple lesions exhibited a higher degree of methylation in tumor samples than those with solitary tumors regarding all evaluated genes. After adjusting for age and gender, binomial logistic regression analysis identified methylation of MGMT2 (OR, 1.48; 95% CI, 1.10 to 1.97; p = 0.008) and RASSF1A (OR, 2.04; 95% CI, 1.01 to 4.13; p = 0.047) as variables independently associated with tumor multiplicity, being the risk related to methylation of any of these two genes 4.57 (95% CI, 1.53 to 13.61; p = 0.006). Moreover, in six patients in whom both tumors were available, we found a correlation in the methylation levels of MGMT2 (r = 0.64, p = 0.17), SFRP1 (r = 0.83, 0.06), HPP1 (r = 0.64, p = 0.17), 3OST2 (r = 0.83, p = 0.06) and GATA4 (r = 0.6, p = 0.24). Methylation in normal appearing colorectal mucosa from patients with multiple and solitary CRC showed no relevant difference in any evaluated gene. These results provide a proof-of-concept that gene promoter methylation is associated with tumor multiplicity. This underlying epigenetic defect may have noteworthy implications in the prevention of patients with sporadic CRC.

Optimization of the poro-serrated trailing edges for airfoil broadband noise reduction.

PubMed

Chong, Tze Pei; Dubois, Elisa

2016-08-01

This paper reports an aeroacoustic investigation of a NACA0012 airfoil with a number of poro-serrated trailing edge devices that contain porous materials of various air flow resistances at the gaps between adjacent members of the serrated-sawtooth trailing edge. The main objective of this work is to determine whether multiple-mechanisms on the broadband noise reduction can co-exist on a poro-serrated trailing edge. When the sawtooth gaps are filled with porous material of low-flow resistivity, the vortex shedding tone at low-frequency could not be completely suppressed at high-velocity, but a reasonably good broadband noise reduction can be achieved at high-frequency. When the sawtooth gaps are filled with porous material of very high-flow resistivity, no vortex shedding tone is present, but the serration effect on the broadband noise reduction becomes less effective. An optimal choice of the flow resistivity for a poro-serrated configuration has been identified, where it can surpass the conventional serrated trailing edge of the same geometry by achieving a further 1.5 dB reduction in the broadband noise while completely suppressing the vortex shedding tone. A weakened turbulent boundary layer noise scattering at the poro-serrated trailing edge is reflected by the lower-turbulence intensity at the near wake centreline across the whole spanwise wavelength of the sawtooth.

Acoustic testing of a 1.5 pressure ratio low tip speed fan with a serrated rotor (QEP fan B scale model). [reduction of engine noise

NASA Technical Reports Server (NTRS)

Kazin, S. B.; Paas, J. E.; Minzner, W. R.

1973-01-01

A scale model of the bypass flow region of a 1.5 pressure ratio, single stage, low tip speed fan was tested with a serrated rotor leading edge to determine its effects on noise generation. The serrated rotor was produced by cutting teeth into the leading edge of the nominal rotor blades. The effects of speed and exhaust nozzle area on the scale models noise characteristics were investigated with both the nominal rotor and serrated rotor. Acoustic results indicate the serrations reduced front quadrant PNL's at takeoff power. In particular, the 200 foot (61.0 m) sideline noise was reduced from 3 to 4 PNdb at 40 deg for nominal and large nozzle operation. However, the rear quadrant maximum sideline PNL's were increased 1.5 to 3 PNdb at approach thust and up to 2 PNdb at takeoff thust with these serrated rotor blades. The configuration with the serrated rotor produced the lowest maximum 200 foot (61.0 m) sideline PNL for any given thust when the large nozzle (116% of design area) was employed.

CpG Island Methylator Phenotype-High Colorectal Cancers and Their Prognostic Implications and Relationships with the Serrated Neoplasia Pathway

PubMed Central

Rhee, Ye-Young; Kim, Kyung-Ju; Kang, Gyeong Hoon

2017-01-01

The concept of a CpG island methylator phenotype (CIMP) was first introduced by Toyota and Issa to describe a subset of colorectal cancers (CRCs) with concurrent hypermethylation of multiple CpG island loci. The concept of CIMP as a molecular carcinogenesis mechanism was consolidated by the identification of the serrated neoplasia pathway, in which CIMP participates in the initiation and progression of serrated adenomas. Distinct clinicopathological and molecular features of CIMP-high (CIMP-H) CRCs have been characterized, including proximal colon location, older age of onset, female preponderance, and frequent associations of high-level microsatellite instability and BRAF mutations. CIMP-H CRCs arise in sessile or traditional serrated adenomas and thus tend to display the morphological characteristics of serrated adenomas, including epithelial serration, vesicular nuclei, and abundant cytoplasm. Both the frequent association of CIMP and poor prognosis and different responses of CRCs to adjuvant therapy depending on CIMP status indicate clinical implications. In this review, we present an overview of the literature documenting the relevant findings of CIMP-H CRCs and their relationships with the serrated neoplasia pathway. PMID:27885175

A fatal case of Churg-Strauss syndrome presenting with acute polyneuropathy mimicking Guillain-Barré syndrome.

PubMed

De Toni Franceschini, Luisa; Amadio, Stefano; Scarlato, Marina; Fazio, Raffaella; Quattrini, Angelo; Dell'antonio, Giacomo; Comi, Giancarlo; Del Carro, Ubaldo

2011-10-01

A 64-year-old woman, with asthma and sinusal polyposis in her history, suddenly developed a painful polyneuropathy with diplopia. Nerve conduction studies, performed at the very onset of the neuropathy, could not definitely rule out a Guillain-Barré syndrome (GBS) and high-dose i.v. immunoglobulins were administered. Clinical and laboratory findings subsequently supported the diagnosis of Churg-Strauss syndrome; corticosteroid therapy was started and clinical stabilisation of neuropathy was apparently achieved. No indicators of unfavourable outcome were present at that time. Nevertheless, 30 days after the onset the patient acutely worsened with severe polyneuropathy relapse and fatal systemic diffusion to heart, kidney and mesenteric district, which a single cyclophosphamide pulse failed to control. This case highlights the possibility that a GBS-like onset of Churg-Strauss syndrome neuropathy should be regarded as a part of multiorgan, severe or even life-threatening vasculitic involvement, requiring the most aggressive treatments, regardless of the presence of recognised factors of poor outcome.

Sessile Serrated Polyps: Detection, Eradication, and Prevention of the Evil Twin

PubMed Central

Obuch, Joshua C.; Pigott, Courtney M.; Ahnen, Dennis J.

2015-01-01

Opinion Statement The sessile serrated polyp (SSP), also known as sessile serrated adenoma, is the evil twin among the colorectal cancer precursors. As will be described, these lesions have multiple aliases (serrated adenoma, serrated polyp or serrated lesion among others), they hang out in a bad neighborhood (the poorly prepped right colon), they hide behind a mask of mucus, they are difficult for witnesses (pathologists) to identify, they are difficult for police (endoscopists) to find, they are difficult to permanently remove from society (high incomplete resection rate), they can be impulsive (progress rapidly to CRC) and enforcers (gastroenterologists) don’t know how best to control them (uncertain surveillance recommendations). There is no wonder that there is a need to understand these lesions well, learn how best to prevent the colonic mucosa from going down this errant path or, if that fails, to detect these deviants and eradicate them from colonic society. These lesions should be on the endoscopists’ most wanted list. PMID:25623474

How does the serrated polyp pathway alter CRC screening and surveillance?

PubMed

Kahi, Charles J

2015-03-01

Screening and surveillance for colorectal cancer (CRC) reduces mortality through the detection of early-stage adenocarcinoma, and more importantly the detection and removal of premalignant polyps. While adenomas have historically been considered the most common and screening-relevant precursor lesions, there is accumulating evidence showing that the serrated pathway is an important contributor to CRC, and a disproportionate contributor to interval or postcolonoscopy CRC, particularly in the proximal colon. The serrated pathway is characterized by mutations in the BRAF gene, high levels of methylation of promoter CpG islands (CIMP-high), and the sessile serrated adenoma/polyp (SSA/P) is the most important precursor lesion. The study of serrated polyps has been complicated by evolving nomenclature, substantial variation among pathologists in the identification of SSA/Ps, high variability in endoscopic detection rates, and uncertainty regarding the relation to synchronous and metachronous colonic neoplasia. This paper presents an overview of the serrated polyp pathway and discusses its clinical implications including its impact on CRC screening.

Exome Sequencing Identifies Biallelic MSH3 Germline Mutations as a Recessive Subtype of Colorectal Adenomatous Polyposis.

PubMed

Adam, Ronja; Spier, Isabel; Zhao, Bixiao; Kloth, Michael; Marquez, Jonathan; Hinrichsen, Inga; Kirfel, Jutta; Tafazzoli, Aylar; Horpaopan, Sukanya; Uhlhaas, Siegfried; Stienen, Dietlinde; Friedrichs, Nicolaus; Altmüller, Janine; Laner, Andreas; Holzapfel, Stefanie; Peters, Sophia; Kayser, Katrin; Thiele, Holger; Holinski-Feder, Elke; Marra, Giancarlo; Kristiansen, Glen; Nöthen, Markus M; Büttner, Reinhard; Möslein, Gabriela; Betz, Regina C; Brieger, Angela; Lifton, Richard P; Aretz, Stefan

2016-08-04

In ∼30% of families affected by colorectal adenomatous polyposis, no germline mutations have been identified in the previously implicated genes APC, MUTYH, POLE, POLD1, and NTHL1, although a hereditary etiology is likely. To uncover further genes with high-penetrance causative mutations, we performed exome sequencing of leukocyte DNA from 102 unrelated individuals with unexplained adenomatous polyposis. We identified two unrelated individuals with differing compound-heterozygous loss-of-function (LoF) germline mutations in the mismatch-repair gene MSH3. The impact of the MSH3 mutations (c.1148delA, c.2319-1G>A, c.2760delC, and c.3001-2A>C) was indicated at the RNA and protein levels. Analysis of the diseased individuals' tumor tissue demonstrated high microsatellite instability of di- and tetranucleotides (EMAST), and immunohistochemical staining illustrated a complete loss of nuclear MSH3 in normal and tumor tissue, confirming the LoF effect and causal relevance of the mutations. The pedigrees, genotypes, and frequency of MSH3 mutations in the general population are consistent with an autosomal-recessive mode of inheritance. Both index persons have an affected sibling carrying the same mutations. The tumor spectrum in these four persons comprised colorectal and duodenal adenomas, colorectal cancer, gastric cancer, and an early-onset astrocytoma. Additionally, we detected one unrelated individual with biallelic PMS2 germline mutations, representing constitutional mismatch-repair deficiency. Potentially causative variants in 14 more candidate genes identified in 26 other individuals require further workup. In the present study, we identified biallelic germline MSH3 mutations in individuals with a suspected hereditary tumor syndrome. Our data suggest that MSH3 mutations represent an additional recessive subtype of colorectal adenomatous polyposis. Copyright © 2016 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Airfoil noise reductions through leading edge serrations

NASA Astrophysics Data System (ADS)

Narayanan, S.; Chaitanya, P.; Haeri, S.; Joseph, P.; Kim, J. W.; Polacsek, C.

2015-02-01

This paper provides an experimental investigation into the use of leading edge (LE) serrations as a means of reducing the broadband noise generated due to the interaction between the aerofoil's LE and impinging turbulence. Experiments are performed on a flat plate in an open jet wind tunnel. Grids are used to generate isotropic homogeneous turbulence. The leading edge serrations are in the form of sinusoidal profiles of wavelengths, λ, and amplitudes, 2h. The frequency and amplitude characteristics are studied in detail in order to understand the effect of LE serrations on noise reduction characteristics and are compared with straight edge baseline flat plates. Noise reductions are found to be insignificant at low frequencies but significant in the mid frequency range (500 Hz-8 kHz) for all the cases studied. The flat plate results are also compared to the noise reductions obtained on a serrated NACA-65 aerofoil with the same serration profile. Noise reductions are found to be significantly higher for the flat plates with a maximum noise reduction of around 9 dB compared with about 7 dB for the aerofoil. In general, it is observed that the sound power reduction level (ΔPWL) is sensitive to the amplitude, 2h of the LE serrations but less sensitive to the serration wavelength, λ. Thus, this paper sufficiently demonstrates that the LE amplitude acts as a key parameter for enhancing the noise reduction levels in flat plates and aerofoils.

MYH-Associated Polyposis

MedlinePlus

... to other hereditary conditions of familial adenomatous polyposis (FAP) and attenuated familial adenomatous polyposis (AFAP). In other ... a mutation in the APC gene associated with FAP and AFAP. It may also be considered if ...

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

PubMed

Stevanato Filho, Paulo Roberto; Aguiar Júnior, Samuel; Begnami, Maria Dirlei; Kuasne, Hellen; Spencer, Ranyell Matheus; Nakagawa, Wilson Toshihiko; Bezerra, Tiago Santoro; Kupper, Bruna Catin; Takahashi, Renata Maymi; Barros Filho, Mateus; Rogatto, Silvia Regina; Lopes, Ademar

2017-11-13

Among the sex hormones, oestrogen may play a role in colorectal cancer, particularly in conjunction with oestrogen receptor-β (ERβ). The expression of ERβ isoform variants and their correlations with familial adenomatous polyposis (FAP) syndrome and sporadic colorectal carcinomas are poorly described. This study aimed to investigate the expression levels of the ERβ1, ERβ2, ERβ4 and ERβ5 isoform variants using quantitative RT-PCR (921 analyses) in FAP, normal mucosa, adenomatous polyps and sporadic colorectal carcinomas. Decreased expression of ERβ isoforms was identified in sporadic polyps and in sporadic colorectal cancer as well as in polyps from FAP syndrome patients compared with normal tissues (p < 0.001). In FAP patients, ERβ1 and ERβ5 isoforms showed significant down-expression in polyps (p < 0.001) compared with matched normal tissues. However, no differences were observed when sporadic colorectal carcinomas were compared to normal mucosa tissues. These findings suggest an association of the ERβ isoform variants in individuals affected by germline mutations of the APC gene. Progressively decreased expression of ERβ was found in polyps at early stages of low-grade dysplasia, followed by T1-T2 and T3-T4 tumours (p < 0.05). In sporadic colorectal cancer, the loss of expression was an independent predictor of recurrence, and ERβ1 and ERβ5 expression levels were associated with better disease-free survival (p = 0.002). These findings may provide a better understanding of oestrogens and their potential preventive and therapeutic effects on sporadic colorectal cancer and cancers associated with FAP syndrome.

MRI of the stomach: a pictorial review with a focus on oncological applications and gastric motility.

PubMed

Sheybani, Arman; Menias, Christine O; Luna, Antonio; Fowler, Kathryn J; Hara, Amy Kiyo; Silva, Alvin C; Yano, Motoyo; Sandrasegaran, Kumar

2015-04-01

The purpose of this pictorial review is to demonstrate gastric pathology seen on magnetic resonance imaging (MRI) and discuss the essential MRI sequences for the evaluation of benign and malignant gastric pathologies. Common tumors of the stomach, polyposis syndromes, iatrogenic conditions, as well as other conditions of the stomach will be reviewed. The utility of MRI in the evaluation of patients with gastric malignancies and disorders of gastric motility will also be discussed.

Pathology of serrated colorectal lesions.

PubMed

Bateman, Adrian C

2014-10-01

The concept of serrated colorectal neoplasia has become recognised as a key process in the development of colorectal cancer (CRC) and an important alternative pathway to malignancy compared with the long established ‘adenoma-carcinoma’ sequence. Increasing recognition of the morphological spectrum of serrated lesions has occurred in parallel with elucidation of the distinct molecular genetic characteristics of progression from normal mucosa, via the ‘serrated pathway’, to CRC. Some of these lesions can be difficult to identify at colonoscopy. Challenges for pathologists include the requirement for accurate recognition of the forms of serrated lesions that are associated with a significant risk of malignant progression and therefore the need for widely disseminated reproducible criteria for their diagnosis. Alongside this process, pathologists and endoscopists need to formulate clear guidelines for the management of patients with these lesions, particularly with respect to the optimal follow-up intervals. This review provides practical guidance for the recognition of these lesions by pathologists, a discussion of ‘serrated adenocarcinoma’ and an insight into the distinct molecular genetic alterations that are seen in this spectrum of lesions in comparison to those that characterise the classic ‘adenoma-carcinoma’ sequence.

Nanoindentation study on the characteristic of shear transformation zone in a Pd-based bulk metallic glass during serrated flow

NASA Astrophysics Data System (ADS)

Liao, G. K.; Long, Z. L.; Zhao, M. S. Z.; Peng, L.; Chai, W.; Ping, Z. H.

2018-04-01

This paper presents the research on the evolution of shear transformation zone (STZ) in a Pd-based bulk metallic glass (BMG) during serrated flow under nanoindentation. A novel method of estimating the STZ volume through statistical analysis of the serrated flow behavior was proposed for the first time. Based on the proposed method, the STZ volume of the studied BMG at various peak loads have been systematically investigated. The results indicate that the measured STZ volumes are in good agreement with that documented in literature, and the STZ size exhibits an increasing trend during indentation. Moreover, the correlation between the serrated flow dynamics and the STZ activation has also been evaluated. It is found that the STZ activation can promote the formation of self-organized critical (SOC) state during serrated flow.

Forensic implications of the variation in morphology of marginal serrations on the teeth of the great white shark.

PubMed

Nambiar, P; Brown, K A; Bridges, T E

1996-06-01

The teeth of the Great White Shark have been examined to ascertain whether there is any commonality in the arrangement or number of the marginal serrations (peaks) or, indeed, whether individual sharks have a unique pattern of shapes or size of the peaks. The teeth of the White Shark are characteristic in size and shape with serrations along almost the entire mesial and distal margins. This study has revealed no consistent pattern of size or arrangement of the marginal serrations that was sufficiently characteristic within an individual shark to serve as a reliable index of identification of a tooth as originating from that particular shark. Nonetheless, the serrations are sufficiently distinctive to enable the potential identification of an individual tooth as having been the cause of a particular bitemark.

Rare combination of familial adenomatous polyposis and gallbladder polyps.

PubMed

Mori, Yasuhisa; Sato, Norihiro; Matayoshi, Nobutaka; Tamura, Toshihisa; Minagawa, Noritaka; Shibao, Kazunori; Higure, Aiichiro; Nakamoto, Mitsuhiro; Taguchi, Masashi; Yamaguchi, Koji

2014-12-14

Familial adenomatous polyposis is associated with a high incidence of malignancies in the upper gastrointestinal tract (particularly ampullary adenocarcinomas). However, few reports have described a correlation between familial adenomatous polyposis and gallbladder neoplasms. We present a case of a 60-year-old woman with familial adenomatous polyposis who presented with an elevated mass in the neck of the gallbladder (measuring 16 mm × 8 mm in diameter) and multiple small cholecystic polyps. She had undergone a total colectomy for ascending colon cancer associated with familial adenomatous polyposis 22 years previously. The patient underwent laparoscopic cholecystectomy under a preoperative diagnosis of multifocal gallbladder polyps. Pathologic examination of the resected gallbladder revealed more than 70 adenomatous lesions, a feature consistent with adenoma of the gallbladder. This case suggests a requirement for long-term surveillance of the biliary system in addition to the gastrointestinal tract in patients with familial adenomatous polyposis.

Sessile serrated adenomas with dysplasia: morphological patterns and correlations with MLH1 immunohistochemistry.

PubMed

Liu, Cheng; Walker, Neal I; Leggett, Barbara A; Whitehall, Vicki Lj; Bettington, Mark L; Rosty, Christophe

2017-12-01

Sessile serrated adenomas are the precursor polyp of approximately 20% of colorectal carcinomas. Sessile serrated adenomas with dysplasia are rarely encountered and represent an intermediate step to malignant progression, frequently associated with loss of MLH1 expression. Accurate diagnosis of these lesions is important to facilitate appropriate surveillance, particularly because progression from dysplasia to carcinoma can be rapid. The current World Health Organization classification describes two main patterns of dysplasia occurring in sessile serrated adenomas, namely, serrated and conventional. However, this may not adequately reflect the spectrum of changes seen by pathologists in routine practice. Furthermore, subtle patterns of dysplasia that are nevertheless associated with loss of MLH1 expression are not encompassed in this classification. We performed a morphological analysis of 266 sessile serrated adenomas with dysplasia with concurrent MLH1 immunohistochemistry with the aims of better defining the spectrum of dysplasia occurring in these lesions and correlating dysplasia patterns with MLH1 expression. We found that dysplasia can be divided morphologically into four major patterns, comprising minimal deviation (19%), serrated (12%), adenomatous (8%) and not otherwise specified (79%) groups. Minimal deviation dysplasia is defined by minor architectural and cytological changes that typically requires loss of MLH1 immunohistochemical expression to support the diagnosis. Serrated dysplasia and adenomatous dysplasia have distinctive histological features and are less frequently associated with loss of MLH1 expression (13 and 5%, respectively). Finally, dysplasia not otherwise specified encompasses most cases and shows a diverse range of morphological changes that do not fall into the other subgroups and are frequently associated with loss of MLH1 expression (83%). This morphological classification of sessile serrated adenomas with dysplasia may represent an improvement on the current description as it correlates with the underlying mismatch repair protein status of the polyps and better highlights the range of morphologies seen by pathologists.

Sessile serrated adenoma (SSA) vs. traditional serrated adenoma (TSA).

PubMed

Torlakovic, Emina Emilia; Gomez, Jose D; Driman, David K; Parfitt, Jeremy R; Wang, Chang; Benerjee, Tama; Snover, Dale C

2008-01-01

The morphologic distinction between various serrated polyps of the colorectum may be challenging. The distinction between sessile serrated adenoma (SSA) and traditional serrated adenoma (TSA) may be difficult using currently available criteria mostly based on cytologic characteristics. We have evaluated 66 serrated polyps including 29 SSA, 18 TSA, and 19 hyperplastic polyps for overall shape of the polyps, architectural features of individual crypts, the presence of eosinophilic cytoplasm, size and distribution of the proliferation and maturation zones, as well as Ki-67 and CK20 expression. The extent of the expression of CK20 and Ki-67 could not distinguish between the 3 types of serrated polyps, but the distribution of their expression was very helpful and differences were statistically significant. The distribution of Ki-67+ cells was the single most helpful distinguishing feature of the serrated polyp type (P<0.0001, chi test). Hyperplastic polyps had regular, symmetric, and increased Ki-67 expression. SSA had irregular, asymmetric, and highly variable expression of Ki-67. TSA had low Ki-67 expression, which was limited to "ectopic crypts" and admixed tubular adenomalike areas. In serrated polyps, ectopic crypt formation (ECF) defined by the presence of ectopic crypts with their bases not seated adjacent to the muscularis mucosae was nearly exclusive to TSA and was found in all cases, while the presence of cytologic atypia and eosinophilia of the cytoplasm were characteristic, but not limited to TSA. No evidence of ECF, but nevertheless abnormal distribution of proliferation zone was characteristic of SSA, whereas HP had neither. The presence of the ECF defines TSA in a more rigorous fashion than previous diagnostic criteria and also explains the biologic basis of exuberant protuberant growth associated with TSA and the lack of such growth in SSA. Recognition of this phenomenon may also help in exploring the genetic and molecular basis for differences between SSA and TSA, because these architectural abnormalities may well be a reflection of abnormalities in genetically programmed mucosal development.

The CIMP Phenotype in BRAF Mutant Serrated Polyps from a Prospective Colonoscopy Patient Cohort

PubMed Central

Fernando, Winnie C.; Miranda, Mariska S.; Worthley, Daniel L.; Togashi, Kazutomo; Watters, Dianne J.; Leggett, Barbara A.; Spring, Kevin J.

2014-01-01

Colorectal cancers arising via the serrated pathway are often associated with BRAF V600E mutation, CpG island methylator phenotype (CIMP), and microsatellite instability. Previous studies have shown a strong association between BRAF V600E mutation and serrated polyps. This study aims to evaluate CIMP status of all the serrated polyp subtypes and its association with functionally important genes such as MLH1, p16, and IGFBP7. CIMP status and methylation were evaluated using the real-time based MethyLight assay in 154 serrated polyps and 63 conventional adenomas. Results showed that CIMP-high serrated polyps were strongly associated with BRAF mutation and proximal colon. CIMP-high was uncommon in conventional adenomas (1.59%), occurred in 8.25% of hyperplastic polyps (HPs), and became common in sessile serrated adenomas (SSAs) (51.43%). MLH1 methylation was mainly observed in the proximal colon and was significantly associated with BRAF mutation and CIMP-high. The number of samples methylated for p16 and IGFBP7 was the highest in SSAs. The methylation panel we used to detect CIMP is highly specific for CIMP-high cancers. With this panel, we demonstrate that CIMP-high is much more common in SSAs than HPs. This suggests that CIMP-high correlates with increased risk of malignant transformation which was also observed in methylation of functionally important genes. PMID:24812557

The CIMP Phenotype in BRAF Mutant Serrated Polyps from a Prospective Colonoscopy Patient Cohort.

PubMed

Fernando, Winnie C; Miranda, Mariska S; Worthley, Daniel L; Togashi, Kazutomo; Watters, Dianne J; Leggett, Barbara A; Spring, Kevin J

2014-01-01

Colorectal cancers arising via the serrated pathway are often associated with BRAF V600E mutation, CpG island methylator phenotype (CIMP), and microsatellite instability. Previous studies have shown a strong association between BRAF V600E mutation and serrated polyps. This study aims to evaluate CIMP status of all the serrated polyp subtypes and its association with functionally important genes such as MLH1, p16, and IGFBP7. CIMP status and methylation were evaluated using the real-time based MethyLight assay in 154 serrated polyps and 63 conventional adenomas. Results showed that CIMP-high serrated polyps were strongly associated with BRAF mutation and proximal colon. CIMP-high was uncommon in conventional adenomas (1.59%), occurred in 8.25% of hyperplastic polyps (HPs), and became common in sessile serrated adenomas (SSAs) (51.43%). MLH1 methylation was mainly observed in the proximal colon and was significantly associated with BRAF mutation and CIMP-high. The number of samples methylated for p16 and IGFBP7 was the highest in SSAs. The methylation panel we used to detect CIMP is highly specific for CIMP-high cancers. With this panel, we demonstrate that CIMP-high is much more common in SSAs than HPs. This suggests that CIMP-high correlates with increased risk of malignant transformation which was also observed in methylation of functionally important genes.

Deep learning of contrast-coated serrated polyps for computer-aided detection in CT colonography

NASA Astrophysics Data System (ADS)

Näppi, Janne J.; Pickhardt, Perry; Kim, David H.; Hironaka, Toru; Yoshida, Hiroyuki

2017-03-01

Serrated polyps were previously believed to be benign lesions with no cancer potential. However, recent studies have revealed a novel molecular pathway where also serrated polyps can develop into colorectal cancer. CT colonography (CTC) can detect serrated polyps using the radiomic biomarker of contrast coating, but this requires expertise from the reader and current computer-aided detection (CADe) systems have not been designed to detect the contrast coating. The purpose of this study was to develop a novel CADe method that makes use of deep learning to detect serrated polyps based on their contrast-coating biomarker in CTC. In the method, volumetric shape-based features are used to detect polyp sites over soft-tissue and fecal-tagging surfaces of the colon. The detected sites are imaged using multi-angular 2D image patches. A deep convolutional neural network (DCNN) is used to review the image patches for the presence of polyps. The DCNN-based polyp-likelihood estimates are merged into an aggregate likelihood index where highest values indicate the presence of a polyp. For pilot evaluation, the proposed DCNN-CADe method was evaluated with a 10-fold cross-validation scheme using 101 colonoscopy-confirmed cases with 144 biopsy-confirmed serrated polyps from a CTC screening program, where the patients had been prepared for CTC with saline laxative and fecal tagging by barium and iodine-based diatrizoate. The average per-polyp sensitivity for serrated polyps >=6 mm in size was 93+/-7% at 0:8+/-1:8 false positives per patient on average. The detection accuracy was substantially higher that of a conventional CADe system. Our results indicate that serrated polyps can be detected automatically at high accuracy in CTC.

Cytokine profile of nasal and middle ear polyps in a patient with Woakes' syndrome and eosinophilic otitis media.

PubMed

De Loof, Marie; De Leenheer, Els; Holtappels, Gabriële; Bachert, Claus

2016-05-03

Woakes' syndrome is characterised by severe recurrent nasal polyps in early childhood with broadening of the nose, nasal dyscrinia, frontal sinus aplasia and bronchiectasis. Eosinophilic otitis media (EOM) is an intractable condition that can cause gradual or sudden deterioration of hearing and is associated with comorbid asthma. For these reasons, both diseases must be recognised and treated appropriately. We present a case of a 20-year-old man with Woakes' syndrome complicated by EOM, with polyps in both middle ears; this condition has so far not been described as an entity of eosinophilic disease in the literature. We have, from reviewing the literature, learned that this is the first time that results of tissue examination on nasal polyposis with respect to tissue IgE, eosinophil-cationic protein, interleukin (IL)-17 and IL-5 in a patient with Woakes' syndrome and EOM, has been reported and discussed. 2016 BMJ Publishing Group Ltd.

Identification of a Novel PMS2 Alteration c.505C>G (R169G) In Trans with a PMS2 Pathogenic Mutation in a Patient with Constitutional Mismatch Repair Deficiency

PubMed Central

Mork, Maureen E.; Borras, Ester; Taggart, Melissa W.; Cuddy, Amanda; Bannon, Sarah A.; You, Y. Nancy; Lynch, Patrick M.; Ramirez, Pedro T.; Rodriguez-Bigas, Miguel A.; Vilar, Eduardo

2016-01-01

Constitutional mismatch repair deficiency syndrome (CMMRD) is a rare autosomal recessive predisposition to colorectal polyposis and other malignancies, often childhood-onset, that is caused by biallelic inheritance of mutations in the same mismatch repair gene. Here, we describe a patient with a clinical diagnosis of CMMRD based on colorectal polyposis and young-onset endometrial cancer who was identified to have two alterations in trans in PMS2: one known pathogenic mutation (c.1831insA; p.Ile611Asnfs*2) and one novel variant of uncertain significance (c.505C>G; p.Arg169Glu), a missense alteration. We describe the clinical and molecular features in the patient harboring this novel alteration c.505C>G, who meets clinical criteria for CMMRD and exhibits molecular evidence supporting a diagnosis of CMMRD. Although experimental validation is needed to confirm its pathogenicity, PMS2 c.505C>G likely has functional consequences that contributes to our patient's phenotype based on the patient's clinical presentation, tumor studies, and bioinformatics analysis. PMID:27017610

Identification of a novel PMS2 alteration c.505C>G (R169G) in trans with a PMS2 pathogenic mutation in a patient with constitutional mismatch repair deficiency.

PubMed

Mork, Maureen E; Borras, Ester; Taggart, Melissa W; Cuddy, Amanda; Bannon, Sarah A; You, Y Nancy; Lynch, Patrick M; Ramirez, Pedro T; Rodriguez-Bigas, Miguel A; Vilar, Eduardo

2016-10-01

Constitutional mismatch repair deficiency syndrome (CMMRD) is a rare autosomal recessive predisposition to colorectal polyposis and other malignancies, often childhood-onset, that is caused by biallelic inheritance of mutations in the same mismatch repair gene. Here, we describe a patient with a clinical diagnosis of CMMRD based on colorectal polyposis and young-onset endometrial cancer who was identified to have two alterations in trans in PMS2: one known pathogenic mutation (c.1831insA; p.Ile611Asnfs*2) and one novel variant of uncertain significance (c.505C>G; p.Arg169Glu), a missense alteration. We describe the clinical and molecular features in the patient harboring this novel alteration c.505C>G, who meets clinical criteria for CMMRD and exhibits molecular evidence supporting a diagnosis of CMMRD. Although experimental validation is needed to confirm its pathogenicity, PMS2 c.505C>G likely has functional consequences that contributes to our patient's phenotype based on the patient's clinical presentation, tumor studies, and bioinformatics analysis.

Temperature effects on deformation and serration behavior of high-entropy alloys (HEAs)

DOE PAGES

Antonaglia, J.; Xie, X.; Tang, Z.; ...

2014-09-16

Many materials are known to deform under shear in an intermittent way with slip avalanches detected as acoustic emission and serrations in the stress–strain curves. Similar serrations have recently been observed in a new class of materials, called high-entropy alloys (HEAs). Here, we discuss the serration behaviors of several HEAs from cryogenic to elevated temperatures. The experimental results of slow compression and tension tests are compared with the predictions of a slip-avalanche model for the deformation of a broad range of solids. The results shed light on the deformation processes in HEAs. Temperature effects on the distributions of stress dropsmore » and the decrease of the cutoff (i.e., of the largest observed slip size) for increasing temperature qualitatively agree with the model predictions. As a result, the model is used to quantify the serration characteristics of HEAs, and pertinent implications are discussed.« less

Effects of temperature on serrated flows of Al 0.5CoCrCuFeNi high-entropy alloy

DOE PAGES

Chen, Shuying; Xie, Xie; Chen, Bilin; ...

2015-08-14

Compression behavior of the Al 0.5CoCrCuFeNi high-entropy alloy (HEA) was studied at different temperatures from 673 K to 873 K at a low strain rate of 5 x 10 –5/s to investigate the temperature effect on the mechanical properties and serration behavior. The face-centered-cubic (fcc) structure is confirmed at the lower temperature of 673 K and 773 K, and a structure of mixed fcc and body-centered cubic (bcc) is identified at a higher temperature of 873 K after compression tests using high-energy synchrotron x-ray diffraction. As a result, by comparing the stress–strain curves at different temperatures, two opposite directions ofmore » serrations types were found, named upward serrations appearing at 673 K and 773 K and downward serrations at 873 K, which may be due to dynamic strain aging.« less

Intestinal flora of FAP patients containing APC-like sequences.

PubMed

Hainova, K; Adamcikova, Z; Ciernikova, S; Stevurkova, V; Tyciakova, S; Zajac, V

2014-01-01

Colorectal cancer mortality is one of the most common cause of cancer-related mortality. A multiple risk factors are associated with colorectal cancer, including hereditary, enviromental and inflammatory syndromes affecting the gastrointestinal tract. Familial adenomatous polyposis (FAP) is characterized by the emergence of hundreds to thousands of colorectal adenomatous polyps and FAP syndrome is caused by mutations within the adenomatous polyposis coli (APC) tumor suppressor gene. We analyzed 21 rectal bacterial subclones isolated from FAP patient 41-1 with confirmed 5bp ACAAA deletion within codons 1060-1063 for the presence of APC-like sequences in longest exon 15. The studied section was defined by primers 15Efor-15Erev, what correlates with mutation cluster region (MCR) in which the 75% of all APC germline mutations were detected. More than 90% homology was showed by sequencing and subsequent software comparison. The expression of APC-like sequences was demostrated by Western blot analysis using monoclonal and polyclonal antibodies against APC protein. To study missing link between the DNA analysis (PCR, DNA sequencing) and protein expresion experiments (Western blotting) we analyzed bacterial transcripts containing the 15Efor-15Erev sequence of APC gene by reverse transcription-PCR, what indicated that an APC gene derived fragment may be produced. We observed 97-100 % homology after computer comparison of cDNA PCR products. Our results suggest that presence of APC-like sequences in intestinal/rectal bacteria is enrichment of bacterial genetic information in which horizontal gene transfer between humans and microflora play an important role.

Hereditary non-polyposis colorectal cancer/Lynch syndrome in three dimensions.

PubMed

Kravochuck, Sara E; Church, James M

2017-12-01

Hereditary non-polyposis colorectal cancer (HNPCC) is defined by family history, and Lynch syndrome (LS) is defined genetically. However, universal tumour testing is now increasingly used to screen for patients with defective mismatch repair. This mixing of the results of family history, tumour testing and germline testing produces multiple permutations and combinations that can foster confusion. We wanted to clarify hereditary colorectal cancer using the three dimensions of classification: family history, tumour testing and germline testing. Family history (Amsterdam I or II criteria versus not Amsterdam criteria) was used to define patients and families with HNPCC. Tumour testing and germline testing were then performed to sub-classify patients and families. The permutations of these classifications are applied to our registry. There were 234 HNPCC families: 129 had LS of which 55 were three-dimensional Lynch (family history, tumour testing and germline testing), 66 were two-dimensional Lynch and eight were one-dimensional Lynch. A total of 10 families had tumour Lynch (tumours with microsatellite instability or loss of expression of a mismatch repair protein but an Amsterdam-negative family and negative germline testing), five were Lynch like (Amsterdam-positive family, tumours with microsatellite instability or loss of expression of a mismatch repair protein on immunohistochemistry but negative germline testing), 26 were familial colorectal cancer type X and 95 were HNPCC. Hereditary colorectal cancer can be confusing. Sorting families in three dimensions can clarify the confusion and may direct further testing and, ultimately, surveillance. © 2016 Royal Australasian College of Surgeons.

A SMAD4 mutation indicative of juvenile polyposis syndrome in a family previously diagnosed with Menetrier's disease.

PubMed

Burmester, James K; Bell, Lauren N; Cross, Deanna; Meyer, Patrick; Yale, Steven H

2016-10-01

Menetrier's disease (MD) is a rare disease with unknown aetiology, characterized by hypertrophic folds within the fundus and body of the stomach. We investigated mutations of the candidate genes SMAD4, BMPR1A, TGF-α, and PDX1 within a family with MD. A large 4-generation family with MD was identified. This family had 5 cases of MD, 1 case of MD and juvenile polyposis syndrome (JPS) and 3 cases of JPS. Participants provided saliva for DNA extraction and completed a health questionnaire designed to assess conditions that may be found in patients with MD. Following pedigree analysis, we sequenced the coding regions of the SMAD4 and BMPR1A genes and the regulatory regions of the TGF-α and PDX1 genes in affected and non-affected family members. No mutations were identified in the sequenced regions of BMPR1A, TGF-α, or PDX1. A dominant 1244_1247delACAG mutation of SMAD4 was identified in each of the subjects with JPS as well as in each of the subjects with MD. Although this mutation segregated with disease, there were also unaffected/undiagnosed carriers. The 1244_1247delACAG mutation of SMAD4 is the cause of JPS and the likely cause of MD in a large family initially diagnosed with MD. Copyright © 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Aggressive fibromatosis (desmoid tumors): definition, occurrence, pathology, diagnostic problems, clinical behavior, genetic background.

PubMed

Ferenc, Tomasz; Sygut, Jacek; Kopczyński, Janusz; Mayer, Magdalena; Latos-Bieleńska, Anna; Dziki, Adam; Kulig, Andrzej

2006-01-01

Aggressive fibromatosis, usually called desmoid tumor develops from muscle connective tissue, fasciae and aponeuroses. This neoplasm is composed of spindle (fibrocyte-like) cells. As regards the site, aggressive fibromatoses can be divided into: extra-abdominal in the area of the shoulder and pelvic girdle or chest and neck wall; abdominal in abdominal wall muscles; intra-abdominal concerning pelvis, mesentery connective tissue or retroperitoneal space. Desmoid tumor is a neoplasm which rarely turns malignant and is non-metastasizing but demonstrates ability to local infiltration into tissue and is characterized by high risk of recurrence (25-65%) after surgical treatment. Desmoid tumor etiology is uncertain. This neoplasm occurs in sporadic (idiopathic) form and is also associated with some familial neoplastic syndromes. Most sporadic cases of aggressive fibromatosis contain a somatic mutation in either the adenomatous polyposis coli (APC) or beta-catenin genes. Sporadic tumors are more frequent in women than in men from 2 : 1 to 5 : 1. In about 10-15 per cent of patients with familial adenomatous polyposis (FAP), aggressive fibromatosis is a parenteral manifestation of this familial syndrome conditioned by APC gene mutation. Abdomen injury--most frequently due to surgery is said to play an important role in the initiation of fibrous tissue proliferative process in the cases of abdominal and intra abdominal forms. High cells growth potential with relatively high local malignancy is observed in about 10% of cases with sporadic tumors as well as in those FAP-associated.

Chemoprevention of Colorectal Cancer

PubMed Central

Lang, Michaela; Gasche, Christoph

2017-01-01

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 extremely 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

Churg–Strauss syndrome in a patient previously diagnosed with multiple sclerosis

PubMed Central

Sarkar, Pamela; Ibitoye, Richard Tolulope; Promnitz, Douglas Anthony

2011-01-01

A lady in her 70s with a background of multiple sclerosis (MS) and late-onset asthma was admitted with a 2-week history of cough and shortness of breath, progressive right-sided weakness and functional decline. Investigation revealed eosinophilia, elevated myeloperoxidase antineutrophil cytoplasmic antibody, CT sinuses showed long-standing inflammatory changes consistent with sinonasal polyposis and MRI head showed lesions consistent with vasculitis. She then developed left-sided weakness and increased wheeze. Review of her case notes demonstrated that, the eosinophilia was long-standing, her asthma was severe and steroid-dependent, and her neurologic syndrome was atypical for MS. Intravenous methylprednisolone then cyclophosphamide were administered. She demonstrated remarkable improvement, becoming more alert, with improvement in left-sided weakness. A diagnosis of Churg–Strauss syndrome was established. She was discharged to a nursing home with outpatient rheumatology follow-up. The diagnosis of MS was revisited. PMID:22679315

Orbital complications of sinusitis in the aspirin triad syndrome.

PubMed

McFadden, E A; Woodson, B T; Massaro, B M; Toohill, R J

1996-09-01

Orbital complications are uncommon in adult sinusitis. In contrast, the sinusitis of the aspirin triad syndrome is often fulminate, expansive, and recurrent, and complications may be more frequent. Of 81 patients with aspirin triad who were treated surgically, 7 patients (8.6%) had orbital complications, including sinus mucoceles in 3 patients, lacrimal gland extension in 2 patients, inflammatory orbital mass in 1 patient, and proptosis from expansile sinonasal polyposis in 1 patient. All complications manifested within 2 years of prior surgery. Two patients suffered blindness. In a group of 120 consecutively treated sinus surgery patients without aspirin triad syndrome (51 of whom were followed for more than 2 years), no patient manifested nonoperative orbital complications. The results of this study suggest that aspirin triad patients are at significant risk for orbital complications and therefore should have long-term follow-up with aggressive treatment of persistent disease.

Therapeutic approaches for patients with coexisting familial adenomatous polyposis and colorectal cancer.

PubMed

Inoue, Yasuhiro; Ishida, Hideyuki; Ueno, Hideki; Kobayashi, Hirotoshi; Yamaguchi, Tatsuro; Konishi, Tsuyoshi; Tomita, Naohiro; Matsubara, Nagahide; Ishida, Fumio; Hinoi, Takao; Kanemitsu, Yukihide; Watanabe, Toshiaki; Sugihara, Kenichi

2016-09-01

Colorectal cancer is a major cause of death in patients with familial adenomatous polyposis. Despite evidence for prophylactic colectomy, there is no ideal therapy for patients with coexisting familial adenomatous polyposis and colorectal cancer. We evaluated the correlation between surgery for familial adenomatous polyposis and multimodal treatment for colorectal cancer, and clarified prognosis of Japanese patients with familial adenomatous polyposis and colorectal cancer. We retrospectively reviewed data from 303 patients who underwent colorectal surgery for familial adenomatous polyposis between 2000 and 2012. Overall, 172 patients had colorectal cancer. The most common procedure for familial adenomatous polyposis was restorative proctocolectomy with ileal pouch anal anastomosis, irrespective of colorectal cancer. Partial colectomy was more frequent in patients with than without colorectal cancer (8.7% and 0%, respectively). Ileal pouch anal anastomosis was frequently (60.6%) performed in patients with Stage I-III colorectal cancer. Overall, 12 of 20 patients with Stage IV colorectal cancer underwent metastasectomy; six patients simultaneously and six metachronously. There were fewer cases of ileal pouch anal anastomosis, but more total colectomy with ileorectal anastomosis was performed metachronously, compared with simultaneous metastasectomy (P = 0.006). More cytotoxic (P = 0.006) and molecular (P = 0.03) agents were administered to the ileorectal anastomosis/partial colectomy patients, compared with total proctocolectomy/ileal pouch anal anastomosis patients. A 5-year overall survival was 100% in Stage 0/I, 89.8% in Stage II, 87.9% in Stage III and 48.4% in Stage IV. In patients with familial adenomatous polyposis and colorectal cancer, primary surgery, metastasectomy and chemotherapy could be compatible with standard surgical approaches for familial adenomatous polyposis . However, modifying surgical procedures for familial adenomatous polyposis might help multimodality therapy for Stage IV colorectal cancer to prolong survival. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

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

Direct Numerical Simulations of Aerofoils with Serrated Trailing-Edge Extensions

NASA Astrophysics Data System (ADS)

Shahab, Muhammad Farrukh; Omidyeganeh, Mohammad; Pinelli, Alfredo

2017-11-01

Owl-feather-inspired technology motivates engineers to develop quieter wings. Direct numerical simulations of NACA-4412 aerofoil with retrofitted flat plate, serrated sawtooth shaped and porous (serrations with filaments) extensions have been performed to study the effects of these modifications on the hydrodynamic characteristics of the turbulent wake and their upstream influence on the interacting boundary layer. A chord based Reynolds number of 100,000 and an angle of attack of 5° has been chosen for all simulations, moreover the surface boundary layers are tripped using a a volume forcing method. This contribution will present a detailed statistical analysis of the mean and fluctuating behaviour of the flow and the key differences in the flow topologies will be highlighted. The preliminary analysis of results identifies a system of counter rotating streamwise vortices for the case of saw-tooth shaped serrations. The presence of the latter is generally considered responsible for an increased parasitic higher frequency noise for serrated aerofoils. To palliate the effect of aforementioned system of streamwise vortices, a filamentous layer occupying the voids of the serrations has been added which is expected to improve the aeroacoustic performance of the system.

The role of illness perceptions in adherence to surveillance in patients with familial adenomatous polyposis (FAP).

PubMed

Eriksson, Lars E; Fritzell, Kaisa; Rixon, Lorna; Björk, Jan; Wettergren, Lena

2016-06-01

The aim of the study was to examine patients' beliefs about having familial adenomatous polyposis (FAP), a hereditary colorectal cancer syndrome, and how these beliefs are associated with adherence to endoscopic surveillance. Adult patients diagnosed with FAP on the national Swedish polyposis register who had undergone prophylactic colorectal surgery (n 209, response rate 76%) completed the Illness Perception Questionnaire (IPQ). Logistic regression analysis was used to investigate the relationships between illness perceptions and adherence, when controlling for demographic and clinical factors. FAP was less distressing in men and those with fewer symptoms, reporting less serious consequences and more coherent understanding of FAP. Non-adherence (14%) to surveillance was associated with being older, having undergone surgery less recently and no history of malignancy. Patients' beliefs about their FAP were able to explain unique variance in non-adherence, in particular those who believed FAP was less distressing. Patients who were non-adherent to endoscopic surveillance had more positive perceptions about their FAP and, in particular, were less emotionally affected compared to those who adhered. As non-adherence implies a greater risk of future malignancies, special efforts are required to effectively prevent cancer in all patients with FAP. Those who have lived with the condition for a long time, and are not troubled by gastrointestinal symptoms or worried about their FAP, may be in need of specific information and support. Further prospective research is required to examine emotional predictors and consequences of non-adherence. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Wide-field piecemeal cold snare polypectomy of large sessile serrated polyps without a submucosal injection is safe.

PubMed

Tate, David J; Awadie, Halim; Bahin, Farzan F; Desomer, Lobke; Lee, Ralph; Heitman, Steven J; Goodrick, Kathleen; Bourke, Michael J

2018-03-01

BACKGROUND AND STUDY AIMS : Large series suggest endoscopic mucosal resection is safe and effective for the removal of large (≥ 10 mm) sessile serrated polyps (SSPs), but it exposes the patient to the risks of electrocautery, including delayed bleeding. We examined the feasibility and safety of piecemeal cold snare polypectomy (pCSP) for the resection of large SSPs.  Sequential large SSPs (10 - 35 mm) without endoscopic evidence of dysplasia referred over 12 months to a tertiary endoscopy center were considered for pCSP. A thin-wire snare was used in all cases. Submucosal injection was not performed. High definition imaging of the defect margin was used to ensure the absence of residual serrated tissue. Adverse events were assessed at 2 weeks and surveillance was planned for between 6 and 12 months.  41 SSPs were completely removed by pCSP in 34 patients. The median SSP size was 15 mm (interquartile range [IQR] 14.5 - 20 mm; range 10 - 35 mm). The median procedure duration was 4.5 minutes (IQR 1.4 - 6.3 minutes). There was no evidence of perforation or significant intraprocedural bleeding. At 2-week follow-up, there were no significant adverse events, including delayed bleeding and post polypectomy syndrome. First follow-up has been undertaken for 15 /41 lesions at a median of 6 months with no evidence of recurrence.  There is potential for pCSP to become the standard of care for non-dysplastic large SSPs. This could reduce the burden of removing SSPs on patients and healthcare systems, particularly by avoidance of delayed bleeding. © Georg Thieme Verlag KG Stuttgart · New York.

Differences in detection rates of adenomas and serrated polyps in screening versus surveillance colonoscopies, based on the new hampshire colonoscopy registry.

PubMed

Anderson, Joseph C; Butterly, Lynn F; Goodrich, Martha; Robinson, Christina M; Weiss, Julia E

2013-10-01

The adenoma detection rate (ADR) is an important quality indicator originally developed for screening colonoscopies. However, it is unclear whether the ADR should be calculated using data from screening and surveillance examinations. The recommended benchmark ADR for screening examinations is 20% (15% for women and 25% for men ≥50 y). There are few data available to compare ADRs from surveillance vs screening colonoscopies. We used a population-based registry to compare ADRs from screening vs surveillance colonoscopies. The serrated polyp detection rate (SDR), a potential new quality indicator, also was examined. By using data from the statewide New Hampshire Colonoscopy Registry, we excluded incomplete and diagnostic colonoscopies, and those performed in patients with inflammatory bowel disease, familial syndromes, or poor bowel preparation. We calculated the ADR and SDR (number of colonoscopies with at least 1 adenoma or serrated polyp detected, respectively, divided by the number of colonoscopies) from 9100 colonoscopies. The ADR and SDR were compared by colonoscopy indication (screening, surveillance), age at colonoscopy (50-64 y, ≥65 y), and sex. The ADR was significantly higher in surveillance colonoscopies (37%) than screening colonoscopies (25%; P < .001). This difference was observed for both sexes and age groups. There was a smaller difference in the SDR of screening (8%) vs surveillance colonoscopies (10%; P < .001). In a population-based study, we found that addition of data from surveillance colonoscopies increased the ADR but had a smaller effect on the SDR. These findings indicate that when calculating ADR as a quality measure, endoscopists should use screening, rather than surveillance colonoscopy, data. Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

Differences in Detection Rates of Adenomas and Serrated Polyps in Screening Versus Surveillance Colonoscopies, Based on the New Hampshire Colonoscopy Registry

PubMed Central

ANDERSON, JOSEPH C.; BUTTERLY, LYNN; GOODRICH, MARTHA; ROBINSON, CHRISTINA M.; WEISS, JULIA E.

2013-01-01

BACKGROUND & AIMS The adenoma detection rate (ADR) is an important quality indicator originally developed for screening colonoscopies. However, it is unclear whether the ADR should be calculated using data from screening and surveillance examinations. The recommended benchmark ADR for screening examinations is 20% (15% for women and 25% for men ≥ 50 y). There are few data available to compare ADRs from surveillance vs screening colonoscopies. We used a population-based registry to compare ADRs from screening vs surveillance colonoscopies. The serrated polyp detection rate (SDR), a potential new quality indicator, also was examined. METHODS By using data from the statewide New Hampshire Colonoscopy Registry, we excluded incomplete and diagnostic colonoscopies, and those performed in patients with inflammatory bowel disease, familial syndromes, or poor bowel preparation. We calculated the ADR and SDR (number of colonoscopies with at least 1 adenoma or serrated polyp detected, respectively, divided by the number of colonoscopies) from 9100 colonoscopies. The ADR and SDR were compared by colonoscopy indication (screening, surveillance), age at colonoscopy (50–64 y, ≥65 y), and sex. RESULTS The ADR was significantly higher in surveillance colonoscopies (37%) than screening colonoscopies (25%; P < .001). This difference was observed for both sexes and age groups. There was a smaller difference in the SDR of screening (8%) vs surveillance colonoscopies (10%; P < .001). CONCLUSIONS In a population-based study, we found that addition of data from surveillance colonoscopies increased the ADR, but had a smaller effect on the SDR. These findings indicate that when calculating ADR as a quality measure, endoscopists should use screening, rather than surveillance colonoscopy, data. PMID:23660415

Traditional serrated adenoma (TSA): morphological questions, queries and quandaries.

PubMed

Chetty, Runjan

2016-01-01

Traditional serrated adenoma (TSA) is an uncommon type of serrated adenoma that can be a precursor to biologically aggressive colorectal cancer that invokes the serrated (accelerated) pathway. The purpose of this review is to address some of the more contentious issues around nomenclature, diagnostic criteria, histological variants, coexistence with other polyp types, the occurrence of dysplasia and the differential diagnosis. While the vast majority of TSAs are exophytic villiform polyps composed of deeply eosinophilic cells, flat top luminal serrations and numerous ectopic crypt foci, histological variants include flat TSA, filiform TSA and one composed of large numbers of mucin-containing cells. It is unlikely that there is any biological difference between the histological variants. There is a contention that TSAs are not dysplastic ab initio and that the majority do not show cytological atypia. Two types of dysplasia are associated with TSA. Serrated dysplasia is less well recognised and less commonly encountered than adenomatous dysplasia. TSA with dysplasia must be separated from TSA with coexisting conventional adenoma. TSA is a characteristic polyp that may be extremely exophytic, flat or composed of mucin-rich cells and is typified by numerous ectopic crypt foci. They may coexist with other serrated polyps and conventional adenomas. Approximately 20-25% will be accompanied by adenomatous dysplasia. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

A Patient With Desmoid Tumors and Familial FAP Having Frame Shift Mutation of the APC Gene.

PubMed

Sadighi, Sanambar; Ghaffari-Moghaddam, Mahsa; Saffari, Mojtaba; Mohagheghi, Mohammad Ali; Shirkoohi, Reza

2017-02-01

Desmoids tumors, characterized by monoclonal proliferation of myofibroblasts, could occur in 5-10% of patients with familial adenomatous polyposis (FAP) as an extra-colonic manifestation of the disease. FAP can develop when there is a germ-line mutation in the adenomatous polyposis coli gene. Although mild or attenuated FAP may follow mutations in 5΄ extreme of the gene, it is more likely that 3΄ extreme mutations haveamore severe manifestation of thedisease. A 28-year-old woman was admitted to the Cancer Institute of Iran with an abdominal painful mass. She had strong family history of FAP and underwent prophylactic total colectomy. Pre-operative CT scans revealed a large mass. Microscopic observation showed diffuse fibroblast cell infiltration of the adjacent tissue structures. Peripheral blood DNA extraction followed by adenomatous polyposis coli gene exon by exon sequencing was performed to investigate the mutation in adenomatous polyposis coli gene. Analysis of DNA sequencing demonstrated a mutation of 4 bpdeletions at codon 1309-1310 of the exon 16 of adenomatous polyposis coli gene sequence which was repeated in 3 members of the family. Some of them had desmoid tumor without classical FAP history. Even when there is no familial history of adenomatous polyposis, the adenomatous polyposis coli gene mutation should be investigated in cases of familial desmoids tumors for a suitable prevention. The 3΄ extreme of the adenomatous polyposis coli gene is still the best likely location in such families.

Integrated Cancer Repository for Cancer Research

ClinicalTrials.gov

2017-05-05

Pancreatic Cancer; Thyroid Cancer; Lung Cancer; Esophageal Cancer; Thymus Cancer; Colon Cancer; Rectal Cancer; GIST; Anal Cancer; Bile Duct Cancer; Duodenal Cancer; Gallbladder Cancer; Gastric Cancer; Liver Cancer; Small Intestine Cancer; Peritoneal Surface Malignancies; Familial Adenomatous Polyposis; Lynch Syndrome; Bladder Cancer; Kidney Cancer; Penile Cancer; Prostate Cancer; Testicular Cancer; Ureter Cancer; Urethral Cancer; Hypopharyngeal Cancer; Laryngeal Cancer; Lip Cancer; Oral Cavity Cancer; Nasopharyngeal Cancer; Oropharyngeal Cancer; Paranasal Sinus Cancer; Nasal Cavity Cancer; Salivary Gland Cancer; Skin Cancer; CNS Tumor; CNS Cancer; Mesothelioma; Breastcancer; Leukemia; Melanoma; Sarcoma; Unknown Primary Tumor; Multiple Myeloma; Ovarian Cancer; Endometrial Cancer; Vaginal Cancer

Portevin-Le Chatelier effect under cyclic loading: experimental and numerical investigations

NASA Astrophysics Data System (ADS)

Mazière, M.; Pujol d'Andrebo, Q.

2015-10-01

The Portevin-Le Chatelier (PLC) effect is generally evidenced by the apparition of serrated yielding under monotonic tensile loading conditions. It appears at room temperature in some aluminium alloys, around ? in some steels and in many other metallic materials. This effect is associated with the propagation of bands of plastic deformation in tensile specimens and can in some cases lead to unexpected failures. The PLC effect has been widely simulated under monotonic conditions using finite elements and an appropriate mechanical model able to reproduce serrations and strain localization. The occurrence of serrations can be predicted using an analytical stability analysis. Recently, this serrated yielding has also been observed in specimens made of Cobalt-based superalloy under cyclic loading, after a large number of cycles. The mechanical model has been identified in this case to accurately reproduce this critical number of cycle where serrations appear. The associated apparition of localized bands of deformation in specimens and their influence on its failure has also been investigated using finite element simulations.

Sessile Serrated Adenomas: How to Detect, Characterize and Resect

PubMed Central

Ma, Michael X.; Bourke, Michael J.

2017-01-01

Serrated polyps are important contributors to the burden of colorectal cancers (CRC). These lesions were once considered to have no malignant potential, but currently up to 30% of all CRC are recognized to arise from the serrated neoplasia pathway. The primary premalignant lesions are sessile serrated adenomas/polyps (SSA/Ps), although traditional serrated adenomas are relatively uncommon. Compared to conventional adenomas, SSA/Ps are morphologically subtle with indistinct borders, may be difficult to detect endoscopically, are more prevalent than previously thought, are associated with synchronous and metachronous advanced neoplasia, and have a higher risk of incomplete resection. Although many lesions remain “dormant,” progressive disease is associated with the development of dysplasia and more rapid progression to CRC. As a result, SSA/Ps are strongly implicated in the development of interval cancers. These factors represent unique challenges that require a meticulous approach to their management. In this review, we summarize the contemporary literature on the characterization, detection and resection of SSA/Ps. PMID:28494577

Striated abrasions from a knife with non-serrated blade--identification of the instrument of crime on the basis of an experiment with material evidence.

PubMed

Kaliszan, Michał; Karnecki, Karol; Akçan, Ramazan; Jankowski, Zbigniew

2011-09-01

This paper presents an experiment with a knife seized as material evidence in a homicide case. The reason for the experiment was the necessity to determine whether the injuries of the deceased could have been inflicted with this instrument since in the course of the investigation doubt arose as to the origin of linear, parallel scratches around one of the wounds and on the abdominal integuments suggesting a serrated blade. The knife found near the crime scene had a smooth blade and small serrations only on the borderline between its blade and hilt. However, the performed experiment showed that if the knife is directed towards the integuments of the body in a special way, its serrations, even though not located on the blade itself, may leave such striated marks on the body, as those found during the autopsy, suggesting their origin from a serrated blade.

Rigidity and retention of root canal posts.

PubMed

Purton, D G; Chandler, N P; Love, R M

1998-03-28

To test the rigidity and the retention into roots of parallel root canal posts, one a spiral vented titanium post and the other a spiral serrated, hollow, stainless steel post. A serrated, stainless steel post was used as the control. A three-point bending test was used to test rigidity. To test retention, ten posts of each type were cemented into the roots of extracted teeth with a resin cement and the tensile loads required to remove them were compared using Student's t and Mann-Whitney U tests. The serrated stainless steel posts were significantly more rigid than either of the other types. The titanium posts and the stainless steel hollow posts were not significantly different in rigidity. The serrated, stainless steel posts were significantly better retained than either of the other types. The titanium posts showed greater retention than the hollow posts. Within the limits of the study the stainless steel, serrated posts were superior to the two newer types in terms of rigidity and retention into roots.

Syndromes with supernumerary teeth.

PubMed

Lubinsky, Mark; Kantaputra, Piranit Nik

2016-10-01

While most supernumerary teeth are idiopathic, they can be associated with a number of Mendelian syndromes. However, this can also be a coincidental finding, since supernumerary teeth occur in 6% or more of the normal population. To better define this relationship, we analyzed the evidence for specific associations. We excluded conditions with a single affected patient reported, supernumerary teeth adjacent to clefts or other forms of alveolar disruption (as secondary rather than primary findings), and natal teeth, which can involve premature eruption of a normal tooth. Since, the cause of supernumerary teeth shows considerable heterogeneity, certain findings are less likely to be coincidental, such as five or more supernumerary teeth in a single patient, or locations outside of the premaxilla. We found only eight genetic syndromes with strong evidence for an association: cleidocranial dysplasia; familial adenomatous polyposis; trichorhinophalangeal syndrome, type I; Rubinstein-Taybi syndrome; Nance-Horan syndrome; Opitz BBB/G syndrome; oculofaciocardiodental syndrome; and autosomal dominant Robinow syndrome. There is also suggestive evidence of an association with two uncommon disorders, Kreiborg-Pakistani syndrome (craniosynostosis and dental anomalies), and insulin-resistant diabetes mellitus with acanthosisnigricans. An association of a Mendelian disorder with a low frequency manifestation of supernumerary teeth is difficult to exclude without large numbers, but several commonly cited syndromes lacked evidence for clear association, including Hallermann-Streiff syndrome, Fabry disease, Ehlers-Danlos syndrome, Apert and Crouzon syndromes, Zimmermann-Laband syndrome, and Ellis-van Creveld syndrome. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Differential expression of CK20, β-catenin, and MUC2/5AC/6 in Lynch syndrome and familial colorectal cancer type X.

PubMed

Haraldsson, Stefan; Klarskov, Louise; Nilbert, Mef; Bernstein, Inge; Bonde, Jesper; Holck, Susanne

2017-01-01

Hereditary non-polyposis colorectal cancer comprises Lynch syndrome and familial colorectal cancer type X (FCCTX). Differences in genetics, demographics and histopathology have been extensively studied. The purpose of this study is to characterize their immunoprofile of markers other than MMR proteins. We compared the expression patterns of cytokeratins (CK7 and CK20), mucins (MUC2/5 AC/6), CDX2 and β-catenin in Lynch syndrome and FCCTX. Differences were identified for CK20 and nuclear β-catenin, which were significantly more often expressed in FCCTX than in Lynch syndrome ( p  < 0.001), whereas MUC2, MUC5AC and MUC6 were overexpressed in Lynch syndrome tumors compared with FCCTX tumors ( p  = 0.001, < 0.01, and < 0.001, respectively). We observed no differences in the expression patterns of CK7 and CDX2. In summary, we identified significant differences in the immunoprofiles of colorectal cancers linked to FCCTX and Lynch syndrome with a more sporadic-like profile in the former group and a more distinct profile with frequent MUC6 positivity in the latter group.

Endoscopic analysis of colorectal serrated lesions with cancer.

PubMed

Nagata, Shuichiro; Mitsuyama, Keiichi; Kawano, Hiroshi; Noda, Tetsuhiro; Maeyama, Yasuhiko; Mukasa, Michita; Takedatsu, Hidetoshi; Yoshioka, Shinichiro; Kuwaki, Kotaro; Akiba, Jun; Tsuruta, Osamu; Torimura, Takuji

2018-06-01

Serrated lesions, including hyperplastic polyps (HPs), traditional serrated adenomas (TSAs) and sessile serrated adenomas/polyps (SSA/Ps), are important contributors to colorectal carcinogenesis. The aim of the present study was to analyze the potential of conventional endoscopy and advanced endoscopic imaging techniques to delineate the characteristic features of serrated lesions with cancer. The present study was a retrospective analysis of the data of 168 patients who had undergone colonoscopy, and a total of 228 serrated lesions (77 HPs, 58 TSAs, 84 SSA/Ps, 9 SSA/P plus TSAs) have been identified in these patients. A cancer component was identified in 2.6% of HPs, 13.8% of TSAs and 10.7% of SSA/Ps, but none of SSA/P plus TSAs. Compared with the lesions without cancer, the lesions with cancer exhibited a larger size (HP, TSA and SSA/P), a reddish appearance (SSA/P), a two-tier raised appearance (HP and SSA/P), a central depression (HP, TSA and SSA/P), the type V pit pattern (HP, TSA and SSA/P), and/or the type III capillary pattern (TSA and SSA/P). Deep invasion was identified in 50.0% of HPs, 12.5% of TSAs and 55.6% of SSA/Ps with cancer. The Ki-67 proliferative zone was distributed diffusely within the area of the cancer, but partially within the non-cancer area of HPs, TSAs and SSA/Ps. The lesion types were also analyzed on the basis of mucin phenotype. The present study suggested that a detailed endoscopic analysis of serrated lesions with cancer is useful for delineating characteristic features, and the analysis aids treatment selection.

Somatic APC mosaicism and oligogenic inheritance in genetically unsolved colorectal adenomatous polyposis patients.

PubMed

Ciavarella, Michele; Miccoli, Sara; Prossomariti, Anna; Pippucci, Tommaso; Bonora, Elena; Buscherini, Francesco; Palombo, Flavia; Zuntini, Roberta; Balbi, Tiziana; Ceccarelli, Claudio; Bazzoli, Franco; Ricciardiello, Luigi; Turchetti, Daniela; Piazzi, Giulia

2018-03-01

Germline variants in the APC gene cause familial adenomatous polyposis. Inherited variants in MutYH, POLE, POLD1, NTHL1, and MSH3 genes and somatic APC mosaicism have been reported as alternative causes of polyposis. However, ~30-50% of cases of polyposis remain genetically unsolved. Thus, the aim of this study was to investigate the genetic causes of unexplained adenomatous polyposis. Eight sporadic cases with >20 adenomatous polyps by 35 years of age or >50 adenomatous polyps by 55 years of age, and no causative germline variants in APC and/or MutYH, were enrolled from a cohort of 56 subjects with adenomatous colorectal polyposis. APC gene mosaicism was investigated on DNA from colonic adenomas by Sanger sequencing or Whole Exome Sequencing (WES). Mosaicism extension to other tissues (peripheral blood, saliva, hair follicles) was evaluated using Sanger sequencing and/or digital PCR. APC second hit was investigated in adenomas from mosaic patients. WES was performed on DNA from peripheral blood to identify additional polyposis candidate variants. We identified APC mosaicism in 50% of patients. In three cases mosaicism was restricted to the colon, while in one it also extended to the duodenum and saliva. One patient without APC mosaicism, carrying an APC in-frame deletion of uncertain significance, was found to harbor rare germline variants in OGG1, POLQ, and EXO1 genes. In conclusion, our restrictive selection criteria improved the detection of mosaic APC patients. In addition, we showed for the first time that an oligogenic inheritance of rare variants might have a cooperative role in sporadic colorectal polyposis onset.

Clinicopathological observations of colorectal serrated lesions associated with invasive carcinoma and high-grade intraepithelial neoplasm

PubMed Central

XU, SHENG; WANG, LUPING; YANG, GUANGZHI; LI, LIN; WANG, JIN; XU, CHUNWEI; GE, CHANG

2013-01-01

The aim of this study was to investigate the clinicopathological characteristics of colorectal serrated lesions associated with invasive carcinoma and high-grade intraepithelial neoplasm (HIN), as well as to determine the immunohistochemical expression of MutL homolog 1 (MLH1), MutS homolog 2 (MSH2), K-ras and O6-methylguanine-DNA methyltransferase (MGMT). A total of 5,347 cases diagnosed with colorectal polyp or adenoma were included in this study from October 2002 to September 2009. A total of 16 cases of colorectal serrated lesions associated with invasive carcinoma/HIN were screened. These comprised seven cases of traditional serrated adenoma (TSA) associated with invasive carcinoma and HIN, six cases of sessile serrated adenoma (SSA) associated with invasive carcinoma/HIN and three cases of hyperplastic polyp (HP) associated with invasive carcinoma/HIN. TSA associated with invasive carcinoma/HIN predominantly occurred in the rectum with a clearly serrated structure and ectopic crypts. High-grade dysplasia was observed in filiform TSA, which was more prone to carcinogenesis. SSA associated with invasive carcinoma/HIN mainly occurred in the ileocecal junction, with the SSA serrated glands closely located adjacent to the muscularis mucosa and the basal crypt expanded with inverted T- or L-shaped branches. HPs were observed in three cases in the cancer-adjacent tissues with invasive carcinoma, while a HP-SSA/TSA-carcinoma sequence was found in two cases. Immunohistochemistry showed that MGMT expression was significantly different in the serrated lesion tissues compared with that in cancer tissues (P=0.022), control cancer tissues (P=0.002) and normal colorectal epithelial tissues (P=0.003). TSA and SSA may progress to cancer or directly develop into invasive adenocarcinoma. Filiform TSA easily develops into HIN, followed by infiltration. HP may arise from the cancer-adjacent tissues of the invasive carcinoma, which are closely adjacent to the cancer tissues. Further research is needed to investigate the potential direct involvement of HP in carcinogenesis. PMID:24223631

IGF2 differentially methylated region hypomethylation in relation to pathological and molecular features of serrated lesions

PubMed Central

Naito, Takafumi; Nosho, Katsuhiko; Ito, Miki; Igarashi, Hisayoshi; Mitsuhashi, Kei; Yoshii, Shinji; Aoki, Hironori; Nomura, Masafumi; Sukawa, Yasutaka; Yamamoto, Eiichiro; Adachi, Yasushi; Takahashi, Hiroaki; Hosokawa, Masao; Fujita, Masahiro; Takenouchi, Toshinao; Maruyama, Reo; Suzuki, Hiromu; Baba, Yoshifumi; Imai, Kohzoh; Yamamoto, Hiroyuki; Ogino, Shuji; Shinomura, Yasuhisa

2014-01-01

AIM: To investigate insulin-like growth factor 2 (IGF2) differentially methylated region (DMR)0 hypomethylation in relation to clinicopathological and molecular features in colorectal serrated lesions. METHODS: To accurately analyze the association between the histological types and molecular features of each type of serrated lesion, we consecutively collected 1386 formalin-fixed paraffin-embedded tissue specimens that comprised all histological types [hyperplastic polyps (HPs, n = 121), sessile serrated adenomas (SSAs, n = 132), traditional serrated adenomas (TSAs, n = 111), non-serrated adenomas (n = 195), and colorectal cancers (CRCs, n = 827)]. We evaluated the methylation levels of IGF2 DMR0 and long interspersed nucleotide element-1 (LINE-1) in HPs (n = 115), SSAs (n = 120), SSAs with cytological dysplasia (n = 10), TSAs (n = 91), TSAs with high-grade dysplasia (HGD) (n = 15), non-serrated adenomas (n = 80), non-serrated adenomas with HGD (n = 105), and CRCs (n = 794). For the accurate quantification of the relative methylation levels (scale 0%-100%) of IGF2 DMR0 and LINE-1, we used bisulfite pyrosequencing method. Tumor specimens were analyzed for microsatellite instability, KRAS (codons 12 and 13), BRAF (V600E), and PIK3CA (exons 9 and 20) mutations; MLH1 and MGMT methylation; and IGF2 expression by immunohistochemistry. RESULTS: The distribution of the IGF2 DMR0 methylation level in 351 serrated lesions and 185 non-serrated adenomas (with or without HGD) was as follows: mean 61.7, median 62.5, SD 18.0, range 5.0-99.0, interquartile range 49.5-74.4. The IGF2 DMR0 methylation level was divided into quartiles (Q1 ≥ 74.5, Q2 62.6-74.4, Q3 49.6-62.5, Q4 ≤ 49.5) for further analysis. With regard to the histological type, the IGF2 DMR0 methylation levels of SSAs (mean ± SD, 73.1 ± 12.3) were significantly higher than those of HPs (61.9 ± 20.5), TSAs (61.6 ± 19.6), and non-serrated adenomas (59.0 ± 15.8) (P < 0.0001). The IGF2 DMR0 methylation level was inversely correlated with the IGF2 expression level (r = -0.21, P = 0.0051). IGF2 DMR0 hypomethylation was less frequently detected in SSAs compared with HPs, TSAs, and non-serrated adenomas (P < 0.0001). Multivariate logistic regression analysis also showed that IGF2 DMR0 hypomethylation was inversely associated with SSAs (P < 0.0001). The methylation levels of IGF2 DMR0 and LINE-1 in TSAs with HGD (50.2 ± 18.7 and 55.7 ± 5.4, respectively) were significantly lower than those in TSAs (61.6 ± 19.6 and 58.8 ± 4.7, respectively) (IGF2 DMR0, P = 0.038; LINE-1, P = 0.024). CONCLUSION: IGF2 DMR0 hypomethylation may be an infrequent epigenetic alteration in the SSA pathway. Hypomethylation of IGF2 DMR0 and LINE-1 may play a role in TSA pathway progression. PMID:25110432

Evidence for chaos in an experimental time series from serrated plastic flow

NASA Astrophysics Data System (ADS)

Venkadesan, S.; Valsakumar, M. C.; Murthy, K. P. N.; Rajasekar, S.

1996-07-01

An experimental time series from a tensile test of an Al-Mg alloy in the serrated plastic flow domain is analyzed for signature of chaos. We employ state space reconstruction by embedding of time delay vectors. The minimum embedding dimension is found to be 4 and the largest Lyapunov exponent is positive, thereby providing prima facie evidence for chaos in an experimental time series of serrated plastic flow data.

Dietary Fiber Treatment Corrects the Composition of Gut Microbiota, Promotes SCFA Production, and Suppresses Colon Carcinogenesis

PubMed Central

Bishehsari, Faraz; Engen, Phillip A.; Naqib, Ankur; Shaikh, Maliha; Rossi, Marco; Wilber, Sherry; Hamaker, Bruce R.; Khazaie, Khashayarsha; Voigt, Robin M.; Forsyth, Christopher B.; Keshavarzian, Ali

2018-01-01

Epidemiological studies propose a protective role for dietary fiber in colon cancer (CRC). One possible mechanism of fiber is its fermentation property in the gut and ability to change microbiota composition and function. Here, we investigate the role of a dietary fiber mixture in polyposis and elucidate potential mechanisms using TS4Cre × cAPCl°x468 mice. Stool microbiota profiling was performed, while functional prediction was done using PICRUSt. Stool short-chain fatty acid (SCFA) metabolites were measured. Histone acetylation and expression of SCFA butyrate receptor were assessed. We found that SCFA-producing bacteria were lower in the polyposis mice, suggesting a decline in the fermentation product of dietary fibers with polyposis. Next, a high fiber diet was given to polyposis mice, which significantly increased SCFA-producing bacteria as well as SCFA levels. This was associated with an increase in SCFA butyrate receptor and a significant decrease in polyposis. In conclusion, we found polyposis to be associated with dysbiotic microbiota characterized by a decline in SCFA-producing bacteria, which was targetable by high fiber treatment, leading to an increase in SCFA levels and amelioration of polyposis. The prebiotic activity of fiber, promoting beneficial bacteria, could be the key mechanism for the protective effects of fiber on colon carcinogenesis. SCFA-promoting fermentable fibers are a promising dietary intervention to prevent CRC. PMID:29462896

Low-level APC mutational mosaicism is the underlying cause in a substantial fraction of unexplained colorectal adenomatous polyposis cases.

PubMed

Spier, Isabel; Drichel, Dmitriy; Kerick, Martin; Kirfel, Jutta; Horpaopan, Sukanya; Laner, Andreas; Holzapfel, Stefanie; Peters, Sophia; Adam, Ronja; Zhao, Bixiao; Becker, Tim; Lifton, Richard P; Perner, Sven; Hoffmann, Per; Kristiansen, Glen; Timmermann, Bernd; Nöthen, Markus M; Holinski-Feder, Elke; Schweiger, Michal R; Aretz, Stefan

2016-03-01

In 30-50% of patients with colorectal adenomatous polyposis, no germline mutation in the known genes APC, causing familial adenomatous polyposis, MUTYH, causing MUTYH-associated polyposis, or POLE or POLD1, causing polymerase-proofreading-associated polyposis can be identified, although a hereditary aetiology is likely. This study aimed to explore the impact of APC mutational mosaicism in unexplained polyposis. To comprehensively screen for somatic low-level APC mosaicism, high-coverage next-generation sequencing of the APC gene was performed using DNA from leucocytes and a total of 53 colorectal tumours from 20 unrelated patients with unexplained sporadic adenomatous polyposis. APC mosaicism was assumed if the same loss-of-function APC mutation was present in ≥ 2 anatomically separated colorectal adenomas/carcinomas per patient. All mutations were validated using diverse methods. In 25% (5/20) of patients, somatic mosaicism of a pathogenic APC mutation was identified as underlying cause of the disease. In 2/5 cases, the mosaic level in leucocyte DNA was slightly below the sensitivity threshold of Sanger sequencing; while in 3/5 cases, the allelic fraction was either very low (0.1-1%) or no mutations were detectable. The majority of mosaic mutations were located outside the somatic mutation cluster region of the gene. The present data indicate a high prevalence of pathogenic mosaic APC mutations below the detection thresholds of routine diagnostics in adenomatous polyposis, even if high-coverage sequencing of leucocyte DNA alone is taken into account. This has important implications for both routine work-up and strategies to identify new causative genes in this patient group. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Nasal polyposis in cystic fibrosis: follow-up of children and adolescents for a 3-year period.

PubMed

Weber, Silke Anna Theresa; Iyomasa, Renata Mizusaki; Corrêa, Camila de Castro; Florentino, Wellington Novais Mafra; Ferrari, Giesela Fleischer

Nasal polyposis is often found in patients with cystic fibrosis. To assess the incidence of nasal polyposis, the response to medical treatment, recurrence and the need for surgical intervention in children and adolescents with cystic fibrosis during a three-year follow-up. Clinical symptoms (pulmonary, pancreatic insufficiency, malnutrition, nasal obstruction), two positive sweat chloride tests, and genotype findings in 23 patients with cystic fibrosis were analyzed. All patients underwent nasal endoscopy every 12 months from January 2005 to December 2007, to assess the presence and grade of Nasal Polyps. Nasal polyposis, when present, were treated with topical corticosteroids for 6-12 months, with progress being evaluated within the 3 years of follow-up. In the first evaluation, nasal polyposis was diagnosed in 30.43% of patients (3 bilateral and 4 unilateral), recurrent pneumonia in 82.6%, pancreatic insufficiency in 87%, and malnutrition in 74%. The presence of nasal polyposis was not associated with chloride values in the sweat, genotype, clinical signs of severity of cystic fibrosis, or nasal symptoms. In the three-year period of follow up, 13 patients (56.52%) had at least one event of polyposis, with the youngest being diagnosed at 32 months of age. Only one patient underwent surgery (polypectomy), and there was one diagnosis of nasopharyngeal carcinoma. The study showed a high incidence of nasal polyposis. Monitoring through routine endoscopy in patients with cystic fibrosis, even in the absence of nasal symptoms, is highly recommended. The therapy with topical corticosteroids achieved good results. Thus, an interaction between pediatricians and otolaryngologists is necessary. Copyright © 2016 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.

Genomic Aberrations Occurring in Subsets of Serrated Colorectal Lesions but not Conventional Adenomas

PubMed Central

Burnett-Hartman, Andrea N.; Newcomb, Polly A.; Potter, John D.; Passarelli, Michael N.; Phipps, Amanda I.; Wurscher, Michelle A.; Grady, William M.; Zhu, Lee-Ching; Upton, Melissa P.; Makar, Karen W.

2013-01-01

A subset of aggressive colorectal cancers exhibit BRAF mutation, MLH1 methylation, and a CpG island methylator phenotype (CIMP), but precursors are poorly established. In this study, we determined the status of these markers in colorectal polyps and evaluated associated risk factors. The study included 771 polyp cases and 1,027 controls who were ages 24-80, part of a group health program, received a colonoscopy from 1998-2007, and completed a structured questionnaire assessing risk factors. Following standard pathology review, polyps were assayed for BRAF mutation (V600E) and tested for MLH1 and CIMP methylation, the latter including the genes: CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1. Polytomous logistic regression was used to estimate odds ratios and 95% confidence intervals for the association between molecularly-defined subsets of polyps and potential risk factors. There were 580 conventional adenomas and 419 serrated lesions successfully assayed. For adenomas, the prevalence of each marker was ≤1%. In contrast, 55% of serrated lesions harbored mutant BRAF, 26% were CIMP-high, and 5% had methylated MLH1. In these lesions, the highest prevalence of markers was in sessile serrated polyps (SSPs) of ≥10 mm that were in the right-side/cecal regions of the colon. Risk factors for CIMP-high serrated lesions included Caucasian race, current smoking status, and a history of polyps, whereas for serrated lesions with mutant BRAF the significant risk factors were male sex, current smoking status, obesity, and a history of polyps. Our results suggest that SSPs and other large, right-sided serrated lesions have a unique molecular profile that is similar to CIMP-high, BRAF-mutated colorectal cancers. PMID:23539450

Enameloid microstructure of the serrated cutting edges in certain fossil carcharhiniform and lamniform sharks.

PubMed

Andreev, Plamen S

2010-07-01

The triple-layered enameloid organization of neoselachian teeth has proven to be a reliable systematic character of the group. This study uses scanning electron microscopy to investigate the orientation of the parallel enameloid bundles in the area of the serrated cutting edges in certain fossil elasmobranchs. The examined teeth come from two Upper Cretaceous Squalicorax species and the Upper Miocene carcharhiniforms Galeocerdo sp., Carcharhinus sp., and Hemipristis serra. The parallel bundles are revealed by surface etching, which removes the superficial shiny-layered enameloid. In the teeth of Squalicorax, the bundles around the cutting edge bend once, before they reach the serrations. The studied carcharhiniform species show a more complicated pattern with a change of parallel bundle course inside the serrations. H. serra teeth do not display the first bending of the bundles, whereas it was present in the other two carcharhiniforms. The course of the crystalline bundles in both Squalicorax species is not affected by the presence of the serrations, regardless of the twofold difference in tooth size between them. In the carcharhiniform species, the bended bundles occur within the primary and secondary serrations and are always associated with them. This feature might have functional significance by strengthening the cutting edge or could simply develop as a consequence of the enameloid mineralization around the individual serrae. (c) 2009 Wiley-Liss, Inc.

Endoscopic Features of Mucous Cap Polyps: A Way to Predict Serrated Polyps.

PubMed

Moy, Brian T; Forouhar, Faripour; Kuo, Chia-Ling; Devers, Thomas J

2018-04-27

The aims of the study were to identify whether a mucous-cap predicts the presence of serrated polyps, and to determine whether additional endoscopic findings predict the presence of a sessile serrated adenomas/polyp (SSA/P). We analyzed 147 mucous-capped polyps with corresponding histology, during 2011-2014. Eight endoscopic features (presence of borders, elevation, rim of debris, location in the colon, size ≥10 mm, varicose vessels, nodularity, and alteration in mucosal folds) of mucous-capped polyps were examined to see if they can predict SSA/Ps. A total of 86% (n=126) of mucous-capped polyps were from the right sided serrated pathway (right-sided hyperplastic [n=83], SSA/Ps [n=43], traditional serrated adenoma [n=1]), 10% (n=15) were left-sided hyperplastic polyps, and 3% (n=5) were from the adenoma-carcinoma sequence. The presence of a mucous cap combined with varicose vessels was the only significant predictor for SSA/Ps. The other seven characteristics were not found to be statistically significant for SSA/Ps, although location in the colon and the presence of nodularity trended towards significance. Our study suggests that mucous-capped polyps have high predictability for being a part of the serrated pathway. Gastroenterologists should be alert for a mucous-capped polyp with varicose veins, as these lesions have a higher risk of SSA/P.

Broadband enhanced transmission of acoustic waves through serrated metal gratings

NASA Astrophysics Data System (ADS)

Qi, Dong-Xiang; Fan, Ren-Hao; Deng, Yu-Qiang; Peng, Ru-Wen; Wang, Mu; Jiangnan University Collaboration

In this talk, we present our studies on broadband properties of acoustic waves through metal gratings. We have demonstrated that serrated metal gratings, which introduce gradient coatings, can give rise to broadband transmission enhancement of acoustic waves. Here, we have experimentally and theoretically studied the acoustic transmission properties of metal gratings with or without serrated boundaries. The average transmission is obviously enhanced for serrated metal gratings within a wide frequency range, while the Fabry-Perot resonance is significantly suppressed. An effective medium hypothesis with varying acoustic impedance is proposed to analyze the mechanism, which was verified through comparison with finite-element simulation. The serrated boundary supplies gradient mass distribution and gradient normal acoustic impedance, which could efficiently reduce the boundary reflection. Further, by increasing the region of the serrated boundary, we present a broadband high-transmission grating for wide range of incident angle. Our results may have potential applications to broadband acoustic imaging, acoustic sensing and new acoustic devices. References: [1] Dong-Xiang Qi, Yu-Qiang Deng, Di-Hu Xu, Ren-Hao Fan, Ru-Wen Peng, Ze-Guo Chen, Ming-Hui Lu, X. R. Huang and Mu Wang, Appl. Phys. Lett. 106, 011906 (2015); [2] Dong-Xiang Qi, Ren-Hao Fan, Ru-Wen Peng, Xian-Rong Huang, Ming-Hui Lu, Xu Ni, Qing Hu, and Mu Wang, Applied Physics Letters 101, 061912 (2012).

Serrated Flow Behavior of Aisi 316l Austenitic Stainless Steel for Nuclear Reactors

NASA Astrophysics Data System (ADS)

Li, Qingshan; Shen, Yinzhong; Han, Pengcheng

2017-10-01

AISI 316L austenitic stainless steel is a candidate material for Generation IV reactors. In order to investigate the influence of temperature on serrated flow behavior, tensile tests were performed at temperatures ranging from 300 to 700 °C at an initial strain rate of 2×10-4 s-1. Another group of tensile tests were carried out at strain rates ranging from 1×10-4 to 1×10-2 s-1 at 600 °C to examine the influence of strain rates on serrated flow behavior. The steel exhibited serrated flow, suggesting the occurrence of dynamic strain ageing at 450-650°C. No plateau of yield stresses of the steel was observed at an initial strain rate of 2×10-4 s-1. The effective activation energy for serrated flow occurrence was calculated to be about 254.72 kJ/mol-1. Cr, Mn, Ni and Mo solute atoms are expected to be responsible for dynamic strain ageing at high temperatures of 450-650 °C in the steel.

Serrated lesions of the appendix: a morphologic and immunohistochemical appraisal.

PubMed

Bellizzi, Andrew M; Rock, Jonathan; Marsh, William L; Frankel, Wendy L

2010-04-01

We performed a histologic and immunohistochemical assessment of 53 noninvasive appendiceal epithelial proliferations, appropriating terminology and using markers shown useful in differentiating serrated colorectal polyps. These were classified as hyperplastic polyp (HP), sessile serrated adenoma (SSA), mixed serrated and adenomatous lesion (MSAL), mucinous cystadenoma (MCA), or conventional adenoma (CAD). Immunohistochemical analysis for cytokeratin (CK) 20, Ki-67, MUC6, and beta-catenin was performed. Diagnoses were as follows: HP, 6; SSA, 12; HP vs SSA, 3; MSAL, 16; MCA, 14; and CAD, 2. All HPs showed expanded (beyond surface) CK20 and expanded or normal (base) Ki-67; 1 was MUC6+. Most SSAs and MSALs were CK20-expanded or expanded with random expression in deep crypts (Ex/I) and Ki-67-expanded, Ex/I (expanded with asymmetry), or normal. All SSAs and 8 of 16 MSALs were MUC6+. CADs were CK20-Ex/I, Ki-67-Ex, and MUC6-; 1 showed nuclear beta-catenin expression. Serrated appendiceal lesions can be categorized using colorectal terminology. MUC6 is associated with SSA morphologic features. Similar immunohistochemical patterns in SSA and MSAL suggest a link between these lesions.

Paediatric intestinal cancer and polyposis due to bi-allelic PMS2 mutations: case series, review and follow-up guidelines.

PubMed

Herkert, Johanna C; Niessen, Renée C; Olderode-Berends, Maria J W; Veenstra-Knol, Hermine E; Vos, Yvonne J; van der Klift, Heleen M; Scheenstra, Rene; Tops, Carli M J; Karrenbeld, Arend; Peters, Frans T M; Hofstra, Robert M W; Kleibeuker, Jan H; Sijmons, Rolf H

2011-05-01

Bi-allelic germline mutations of one of the DNA mismatch repair genes, so far predominantly found in PMS2, cause constitutional MMR-deficiency syndrome. This rare disorder is characterised by paediatric intestinal cancer and other malignancies. We report the clinical, immunohistochemical and genetic characterisation of four families with bi-allelic germline PMS2 mutations. We present an overview of the published gastrointestinal manifestations of CMMR-D syndrome and propose recommendations for gastro-intestinal screening. The first proband developed a cerebral angiosarcoma at age 2 and two colorectal adenomas at age 7. Genetic testing identified a complete PMS2 gene deletion and a frameshift c.736_741delinsTGTGTGTGAAG (p.Pro246CysfsX3) mutation. In the second family, both the proband and her brother had multiple intestinal adenomas, initially wrongly diagnosed as familial adenomatous polyposis. A splice site c.2174+1G>A, and a missense c.137G>T (p.Ser46Ile) mutation in PMS2 were identified. The third patient was diagnosed with multiple colorectal adenomas at age 11; he developed a high-grade dysplastic colorectal adenocarcinoma at age 21. Two intragenic PMS2 deletions were found. The fourth proband developed a cerebral anaplastic ganglioma at age 9 and a high-grade colerectal dysplastic adenoma at age 10 and carries a homozygous c.2174+1G>A mutation. Tumours of all patients showed microsatellite instability and/or loss of PMS2 expression. Our findings show the association between bi-allelic germline PMS2 mutations and severe childhood-onset gastrointestinal manifestations, and support the notion that patients with early-onset gastrointestinal adenomas and cancer should be investigated for CMMR-D syndrome. We recommend yearly follow-up with colonoscopy from age 6 and simultaneous video-capsule small bowel enteroscopy from age 8. Copyright © 2011 Elsevier Ltd. All rights reserved.

Upper GI tract lesions in familial adenomatous polyposis (FAP): enrichment of pyloric gland adenomas and other gastric and duodenal neoplasms.

PubMed

Wood, Laura D; Salaria, Safia N; Cruise, Michael W; Giardiello, Francis M; Montgomery, Elizabeth A

2014-03-01

Patients with familial adenomatous polyposis (FAP), an autosomal dominant cancer predisposition syndrome caused by mutations in the APC gene, develop neoplasms in both the upper and lower gastrointestinal (GI) tract. To clarify the upper GI tract lesions in FAP patients in a tertiary care setting, we reviewed specimens from 321 endoscopies in 66 patients with FAP. Tubular adenomas in the small bowel were the most common neoplasms (present in 89% of patients), although only 1 patient developed invasive carcinoma of the small bowel. Several types of gastric neoplasms were identified--65% of patients had at least 1 fundic gland polyp, and 23% of patients had at least 1 gastric foveolar-type gastric adenoma. Pyloric gland adenomas were also enriched, occurring in 6% of patients--this is a novel finding in FAP patients. Despite the high frequency of gastric neoplasms, only 1 patient developed carcinoma in the stomach. The very low frequency of carcinoma in these patients suggests that current screening procedures prevent the vast majority of upper GI tract carcinomas in patients with FAP, at least in the tertiary care setting.

Dental anomalies in pediatric patients with familial adenomatous polyposis.

PubMed

Septer, Seth; Bohaty, Brenda; Onikul, Robin; Kumar, Vandana; Williams, Karen B; Attard, Thomas M; Friesen, Craig A; Friesen, Lynn Roosa

2018-04-01

Familial adenomatous polyposis patients often present with non-malignant extra-intestinal manifestations which include dental anomalies that may be evident prior to the appearance of the colonic adenomas. The aims of this study were to describe the prevalence and type of dental anomalies and the relationships between gene mutations and dental anomalies in these patients. Twenty-two pediatric familial adenomatous polyposis patients and 46 controls, who were age and gender matched participated. Familial adenomatous polyposis patient's had a dental examination with panoramic radiograph and medical record review for age at diagnosis, the presence of the adenomatous polyposis coli gene mutation, and determination of other extra-intestinal manifestations on the body. The control group was identified from a retrospective chart review and selected if there was a current panoramic radiograph. The only significant difference between familial adenomatous polyposis patients and controls were the presence of jaw osteomas and sclerosis (p = .0001). Patients with a mutation in, or upstream of codon 1309 had a higher frequency of osteomas (77.8%) and jaw-bone sclerosis (44.4%), and 77% of these had at least one dental anomaly. This preliminary study showed an association between a genetic variant at, or upstream of codon 1309, and radiographic dental anomalies.

Advances in the study of Lynch syndrome in China.

PubMed

Lu, Jun-Yu; Sheng, Jian-Qiu

2015-06-14

Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer, is an autosomal dominant genetic condition that has a high risk of colon cancer as well as other cancers due to inherited mutations in mismatch repair (MMR) genes. During the last decades, there have been great advances in research on Chinese Lynch syndrome. This review mainly focuses on the genetic basis, clinicopathologic features, diagnosis, intervention, chemoprevention, and surveillance of Lynch syndrome in China. In addition to frequently altered MMR genes, such as MLH1, MSH2, MSH6, and MLH3, other MMR-associated genes, such as those encoding human exonuclease 1, transforming growth factor β receptor 2, and alanine aminopeptidase, metastasis-associated protein 2, adenomatosis polyposis coli down-regulated 1, and hepatic and glial cell adhesion molecule have also been implicated in Chinese Lynch syndrome. Most Chinese researchers focused on the clinicopathologic features of Lynch syndrome, and it is noticeable that the most frequent extracolonic tumor in northeast China is lung cancer, which is different from other areas in China. The Chinese diagnostic criteria for Lynch syndrome have been established to identify gene mutation or methylation. With regard to chemoprevention, celecoxib may be effective to prevent polyps relapse in Lynch syndrome carriers. Additionally, a colonoscopy-based surveillance strategy for the prevention and early detection of neoplasms in Lynch-syndrome carriers has been proposed.

Pancreatic ductal adenocarcinoma: Risk factors, screening, and early detection

PubMed Central

Becker, Andrew E; Hernandez, Yasmin G; Frucht, Harold; Lucas, Aimee L

2014-01-01

Pancreatic cancer is the fourth most common cause of cancer-related deaths in the United States, with over 38000 deaths in 2013. The opportunity to detect pancreatic cancer while it is still curable is dependent on our ability to identify and screen high-risk populations before their symptoms arise. Risk factors for developing pancreatic cancer include multiple genetic syndromes as well as modifiable risk factors. Genetic conditions include hereditary breast and ovarian cancer syndrome, Lynch Syndrome, familial adenomatous polyposis, Peutz-Jeghers Syndrome, familial atypical multiple mole melanoma syndrome, hereditary pancreatitis, cystic fibrosis, and ataxia-telangiectasia; having a genetic predisposition can raise the risk of developing pancreatic cancer up to 132-fold over the general population. Modifiable risk factors, which include tobacco exposure, alcohol use, chronic pancreatitis, diet, obesity, diabetes mellitus, as well as certain abdominal surgeries and infections, have also been shown to increase the risk of pancreatic cancer development. Several large-volume centers have initiated such screening protocols, and consensus-based guidelines for screening high-risk groups have recently been published. The focus of this review will be both the genetic and modifiable risk factors implicated in pancreatic cancer, as well as a review of screening strategies and their diagnostic yields. PMID:25170203

[Constitutional mismatch repair-deficiency syndrome (CMMR-D) - a case report of a family with biallelic MSH6 mutation].

PubMed

Ilenčíková, D

2012-01-01

This work gives comprehensive information about new recessively inherited syndrome characterized by development of childhood malignancies. Behind this new described syndrome, called Constitutional mismatch repair-deficiency syndrome (CMMR-D), there are biallelic mutations in genes, which cause adult cancer syndrom termed Lynch syndrom (Hereditary non-polyposis cancer syndrom-HNPCC) if they are heterozygous mutations. Biallelic germline mutations of genes MLH1, MSH2, MSH6 and PMS2 in CMMR-D are characterized by increased risk of hematological malignancies, atypical brain tumors and early onset of colorectal cancers. An accompanying manifestation of the disease are skin spots with diffuse margins and irregular pigmentation reminiscent of Café au lait spots of NF1. This paper reports a case of a family with CMMR-D caused by novel homozygous MSH6 mutations leading to gliomatosis cerebri, T-ALL in an 11-year-old female and glioblastoma multiforme in her 10-year-old brother, both with rapid progression of the diseases. A literature review of brain tumors in CMMR-D families shows that they are treatment-resistant and lead to early death. Therefore, this work highlights the importance of early identification of patients with CMMR-D syndrome - in terms of initiation of a screening program for early detection of malignancies as well as early surgical intervention.

Immunohistochemical testing for colon cancer--what do New Zealand surgeons know?

PubMed

Harper, Simon J; McEwen, Alison R; Dennett, Elizabeth R

2010-11-05

8-12% of colorectal cancers are associated with genetic syndromes. The most common of these is Lynch syndrome (also known as Hereditary Non-Polyposis Colorectal Cancer). Clinical criteria (Besthesda criteria) exist that can be used to identify colorectal cancer patients who may benefit from immunohistochemical screening of their tumour for Lynch syndrome. Treating surgeons need to know these criteria in order to request appropriate testing. The aim of this study was to assess the knowledge of New Zealand surgeons about the Bethesda criteria. We conducted a postal survey of all New Zealand General Surgical Fellows of the Royal Australasian College of Surgeons. Of the surgeons returning surveys 88% knew screening using immunohistochemistry was available; 7% would not refer an abnormal result to a genetic service. Results of the practice based questions showed only 45% of respondents knew that a colorectal cancer diagnosed before the age of 50 was one of the Besthesda criteria. The correct response rates for the rest of the survey ranged from 32-96%. Questions about Lynch syndrome associated cancers returned fewest correct answers. In general, surgeons are poorly informed about cancers associated with Lynch syndrome. The study demonstrates limited awareness of the Besthesda criteria amongst New Zealand General Surgeons. Those treating colorectal cancer should be aware of the classic features of Lynch syndrome and test appropriately.

What the physician needs to know about Lynch syndrome: an update.

PubMed

Lynch, Henry T; Lynch, Jane F

2005-04-01

The Lynch syndrome (hereditary nonpolyposis colorectal cancer [HNPCC]), is the most common form of hereditary colorectal cancer (CRC), accounting for 2% to 7% of all CRC cases. The next most common hereditary CRC syndrome is familial adenomatous polyposis (FAP), which accounts for less than 1% of all CRC. Lynch syndrome is of crucial clinical importance due to the fact that it predicts the lifetime risk for CRC and a litany of extra-CRC cancers (of the endometrium, ovary, stomach, small bowel, hepatobiliary tract, upper uroepithelial tract, and brain) through assessment of a well-orchestrated family history. A Lynch syndrome diagnosis is almost certain when a mutation in a mismatch repair gene--most commonly MSH2, MLHI, or, to a lesser degree, MSH6--is identified. Once diagnosed, the potential for significant reduction in cancer-related morbidity and mortality through highly targeted surveillance may be profound. Particularly important is colonoscopy initiated at an early age (ie, 25 years) and repeated annually due to accelerated carcinogenesis. In women, endometrial aspiration biopsy and transvaginal ultrasound are important given the extraordinarily high risk for endometrial and ovarian carcinoma. These cancer control strategies have a major impact on at-risk family members once they have been counseled and educated thoroughly about Lynch syndrome's natural history and their own hereditary cancer risk.

Hereditary Nonpolyposis Colorectal Cancer and Cancer Syndromes: Recent Basic and Clinical Discoveries

PubMed Central

Chen, Erbao; Xu, Xiaojing

2018-01-01

Approximately one-third of individuals diagnosed with colorectal cancer have a family history of cancer, suggesting that CRCs may result from a heritable component. Despite the availability of current gene-identification techniques, only 5% of all CRCs emerge from well-identifiable inherited causes for predisposition, including polyposis and nonpolyposis syndromes. Hereditary nonpolyposis colorectal cancer represents a large proportion of cases, and robustly affected patients are at increased risk for early onset, synchronous, and metachronous colorectal malignancies and extracolonic malignancies. HNPCC encompasses several cancer syndromes, such as Lynch syndrome, Lynch-like syndrome, and familial colorectal cancer type X, which have remarkable clinical presentations and overlapping genetic profiles that make clinical diagnosis a challenging task. Therefore, distinguishing between the HNPCC disorders is crucial for physicians as an approach to tailor different recommendations for patients and their at-risk family members according to the risks for colonic and extracolonic cancer associated with each syndrome. Identification of these potential patients through epidemiological characteristics and new genetic testing can estimate the individual risk, which informs appropriate cancer screening, surveillance, and/or treatment strategies. In the past three years, many appealing and important advances have been made in our understanding of the relationship between HNPCC and CRC-associated syndromes. The knowledge from the genetic profile of cancer syndromes and unique genotype-phenotype profiles in the different syndromes has changed our cognition. Therefore, this review presents and discusses HNPCC and several common nonpolyposis syndromes with respect to molecular phenotype, histopathologic features, and clinical presentation. PMID:29849630

Recurrent Obstructive Giant Inflammatory Polyposis of the Colon

PubMed Central

Budhraja, Vikram

2016-01-01

Inflammatory polyps are relatively common in patients with inflammatory bowel disease. The term giant inflammatory polyposis is used to describe inflammatory polyps greater than 1.5 cm in any dimension. Their clinical presentation can be varied, ranging from asymptomatic, with incidental detection on radiological or endoscopic testing, to symptomatic, with rectal bleeding and colonic obstruction. Although giant inflammatory polyposis is a rare finding, it is of clinical importance, since it is easily mistaken for colon cancer, with patients sometimes undergoing radical surgeries. We describe an unusual case of giant inflammatory polyposis causing recurrent symptomatic obstruction despite multiple segmental colectomies in a patient with indeterminate colitis. This is the first such reported case in English literature to the best of our knowledge. PMID:27807551

Recurrent Obstructive Giant Inflammatory Polyposis of the Colon.

PubMed

Syal, Gaurav; Budhraja, Vikram

2016-08-01

Inflammatory polyps are relatively common in patients with inflammatory bowel disease. The term giant inflammatory polyposis is used to describe inflammatory polyps greater than 1.5 cm in any dimension. Their clinical presentation can be varied, ranging from asymptomatic, with incidental detection on radiological or endoscopic testing, to symptomatic, with rectal bleeding and colonic obstruction. Although giant inflammatory polyposis is a rare finding, it is of clinical importance, since it is easily mistaken for colon cancer, with patients sometimes undergoing radical surgeries. We describe an unusual case of giant inflammatory polyposis causing recurrent symptomatic obstruction despite multiple segmental colectomies in a patient with indeterminate colitis. This is the first such reported case in English literature to the best of our knowledge.

Management strategies in Lynch syndrome and familial adenomatous polyposis: a national healthcare survey in Japan.

PubMed

Yamano, Tomoki; Hamanaka, Michiko; Babaya, Akihito; Kimura, Kei; Kobayashi, Masayoshi; Fukumoto, Miki; Tsukamoto, Kiyoshi; Noda, Masafumi; Matsubara, Nagahide; Tomita, Naohiro; Sugihara, Kenichi

2017-02-01

Lynch syndrome (LS) and familial adenomatous polyposis (FAP) are major sources of hereditary colorectal cancer (CRC) and are associated with other malignancies. There is some heterogeneity in management strategies in Japan. We undertook a survey of management of hereditary CRC in hospitals that are members of the Japan Society of Colorectal Cancer Research. One hundred and ninety departments responded, of which 127 were from designated cancer care hospitals (DCCHs) according to the Japanese government. There were 25 488 operations for CRC in these departments in 2015. The DCCHs performed better with regard to usage of Japan Society of Colorectal Cancer Research guidelines, referring new CRC patients for LS screening, and having in-house genetic counselors and knowledge of treatment for LS. There were 174 patients diagnosed with LS and 602 undergoing follow-up in 2011-2015, which is fewer than the number expected from CRC operations in 2015. These numbers were not affected by whether the institution was a DCCH. Universal screening for LS was carried out in 8% of the departments. In contrast, 541 patients were diagnosed with FAP and 273 received preventive proctocolectomy/colectomy in 2011-2015. The DCCH departments undertook more surgery than non-DCCH departments, although most of the management, including surgical procedures and use of non-steroidal anti-inflammatory drugs, was similar. Management of desmoid tumor in the abdominal cavity differed according to the number of patients treated. In conclusion, there was heterogeneity in management of LS but not FAP. Most patients with LS may be overlooked and universal screening for LS is not common in Japan. © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Pressure flaking to serrate bifacial points for the hunt during the MIS5 at Sibudu Cave (South Africa)

PubMed Central

Lentfer, Carol; Schmid, Viola C.; Porraz, Guillaume; Conard, Nicholas J.

2017-01-01

Projectile technology is considered to appear early in the southern African Middle Stone Age (MSA) and the rich and high resolution MSA sequence of Sibudu Cave in KwaZulu-Natal has provided many new insights about the use and hafting of various projectile forms. We present the results of a functional and technological analysis on a series of unpublished serrated bifacial points recently recovered from the basal deposits of Sibudu Cave. These serrated tools, which only find equivalents in the neighbouring site of Umhlatuzana, precede the Still Bay techno-complex and are older than 77 ka BP. Independent residue and use-wear analyses were performed in a phased procedure involving two separate analysts, which allowed the engagement between two separate lines of functional evidence. Thanks to the excellent preservation at Sibudu Cave, a wide range of animal, plant and mineral residues were observed in direct relation with diagnostic wear patterns. The combination of technological, wear and residue evidence allowed us to confirm that the serration was manufactured with bone compressors and that the serrated points were mounted with a composite adhesive as the tips of projectiles used in hunting activities. The suite of technological and functional data pushes back the evidence for the use of pressure flaking during the MSA and highlights the diversity of the technical innovations adopted by southern African MSA populations. We suggest the serrated points from the stratigraphic units Adam to Darya of Sibudu illustrate one important technological adaptation of the southern African MSA and provide another example of the variability of MSA bifacial technologies. PMID:28445544

Pressure flaking to serrate bifacial points for the hunt during the MIS5 at Sibudu Cave (South Africa).

PubMed

Rots, Veerle; Lentfer, Carol; Schmid, Viola C; Porraz, Guillaume; Conard, Nicholas J

2017-01-01

Projectile technology is considered to appear early in the southern African Middle Stone Age (MSA) and the rich and high resolution MSA sequence of Sibudu Cave in KwaZulu-Natal has provided many new insights about the use and hafting of various projectile forms. We present the results of a functional and technological analysis on a series of unpublished serrated bifacial points recently recovered from the basal deposits of Sibudu Cave. These serrated tools, which only find equivalents in the neighbouring site of Umhlatuzana, precede the Still Bay techno-complex and are older than 77 ka BP. Independent residue and use-wear analyses were performed in a phased procedure involving two separate analysts, which allowed the engagement between two separate lines of functional evidence. Thanks to the excellent preservation at Sibudu Cave, a wide range of animal, plant and mineral residues were observed in direct relation with diagnostic wear patterns. The combination of technological, wear and residue evidence allowed us to confirm that the serration was manufactured with bone compressors and that the serrated points were mounted with a composite adhesive as the tips of projectiles used in hunting activities. The suite of technological and functional data pushes back the evidence for the use of pressure flaking during the MSA and highlights the diversity of the technical innovations adopted by southern African MSA populations. We suggest the serrated points from the stratigraphic units Adam to Darya of Sibudu illustrate one important technological adaptation of the southern African MSA and provide another example of the variability of MSA bifacial technologies.

Owl-inspired leading-edge serrations play a crucial role in aerodynamic force production and sound suppression.

PubMed

Rao, Chen; Ikeda, Teruaki; Nakata, Toshiyuki; Liu, Hao

2017-07-04

Owls are widely known for silent flight, achieving remarkably low noise gliding and flapping flights owing to their unique wing morphologies, which are normally characterized by leading-edge serrations, trailing-edge fringes and velvet-like surfaces. How these morphological features affect aerodynamic force production and sound suppression or noise reduction, however, is still not well known. Here we address an integrated study of owl-inspired single feather wing models with and without leading-edge serrations by combining large-eddy simulations (LES) with particle-image velocimetry (PIV) and force measurements in a low-speed wind tunnel. With velocity and pressure spectra analysis, we demonstrate that leading-edge serrations can passively control the laminar-turbulent transition over the upper wing surface, i.e. the suction surface at all angles of attack (0°  <  AoA  <  20°), and hence play a crucial role in aerodynamic force and sound production. We find that there exists a tradeoff between force production and sound suppression: serrated leading-edges reduce aerodynamic performance at lower AoAs  <  15° compared to clean leading-edges but are capable of achieving both noise reduction and aerodynamic performance at higher AoAs  >  15° where owl wings often reach in flight. Our results indicate that the owl-inspired leading-edge serrations may be a useful device for aero-acoustic control in biomimetic rotor designs for wind turbines, aircrafts, multi-rotor drones as well as other fluid machinery.

An experimental study of airfoil instability tonal noise with trailing edge serrations

NASA Astrophysics Data System (ADS)

Chong, Tze Pei; Joseph, Phillip F.

2013-11-01

This paper presents an experimental study of the effect of trailing edge serrations on airfoil instability noise. Detailed aeroacoustic measurements are presented of the noise radiated by an NACA-0012 airfoil with trailing edge serrations in a low to moderate speed flow under acoustical free field conditions. The existence of a separated boundary layer near the trailing edge of the airfoil at an angle of attack of 4.2 degree has been experimentally identified by a surface mounted hot-film arrays technique. Hot-wire results have shown that the saw-tooth surface can trigger a bypass transition and prevent the boundary layer from becoming separated. Without the separated boundary layer to act as an amplifier for the incoming Tollmien-Schlichting waves, the intensity and spectral characteristic of the radiated tonal noise can be affected depending upon the serration geometry. Particle Imaging Velocimetry (PIV) measurements of the airfoil wakes for a straight and serrated trailing edge are also reported in this paper. These measurements show that localized normal-component velocity fluctuations that are present in a small region of the wake from the laminar airfoil become weakened once serrations are introduced. Owing to the above unique characteristics of the serrated trailing edges, we are able to further investigate the mechanisms of airfoil instability tonal noise with special emphasis on the assessment of the wake and non-wake based aeroacoustic feedback models. It has been shown that the instability tonal noise generated at an angle of attack below approximately one degree could involve several complex mechanisms. On the other hand, the non-wake based aeroacoustic feedback mechanism alone is sufficient to predict all discrete tone frequencies accurately when the airfoil is at a moderate angle of attack. Larger Δf, which is defined as (fn+1-fn). In other words, a larger margin of velocity increase is required in order to "shift" the fn and fn+1 across fs sequentially, which is the condition for a ladder jump to occur. Lower amplification factor A for the T-S waves, which can result in a radiation of lower noise levels for the broadband hump peak at fs. This phenomenon will proportionally reduce the noise level difference for fn and fn+1, thus making an identification of a ladder jump event more difficult. Finally, we believe that the tone noise generated in this experimental study is of genuine tones of an isolated airfoil. This can be supported by the fact that, when considering either a straight trailing edge or a serrated trailing edge, the overall airfoil geometry at the same angle of attack is still retained and the wind tunnel setup and locations of the laboratory equipment, which could potentially become an anchor point for the acoustic feedback loop, are exactly the same. However, the straight S0 and serrated S2" trailing edges have been shown to produce systematically different spectral characteristics, especially in the forms of tonal rungs, which can be predicted accurately by the original and slightly modified acoustic feedback Model A respectively. In summary, the trailing edge serration is a useful device for the suppression of airfoil instability self-noise. For greater control effectiveness, however, the laminar separation bubble must be situated within the serration region of the trailing edge. This connection imposes restrictions on the angle of attack and velocity over which trailing edge serrations are effective. The feedback loop structure about the wake noise source and the suction surface of the airfoil in Model B is ignored in the present case. This assumption should be reasonably valid given that, in our previous study [3], we cannot identify any significant role of the boundary layer flow at the suction surface in contributing the instability tonal noise radiation across a wide range of Reynolds numbers.

Microdeletion of 19p13.3 in a girl with Peutz-Jeghers syndrome, intellectual disability, hypotonia, and distinctive features.

PubMed

Kuroda, Yukiko; Saito, Toshiyuki; Nagai, Jun-Ichi; Ida, Kazumi; Naruto, Takuya; Masuno, Mitsuo; Kurosawa, Kenji

2015-02-01

Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant disease characterized by gastrointestinal polyposis and mucocutaneous pigmentation. Germline point mutations in the serine/threonine kinase 11 (STK11) have been identified in about 70% of patients with PJS. Only a few large genomic deletions have been identified. We report on a girl with PJS and multiple congenital anomalies. She had intellectual disability, umbilical hernia, bilateral inguinal hernias, scoliosis, and distinct facial appearance including prominent mandible, smooth philtrum, and malformed ears. She developed lip pigmentation at the age of 12 years but had no gastrointestinal polyps. Array comparative genomic hybridization revealed an approximately 610 kb deletion at 19p13.3, encompassing STK11. Together with previous reports, the identification of common clinical features suggests that microdeletion at 19p13.3 encompassing STK11 constitutes a distinctive phenotype. © 2014 Wiley Periodicals, Inc.

Identity, community and care in online accounts of hereditary colorectal cancer syndrome.

PubMed

Ross, Emily; Broer, Tineke; Kerr, Anne; Cunningham-Burley, Sarah

2018-01-01

Sociological literature has explored how shifts in the point at which individuals may be designated as diseased impact upon experiences of ill health. Research has shown that experiences of being genetically "at risk" are shaped by and shape familial relations, coping strategies, and new forms of biosociality. Less is known about how living with genetic risk is negotiated in the everyday and over time, and the wider forms of identity, communities and care this involves. This article explores these arrangements drawing on online bloggers' accounts of Familial Adenomatous Polyposis (FAP). We show how accounts of genetic risk co-exist with more palpable experiences of FAP in everyday life, notably the consequences of prophylactic surgeries. We consider how the act of blogging represents but also constitutes everyday experiences of hereditary cancer syndrome as simultaneously ordinary and exceptional, and reflect on the implications of our analysis for understanding experiences of genetic cancer risk.

Direct current induced suppression of the Portevin-Le Chatelier serrated deformation in the aluminum-magnesium alloy 5056

NASA Astrophysics Data System (ADS)

Shibkov, A. A.; Denisov, A. A.; Zheltov, M. A.; Zolotov, A. E.; Gasanov, M. F.; Kochegarov, S. S.

2015-02-01

The effect of direct current induced suppression of the Portevin-Le Chatelier serrated deformation in the aluminum-magnesium alloy 5056 has been revealed experimentally. This effect manifests itself as an increase in the critical plastic strain, which precedes the onset of serrations in the stress-strain curve, with an increase in the current density in the range from 15 to 60 A/mm2. It has been shown that the observed effect is not related to the Joule heating of the entire specimen. Possible mechanisms of the phenomenon have been discussed.

Serrated yielding in Al-Li alloys

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kumar, S.; McShane, H.B.

1993-05-01

Serrated yielding (SY) during tensile testing has been observed in Al-Li alloys, both in the binary and the commercial quaternary alloys, in single crystal as well as polycrystalline materials. Serrated yielding is commonly explained by a dynamic strain aging (DSA) model developed by McCormick and van den Beukel. All the solute elements present in Al-Li alloys, viz., Mg, Cu and Li are known to give DSA and SY. Several researchers believe the DSA to be the cause of SY and they attribute the disappearance of SY simply to the removal of solute from the matrix with aging. However, this argumentmore » has serious flaws. The present paper examines this aspect critically. The authors concluded that Al-Li alloys the disappearance of serrated yielding at a certain stage of aging is not due to removal of the solute from the matrix but due to the change in the nature of the metastable [delta][prime] precipitates - from fine coherent shearable precipitates to larger noncoherent nonshearable precipitates - which prevents the formation of the deformation bands. The serrated yielding reappears with extensive over aging due to the dissolution of these precipitates in favor of the equilibrium precipitates. The equilibrium precipitates, being widely spaced, are ineffective in preventing the formation of deformation bands.« less

Biallelic MLH1 SNP cDNA expression or constitutional promoter methylation can hide genomic rearrangements causing Lynch syndrome.

PubMed

Morak, Monika; Koehler, Udo; Schackert, Hans Konrad; Steinke, Verena; Royer-Pokora, Brigitte; Schulmann, Karsten; Kloor, Matthias; Höchter, Wilhelm; Weingart, Josef; Keiling, Cortina; Massdorf, Trisari; Holinski-Feder, Elke

2011-08-01

A positive family history, germline mutations in DNA mismatch repair genes, tumours with high microsatellite instability, and loss of mismatch repair protein expression are the hallmarks of hereditary non-polyposis colorectal cancer (Lynch syndrome). However, in ~10-15% of cases of suspected Lynch syndrome, no disease-causing mechanism can be detected. Oligo array analysis was performed to search for genomic imbalances in patients with suspected mutation-negative Lynch syndrome with MLH1 deficiency in their colorectal tumours. A deletion in the LRRFIP2 (leucine-rich repeat flightless-interacting protein 2) gene flanking the MLH1 gene was detected, which turned out to be a paracentric inversion on chromosome 3p22.2 creating two new stable fusion transcripts between MLH1 and LRRFIP2. A single-nucleotide polymorphism in MLH1 exon 8 was expressed from both alleles, initially pointing to appropriate MLH1 function at least in peripheral cells. In a second case, an inherited duplication of the MLH1 gene region resulted in constitutional MLH1 promoter methylation. Constitutional MLH1 promoter methylation may therefore in rare cases be a heritable disease mechanism and should not be overlooked in seemingly sporadic patients.

Mutator gene and hereditary non-polyposis colorectal cancer

DOEpatents

de la Chapelle, Albert [Helsingfors, FI; Vogelstein, Bert [Baltimore, MD; Kinzler, Kenneth W [Baltimore, MD

2008-02-05

The human MSH2 gene, responsible for hereditary non-polyposis colorectal cancer, was identified by virtue of its homology to the MutS class of genes, which are involved in DNA mismatch repair. The sequence of cDNA clones of the human gene are provided, and the sequence of the gene can be used to demonstrate the existence of germ line mutations in hereditary non-polyposis colorectal cancer (HNPCC) kindreds, as well as in replication error.sup.+ (RER.sup.+) tumor cells.

MicroRNA signatures of colonic polyps on screening and histology

PubMed Central

Tsikitis, Vassiliki L.; Potter, Amiee; Mori, Motomi; Buckmeier, Julie A.; Preece, Christina R.; Harrington, Christina A.; Bartley, Angela N.; Bhattacharyya, Achyut K.; Hamilton, Stanley R.; Lance, M. Peter; Thompson, Patricia A.

2016-01-01

Colorectal cancer (CRC) and adenoma adjacent to cancer exhibit distinct microRNA (miR) alterations in an apparent mucosa-to-adenocarcinoma sequence. The pattern of microRNAs in screen-detected polyps in relation to histologic features and cancer risk has not been investigated. miR expression analysis was performed on normal mucosa (NM), hyperplastic polyps (HPs), tubular adenomas (TAs), tubulovillous adenomas or high-grade dysplasia (TVHGs), and serrated polyps (sessile serrated adenoma/polyps, SSA/Ps, and traditional serrated adenomas, TSAs) in biopsy specimens from 109 patients undergoing screening/surveillance colonoscopy. Generalized linear models were used to identify differentially expressed miRs by histologic type and logistic regression to identify miR predictors of histopathology. False discovery rate (FDR) was used to control for multiple comparisons. We identified 99 miRs differing in at least one of five histopathologic groups (FDR ≤ 0.05). In a comparison of HPNM vs. TVHG, the top most up- and down-regulated miRs in HPNM included miR-145, -143, -107, -194, and -26a (upregulated), and miR-663, -1268, -320b, -1275, and -320b (down-regulated) (FDR P-value < 0.05). miR-145 and -619 showed high accuracy to discriminate low- from high-risk polyps without serrated histology (TVHG vs. HPNM+TA) (CI= 95.6%), whereas miRs-124, -143, and -30a showed high accuracy of separating high-risk polyps (TVHG+TSA) from low-risk polyps (HPNM+TA+SSA/P) (CI=96.0%). For TSAs, miRs-125b and -199a were uniquely downregulated relative to HPNMs, and miR-335, -222 and -214 discriminated between non-serrated and serrated histology. Our data support the presence of CRC-associated miR alterations in screen-detected adenomas that may be useful for risk stratification for surveillance interval planning. PMID:27658891

Comparison of Performance Characteristics of Oval Cup Forceps Versus Serrated Jaw Forceps in Gastric Biopsy.

PubMed

Sussman, Daniel A; Deshpande, Amar R; Shankar, Uday; Barkin, Jodie A; Medina, Ana Maria; Poppiti, Robert J; Cubeddu, Luigi X; Barkin, Jamie S

2016-08-01

Obtaining quality endoscopic biopsy specimens is vital in making successful histological diagnoses. The influence of forceps cup shape and size on quality of biopsy specimens is unclear. To identify whether oval cup or two different serrated jaw biopsy forceps could obtain specimens of superior size. Secondary endpoints were tissue adequacy, depth of tissue acquisition, and crush artifact. A single-center, prospective, pathologist-masked, randomized controlled trial was performed. In total 136 patients with a clinical indication for esophagogastroduodenoscopy with biopsy were randomized to receive serial biopsies with a large-capacity serrated forceps with jaw diameter 2.2 mm (SER1) and either a large-capacity oval forceps with jaw diameter 2.4 mm (OVL) or large-capacity serrated biopsy forceps with jaw diameter 2.4 mm (SER2) in two parallel groups. SER2 provided significantly larger specimens than did the other forceps (SER2 3.26 ± 1.09 vs. SER1 2.92 ± 0.88 vs. OVL 2.92 ± 0.76; p = 0.026), with an average size difference of 0.34 mm greater with SER2 compared to SER1 and OVL. OVL provided significantly deeper biopsies compared to SER1 and SER2 (p = 0.02), with 31 % of OVL biopsies reaching the submucosa. SER2 had significantly less crush artifact than SER1 and OVL (p < 0.0001). Serrated forceps provided larger samples compared to oval jaw forceps of the same size, with SER2 providing the largest specimen size. Oval cup forceps had deeper penetration of epithelium, while the larger jaw diameter serrated jaw forceps had less crush artifact. All three forceps provided specimens adequate for diagnostic purposes.

Influence of post pattern and resin cement curing mode on the retention of glass fibre posts.

PubMed

Poskus, L T; Sgura, R; Paragó, F E M; Silva, E M; Guimarães, J G A

2010-04-01

To evaluate the influence of post design and roughness and cement system (dual- or self-cured) on the retention of glass fibre posts. Two tapered and smooth posts (Exacto Cônico No. 2 and White Post No. 1) and two parallel-sided and serrated posts (Fibrekor 1.25 mm and Reforpost No. 2) were adhesively luted with two different resin cements--a dual-cured (Rely-X ARC) and a self-cured (Cement Post)--in 40 single-rooted teeth. The teeth were divided into eight experimental groups (n = 5): PFD--Parallel-serrated-Fibrekor/dual-cured; PRD--Parallel-serrated-Reforpost/dual-cured; TED--Tapered-smooth-Exacto Cônico/dual-cured; TWD--Tapered-smooth-White Post/dual-cured; PFS--Parallel-serrated-Fibrekor/self-cured; PRS--Parallel-serrated-Reforpost/self-cured; TES--Tapered-smooth-Exacto Cônico/self-cured; TWS--Tapered-smooth-White Post/self-cured. The specimens were submitted to a pull-out test at a crosshead speed of 0.5 mm min(-1). Data were analysed using analysis of variance and Bonferroni's multiple comparison test (alpha = 0.05). Pull-out results (MPa) were: PFD = 8.13 (+/-1.71); PRD = 8.30 (+/-0.46); TED = 8.68 (+/-1.71); TWD = 9.35 (+/-1.99); PFS = 8.54 (+/-2.23); PRS = 7.09 (+/-1.96); TES = 8.27 (+/-3.92); TWS = 7.57 (+/-2.35). No statistical significant difference was detected for posts and cement factors and their interaction. The retention of glass fibre posts was not affected by post design or surface roughness nor by resin cement-curing mode. These results imply that the choice for serrated posts and self-cured cements is not related to an improvement in retention.

Signal transduction and oxidative processes in sinonasal polyposis.

PubMed

Cannady, Steven B; Batra, Pete S; Leahy, Rachel; Citardi, Martin J; Janocha, Allison; Ricci, Kristin; Comhair, Suzy A A; Bodine, Melanie; Wang, Zeneng; Hazen, Stanley L; Erzurum, Serpil C

2007-12-01

Nasal polyposis is characterized by impaired regulation of nasal tissue growth and is associated with chronic inflammation, sinus infections, and low levels of nitric oxide (NO). Based on its critical role in mediating cell growth and antimicrobial function, decrease of NO levels has been implicated in the pathogenesis of nasal polyposis. We sought to evaluate mechanisms for the low NO level in polyposis, including factors regulating NO synthase (NOS) expression and activity and NO consumptive processes in nasal epithelial cells and nasal lavage fluid. Eighteen patients with nasal polyposis and 8 healthy control subjects were studied. Nasal brushings, nasal lavage fluid, and nasal biopsy specimens were collected and analyzed. NO metabolite levels (nitrite and nitrate) in nasal lavage fluid from patients with polyps were less than those in control subjects, but activation of signal transduction and inducer of transcription 1, which regulates inducible NOS gene expression and protein expression, was present at higher levels in polyp than in healthy control tissue. Levels of arginine, methylarginine, and endogenous NOS inhibitors were similar between polyp and control tissue. In contrast, superoxide dismutase activity of polyp tissues was lower than that seen in control tissue and associated with increased nitrotyrosine, a biomarker of oxidant consumptive products of NO. Taken together, these data suggest that the nasal polyp environment is characterized by abnormalities in NO metabolism that might predispose to altered regulation of tissue growth and infection. Identification of NO metabolic abnormalities might lead to novel treatments for sinonasal polyposis targeted against the pathways identified within this study.

Providing data for serrated polyp detection rate benchmarks: an analysis of the New Hampshire Colonoscopy Registry.

PubMed

Anderson, Joseph C; Butterly, Lynn F; Weiss, Julia E; Robinson, Christina M

2017-06-01

Similar to achieving adenoma detection rate (ADR) benchmarks to prevent colorectal cancer (CRC), achieving adequate serrated polyp detection rates (SDRs) may be essential to the prevention of CRC associated with the serrated pathway. Previous studies have been based on data from high-volume endoscopists at single academic centers. Based on a hypothesis that ADR is correlated with SDR, we stratified a large, diverse group of endoscopists (n = 77 practicing at 28 centers) into high performers and low performers, based on ADR, to provide data for corresponding target SDR benchmarks. By using colonoscopies in adults aged ≥50 years (4/09-12/14), we stratified endoscopists by high and low ADRs (<15%, 15%-<25%, 25%-<35%, ≥35%) to determine corresponding SDRs by using 2 SDR measures, for screening and surveillance colonoscopies separately: (1) Clinically significant SDR (CSSDR), meaning colonoscopies with any sessile serrated adenoma/polyp (SSA/P), traditional serrated adenoma (TSA), or hyperplastic polyp (HP) >1 cm anywhere in the colon or HP >5 mm in the proximal colon only divided by the total number of screening and surveillance colonoscopies, respectively. (2) Proximal SDR (PSDR) meaning colonoscopies with any serrated polyp (SSA/P, HP, TSA) of any size proximal to the sigmoid colon divided by the total number of screening and surveillance colonoscopies, respectively. A total of 45,996 (29,960 screening) colonoscopies by 77 endoscopists (28 facilities) were included. Moderately strong positive correlation coefficients were observed for screening ADR/CSSDR (P = .69) and ADR/PSDR (P = .79) and a strong positive correlation (P = .82) for CSSDR/PSDR (P < .0001 for all) was observed. For ADR ≥25%, endoscopists' median (interquartile range) screening CSSDR was 6.8% (4.3%-8.6%) and PSDR was 10.8% (8.6%-16.1%). Derived from ADR, the primary colonoscopy quality indicator, our results suggest potential SDR benchmarks (CSSDR = 7% and PSDR = 11%) that may guide adequate serrated polyp detection. Because CSSDR and PSDR are strongly correlated, endoscopists could use the simpler PSDR calculation to assess quality. Published by Elsevier Inc.

Effect of geometrical stress concentrators on the current-induced suppression of the serrated deformation in an aluminum-magnesium AlMg5 alloy

NASA Astrophysics Data System (ADS)

Shibkov, A. A.; Zolotov, A. E.; Zheltov, M. A.; Denisov, A. A.; Gasanov, M. F.; Kochegarov, S. S.

2016-05-01

The effect of an electric current on the band formation and the serrated deformation of planar specimens made of an aluminum-magnesium AlMg5 alloy and weakened by holes is experimentally studied. It is found that the concentration of elastic stress fields and the self-localized unstable plastic deformation field near a hole decreases the critical strain of appearance of the first stress drop and hinders the currentinduced suppression of band formation and the serrated Portevin-Le Chatelier deformation. These results are shown not to be related to the concentration of Joule heat near a hole.

Ibuprofen Inhibits Colitis-Induced Overexpression of Tumor-Related Rac1b1

PubMed Central

Matos, Paulo; Kotelevets, Larissa; Goncalves, Vania; Henriques, Andreia; Zerbib, Philippe; Moyer, Mary Pat; Chastre, Eric; Jordan, Peter

2013-01-01

The serrated pathway to colorectal tumor formation involves oncogenic mutations in the BRAF gene, which are sufficient for initiation of hyperplastic growth but not for tumor progression. A previous analysis of colorectal tumors revealed that overexpression of splice variant Rac1b occurs in around 80% of tumors with mutant BRAF and both events proved to cooperate in tumor cell survival. Here, we provide evidence for increased expression of Rac1b in patients with inflamed human colonic mucosa as well as following experimentally induced colitis in mice. The increase of Rac1b in the mouse model was specifically prevented by the nonsteroidal anti-inflammatory drug ibuprofen, which also inhibited Rac1b expression in cultured HT29 colorectal tumor cells through a cyclooxygenase inhibition.independent mechanism. Accordingly, the presence of ibuprofen led to a reduction of HT29 cell survival in vitro and inhibited Rac1b-dependent tumor growth of HT29 xenografts. Together, our results suggest that stromal cues, namely, inflammation, can trigger changes in Rac1b expression in the colon and identify ibuprofen as a highly specific and efficient inhibitor of Rac1b overexpression in colorectal tumors. Our data suggest that the use of ibuprofen may be beneficial in the treatment of patients with serrated colorectal tumors or with inflammatory colon syndromes. PMID:23359345

Genetics Home Reference: familial adenomatous polyposis

MedlinePlus

... Järvinen HJ, Peltomäki P. The complex genotype-phenotype relationship in familial adenomatous polyposis. Eur J Gastroenterol Hepatol. ... for Links Data Files & API Site Map Subscribe Customer Support USA.gov Copyright Privacy Accessibility FOIA Viewers & ...

Serum Cytokine Profile in Patients with Chronic Rhinosinusitis with Nasal Polyposis Infected by Aspergillus flavus.

PubMed

Rai, Gargi; Ansari, Mohammad Ahmad; Dar, Sajad Ahmad; Datt, Shyama; Gupta, Neelima; Sharma, Sonal; Haque, Shafiul; Ramachandran, Vishnampettai Ganapathysubramanian; Mazumdar, Arpeeta; Rudramurthy, Shivprakash; Chakrabarti, Arunaloke; Das, Shukla

2018-03-01

Fungi, especially Aspergillus flavus, can cause chronic rhinosinusitis with nasal polyposis and modulate host innate immune components. The objective of this study was to examine the serum levels of T helper (Th) cell subset Th1, Th2, and Th17 cytokines and total IgE in patients having chronic rhinosinusitis with nasal polyposis and Aspergillus flavus infection. A case-control study including 40 patients with chronic rhinosinusitis with nasal polyposis and 20 healthy controls was conducted. Aspergillus flavus infection was confirmed by standard potassium hydroxide (KOH) testing, culture, and PCR. Serum samples of all patients and controls were analyzed for various cytokines (interleukins [IL]-1β, IL-2, IL-4, IL-6, IL-17, IL-21, IL-27, TGF-β) and total IgE by ELISA. Data from patients with Aspergillus flavus infection and healthy volunteers were compared using the independent t-test and non-parametric Mann-Whitney U test. Aspergillus flavus infection was found in 31 (77.5%) patients with chronic rhinosinusitis with nasal polyposis. IL-1β, IL-17, IL-21, and TGF-β serum levels were significantly higher in these patients than in controls; however, IL-2, IL-4, IL-6, and IL-27 levels were lower. Compared with nine (22.5%) patients without Aspergillus flavus infection, IL-17 level was higher while IL-2 level was lower in patients with Aspergillus flavus infection. Total IgE was significantly higher in patients with Aspergillus flavus infection than in controls. High levels of IL-17 and its regulatory cytokines in patients with chronic rhinosinusitis with nasal polyposis infected by Aspergillus flavus raise a concern about effective disease management and therapeutic recovery. Surgical removal of the nasal polyp being the chief management option, the choice of post-operative drugs may differ in eosinophilic vs. non-eosinophilic nasal polyposis. The prognosis is likely poor, warranting extended care. © The Korean Society for Laboratory Medicine

[Treatment of ASS-Associated Polyposis (ASSAP) with a cysteinyl leukotriene receptor antagonist - a prospective drug study on its antiinflammatory effects].

PubMed

Grundmann, T; Töpfner, M

2001-10-01

In a high rate of cases with recurrent polyposis an association with ASS-intolerance is detectable despite missing pulmonary symptoms. New examinations of a disturbed arachidonic acid metabolism lead to the development of new therapeutical options. Treatment with leukotriene-receptor antogonists (LTA) showed primarily good results in therapy of ASS-associated asthma. 18 patients with ASS-intolerance trias - diagnosed by oral provocation - were treated with the LTA Montelukast, after undergoing sinus surgery. Patients underwent a diagnostic pathway of provocation including four groups: recurrent chronic sinusitis, excessive polyposis, polyposis associated with asthma and anaphylactic symptoms after oral ASS-intake. Clinically we examined the following parameters periodically after sinus surgery: nasal and pulmonal symptoms by scoring levels, recurrency of polypoid hyperplasia by endoscopic follow-ups and serum ECP-levels. To evaluate antiinflammatory tissue effects of LTA EG1/EG2 labelled cells and cytokine levels of Interleukin 5 in mucosa samples of the lower turbinate were analysed under LTA-therapy. Under therapy with LTA we saw a beneficial effect on nasal and pulmonary symptoms and a significant reduction of recurrent polyposis in endoscopic examinations in relation to the untreated group. Results were proven by a permanent reduction of serum ECP-level. A reduction of the rate of EG2-positive cells according to decreased Interleukin 5 levels in the nasal mucosa unter LTA-treatment assumed antiinflammatory effects on ASS-associated polyposis. We could demonstrate antiinflammatory effects of Leukotriene-Receptor-Antagonists primarily during postoperative treatment of patients with ASS-associated nasal polyps.

On the aeroacoustic and flow structures developed on a flat plate with a serrated sawtooth trailing edge

NASA Astrophysics Data System (ADS)

Chong, Tze Pei; Vathylakis, Alexandros

2015-10-01

Results of an experimental study on turbulent flow over a flat plate with a serrated sawtooth trailing edge are presented in this paper. After tripping the boundary layer to become turbulent, the broadband noise sources at the sawtooth serrated trailing edge is studied by several experimental techniques. Broadband noise reduction by the serrated sawtooth trailing edge can be realistically achieved in the flat plate configuration. The variations of wall pressure power spectral density and the spanwise coherence (which relates to the spanwise correlation length) in a sawtooth trailing edge play a minor role in the mechanisms underpinning the reduction of self noise radiation. Conditional-averaging technique was applied in the boundary layer data where a pair of pressure-driven oblique vortical structures near the sawtooth side edges is identified. In the current flat plate configuration, the interaction between the vortical structures and the local turbulent boundary layer results in a redistribution of the momentum transport and turbulent shear stress near the sawtooth side edges as well as the sawtooth tip, thus affecting the efficiency of self noise radiation.

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. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

[Hepatoblastoma, Etiology, Case Reports].

PubMed

Puchmajerová, A; Křepelová, A; Indráková, J; Sítková, R; Balaščak, I; Kruseová, J; Švojgr, K; Kodet, R; Kynčl, M; Vícha, A; Macek, M

2016-01-01

Hepatoblastoma is an uncommon malignant neoplasm in general, yet, it is the most common liver malignancy in children with the incidence about one per milion children. This type of liver tumor usually occurs before the age of three years. The etiology of hepatoblastoma remains unknown. However, there are some genetic conditions known to be associated with an increased risk of developing hepatoblastoma such as Beckwith-Wiedemann syndrome, hemihypertrophy, APC-associated polyposis, α-1-antitrypsin defficiency and some metabolic disorders including tyrosinemia, galactosemia and glycogen storage disease type 1. There is a higher risk of hepatoblastoma in children with very low birthweight, children who acquire hepatitis B at an early age and children with congenital biliary atresia.

A standardized imaging protocol for the endoscopic prediction of dysplasia within sessile serrated polyps (with video).

PubMed

Tate, David J; Jayanna, Mahesh; Awadie, Halim; Desomer, Lobke; Lee, Ralph; Heitman, Steven J; Sidhu, Mayenaaz; Goodrick, Kathleen; Burgess, Nicholas G; Mahajan, Hema; McLeod, Duncan; Bourke, Michael J

2018-01-01

Dysplasia within sessile serrated polyps (SSPs) is difficult to detect and may be mistaken for an adenoma, risking incomplete resection of the background serrated tissue, and is strongly implicated in interval cancer after colonoscopy. The use of endoscopic imaging to detect dysplasia within SSPs has not been systematically studied. Consecutively detected SSPs ≥8 mm in size were evaluated by using a standardized imaging protocol at a tertiary-care endoscopy center over 3 years. Lesions suspected as SSPs were analyzed with high-definition white light then narrow-band imaging. A demarcated area with a neoplastic pit pattern (Kudo type III/IV, NICE type II) was sought among the serrated tissue. If this was detected, the lesion was labeled dysplastic (sessile serrated polyp with dysplasia); if not, it was labeled non-dysplastic (sessile serrated polyp without dysplasia). Histopathology was reviewed by 2 blinded specialist GI pathologists. A total of 141 SSPs were assessed in 83 patients. Median lesion size was 15.0 mm (interquartile range 10-20), and 54.6% were in the right side of the colon. Endoscopic evidence of dysplasia was detected in 36 of 141 (25.5%) SSPs; of these, 5 of 36 (13.9%) lacked dysplasia at histopathology. Two of 105 (1.9%) endoscopically designated non-dysplastic SSPs had dysplasia at histopathology. Endoscopic imaging, therefore, had an accuracy of 95.0% (95% confidence interval [CI], 90.1%-97.6%) and a negative predictive value of 98.1% (95% CI, 92.6%-99.7%) for detection of dysplasia within SSPs. Dysplasia within SSPs can be detected accurately by using a simple, broadly applicable endoscopic imaging protocol that allows complete resection. Independent validation of this protocol and its dissemination to the wider endoscopic community may have a significant impact on rates of interval cancer. (Clinical trial registration number: NCT03100552.). Copyright © 2018 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.

Serrated and adenomatous polyp detection increases with longer withdrawal time: results from the New Hampshire Colonoscopy Registry.

PubMed

Butterly, Lynn; Robinson, Christina M; Anderson, Joseph C; Weiss, Julia E; Goodrich, Martha; Onega, Tracy L; Amos, Christopher I; Beach, Michael L

2014-03-01

Detection and removal of adenomas and clinically significant serrated polyps (CSSPs) is critical to the effectiveness of colonoscopy in preventing colorectal cancer. Although longer withdrawal time has been found to increase polyp detection, this association and the use of withdrawal time as a quality indicator remains controversial. Few studies have reported on withdrawal time and serrated polyp detection. Using data from the New Hampshire Colonoscopy Registry, we examined how an endoscopist's withdrawal time in normal colonoscopies affects adenoma and serrated polyp detection. We analyzed 7,996 colonoscopies performed in 7,972 patients between 2009 and 2011 by 42 endoscopists at 14 hospitals, ambulatory surgery centers, and community practices. CSSPs were defined as sessile serrated polyps and hyperplastic polyps proximal to the sigmoid. Adenoma and CSSP detection rates were calculated based on median endoscopist withdrawal time in normal exams. Regression models were used to estimate the association of increased normal withdrawal time and polyp, adenoma, and CSSP detection. Polyp and adenoma detection rates were highest among endoscopists with 9 min median normal withdrawal time, and detection of CSSPs reached its highest levels at 8-9 min. Incident rate ratios for adenoma and CSSP detection increased with each minute of normal withdrawal time above 6 min, with maximum benefit at 9 min for adenomas (1.50, 95% confidence interval (CI) (1.21, 1.85)) and CSSPs (1.77, 95% CI (1.15, 2.72)). When modeling was used to set the minimum withdrawal time at 9 min, we predicted that adenomas and CSSPs would be detected in 302 (3.8%) and 191 (2.4%) more patients. The increase in detection was most striking for the CSSPs, with nearly a 30% relative increase. A withdrawal time of 9 min resulted in a statistically significant increase in adenoma and serrated polyp detection. Colonoscopy quality may improve with a median normal withdrawal time benchmark of 9 min.

Characteristics and time-dependence of cut marks and blunt force fractures on costal cartilages: an experimental study.

PubMed

Spagnoli, Laura; Amadasi, Alberto; Frustaci, Michela; Mazzarelli, Debora; Porta, Davide; Cattaneo, Cristina

2016-03-01

The distinction between cut marks and blunt force injuries on costal cartilages is a crucial issue in the forensic field. Moreover, a correct distinction may further be complicated by decomposition, so the need arises to investigate the distinctive features of lesions on cartilage and their changes over time. This study aimed to assess the stereomicroscopic features of cut marks (performed with six different knives) and blunt fractures (performed with a hammer and by means of manual bending) on 48 fragments of human costal cartilages. Moreover, in order to simulate decomposition, the cut and fractured surfaces were checked with stereomicroscopy and through casts after 1 and 2 days, 1 week, and 1, 2 and 4 months of drying in ambient air. In fresh samples, for single and unique cuts, striations were observed in between 44 and 88% of cases when non-serrated blades were used, and between 77 and 88% for serrated blades; in the case of "repeated" (back and forth movement) cuts, striations were detected in between 56 and 89% of cases for non-serrated blades, and between 66 and 100% for serrated blades. After only 1 week of decomposition the detection rates fell to percentages of between 28 and 39% for serrated blades and between 17 and 33% for non-serrated blades. Blunt force injuries showed non-specific characteristics, which, if properly assessed, may lead to a reliable distinction between different cut marks in fresh samples. The most evident alterations of the structure of the cartilage occurred in the first week of decomposition in ambient air. After one week of drying, the characteristics of cut marks were almost undetectable, thereby making it extremely challenging to distinguish between cut marks, blunt force fractures and taphonomic effects. The study represents a contribution to the correct assessment and distinction of cut marks and blunt force injuries on cartilages, providing a glimpse on the modifications such lesions may undergo with decomposition.

A De Novo Germline APC Mutation (3927del5) in a Patient with Familial Adenomatous Polyposis: Case Report and Literature Review

PubMed Central

Zeichner, Simon B.; Raj, Naveen; Cusnir, Mike; Francavilla, Michael; Hirzel, Alicia

2012-01-01

Introduction Characterized by the development of hundreds to thousands of colonic adenomas, classic familial adenomatous polyposis (FAP) is one of the most common hereditary syndromes associated with an increased risk of colorectal cancer. Several studies have attempted to correlate specific APC mutations with clinical phenotype.6 However, there is considerable variability in the expression of specific phenotypes within families and among individuals with identical mutations.7 Case presentation A 30 year-old Hispanic female presented to the emergency department with a 2-week history of persistent, worsening, left lower quadrant abdominal pain. She had no family history of malignancy. Sigmoidoscopy revealed innumerable polyps in the rectum and sigmoid colon and a large mass in the sigmoid colon. Biopsy of the mass revealed a moderately differentiated adenocarcinoma invading the subserosa. Endoscopy revealed innumerable polyps. Genetic testing of the patient via southern blot revealed a germline APC mutation 3927del5, resulting in a premature truncation of the APC protein at amino acid position 1312. Conclusion Genetic information has only recently started being incorporated into clinical care. More research and randomized clinical trials need to be conducted to definitively characterize random mutations. Once these mutations are further understood, FAP patients may be able to be risk stratified and this may ultimately improve the screening, diagnosis, and treatment of this rare condition. PMID:23115482

Novel mutations and phenotypic associations identified through APC, MUTYH, NTHL1, POLD1, POLE gene analysis in Indian Familial Adenomatous Polyposis cohort.

PubMed

Khan, Nikhat; Lipsa, Anuja; Arunachal, Gautham; Ramadwar, Mukta; Sarin, Rajiv

2017-05-22

Colo-Rectal Cancer is a common cancer worldwide with 5-10% cases being hereditary. Familial Adenomatous Polyposis (FAP) syndrome is due to germline mutations in the APC or rarely MUTYH gene. NTHL1, POLD1, POLE have been recently reported in previously unexplained FAP cases. Unlike the Caucasian population, FAP phenotype and its genotypic associations have not been widely studied in several geoethnic groups. We report the first FAP cohort from South Asia and the only non-Caucasian cohort with comprehensive analysis of APC, MUTYH, NTHL1, POLD1, POLE genes. In this cohort of 112 individuals from 53 FAP families, we detected germline APC mutations in 60 individuals (45 families) and biallelic MUTYH mutations in 4 individuals (2 families). No NTHL1, POLD1, POLE mutations were identified. Fifteen novel APC mutations and a new Indian APC mutational hotspot at codon 935 were identified. Eight very rare FAP phenotype or phenotypes rarely associated with mutations outside specific APC regions were observed. APC genotype-phenotype association studies in different geo-ethnic groups can enrich the existing knowledge about phenotypic consequences of distinct APC mutations and guide counseling and risk management in different populations. A stepwise cost-effective mutation screening approach is proposed for genetic testing of south Asian FAP patients.

Coherent structures shed by multiscale cut-in trailing edge serrations on lifting wings

NASA Astrophysics Data System (ADS)

Prigent, S. L.; Buxton, O. R. H.; Bruce, P. J. K.

2017-07-01

This experimental study presents the effect of multiscale cut-in trailing edge serrations on the coherent structures shed into the wake of a lifting wing. Two-probe span-wise hot-wire traverses are performed to study spectra, coherence, and phase shift. In addition, planar particle image velocimetry is used to study the spatio-temporal structure of the vortices shed by the airfoils. Compared with a single tone sinusoidal serration, the multiscale ones reduce the vortex shedding energy as well as the span-wise coherence. Results indicate that the vortex shedding is locked into an arch-shaped cell structure. This structure is weakened by the multiscale patterns, which explains the reduction in both shedding energy and coherence.

Cavity closure arrangement for high pressure vessels

DOEpatents

Amtmann, Hans H.

1981-01-01

A closure arrangement for a pressure vessel such as the pressure vessel of a high temperature gas-cooled reactor wherein a liner is disposed within a cavity penetration in the reactor vessel and defines an access opening therein. A closure is adapted for sealing relation with an annular mounting flange formed on the penetration liner and has a plurality of radially movable locking blocks thereon having outer serrations adapted for releasable interlocking engagement with serrations formed internally of the upper end of the penetration liner so as to effect high strength closure hold-down. In one embodiment, ramping surfaces are formed on the locking block serrations to bias the closure into sealed relation with the mounting flange when the locking blocks are actuated to locking positions.

Epimutation and cancer: A new carcinogenic mechanism of Lynch syndrome

PubMed Central

BANNO, KOUJI; KISU, IORI; YANOKURA, MEGUMI; TSUJI, KOSUKE; MASUDA, KENTA; UEKI, ARISA; KOBAYASHI, YUSUKE; YAMAGAMI, WATARU; NOMURA, HIROYUKI; TOMINAGA, EIICHIRO; SUSUMU, NOBUYUKI; AOKI, DAISUKE

2012-01-01

Epimutation is defined as abnormal transcriptional repression of active genes and/or abnormal activation of usually repressed genes caused by errors in epigenetic gene repression. Epimutation arises in somatic cells and the germline, and constitutional epimutation may also occur. Epimutation is the first step of tumorigenesis and can be a direct cause of carcinogenesis. Cancers associated with epimutation include Lynch syndrome (hereditary non-polyposis colorectal cancer, HNPCC), chronic lymphocytic leukemia, breast cancer and ovarian cancer. Epimutation has been shown for many tumor suppressor genes, including RB, VHL, hMLH1, APC and BRCA1, in sporadic cancers. Methylation has recently been shown in DNA from normal tissues and peripheral blood in cases of sporadic colorectal cancer and many studies show constitutive epimutation in cancers. Epimutation of DNA mismatch repair (MMR) genes (BRCA1, hMLH1 and hMSH2) involved in development familial cancers has also been found. These results have led to a focus on epimutation as a novel oncogenic mechanism. PMID:22735547

The role of STK 11 gene testing in individuals with oral pigmentation.

PubMed

Duong, Bich-Thu; Winship, Ingrid

2017-05-01

Peutz-Jeghers syndrome (PJS) is a rare, autosomal dominant condition characterised by mucocutaneous pigmented lesions, gastrointestinal polyposis and a significant risk of cancer. Laugier-Hunziker syndrome (LHS) is a benign condition with similar dermatological features, but with no systemic complications. STK 11 gene testing allows clinicians to differentiate between these two disorders. This case report compares the dermatological similarities in four individuals with PJS or LHS and illustrates the potential benefit of genetic testing. There is > 90% likelihood of identifying a mutation in STK 11 if a patient fulfils the diagnostic criteria for PJS. Lifelong risk management is advised for these individuals with confirmed PJS. Diagnostic confirmation is important to provide rational management, in particular, endoscopic cancer surveillance, and psychological support. STK 11 testing can confirm those at risk of PJS, who require lifelong surveillance, and possibly release those with a simple dermatosis, such as LHS, from invasive and thus potentially harmful surveillance. © 2016 The Australasian College of Dermatologists.

Distinct features between MLH1-methylated and unmethylated colorectal carcinomas with the CpG island methylator phenotype: implications in the serrated neoplasia pathway

PubMed Central

Cho, Nam-Yun; Kang, Gyeong Hoon

2016-01-01

The presence or absence of MLH1 methylation may critically affect the heterogeneity of colorectal carcinoma (CRC) with the CpG island methylator phenotype (CIMP). Here, we investigated the differential characteristics of CIMP-high (CIMP-H) CRCs according to MLH1 methylation status. To further confirm the MLH1-dependent features in CIMP-H CRC, an independent analysis was performed using data from The Cancer Genome Atlas (TCGA). In our CIMP-H CRC samples, MLH1-methylated tumors were characterized by older patient age, proximal colonic location, mucinous histology, intense lymphoid reactions, RUNX3/SOCS1 promoter methylation, BRAF mutations, and microsatellite instability-high (MSI-H) status. By contrast, MLH1-unmethylated tumors were associated with earlier age of onset, increased distal colorectal localization, adverse pathologic features, and KRAS mutations. In the TCGA dataset, the MLH1-silenced CIMP-H CRC demonstrated proximal location, MSI-H status, hypermutated phenotype, and frequent BRAF mutations, but the MLH1-non-silenced CIMP-H CRC was significantly associated with high frequencies of KRAS and APC mutations. In conclusion, the differential nature of CIMP-H CRCs depends primarily on the MLH1 methylation status. Based on the current knowledge, the sessile serrated adenoma/polyp may be the major precursor of MLH1-methylated CIMP-H CRCs, whereas MLH1-unmethylated CIMP-H CRCs may develop predominantly from KRAS-mutated traditional serrated adenomas and less commonly from BRAF-mutated traditional serrated adenomas and/or sessile serrated adenomas/polyps. PMID:26883113

Distinct features between MLH1-methylated and unmethylated colorectal carcinomas with the CpG island methylator phenotype: implications in the serrated neoplasia pathway.

PubMed

Kim, Jung Ho; Bae, Jeong Mo; Cho, Nam-Yun; Kang, Gyeong Hoon

2016-03-22

The presence or absence of MLH1 methylation may critically affect the heterogeneity of colorectal carcinoma (CRC) with the CpG island methylator phenotype (CIMP). Here, we investigated the differential characteristics of CIMP-high (CIMP-H) CRCs according to MLH1 methylation status. To further confirm the MLH1-dependent features in CIMP-H CRC, an independent analysis was performed using data from The Cancer Genome Atlas (TCGA). In our CIMP-H CRC samples, MLH1-methylated tumors were characterized by older patient age, proximal colonic location, mucinous histology, intense lymphoid reactions, RUNX3/SOCS1 promoter methylation, BRAF mutations, and microsatellite instability-high (MSI-H) status. By contrast, MLH1-unmethylated tumors were associated with earlier age of onset, increased distal colorectal localization, adverse pathologic features, and KRAS mutations. In the TCGA dataset, the MLH1-silenced CIMP-H CRC demonstrated proximal location, MSI-H status, hypermutated phenotype, and frequent BRAF mutations, but the MLH1-non-silenced CIMP-H CRC was significantly associated with high frequencies of KRAS and APC mutations. In conclusion, the differential nature of CIMP-H CRCs depends primarily on the MLH1 methylation status. Based on the current knowledge, the sessile serrated adenoma/polyp may be the major precursor of MLH1-methylated CIMP-H CRCs, whereas MLH1-unmethylated CIMP-H CRCs may develop predominantly from KRAS-mutated traditional serrated adenomas and less commonly from BRAF-mutated traditional serrated adenomas and/or sessile serrated adenomas/polyps.

The frequency of early colorectal cancer derived from sessile serrated adenoma/polyps among 1858 serrated polyps from a single institution.

PubMed

Chino, A; Yamamoto, N; Kato, Y; Morishige, K; Ishikawa, H; Kishihara, T; Fujisaki, J; Ishikawa, Y; Tamegai, Y; Igarashi, M

2016-02-01

Sessile serrated adenoma/polyps (SSAPs) are suspected to have a high malignant potential, although few reports have evaluated the incidence of carcinomas derived from SSAPs using the new classification for serrated polyps (SPs). The aim of study was to compare the frequency of cancer coexisting with the various SP subtypes including mixed polyps (MIXs) and conventional adenomas (CADs). A total of 18,667 CADs were identified between April 2005 and December 2011, and 1858 SPs (re-classified as SSAP, hyperplastic polyp (HP), traditional serrated adenoma (TSA), or MIX) were removed via snare polypectomy, endoscopic mucosal resection, or endoscopic sub-mucosal dissection. Among 1160 HP lesions, 1 (0.1%) coexisting sub-mucosal invasive carcinoma (T1) was detected. Among 430 SSAP lesions, 3 (0.7%) high-grade dysplasia (HGD/Tis) and 1 (0.2%) T1 were detected. All of the lesions were detected in the proximal colon, with a mean tumor diameter of 18 mm (SD 9 mm). Among 212 TSA lesions, 3 (1%) HGD/Tis were detected but no T1 cancer. Among 56 MIX lesions, 9 (16%) HGD/Tis and 1 (2%) T1 cancers were detected, and among 18,677 CAD lesions, 964 (5%) HGD/Tis and 166 (1%) T1 cancers were identified. Among the resected lesions that were detected during endoscopic examination, a smaller proportion (1%) of SSAPs harbored HGD or coexisting cancer, compared to CAD or MIX lesions. Therefore, more attention should be paid to accurately identifying lesions endoscopically for intentional resection and the surveillance of each SP subtype.

Novel Implications in Molecular Diagnosis of Lynch Syndrome

PubMed Central

Liccardo, Raffaella; Izzo, Paola

2017-01-01

About 10% of total colorectal cancers are associated with known Mendelian inheritance, as Familial Adenomatous Polyposis (FAP) and Lynch syndrome (LS). In these cancer types the clinical manifestations of disease are due to mutations in high-risk alleles, with a penetrance at least of 70%. The LS is associated with germline mutations in the DNA mismatch repair (MMR) genes. However, the mutation detection analysis of these genes does not always provide informative results for genetic counseling of LS patients. Very often, the molecular analysis reveals the presence of variants of unknown significance (VUSs) whose interpretation is not easy and requires the combination of different analytical strategies to get a proper assessment of their pathogenicity. In some cases, these VUSs may make a more substantial overall contribution to cancer risk than the well-assessed severe Mendelian variants. Moreover, it could also be possible that the simultaneous presence of these genetic variants in several MMR genes that behave as low risk alleles might contribute in a cooperative manner to increase the risk of hereditary cancer. In this paper, through a review of the recent literature, we have speculated a novel inheritance model in the Lynch syndrome; this could pave the way toward new diagnostic perspectives. PMID:28250766

Water Tunnel Flow Visualization Study Through Poststall of 12 Novel Planform Shapes

NASA Technical Reports Server (NTRS)

Gatlin, Gregory M.; Neuhart, Dan H.

1996-01-01

To determine the flow field characteristics of 12 planform geometries, a flow visualization investigation was conducted in the Langley 16- by 24-Inch Water Tunnel. Concepts studied included flat plate representations of diamond wings, twin bodies, double wings, cutout wing configurations, and serrated forebodies. The off-surface flow patterns were identified by injecting colored dyes from the model surface into the free-stream flow. These dyes generally were injected so that the localized vortical flow patterns were visualized. Photographs were obtained for angles of attack ranging from 10' to 50', and all investigations were conducted at a test section speed of 0.25 ft per sec. Results from the investigation indicate that the formation of strong vortices on highly swept forebodies can improve poststall lift characteristics; however, the asymmetric bursting of these vortices could produce substantial control problems. A wing cutout was found to significantly alter the position of the forebody vortex on the wing by shifting the vortex inboard. Serrated forebodies were found to effectively generate multiple vortices over the configuration. Vortices from 65' swept forebody serrations tended to roll together, while vortices from 40' swept serrations were more effective in generating additional lift caused by their more independent nature.

Serrated adenocarcinoma morphology in colorectal mucinous adenocarcinoma is associated with improved patient survival

PubMed Central

Lee, Chung-Ta; Chow, Nan-Haw; Su, Pei-Fang; Ho, Chung-Liang; Tsai, Hung-Wen; Chen, Yi-Lin; Lin, Shao-Chieh; Lin, Bo-Wen; Lin, Peng-Chan; Lee, Jenq-Chang

2017-01-01

Colorectal mucinous adenocarcinoma (MAC) and serrated adenocarcinoma (SAC) share many characteristics, including right-side colon location, frequent mucin production, and various molecular features. This study examined the frequency of SAC morphology in MACs. We assessed the correlation of SAC morphology with clinicopathological parameters, molecular characteristics, and patient prognosis. Eighty-eight colorectal MACs were collected and reviewed for SAC morphology according to Makinen's criteria. We sequenced KRAS and BRAF, assessed CpG island methylator phenotype (CIMP) frequency, and analyzed DNA mismatch repair enzyme levels using immunohistochemistry in tumor samples. SAC morphology was observed in 38% of MACs, and was associated with proximal location (P=0.001), BRAF mutation (P=0.042), CIMP-positive status (P=0.023), and contiguous traditional serrated adenoma (P=0.019). Multivariate analysis revealed that MACs without both SAC morphology and CIMP-positive status exhibited 3.955 times greater risk of cancer relapse than MACs having both characteristics or either one (P=0.035). Our results show that two MAC groups with distinct features can be identified using Makinen's criteria, and suggest a favorable prognostic role for the serrated neoplastic pathway in colorectal MAC. PMID:28422723

Contiguous gene deletion of chromosome 2p16.3-p21 as a cause of Lynch syndrome.

PubMed

Salo-Mullen, Erin E; Lynn, Patricio B; Wang, Lu; Walsh, Michael; Gopalan, Anuradha; Shia, Jinru; Tran, Christina; Man, Fung Ying; McBride, Sean; Schattner, Mark; Zhang, Liying; Weiser, Martin R; Stadler, Zsofia K

2018-01-01

Lynch syndrome is an autosomal dominant condition caused by pathogenic mutations in the DNA mismatch repair (MMR) genes. Although commonly associated with clinical features such as intellectual disability and congenital anomalies, contiguous gene deletions may also result in cancer predisposition syndromes. We report on a 52-year-old male with Lynch syndrome caused by deletion of chromosome 2p16.3-p21. The patient had intellectual disability and presented with a prostatic adenocarcinoma with an incidentally identified synchronous sigmoid adenocarcinoma that exhibited deficient MMR with an absence of MSH2 and MSH6 protein expression. Family history was unrevealing. Physical exam revealed short stature, brachycephaly with a narrow forehead and short philtrum, brachydactyly of the hands, palmar transverse crease, broad and small feet with hyperpigmentation of the soles. The patient underwent total colectomy with ileorectal anastomosis for a pT3N1 sigmoid adenocarcinoma. Germline genetic testing of the MSH2, MSH6, and EPCAM genes revealed full gene deletions. SNP-array based DNA copy number analysis identified a deletion of 4.8 Mb at 2p16.3-p21. In addition to the three Lynch syndrome associated genes, the deleted chromosomal section encompassed genes including NRXN1, CRIPT, CALM2, FBXO11, LHCGR, MCFD2, TTC7A, EPAS1, PRKCE, and 15 others. Contiguous gene deletions have been described in other inherited cancer predisposition syndromes, such as Familial Adenomatous Polyposis. Our report and review of the literature suggests that contiguous gene deletion within the 2p16-p21 chromosomal region is a rare cause of Lynch syndrome, but presents with distinct phenotypic features, highlighting the need for recognition and awareness of this syndromic entity.

Initiation of universal tumor screening for Lynch syndrome in colorectal cancer patients as a model for the implementation of genetic information into clinical oncology practice.

PubMed

Cohen, Stacey A; Laurino, Mercy; Bowen, Deborah J; Upton, Melissa P; Pritchard, Colin; Hisama, Fuki; Jarvik, Gail; Fichera, Alessandro; Sjoding, Britta; Bennett, Robin L; Naylor, Lorraine; Jacobson, Angela; Burke, Wylie; Grady, William M

2016-02-01

Lynch syndrome confers a hereditary predisposition to colorectal and other cancers. Universal tumor screening (UTS) for Lynch syndrome is recommended by several professional societies, but the implementation can be complex. This article describes the evaluation, process development, and initiation of Lynch syndrome UTS at a tertiary referral cancer center. A multidisciplinary team developed the new process design. Issues in 5 themes were noted: timing, funding, second-opinion patients, result processing, and the role of genetics providers. A committee approach was used to examine each issue for process-improvement development. The issues related to testing were addressed individually for the successful implementation of UTS at the institutional level. In the conventional-care period, 9 of 30 cases (30%) received Lynch syndrome screening, and 4 cases were referred to medical genetics. During the 6 months following the implementation of UTS, 32 of 44 patients (73%) received Lynch syndrome screening. The 13 unscreened patients all had identified reasons for nonscreening (eg, financial limitations). Ten patients were referred to medical genetics, which identified no new cases of Lynch syndrome, but a low-risk adenomatous polyposis coli (APC) variant was detected in 1 individual. The implementation of effective Lynch syndrome UTS can feasibly alter practice at the institutional level. This experience with the assessment and management of issues relevant to the successful implementation of a new clinical care paradigm based on emerging technology has implications for the uptake of advances across molecular oncology into clinical practice, and this is highly relevant in the current era of rapidly evolving genomic technology. © 2015 American Cancer Society.

Tegaserod Mimics the Neurostimulatory Glycan Polysialic Acid and Promotes Nervous System Repair

DTIC Science & Technology

2014-01-01

cyclooxyenase-2 (Phillips et al., 2002). Other compounds, such as b-lactam antibiotics and minocycline , have been found to act via thus far undefined...polyposis in familial adenomatous polyposis. Gut 50, 857e860. Plane, J.M., Shen, Y., Pleasure, D.E., Deng, W., 2010. Prospects for minocycline

77 FR 34052 - Pfizer, Inc.; Withdrawal of Approval of Familial Adenomatous Polyposis Indication for CELEBREX

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-08

... withdrawing approval of the familial adenomatous polyposis (FAP) indication for CELEBREX (celecoxib) Capsules... Spring, MD 20993-0002, 301- 796-3601. SUPPLEMENTARY INFORMATION: FDA approved the FAP indication for..., subpart H. In addition to FAP, CELEBREX is indicated for the relief of the signs and symptoms of...

Carcinoma of the colon and rectum with deregulation of insulin-like growth factor 2 signaling: clinical and molecular implications.

PubMed

Belharazem, Djeda; Magdeburg, Julia; Berton, Ann-Kristin; Beissbarth, Li; Sauer, Christian; Sticht, Carsten; Marx, Alexander; Hofheinz, Ralf; Post, Stefan; Kienle, Peter; Ströbel, Philipp

2016-10-01

Loss of imprinting (LOI) of the insulin-like growth factor 2 (IGF2) is an early event in the development of colorectal cancer (CRC). Whether LOI of IGF2 denotes a molecular or clinical cancer subgroup is currently unknown. Tumor biopsies and paired normal mucosa from 399 patients with extensive clinical annotations were analyzed for LOI and IGF2 expression. LOI status in 140 informative cases was correlated with clinicopathologic parameters and outcome. LOI was frequent in normal mucosa and tumors and occurred throughout the large intestine. LOI was unrelated to microsatellite instability, KRAS mutation status, stage, and survival. However, CRC with LOI showed increased IGF2 protein levels and activation of AKT1. Gene expression analysis of tumors with and without LOI and knockdown of IGF2 in cell lines revealed that IGF2 induced distinct sets of activated and repressed genes, including Wnt5a, CEACAM6, IGF2BP3, KPN2A, BRCA2, and CDK1. Inhibition of AKT1 in IGF2-stimulated cells showed that the downstream effects of IGF2 on cell proliferation and gene expression were strictly AKT1-dependent. LOI of IGF2 is a frequent and early event in CRC that occurs both in the adenomatous polyposis coli (APC) gene-mutated and serrated route of carcinogenesis. LOI leads to overexpression of IGF2, activates IGF1R and AKT1, and is a powerful driver of cell proliferation. Moreover, our results suggest that IGF2 via AKT1 also contributes to non-canonical wnt signaling. Although LOI had no significant impact on major clinical parameters and outcome, its potential as a target for preventive and therapeutic interventions merits further investigation.

Subtypes of the Type II Pit Pattern Reflect Distinct Molecular Subclasses in the Serrated Neoplastic Pathway.

PubMed

Aoki, Hironori; Yamamoto, Eiichiro; Yamano, Hiro-O; Sugai, Tamotsu; Kimura, Tomoaki; Tanaka, Yoshihito; Matsushita, Hiro-O; Yoshikawa, Kenjiro; Takagi, Ryo; Harada, Eiji; Nakaoka, Michiko; Yoshida, Yuko; Harada, Taku; Sudo, Gota; Eizuka, Makoto; Yorozu, Akira; Kitajima, Hiroshi; Niinuma, Takeshi; Kai, Masahiro; Nojima, Masanori; Suzuki, Hiromu; Nakase, Hiroshi

2018-03-15

Colorectal serrated lesions (SLs) are important premalignant lesions whose clinical and biological features are not fully understood. We aimed to establish accurate colonoscopic diagnosis and treatment of SLs through evaluation of associations among the morphological, pathological, and molecular characteristics of SLs. A total of 388 premalignant and 18 malignant colorectal lesions were studied. Using magnifying colonoscopy, microsurface structures were assessed based on Kudo's pit pattern classification system, and the Type II pit pattern was subcategorized into classical Type II, Type II-Open (Type II-O) and Type II-Long (Type II-L). BRAF/KRAS mutations and DNA methylation of CpG island methylator phenotype (CIMP) markers (MINT1, - 2, - 12, - 31, p16, and MLH1) were analyzed through pyrosequencing. Type II-O was tightly associated with sessile serrated adenoma/polyps (SSA/Ps) with BRAF mutation and CIMP-high. Most lesions with simple Type II or Type II-L were hyperplastic polyps, while mixtures of Type II or Type II-L plus more advanced pit patterns (III/IV) were characteristic of traditional serrated adenomas (TSAs). Type II-positive TSAs frequently exhibited BRAF mutation and CIMP-low, while Type II-L-positive TSAs were tightly associated with KRAS mutation and CIMP-low. Analysis of lesions containing both premalignant and cancerous components suggested Type II-L-positive TSAs may develop into KRAS-mutated/CIMP-low/microsatellite stable cancers, while Type II-O-positive SSA/Ps develop into BRAF-mutated/CIMP-high/microsatellite unstable cancers. These results suggest that Type II subtypes reflect distinct molecular subclasses in the serrated neoplasia pathway and that they could be useful hallmarks for identifying SLs at high risk of developing into CRC.

Changing pathological diagnosis from hyperplastic polyp to sessile serrated adenoma: systematic review and meta-analysis.

PubMed

Niv, Yaron

2017-12-01

The WHO published a new classification of colonic polyps in 2010, including the group of serrated polyps, which can be divided into hyperplastic polyps (HP), traditional serrated adenomas, and sessile serrated adenomas (SSA) or polyps. To assess the rate of re-diagnosis of HP to SSA and to look for possible predictors for changing the diagnosis. English Medical literature searches were performed for 'reassessment' OR 'reclassification' AND 'hyperplastic polyp' OR 'sessile serrated adenoma' till 31 January 2017. PRISMA guidelines for systematic reviews were followed. Studies that included a precise re-diagnosis of HP into SSA were included. We also looked for predictors of SSA diagnosis such as polyp location and size, patient sex and age, and synchronous advanced adenoma. Altogether, we found 220 eligible studies; 212 were excluded as they did not fulfill the inclusion criteria and we were left with eight studies including 2625 patients. The odds ratio for the number of polyps with changed pathological diagnosis from HP to SSA was 0.112 with 95% confidence interval (CI): 0.099-0.126 (P<0.0001) or 11.2%. Heterogeneity between studies was significant with Q=199.4, d.f. (Q)=9, P<0.0001, and I=95.486%. The odds ratio for changing the pathological diagnosis from HP to SSA for polyp proximal location and polyp size more than 5 mm were 4.401, 95% CI: 2.784-6.958, P<0.0001, and 8.336, 95% CI: 4.963-15.571, P<0.0001, respectively. Endoscopists and pathologists should be aware of the SSA diagnosis when finding HPs larger than 5 mm in the right colon. The diagnosis of HP in these cases should be reassessed by experienced gastrointestinal pathologists.

DNA Methylation and Mutation of Small Colonic Neoplasms in Ulcerative Colitis and Crohn's Colitis: Implications for Surveillance.

PubMed

Johnson, David H; Taylor, William R; Aboelsoud, Mohammed M; Foote, Patrick H; Yab, Tracy C; Cao, Xiaoming; Smyrk, Thomas C; Loftus, Edward V; Mahoney, Douglas W; Ahlquist, David A; Kisiel, John B

2016-07-01

Stool DNA testing in patients with inflammatory bowel disease (IBD) may detect colorectal cancer and advanced precancers with high sensitivity; less is known about the presence of DNA markers in small IBD lesions, their association with metachronous neoplasia, or contribution to stool test positivity. At a single center in 2 blinded phases, we assayed methylated bone morphogenic protein 3, methylated N-Myc downstream-regulated gene 4, and mutant KRAS in DNA extracted from paraffin-embedded benign lesions, and matched control tissues of patients with IBD, who were followed for subsequent colorectal dysplasia. Stool samples from independent cases and controls with lesions <1 cm or advanced neoplasms were assayed for the same markers. Among IBD lesions (29 low-grade dysplasia, 19 serrated epithelial change, and 10 sessile serrated adenoma/polyps), the prevalence of methylation was significantly higher than in mucosae from 44 matched IBD controls (P < 0.0001 for methylated bone morphogenic protein 3 or methylated N-Myc downstream-regulated gene 4). KRAS mutations were more abundant in serrated epithelial change than all other groups (P < 0.001). Subsequent dysplasia was not associated with DNA marker levels. In stools, the sensitivity of methylated bone morphogenic protein 3 as a single marker was 60% for all lesions <1 cm, 63% for low-grade dysplasia ≥1 cm and 81% for high-grade dysplasia/colorectal cancer, all at 91% specificity (P < 0.0001). Selected DNA markers known to be present in advanced IBD neoplasia can also be detected in both tissues and stools from IBD patients with small adenomas and serrated lesions. Mutant KRAS exfoliated from serrated epithelial change lesions might raise false-positive rates. These findings have relevance to potential future applications of stool DNA testing for IBD surveillance.

The clinical impact of serrated colorectal polyps

PubMed Central

O’Connell, Brendon M; Crockett, Seth D

2017-01-01

Serrated polyps (SPs) of the colorectum pose a novel challenge to practicing gastroenterologists. Previously thought benign and unimportant, there is now compelling evidence that SPs are responsible for a significant percentage of incident colorectal cancer worldwide. In contrast to conventional adenomas, which tend to be slow growing and polypoid, SPs have unique features that undermine current screening and surveillance practices. For example, sessile serrated polyps (SSPs) are flat, predominately right-sided, and thought to have the potential for rapid growth. Moreover, SSPs are subject to wide variations in endoscopic detection and pathologic interpretation. Unfortunately, little is known about the natural history of SPs, and current guidelines are based largely on expert opinion. In this review, we outline the current taxonomy, epidemiology, and management of SPs with an emphasis on the clinical and public health impact of these lesions. PMID:28260946

Parametric study on the characteristics of a SDBD actuator with a serrated electrode

NASA Astrophysics Data System (ADS)

Gao, Guoqiang; Peng, Kaisheng; Dong, Lei; Wei, Wenfu; Wu, Guangning

2017-06-01

Active flow control based on surface dielectric barrier discharge (SDBD) has become a focus of research in recent years, due to its unique advantages and diverse potential applications. Compared with the conventional SDBD with straight electrodes, the serrated electrode-based SDBD has a great advantage due to its 3D flow topology. It is believed that the boundary layer separation of moving objects can be controlled more effectively with this new type of SDBD. In SDBD with a serrated electrode, the R (tip sharpness) and N (tip number per unit length) have a great influence on the discharge and induced airflow characteristics. In this paper, a parametric study of the characteristics of SDBD with a serrated electrode has been conducted with different ranges of R and N. Aspects of the power consumption, the steady medium temperature distribution, and the maximum induced airflow velocity have been investigated. The results indicate that there is a critical value of R and N where the maximum power consumption and induced airflow velocity are achieved. The uniformity of the steady temperature distribution of the medium surface is found to be more dependent on N. We found that the accelerating effects of the induced airflow can be evaluated with the Schlieren technique, which agree well with the results from the pitot tube.

The TP53 gene promoter is not methylated in families suggestive of Li-Fraumeni syndrome with no germline TP53 mutations.

PubMed

Finkova, Alena; Vazna, Alzbeta; Hrachovina, Ondrej; Bendova, Sarka; Prochazkova, Kamila; Sedlacek, Zdenek

2009-08-01

Germline TP53 mutations are found in only 70% of families with the Li-Fraumeni syndrome (LFS), and with an even lower frequency in families suggestive of LFS but not meeting clinical criteria of the syndrome. Despite intense efforts, to date, no other genes have been associated with the disorder in a significant number of TP53 mutation-negative families. A search for defects in TP53 other than heterozygous missense mutations showed that neither intron variants nor sequence variants in the TP53 promoter are frequent in LFS, and multiexon deletions have been found to be responsible for LFS only in several cases. Another cancer predisposition syndrome, hereditary non-polyposis colon cancer, has been associated with epigenetic silencing of one allele of the MLH1 or MSH2 genes. This prompted us to test the methylation of the TP53 gene promoter in a set of 14 families suggestive of LFS using bisulphite sequencing of three DNA fragments from the 5' region of the gene. We found no detectable methylation at any of the CG dinucleotides tested. Thus, epigenetic silencing of the TP53 promoter is not a frequent cause of the disorder in families suggestive of LFS but with no germline mutations in the coding part of the gene.

Spontaneous Aberrant Crypt Foci in Apc1638N Mice with a Mutant Apc Allele

PubMed Central

Pretlow, Theresa P.; Edelmann, Winfried; Kucherlapati, Raju; Pretlow, Thomas G.; Augenlicht, Leonard H.

2003-01-01

The Apc1638N/+ mouse has a chain-terminating mutation in one allele of the adenomatous polyposis coli (Apc) gene that is similar to most mutations observed in the human familial adenomatous polyposis syndrome. Aberrant crypt foci (ACF), the earliest identified neoplastic lesions in the colon, are morphologically abnormal structures that are identifiedmicroscopically in the grossly normal colonic mucosas of rodents treated with colon carcinogens and of human patients. The colons and cecums of 62 Apc1638N/+ mice were evaluated for the spontaneous occurrence of ACF and tumors. Both male and female mice were killed at different times between 5 and 28 weeks of age. Wild-type littermates, ie, Apc+/+ mice, at 22 to 26 weeks of age served as controls. ACF were identified in 97% of the Apc1638N/+ mice starting at 5 weeks of age and not in any wild-type littermates. Although the number of ACF increased with age (P < 0.0001), the average number of crypts per focus of the ACF did not increase significantly. In addition, wild-type Apc protein was detected by immunohistochemistry in all 22 ACF evaluated. Together these data suggest that heterozygous loss of Apc may be sufficient to initiate ACF in these mice and that these mice may be suitable models to study the interaction of environmental factors with an inherited mutation of the Apc gene that is associated with colon cancer. PMID:14578176

Rapid detection of translation-terminating mutations at the adenomatous polyposis coli (APC) gene by direct protein truncation test

DOE Office of Scientific and Technical Information (OSTI.GOV)

Van Der Luut, R.; Khan, P.M.; Van Leeuwen, C.

Familial adenomatous polyposis (FAP) is usually associated with protein truncating mutations in the adenomatous polyposis coli (APC) gene. The APC mutations are known to play a major role in colorectal carcinogensis. For the identification of protein truncating mutations of the APC gene, the authors developed a rapid, sensitive, and direct screening procedure. The technique is based on the in vitro transcription and translation of the genomic PCR products and is called the protein truncation test. Samples of DNA from individual FAP patients, members of a FAP family, colorectal tumors, and colorectal tumor-derived cell lines were used to show the effectivenessmore » of this method. 9 refs., 2 figs.« less

Acoustic test results from a 36 inch (0.914m) statorless lift fan with serrated and unserrated rotor blades

NASA Technical Reports Server (NTRS)

Stimpert, D. L.

1975-01-01

Test results of the LF336/E statorless lift fan with serrated and unserrated rotor leading edges are presented. Fan broadband noise reductions from 2 to 5 dB were achieved in the forward quadrant at frequencies from 100 to 2500 Hz. Broadband noise near and above the blade passing frequency was reduced only at angles of 80 to 100 degrees.

Screening, management and surveillance for the sessile serrated adenomas/polyps.

PubMed

Fu, Xiangsheng; Qiu, Ye; Zhang, Yali

2014-01-01

The incidence and mortality rates from right-sided colorectal cancers (CRCs) have not decreased, compared with the significant reduction of CRCs in the left colon in recent years. It is likely that a significant proportion of right-sided CRCs evolve from undetected sessile serrated adenomas/polyps (SSA/Ps) in the primary colonoscopy. Increasing evidences suggest that SSA/Ps are high-risk lesions, with 15% of the SSA/P patients developing subsequent CRCs or adenomas with high-grade dysplasia. However, there are many issues in the screening, management and surveillance of SSA/Ps. Based on new evidences, this review addresses major issues in the diagnostic criteria for the serrated polyps of the colorectum, new endoscopic techniques (high-resolution magnifying endoscopy, narrow-band imaging, autofluorescence imaging, confocal laser endoscopy, and endocytoscopy) for the realtime identification of SSA/Ps, and the management of SSA/Ps by endoscopic mucosal resection, endoscopic sub-mucosal dissection or surgical resection in practice.

Serrated pathway: Alternative route to colorectal cancer

PubMed Central

Patai, Árpád V; Molnár, Béla; Tulassay, Zsolt; Sipos, Ferenc

2013-01-01

Serrated polyps have been an area of intense focus for gastroenterologists over the past several years. Contrary to what was thought before, a growing body of literature indicates that these polyps can be precursors of colorectal cancer (CRC). Most of these lesions, particularly those in the proximal colon, have so far been under-recognized and missed during colonoscopy, qualifying these lesions to be the main cause of interval cancers. It is estimated that 10%-20% of CRCs evolve through this alternative, serrated pathway, with a distinct genetic and epigenetic profile. Aberrant DNA methylation plays a central role in the development of this CRC subtype. This characteristic molecular background is reflected in a unique pathological and clinical manifestation different from cancers arising via the traditional pathway. In this review we would like to highlight morphological, molecular and clinical features of this emerging pathway that are essential for gastroenterologists and may influence their everyday practice. PMID:23431044

Serrated Flow and Dynamic Strain Aging in Fe-Mn-C TWIP Steel

NASA Astrophysics Data System (ADS)

Lan, Peng; Zhang, Jiaquan

2018-01-01

The tensile behavior, serrated flow, and dynamic strain aging of Fe-(20 to 24)Mn-(0.4 to 0.6)C twinning-induced plasticity (TWIP) steel have been investigated. A mathematical approach to analyze the DSA and PLC band parameters has been developed. For Fe-(20 to 24)Mn-(0.4 to 0.6)C TWIP steel with a theoretical ordering index (TOI) between 0.1 and 0.3, DSA can occur at the very beginning of plastic deformation and provide serrations during work hardening, while for TOI less than 0.1 the occurrence of DSA is delayed and twinning-dominant work hardening remains relatively smooth. The critical strain for the onset of DSA and PLC bands in Fe-Mn-C TWIP steels decreases as C content increases, while the numbers of serrations and bands increase. As Mn content increases, the critical strain for DSA and PLC band varies irregularly, but the numbers of serrations and bands increase. For Fe-(20 to 24)Mn-(0.4 to 0.6)C TWIP steel with grain size of about 10 to 20 μm, the twinning-induced work hardening rate is about 2.5 to 3.0 GPa, while the DSA-dominant hardening rate is about 2.0 GPa on average. With increasing engineering strain from 0.01 to 0.55 at an applied strain rate of 0.001s-1, the cycle time for PLC bands in Fe-Mn-C TWIP steel increases from 6.5 to 162 seconds, while the band velocity decreases from 4.5 to 0.5 mm s-1, and the band strain increases from 0.005 to 0.08. Increasing applied strain rate leads to a linear increase of band velocity despite composition differences. In addition, the influence of the Mn and C content on the tensile properties of Fe-Mn-C TWIP steel has been also studied. As C content increases, the yield strength and tensile strength of Fe-Mn-C TWIP steel increase, but the total elongation variation against C content is dependent on Mn content. As Mn content increases, the yield strength and tensile strength decrease, while the total elongation increases, despite C content. Taking both tensile properties and serrated flow behavior into consideration, Fe-22Mn-0.4C TWIP steel shows excellent mechanical performance with a high product of tensile strength and total elongation and a slightly serrated stress-strain response. To suppress the negative effect of DSA in Fe-Mn-C TWIP steels on the stability of tensile behavior, a TOI lower than 0.1 is strongly suggested.

French experts report on MUTYH-associated polyposis (MAP).

PubMed

Buecher, Bruno; Bonaïti, Catherine; Buisine, Marie-Pierre; Colas, Chrystelle; Saurin, Jean-Christophe

2012-09-01

Recent years have been characterised by an improvement in our knowledge of genetic determinism of adenomatous polyposes and by the description in 2002 of a new entity called "MUTYH-associated polyposis" (MAP), related to biallelic mutations of this gene. Its autosomal recessive mode of inheritance contrasts with the autosomal dominant inheritance of the classical "familial adenomatous polyposis" (FAP), associated with an APC germline mutation. Although some phenotypic features may be of value to distinguish these two conditions, their clinical "spectra" largely overlap and the differential diagnosis may be difficult. The purpose of this expertise conducted under the auspices of the French Institut National du Cancer (INCa) was to assess the current state of knowledge on MUTYH-associated polyposis and to establish some recommendations in the field of molecular analysis (indications of tests and analysis strategies for affected patients and their relatives) and of clinical management based on available data in the literature, on the results from the French molecular genetics laboratories performing MUTYH analysis and on the opinions of biologists and clinicians experts (genetic counsellors and gastroenterologists). The risk of colorectal cancer among relatives carrying a monoallelic MUTYH mutation was also studied.

Preimplantation genetic diagnosis for cancer predisposition.

PubMed

Rechitsky, Svetlana; Verlinsky, Oleg; Chistokhina, Anna; Sharapova, Tatyana; Ozen, Seckin; Masciangelo, Christina; Kuliev, Anver; Verlinsky, Yury

2002-01-01

Preimplantation genetic diagnosis (PGD) has recently been offered for couples with an inherited predisposition for late onset disorders. This paper presents the results of PGD for a group of couples at risk for producing children with cancer predisposition. Using a standard IVF procedure, oocytes or embryos were tested for different mutations predisposing to cancer, preselecting and transferring only mutation-free embryos back to the patients. The procedure was performed for patients with predisposition to familial adenomatous polyposis coli (FAP), Von Hippel-Lindau syndrome (VHL), retinoblastoma, Li-Fraumeni syndrome, determined by p53 tumour suppressor gene mutations, neurofibromatosis types I and II and familial posterior fossa brain tumour (hSNF5). Overall, 20 PGD cycles were performed for 10 couples, resulting in preselection and transfer of 40 mutation-free embryos, which resulted in five unaffected clinical pregnancies and four healthy children born by the present time. Despite the controversy of PGD use for late onset disorders, the data demonstrate the usefulness of this approach as the only acceptable option for at-risk couples to avoid the birth of children with an inherited predisposition to cancer, and to have a healthy child.

JP-HHT phenotype in Danish patients with SMAD4 mutations.

PubMed

Jelsig, A M; Tørring, P M; Kjeldsen, A D; Qvist, N; Bojesen, A; Jensen, U B; Andersen, M K; Gerdes, A M; Brusgaard, K; Ousager, L B

2016-07-01

Patients with germline mutations in SMAD4 can present symptoms of both juvenile polyposis syndrome (JPS) and hereditary hemorrhagic telangiectasia (HHT): the JP-HHT syndrome. The complete phenotypic picture of this syndrome is only just emerging. We describe the clinical characteristics of 14 patients with SMAD4-mutations. The study was a retrospective, register-based study. SMAD4 mutations carriers were identified through the Danish HHT-registry, the genetic laboratories - and the genetic departments in Denmark. The medical files from relevant departments were reviewed and symptoms of HHT, JPS, aortopathy and family history were noted. We detected 14 patients with SMAD4 mutations. All patients had polyps removed and 11 of 14 fulfilled the diagnostic criteria for JPS. Eight patients were screened for HHT-symptoms and seven of these fulfilled the Curaçao criteria. One patient had aortic root dilation. Our findings support that SMAD4 mutations carriers have symptoms of both HHT and JPS and that the frequency of PAVM and gastric involvement with polyps is higher than in patients with HHT or JPS not caused by a SMAD4 mutation. Out of eight patients screened for aortopathy, one had aortic root dilatation, highlighting the need for additional screening for aortopathy. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Small bowel capsule endoscopy: Where are we after almost 15 years of use?

PubMed Central

Van de Bruaene, Cedric; De Looze, Danny; Hindryckx, Pieter

2015-01-01

The development of capsule endoscopy (CE) in 2001 has given gastroenterologists the opportunity to investigate the small bowel in a non-invasive way. CE is most commonly performed for obscure gastrointestinal bleeding, but other indications include diagnosis or follow-up of Crohn’s disease, suspicion of a small bowel tumor, diagnosis and surveillance of hereditary polyposis syndromes, Nonsteroidal anti-inflammatory drug-induced small bowel lesions and celiac disease. Almost fifteen years have passed since the release of the small bowel capsule. The purpose of this review is to offer the reader a brief but complete overview on small bowel CE anno 2014, including the technical and procedural aspects, the possible complications and the most important indications. We will end with some future perspectives of CE. PMID:25610531

Efficacy and safety of eflornithine (CPP-1X)/sulindac combination therapy versus each as monotherapy in patients with familial adenomatous polyposis (FAP): design and rationale of a randomized, double-blind, Phase III trial.

PubMed

Burke, Carol A; Dekker, Evelien; Samadder, N Jewel; Stoffel, Elena; Cohen, Alfred

2016-08-02

Molecular studies suggest inhibition of colorectal mucosal polyamines (PAs) may be a promising approach to prevent colorectal cancer (CRC). Inhibition of ornithine decarboxylase (ODC) using low-dose eflornithine (DFMO, CPP-1X), combined with maximal PA export using low-dose sulindac, results in greatly reduced levels of normal mucosal PAs. In a clinical trial, this combination (compared with placebo) reduced the 3-year incidence of subsequent high-risk adenomas by >90 %. Familial Adenomatous Polyposis (FAP) is characterized by marked up-regulation of ODC in normal intestinal epithelial and adenoma tissue, and therefore PA reduction might be a potential strategy to control progression of FAP-related intestinal polyposis. CPP FAP-310, a randomized, double-blind, Phase III trial was designed to examine the safety and efficacy of sulindac and DFMO (alone or in combination) for preventing a clinically relevant FAP-related progression event in individuals with FAP. Eligible adults with FAP will be randomized to: CPP-1X 750 mg and sulindac 150 mg, CPP-1X placebo and sulindac 150 mg, or CPP-1X 750 mg and sulindac placebo once daily for 24 months. Patients will be stratified based on time-to-event prognosis into one of the three treatment arms: best (ie, longest time to first FAP-related event [rectal/pouch polyposis]), intermediate (duodenal polyposis) and worst (pre-colectomy). Stage-specific, "delayed time to" FAP-related events are the primary endpoints. Change in polyp burden (upper and/or lower intestine) is a key secondary endpoint. The trial is ongoing. As of February 1, 2016, 214 individuals have been screened; 138 eligible subjects have been randomized to three treatment groups at 15 North American sites and 6 European sites. By disease strata, 26, 80 and 32 patients are included for assessment of polyp burden in the rectum/pouch, duodenal polyposis and pre-colectomy groups, respectively. Median age is 40 years; 59 % are men. The most common reasons for screening failure include minimal polyp burden (n = 22), withdrawal of consent (n = 9) and extensive polyposis requiring immediate surgical intervention (n = 9). Enrollment is ongoing. This trial is registered at ClinicalTrials.gov ( NCT01483144 ; November 21, 2011) and the EU Clinical Trials Register( EudraCT 2012-000427-41 ; May 15, 2014).

Microstructure and mechanical properties of hip-consolidated Rene 95 powders. [hot-isostatic pressed nickel-based powder metal

NASA Technical Reports Server (NTRS)

Shimanuki, Y.; Nishino, Y.; Masui, M.; Doi, H.

1980-01-01

The effects of heat-treatments on the microstructure of P/M Rene 95 (a nickel-based powder metal), consolidated by the hot-isostatic pressing (HIP), were examined. The microstructure of as-HIP'd specimen was characterized by highly serrated grain boundaries. Mechanical tests and microstructural observations reveal that the serrated grain boundaries improved ductility at both room and elevated temperatures by retarding crack propagation along grain boundaries.

Automatic locking orthotic knee device

NASA Technical Reports Server (NTRS)

Weddendorf, Bruce C. (Inventor)

1993-01-01

An articulated tang in clevis joint for incorporation in newly manufactured conventional strap-on orthotic knee devices or for replacing such joints in conventional strap-on orthotic knee devices is discussed. The instant tang in clevis joint allows the user the freedom to extend and bend the knee normally when no load (weight) is applied to the knee and to automatically lock the knee when the user transfers weight to the knee, thus preventing a damaged knee from bending uncontrollably when weight is applied to the knee. The tang in clevis joint of the present invention includes first and second clevis plates, a tang assembly and a spacer plate secured between the clevis plates. Each clevis plate includes a bevelled serrated upper section. A bevelled shoe is secured to the tank in close proximity to the bevelled serrated upper section of the clevis plates. A coiled spring mounted within an oblong bore of the tang normally urges the shoes secured to the tang out of engagement with the serrated upper section of each clevic plate to allow rotation of the tang relative to the clevis plate. When weight is applied to the joint, the load compresses the coiled spring, the serrations on each clevis plate dig into the bevelled shoes secured to the tang to prevent relative movement between the tang and clevis plates. A shoulder is provided on the tang and the spacer plate to prevent overextension of the joint.

Comparison of tissue loss by different punches: A new A-design.

PubMed

Ahmad, Muhammad

2018-06-19

To compare the amount of tissue loss using different FUE punches. The study was conducted in 5 patients undergoing hair restoration surgery by FUE. Four different kinds of punches were used, that is, sharp, blunt, serrated, and new "A-design." All the punches had a total cutting edge of 0.8 mm. In each patient, 4 punches were used to make insertion at right angle with the skin. Immediately after the punch use, the diameter of the hole was measured. The same areas were also measured after 24 hours and after 1 month. The data were collected and analyzed by Multiple t test (with Bonferroni's correction). The average size of the wound immediately at the end of the procedure was 0.826 mm for sharp, 0.858 mm for blunt, 0.892 mm for serrated, and 0.932 mm for A-design. Similarly, the wounds decreased to 0.752, 0.778, 0.774, and 0.696 mm for sharp, blunt, serrated, and A-design, respectively, after 24 hours. The final wound/scar size was 0.640 mm for punch, 0.660 mm for blunt punch, 0.668 mm for serrated punch, and 0.598 mm for A-design punch after 1 month. The new A-design resulted in the minimum scar size after 1 month. © 2018 Wiley Periodicals, Inc.

Molecular Diagnostics in Colorectal Carcinoma: Advances and Applications for 2018.

PubMed

Bhalla, Amarpreet; Zulfiqar, Muhammad; Bluth, Martin H

2018-06-01

The molecular pathogenesis and classification of colorectal carcinoma are based on the traditional adenomaecarcinoma sequence, serrated polyp pathway, and microsatellite instability (MSI). The genetic basis for hereditary nonpolyposis colorectal cancer is the detection of mutations in the MLH1, MSH2, MSH6, PMS2, and EPCAM genes. Genetic testing for Lynch syndrome includes MSI testing, methylator phenotype testing, BRAF mutation testing, and molecular testing for germline mutations in MMR genes. Molecular makers with predictive and prognostic implications include quantitative multigene reverse transcriptase polymerase chain reaction assay and KRAS and BRAF mutation analysis. Mismatch repair-deficient tumors have higher rates of programmed death-ligand 1 expression. Cell-free DNA analysis in fluids are proving beneficial for diagnosis and prognosis in these disease states towards effective patient management. Copyright © 2018 Elsevier Inc. All rights reserved.

Evaluation of magnifying colonoscopy in the diagnosis of serrated polyps.

PubMed

Ishigooka, Shinya; Nomoto, Masahito; Obinata, Nobuyuki; Oishi, Yoshichika; Sato, Yoshinori; Nakatsu, Satoko; Suzuki, Midori; Ikeda, Yoshiko; Maehata, Tadateru; Kimura, Tomoaki; Watanabe, Yoshiyuki; Nakajima, Takashi; Yamano, Hiro-o; Yasuda, Hiroshi; Itoh, Fumio

2012-08-28

To elucidate the colonoscopic features of serrated lesions of the colorectum using magnifying colonoscopy. Broad division of serrated lesions of the colorectum into hyperplastic polyps (HPs), traditional serrated adenomas (TSAs), and sessile serrated adenomas/polyps (SSA/Ps) has been proposed on the basis of recent molecular biological studies. However, few reports have examined the colonoscopic features of these divisions, including magnified colonoscopic findings. This study examined 118 lesions excised in our hospital as suspected serrated lesions after magnified observation between January 2008 and September 2011. Patient characteristics (sex, age), conventional colonoscopic findings (location, size, morphology, color, mucin) and magnified colonoscopic findings (pit pattern diagnosis) were interpreted by five colonoscopists with experience in over 1000 colonoscopies, and were compared with histopathological diagnoses. The pit patterns were categorized according to Kudo's classification, but a more detailed investigation was also performed using the subclassification [type II-Open (type II-O), type II-Long (type II-L), or type IV-Serrated (type IV-S)] proposed by Kimura T and Yamano H. Lesions comprised 23 HPs (23/118: 19.5%), 39 TSAs (39/118: 33.1%: with cancer in one case), 50 SSA/Ps (50/118: 42.4%: complicated with cancer in three cases), and six others (6/118: 5.1%). We excluded six others, including three regular adenomas, one hamartoma, one inflammatory polyp, and one juvenile polyp for further analysis. Conventional colonoscopy showed that SSA/Ps were characterized as larger in diameter than TSAs and HPs (SSA/P vs HP, 13.62 ± 8.62 mm vs 7.74 ± 3.24 mm, P < 0.001; SSA/Ps vs TSA, 13.62 ± 8.62 mm vs 9.89 ± 5.73 mm, P < 0.01); common in the right side of the colon [HPs, 30.4% (7/23): TSAs, 20.5% (8/39): SSA/P, 84.0% (42/50), P < 0.001]; flat-elevated lesion [HPs, 30.4% (7/23): TSAs, 5.1% (2/39): SSA/Ps, 90.0% (45/50), P < 0.001]; normal-colored or pale imucosa [HPs, 34.8% (8/23): TSAs, 10.3% (4/39): SSA/Ps, 80% (40/50), P < 0.001]; and with large amounts of mucin [HPs, 21.7% (5/23): TSAs, 17.9% (7/39): SSA/Ps, 72.0% (36/50), P < 0.001]. In magnified colonoscopic findings, 17 lesions showed either type II pit pattern alone or partial type II pit pattern as the basic architecture, with 14 HPs (14/17, 70.0%) and 3 SSA/Ps. Magnified colonoscopy showed the type II-O pit pattern as characteristic of SSA/Ps [sensitivity 83.7% (41/49), specificity 85.7% (54/63)]. Cancer was also present in three lesions, in all of which a type VI pit pattern was also present within the same lesion. There were four HPs and four TSAs each. The type IV-S pit pattern was characteristic of TSAs [sensitivity 96.7% (30/31), specificity 89.9% (72/81)]. Cancer was present in one lesion, in which a type VI pit pattern was also present within the same lesion. In our study, serrated lesions of the colorectum also possessed the features described in previous reports of conventional colonoscopic findings. The pit pattern diagnosis using magnifying colonoscopy, particularly magnified colonoscopic findings using subclassifications of surface architecture, reflected the pathological characteristics of SSA/Ps and TSAs, and will be useful for colonoscopic diagnosis. We suggest that this system could be a good diagnostic tool for SSA/Ps using magnifying colonoscopy.

Identification of risk factors for sessile and traditional serrated adenomas of the colon by using big data analysis.

PubMed

Pyo, Jeung Hui; Ha, Sang Yun; Hong, Sung Noh; Chang, Dong Kyung; Son, Hee Jung; Kim, Kyoung-Mee; Kim, Hyeseung; Kim, Kyunga; Kim, Jee Eun; Choi, Yoon-Ho; Kim, Young-Ho

2018-05-01

Little is known about the risk factors associated with serrated polyps, because the early studies, which occurred before the new World Health Organization classification was introduced, included mixtures of serrated polyps. This study aimed to evaluate the risk factors associated with the presence of sessile serrated adenomas (SSAs) and traditional serrated adenomas (TSAs) using big data analytics. Using a case-control design, we evaluated the risk factors associated with the presence of SSAs and TSAs. Subjects who underwent colonoscopies from 2002 to 2012 as part of the comprehensive health screening programs undertaken at the Samsung Medical Center, Korea, participated in this study. Of the 48 677 individuals who underwent colonoscopies, 183 (0.4%) had SSAs and 212 (0.4%) had TSAs. The multivariate analysis determined that being aged ≥ 50 years (odds ratio [OR] 1.91, 95% confidential interval [CI] 1.27-2.90, P = 0.002) and a history of colorectal cancer among first-degree relatives (OR 3.14, 95% CI 1.57-6.27, P = 0.001) were significant risk factors associated with the presence of SSAs and that being aged ≥ 50 years (OR 2.61, 95% CI 1.79-3.80, P < 0.001), obesity (OR 1.63, 95% CI 1.12-2.36, P = 0.010), and a higher triglyceride level (OR 1.63, 95% CI 1.12-2.36, P = 0.010) were independent risk factors associated with the presence of TSAs. We used big data analytics to determine the risk factors associated with the presence of specific polyp subgroups, and individuals who have these risk factors should be carefully scrutinized for the presence of SSAs or TSAs during screening colonoscopies. © 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

Nasal mucosal gene expression in patients with allergic rhinitis with and without nasal polyps.

PubMed

Fritz, Stephen B; Terrell, Jeffrey E; Conner, Edward R; Kukowska-Latallo, Jolanta F; Baker, James R

2003-12-01

Nasal polyps are a common problem that is difficult to diagnose and treat, in part because the cause of nasal polyposis is unknown. Although information on the pathogenesis of polyposis is lacking, there are reports suggesting that a genetic predisposition underlies this disorder. We sought to better understand the basis of nasal polyposis associated with allergic rhinitis. We hypothesize that the expression of unique genes is associated with the nasal polyposis phenotype. We examined 12000 human genes transcribed in the nasal mucosa of patients with allergic rhinitis with and without nasal polyps. Biopsy specimens of the mucosa of patients with and without polyps were obtained after the patients refrained from the use of topical or systemic steroid therapy for 2 weeks. Thirty-four genes were differentially expressed between the patient groups, including those for inflammatory molecules and putative growth factors. The greatest differential expression identified by the array analysis was for a group of genes associated with neoplasia, including mammaglobin, a gene transcribed 12-fold higher in patients with polyps compared with control patients with rhinitis alone. Quantitative RT-PCR confirmed this differential expression and documented that the number of mammaglobin mRNA copies is actually 64-fold greater in tissues of patients with polyps versus control patients. The specificity of mammaglobin protein expression was evaluated by means of immunohistochemistry, which showed specific staining in nasal polyp mucosal goblet cells only in patients with polyps. These data suggest that nasal polyposis involves deregulated cell growth, using gene activation in some ways similar to a neoplasm. In addition, mammaglobin, a gene of unknown function associated with breast neoplasia, might be related to polyp growth.

Mutation analysis of the APC gene in Taiwanese FAP families: low incidence of APC germline mutation in a distinct subgroup of FAP families.

PubMed

Chiang, J M; Chen, H W; Tang, R P; Chen, J S; Changchien, C R; Hsieh, P S; Wang, J Y

2010-06-01

Familial adenomatous polyposis (FAP) is an autosomal-dominant disease caused by germline mutations in the adenomatous polyposis coli (APC) gene. The affected individuals develop colorectal polyposis and show various extra-colonic manifestations. In this study, we aimed to investigate the genetic and clinical characteristics of FAP in Taiwanese families and analyze the genotype-phenotype correlations. Blood samples were obtained from 66 FAP patients registered in the hereditary colorectal cancer database. Then, germline mutations in the APC genes of these 66 polyposis patients from 47 unrelated FAP families were analyzed. The germline-mutation-negative cases were analyzed by performing multiplex ligation-dependent probe amplification (MLPA) and single-strand conformation polymorphism (SSCP) analysis of the MUTYH gene. Among the analyzed families, 79% (37/47) of the families showed 28 APC mutations, including 19 frameshift mutations, 4 nonsense mutations, 3 genomic deletion mutations, 1 missense mutation, and 1 splice-site mutation. In addition, we identified 15 novel mutations in 32% (15/47) of the families. The cases in which APC mutations were not identified showed significantly lower incidence of profuse polyposis (P = 0.034) and gastroduodenal polyps (P = 0.027). Furthermore, FAP families in which some affected individuals had less than 100 polyps showed significant association with low incidence of APC germline mutations (P = 0.002). We have added the APC germline-mutation data for Taiwanese FAP patients and indicated the presence of an FAP subgroup comprising affected individuals with nonadenomatous polyps or less than 100 adenomatous polyps; this form of FAP is less frequently caused by germline mutations of the APC gene.

Multiple lymphomatous polyposis.

PubMed

Kadayifçi, A; Benekli, M; Savaş, M C; Arslan, S; Uzunalimoğlu, B; Barişta, I; Güllü, I H; Tekuzman, G

1997-04-01

Multiple lymphomatous polyposis (MLP) is a distinctive and particularly rare clinical type of malignant gastrointestinal lymphoma, which is classified as B-cell centrocytic non-Hodgkin's lymphoma. this rare entity has been recently reclassified as mantle cell lymphoma. We herein report three additional cases of MLP involving various segments of the gastrointestinal tract. MLP has an aggressive biologic behavior and a relatively poor prognosis and must be treated accordingly as a high-grade lymphoma with systemic chemotherapy.

Combinatorial prevention of carcinogenic risk in a model for familial colon cancer.

PubMed

Telang, Nitin; Katdare, Meena

2007-04-01

Germ line mutations in the tumor suppressor adenomatous polyposis coli (APC) gene, predispose for the clinical familial adenomatous polyposis (FAP) syndrome, a high risk precursor for early onset colon cancer. Similar mutations in the murine homolog of the APC gene, however, produce adenomas predominantly in the small intestine, rather than in the colon. The objectives of the present study were: i) to develop a preclinical cell culture model for human FAP syndrome and ii) to validate this model as a rapid mechanism-based approach for evaluation of the preventive efficacy of combinations of synthetic pharmacological agents or naturally-occurring phytochemicals, for the risk of colon carcinogenesis. The clonally selected 850Min COL-Cl1 cell line derived from histologically normal colon of ApcMin/+ mouse exhibited aberrant proliferation (64.7% decrease in population doubling time, 820% increase in saturation density, and 81.4% decrease in spontaneous apoptosis), relative to that observed in the colon epithelial cell line C57 COL established from Apc [+/+] C57BL/6J mouse. In addition, unlike the Apc [+/+] C57 COL cells, the Apc mutant cells exhibited enhanced risk for spontaneous carcinogenic transformation as evidenced by 100% increase in anchorage-independent colony formation (C57 COL: 0/12; 850Min COL-Cl1: 12/12, mean colony number 23.6+/-2.7). Treatment of Apc mutant cells with low dose combination of select mechanistically distinct synthetic chemopreventive agents such as celecoxib (CLX) + difluoro methylornithine (DFMO), or naturally-occurring epigallocatechin gallate (EGCG) + curcumin (CUR) produced 160-400% and 220-430% decrease in the viable cell number respectively, relative to these agents used independently. Furthermore, relative to independent agents, CLX+DFMO and EGCG+CUR combinations produced 31.5-82.1% and 45.9-105.4% greater reduction in the number of anchorage-independent colonies. Thus, aberrant proliferation and increased risk for carcinogenesis in the Apc mutant cells, and their susceptibility to low dose combinations of mechanistically distinct chemopreventive agents validate a rapid approach to prioritize efficacious combinations for long-term animal studies and future clinical trials on prevention of colon cancer.

Nasal polyposis (or chronic olfactory rhinitis).

PubMed

Jankowski, R; Rumeau, C; Gallet, P; Nguyen, D T

2018-06-01

The concept of chronic rhinosinusitis with or without polyps is founded on the structural and functional unicity of the pituitary mucosa and its united response to environmental aggression by allergens, viruses, bacteria, pollution, etc. The present review sets this concept against the evo-devo three-nose theory, in which nasal polyposis is distinguished as specific to the olfactory nose and in particular to the non-olfactory mucosa of the ethmoid, which is considered to be not a sinus but rather the skull-base bone harboring the olfactory mucosa. The evo-devo approach enables simple and precise positive diagnosis of nasal polyposis and its various clinical forms, improves differential diagnosis by distinguishing chronic diseases of the respiratory nose and those of the paranasal sinuses, hypothesizes an autoimmune origin specifically aimed at olfactory system auto-antigens, and supports the surgical concept of nasalization against that of functional sinus and ostiomeatal-complex surgery. The ventilation function of the sinuses seems minor compared to their production, storage and active release of nitric oxide (NO) serving to oxygenate arterial blood in the pulmonary alveoli. This respiratory function of the paranasal sinuses may indeed be their most important. NO trapped in the ethmoidal spaces also accounts for certain radiographic aspects associated with nasal polyposis. Copyright © 2018. Published by Elsevier Masson SAS.

Serrating Nozzle Surfaces for Complete Transfer of Droplets

NASA Technical Reports Server (NTRS)

Kim, Chang-Jin " CJ" ; Yi, Uichong

2010-01-01

A method of ensuring the complete transfer of liquid droplets from nozzles in microfluidic devices to nearby surfaces involves relatively simple geometric modification of the nozzle surfaces. The method is especially applicable to nozzles in print heads and similar devices required to dispense liquid droplets having precise volumes. Examples of such devices include heads for soft printing of ink on paper and heads for depositing droplets of deoxyribonucleic acid (DNA) or protein solutions on glass plates to form microarrays of spots for analysis. The main purpose served by the present method is to ensure that droplets transferred from a nozzle have consistent volume, as needed to ensure accuracy in microarray analysis or consistent appearance of printed text and images. In soft printing, droplets having consistent volume are generated inside a print head, but in the absence of the present method, the consistency is lost in printing because after each printing action (in which a drop is ejected from a nozzle), a small residual volume of liquid remains attached to the nozzle. By providing for complete transfer of droplets (and thus eliminating residual liquid attached to the nozzle) the method ensures consistency of volume of transferred droplets. An additional benefit of elimination of residue is prevention of cross-contamination among different liquids printed through the same nozzle a major consideration in DNA microarray analysis. The method also accelerates the printing process by minimizing the need to clean a printing head to prevent cross-contamination. Soft printing involves a hydrophobic nozzle surface and a hydrophilic print surface. When the two surfaces are brought into proximity such that a droplet in the nozzle makes contact with the print surface, a substantial portion of the droplet becomes transferred to the print surface. Then as the nozzle and the print surface are pulled apart, the droplet is pulled apart and most of the droplet remains on the print surface. The basic principle of the present method is to reduce the liquid-solid surface energy of the nozzle to a level sufficiently below the intrinsic solid-liquid surface energy of the nozzle material so that the droplet is not pulled apart and, instead, the entire droplet volume becomes transferred to the print surface. In this method, the liquid-solid surface energy is reduced by introducing artificial surface roughness in the form of micromachined serrations on the inner nozzle surface (see figure). The method was tested in experiments on soft printing of DNA solutions and of deionized water through 0.5-mm-diameter nozzles, of which some were not serrated, some were partially serrated, and some were fully serrated. In the nozzles without serrations, transfer was incomplete; that is, residual liquids remained in the nozzles after printing. However, in every nozzle in which at least half the inner surface was serrated, complete transfer of droplets to the print surface was achieved.

The role of the cilium in hereditary tumor predisposition syndromes

PubMed Central

Klasson, Timothy D.; Giles, Rachel H.

2014-01-01

The primary cilium is a highly conserved cell organelle that is closely connected to processes involved in cell patterning and replication. Amongst their many functions, cilia act as “signal towers” through which cell-cell signaling cascades pass. Dysfunction of cilia or the myriad processes that are connected with cilium function can lead to disease. Due to the sheer number of cellular processes that at some point involve the primary cilium, the effects of misregulation are highly heterogeneous between different cell populations. However, because of the importance of primary cilia in the development, growth, patterning and orientation of cells and tissues, a common thread has emerged in which defective cilia can lead to disorganization, which can contribute to the growth of neoplasms, including cancer and pre-cancerous phenotypes. Because cilia are so vital for signaling during cell replication and the cell fate decisions that are important in childhood growth, symptoms often arise early in life. Here we review recent work connecting misregulation of the primary cilium with tumor formation in a variety of tissues in the developing body, with a particular focus on the syndromes in which classic tumor genes are mutated, including von Hippel-Lindau disease (OMIM 193300), adenomatous polyposis coli (OMIM 175100), tuberous sclerosis (OMIM 191100) and Birt-Hogg-Dubé syndrome (OMIM 135150). Timely diagnosis of these syndromes is essential for entry into appropriate screening protocols, which have been shown to effectively prolong life expectancy in these cohorts of patients. PMID:27625869

Disruption of the APC gene by t(5;7) translocation in a Turcot family.

PubMed

Sahnane, Nora; Bernasconi, Barbara; Carnevali, Ileana; Furlan, Daniela; Viel, Alessandra; Sessa, Fausto; Tibiletti, Maria Grazia

2016-03-01

Turcot syndrome (TS) refers to the combination of colorectal polyps and primary tumours of the central nervous system. TS is a heterogeneous genetic condition due to APC and/or mismatch repair germline mutations. When APC is involved the vast majority of mutations are truncating, but in approximately 20%-30% of patients with familial polyposis no germline mutation can be found. A 30-year-old Caucasian woman with a positive pedigree for TS was referred to our Genetic Counselling Service. She was negative for APC and MUTYH but showed a reciprocal balanced translocation t(5;7)(q22;p15) at chromosome analysis. FISH analysis using specific BAC probes demonstrated that 5q22 breakpoint disrupted the APC gene. Transcript analysis by MLPA and digital PCR revealed that the cytogenetic rearrangement involving the 3' end of the APC gene caused a defective expression of a truncated transcript. This result allowed cytogenetic analysis to be offered to all the other family members and segregation analysis clearly demonstrated that all the carriers were affected, whereas non-carriers did not have the polyposis. A cytogenetic approach permitted the identification of the mutation-causing disease in this family, and the segregation analysis together with the transcript study supported the pathogenetic role of this mutation. Karyotype analysis was used as a predictive test in all members of this family. This family suggests that clinically positive TS and FAP cases, which test negative with standard molecular analysis, could be easily and cost-effectively resolved by a classical and molecular cytogenetic approach. Copyright © 2015 Elsevier Inc. All rights reserved.

Design and simulation of Macro-Fiber composite based serrated microflap for wind turbine blade fatigue load reduction

NASA Astrophysics Data System (ADS)

Sun, Xiao; Dai, Qingli; Bilgen, Onur

2018-05-01

A Macro-Fiber Composite (MFC) based active serrated microflap is designed in this research for wind turbine blades. Its fatigue load reduction potential is evaluated in normal operating conditions. The force and displacement output of the MFC-based actuator are simulated using a bimorph beam model. The work done by the aerodynamic, centripetal and gravitational forces acting on the microflap were calculated to determine the required capacity of the MFC-based actuator. MFC-based actuators with a lever mechanical linkage are designed to achieve the required force and displacement to activate the microflap. A feedback control scheme is designed to control the microflap during operation. Through an aerodynamic-aeroelastic time marching simulation with the designed control scheme, the time responses of the wind turbine blades are obtained. The fatigue analysis shows that the serrated microflap can reduce the standard deviation of the blade root flapwise bending moment and the fatigue damage equivalent loads.

A novel mutation of adenomatous polyposis coli (APC) gene results in the formation of supernumerary teeth.

PubMed

Yu, Fang; Cai, Wenping; Jiang, Beizhan; Xu, Laijun; Liu, Shangfeng; Zhao, Shouliang

2018-01-01

Supernumerary teeth are teeth that are present in addition to normal teeth. Although several hypotheses and some molecular signalling pathways explain the formation of supernumerary teeth, but their exact disease pathogenesis is unknown. To study the molecular mechanisms of supernumerary tooth-related syndrome (Gardner syndrome), a deeper understanding of the aetiology of supernumerary teeth and the associated syndrome is needed, with the goal of inhibiting disease inheritance via prenatal diagnosis. We recruited a Chinese family with Gardner syndrome. Haematoxylin and eosin staining of supernumerary teeth and colonic polyp lesion biopsies revealed that these patients exhibited significant pathological characteristics. APC gene mutations were detected by PCR and direct sequencing. We revealed the pathological pathway involved in human supernumerary tooth development and the mouse tooth germ development expression profile by RNA sequencing (RNA-seq). Sequencing analysis revealed that an APC gene mutation in exon 15, namely 4292-4293-Del GA, caused Gardner syndrome in this family. This mutation not only initiated the various manifestations typical of Gardner syndrome but also resulted in odontoma and supernumerary teeth in this case. Furthermore, RNA-seq analysis of human supernumerary teeth suggests that the APC gene is the key gene involved in the development of supernumerary teeth in humans. The mouse tooth germ development expression profile shows that the APC gene plays an important role in tooth germ development. We identified a new mutation in the APC gene that results in supernumerary teeth in association with Gardner syndrome. This information may shed light on the molecular pathogenesis of supernumerary teeth. Gene-based diagnosis and gene therapy for supernumerary teeth may become available in the future, and our study provides a high-resolution reference for treating other syndromes associated with supernumerary teeth. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Investigation of wave phenomena on a blunt airfoil with straight and serrated trailing edges

NASA Astrophysics Data System (ADS)

Nies, Juliane M.; Gageik, Manuel A.; Klioutchnikov, Igor; Olivier, Herbert

2015-07-01

An investigation of pressure waves in compressible subsonic and transonic flow around a generic airfoil is performed in a modified shock tube. New comprehensive results are presented on pressure waves in compressible flow. For the first time, the influence of trailing edge serration will be examined in terms of the reduction in pressure wave amplitude. A generic airfoil is tested in two main configurations, one with blunt trailing edges and the other one with serrated trailing edges in a Mach number range from 0.6 to 0.8 and at chord Reynolds numbers of 1 × 106 < Re c < 5 ×106. The flow of the blunt trailing edge is characterized by a regular vortex street in the wake creating a regular pattern of upstream-moving pressure waves along the airfoil. The observed pressure waves lead to strong pressure fluctuations within the local flow field. A reduction in the trailing edge thickness leads to a proportional increase in the frequency of the vortex street in the wake as well as the frequency of the waves deduced from constant Strouhal number. By serrating the trailing edge, the formation of vortices in the wake is disturbed. Therefore, also the upstream-moving waves are influenced and reduced in their strength resulting in a steadier flow. An increasing length of the saw tooth enhances the three dimensionality of the structures in the wake and causes a strong decrease in the wave amplitude.

A CpG island methylator phenotype of colorectal cancer that is contiguous with conventional adenomas, but not serrated polyps

PubMed Central

HOKAZONO, KOJI; UEKI, TAKASHI; NAGAYOSHI, KINUKO; NISHIOKA, YASUNOBU; HATAE, TATSUNOBU; KOGA, YUTAKA; HIRAHASHI, MINAKO; ODA, YOSHINAO; TANAKA, MASAO

2014-01-01

A subset of colorectal cancers (CRCs) harbor the CpG island methylator phenotype (CIMP), with concurrent multiple promoter hypermethylation of tumor-related genes. A serrated pathway in which CIMP is developed from serrated polyps is proposed. The present study characterized CIMP and morphologically examined precursor lesions of CIMP. In total, 104 CRCs treated between January 1996 and December 2004 were examined. Aberrant promoter methylation of 15 cancer-related genes was analyzed. CIMP status was classified according to the number of methylated genes and was correlated with the clinicopathological features, including the concomitant polyps in and around the tumors. The frequency of aberrant methylation in each CRC showed a bimodal pattern, and the CRCs were classified as CIMP-high (CIMP-H), CIMP-low (CIMP-L) and CIMP-negative (CIMP-N). CIMP-H was associated with aberrant methylation of MLH1 (P=0.005) and with an improved recurrence-free survival (RFS) rate following curative resection compared with CIMP-L/N (five-year RFS rate, 93.8 vs. 67.1%; P=0.044), while CIMP-N tumors were associated with frequent distant metastases at diagnosis (P=0.023). No concomitant serrated lesions were present in the tumors, whereas conventional adenoma was contiguous with 11 (10.6%) of 104 CRCs, including four CIMP-H CRCs. CIMP-H was classified in CRCs by a novel CIMP marker panel and the presence of concomitant tumors revealed that certain CIMP-H CRCs may have arisen from conventional adenomas. PMID:25289081

A CpG island methylator phenotype of colorectal cancer that is contiguous with conventional adenomas, but not serrated polyps.

PubMed

Hokazono, Koji; Ueki, Takashi; Nagayoshi, Kinuko; Nishioka, Yasunobu; Hatae, Tatsunobu; Koga, Yutaka; Hirahashi, Minako; Oda, Yoshinao; Tanaka, Masao

2014-11-01

A subset of colorectal cancers (CRCs) harbor the CpG island methylator phenotype (CIMP), with concurrent multiple promoter hypermethylation of tumor-related genes. A serrated pathway in which CIMP is developed from serrated polyps is proposed. The present study characterized CIMP and morphologically examined precursor lesions of CIMP. In total, 104 CRCs treated between January 1996 and December 2004 were examined. Aberrant promoter methylation of 15 cancer-related genes was analyzed. CIMP status was classified according to the number of methylated genes and was correlated with the clinicopathological features, including the concomitant polyps in and around the tumors. The frequency of aberrant methylation in each CRC showed a bimodal pattern, and the CRCs were classified as CIMP-high (CIMP-H), CIMP-low (CIMP-L) and CIMP-negative (CIMP-N). CIMP-H was associated with aberrant methylation of MLH1 (P=0.005) and with an improved recurrence-free survival (RFS) rate following curative resection compared with CIMP-L/N (five-year RFS rate, 93.8 vs. 67.1%; P=0.044), while CIMP-N tumors were associated with frequent distant metastases at diagnosis (P=0.023). No concomitant serrated lesions were present in the tumors, whereas conventional adenoma was contiguous with 11 (10.6%) of 104 CRCs, including four CIMP-H CRCs. CIMP-H was classified in CRCs by a novel CIMP marker panel and the presence of concomitant tumors revealed that certain CIMP-H CRCs may have arisen from conventional adenomas.

A review of nasal polyposis

PubMed Central

Newton, Jonathan Ray; Ah-See, Kim Wong

2008-01-01

Nasal polyps are common, affecting up to four percent of the population. Their etiology remains unclear, but they are known to have associations with allergy, asthma, infection, cystic fibrosis, and aspirin sensitivity. They present with nasal obstruction, anosmia, rhinorrhoea, post nasal drip, and less commonly facial pain. Clinical examination reveals single or multiple grey polypoid masses in the nasal cavity. Computerized tomography allows evaluation of the extent of the disease and is essential if surgical treatment is to be considered. Management of polyposis involves a combination of medical therapy and surgery. There is good evidence for the use of corticosteroids (systemic and topical) both as primary treatment and as postoperative prophylaxis against recurrence. Surgical treatment has been refined significantly over the past twenty years with the advent of endoscopic sinus surgery and, in general, is reserved for cases refractory to medical treatment. Recurrence of the polyposis is common with severe disease recurring in up to ten percent of patients. PMID:18728843

Risk of Metachronous High-Risk Adenomas and Large Serrated Polyps in Individuals With Serrated Polyps on Index Colonoscopy: Data From the New Hampshire Colonoscopy Registry.

PubMed

Anderson, Joseph C; Butterly, Lynn F; Robinson, Christina M; Weiss, Julia E; Amos, Christopher; Srivastava, Amitabh

2018-01-01

Surveillance guidelines for serrated polyps (SPs) are based on limited data on longitudinal outcomes of patients. We used the New Hampshire Colonoscopy Registry to evaluate risk of clinically important metachronous lesions associated with SPs detected during index colonoscopies. We collected data from a population-based colonoscopy registry that has been collecting and analyzing data on colonoscopies across the state of New Hampshire since 2004, including rates of adenoma and SP detection. Patients completed a questionnaire to determine demographic characteristics, health history, and risk factors for colorectal cancer, and were followed from index colonoscopy through all subsequent surveillance colonoscopies. Our analyses included 5433 participants (median age, 61 years; 49.7% male) with 2 colonoscopies (median time to surveillance, 4.9 years). We used multivariable logistic regression models to assess effects of index SPs (n = 1016), high-risk adenomas (HRA, n = 817), low-risk adenomas (n = 1418), and no adenomas (n = 3198) on subsequent HRA or large SPs (>1 cm) on surveillance colonoscopy (metachronous lesions). Synchronous SPs, within each index risk group, were assessed for size and by histology. SPs comprise hyperplastic polyps, sessile serrated adenomas/polyps (SSA/Ps), and traditional serrated adenomas. In this study, SSA/Ps and traditional serrated adenomas are referred to collectively as STSAs. HRA and synchronous large SP (odds ratio [OR], 5.61; 95% confidence interval [CI], 1.72-18.28), HRA with synchronous STSA (OR, 16.04; 95% CI, 6.95-37.00), and HRA alone (OR, 3.86; 95% CI, 2.77-5.39) at index colonoscopy significantly increased the risk of metachronous HRA compared to the reference group (no index adenomas or SPs). Large index SPs alone (OR, 14.34; 95% CI, 5.03-40.86) or index STSA alone (OR, 9.70; 95% CI, 3.63-25.92) significantly increased the risk of a large metachronous SP. In an analysis of data from a population-based colonoscopy registry, we found index large SP or index STSA with no index HRA increased risk of metachronous large SPs but not metachronous HRA. HRA and synchronous SPs at index colonoscopy significantly increased risk of metachronous HRA. Individuals with HRA and synchronous large SP or any STSA could therefore benefit from close surveillance. Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.

Psychosis-related matricide associated with a lesion of the ventromedial prefrontal cortex.

PubMed

Orellana, Gricel; Alvarado, Luis; Muñoz-Neira, Carlos; Ávila, Rodrigo; Méndez, Mario F; Slachevsky, Andrea

2013-01-01

Matricide, the killing of a mother by her biological child, is a rare event. We report a case of matricide associated with a woman who sustained a right ventromedial prefrontal lesion during surgery for nasal polyposis that was performed when she was 40 years old. After her surgery, she developed psychotic symptoms associated with the emergence of antisocial behavior. She committed matricide 22 years later. Neuropsychological evaluation showed decreased frontal-executive deficits, and magnetic resonance imaging revealed a lesion in the right gyrus rectus area of the ventromedial prefrontal region. This case suggests that a secondary psychotic syndrome associated with a lesion in the frontal neural network, which is disturbed in psychopathy, could facilitate homicidal behavior. Furthermore, this case has legal implications for the prosecution of murder associated with a brain lesion.

Profile of lower gastrointestinal bleeding in children from a tropical country.

PubMed

Khurana, A K; Saraya, A; Jain, N; Chandra, M; Kulshreshta, R

1998-01-01

Eighty five children were evaluated endoscopically for recurrent lower gastrointestinal (GI) bleeding. The male: female ratio was 2.4:1 with a mean age of 6 years (range 8 months to 2 years). After adequate bowel preparation endoscopic evaluation was done using olympus CF 101 colonoscope. Sedation was given only in two patients. Full length colonoscopy had been done in 16 cases only, to look for extent of disease in 8 cases and to ascertain site of bleeding when no lesion could be seen on sigmoidoscopy. Juvenile polyps were seen in 40 cases, amoebic ulcer in 20, solitary rectal ulcer in 4 and polyposis syndrome in 5 cases. Sigmoidoscopy alone could establish the diagnose in 76 cases. We conclude that flexible sigmoidoscopy alone is safe and adequate in ascertaining the cause of prolonged recurrent lower GI bleeding.

Dislocation Decorrelation and Relationship to Deformation Microtwins during Creep of a Gamma’ Precipitate Strengthened Ni-based Superalloy

DTIC Science & Technology

2011-11-01

Deformation is highly localized around stress concentrators such as carbides, borides and serrated grain boundaries, which act as sources of a/2h110i...highly localized around stress concentrators such as carbides, borides and serrated grain boundaries, which act as sources of a/2h110i matrix-type...phase at different thicknesses. 7328 R.R. Unocic et al. / Acta Materialia 59 (2011) 7325–7339 the image. A number of carbide and/or boride phases are

Human MSH2 protein

DOEpatents

Chapelle, A. de la; Vogelstein, B.; Kinzler, K.W.

1997-01-07

The human MSH2 gene, responsible for hereditary non-polyposis colorectal cancer, was identified by virtue of its homology to the MutS class of genes, which are involved in DNA mismatch repair. The sequence of cDNA clones of the human gene are provided, and the sequence of the gene can be used to demonstrate the existence of germ line mutations in hereditary non-polyposis colorectal cancer (HNPCC) kindreds, as well as in replication error{sup +} (RER{sup +}) tumor cells. 19 figs.

Diagnostic method employing MSH2 protein

DOEpatents

de la Chapelle, Albert; Vogelstein, Bert; Kinzler, Kenneth W.

1998-01-01

The human MSH2 gene, responsible for hereditary non-polyposis colorectal cancer, was identified by virtue of its homology to the MutS class of genes, which are involved in DNA mismatch repair. The sequence of cDNA clones of the human gene are provided, and the sequence of the gene can be used to demonstrate the existence of germ line mutations in hereditary non-polyposis colorectal cancer (HNPCC) kindreds, as well as in replication error.sup.+ (RER.sup.+) tumor cells.

Human MSH2 protein

DOEpatents

de la Chapelle, Albert; Vogelstein, Bert; Kinzler, Kenneth W.

1997-01-01

The human MSH2 gene, responsible for hereditary non-polyposis colorectal cancer, was identified by virtue of its homology to the MutS class of genes, which are involved in DNA mismatch repair. The sequence of cDNA clones of the human gene are provided, and the sequence of the gene can be used to demonstrate the existence of germ line mutations in hereditary non-polyposis colorectal cancer (HNPCC) kindreds, as well as in replication error.sup.+ (RER.sup.+) tumor cells.

A cost-effectiveness analysis of prophylactic surgery versus gynecologic surveillance for women from hereditary non-polyposis colorectal cancer (HNPCC) Families.

PubMed

Yang, Kathleen Y; Caughey, Aaron B; Little, Sarah E; Cheung, Michael K; Chen, Lee-May

2011-09-01

Women at risk for Lynch Syndrome/HNPCC have an increased lifetime risk of endometrial and ovarian cancer. This study investigates the cost-effectiveness of prophylactic surgery versus surveillance in women with Lynch Syndrome. A decision analytic model was designed incorporating key clinical decisions and existing probabilities, costs, and outcomes from the literature. Clinical forum where risk-reducing surgery and surveillance were considered. A theoretical population of women with Lynch Syndrome at age 30 was used for the analysis. A decision analytic model was designed comparing the health outcomes of prophylactic hysterectomy with bilateral salpingo-oophorectomy at age 30 versus annual gynecologic screening versus annual gynecologic exam. The literature was searched for probabilities of different health outcomes, results of screening modalities, and costs of cancer diagnosis and treatment. Cost-effectiveness expressed in dollars per discounted life-years. Risk-reducing surgery is the least expensive option, costing $23,422 per patient for 25.71 quality-adjusted life-years (QALYs). Annual screening costs $68,392 for 25.17 QALYs; and annual examination without screening costs $100,484 for 24.60 QALYs. Further, because risk-reducing surgery leads to both the lowest costs and the highest number of QALYs, it is a dominant strategy. Risk-reducing surgery is the most cost-effective option from a societal healthcare cost perspective.

Elucidating the clinical significance of two PMS2 missense variants coexisting in a family fulfilling hereditary cancer criteria.

PubMed

González-Acosta, Maribel; Del Valle, Jesús; Navarro, Matilde; Thompson, Bryony A; Iglesias, Sílvia; Sanjuan, Xavier; Paúles, María José; Padilla, Natàlia; Fernández, Anna; Cuesta, Raquel; Teulé, Àlex; Plotz, Guido; Cadiñanos, Juan; de la Cruz, Xavier; Balaguer, Francesc; Lázaro, Conxi; Pineda, Marta; Capellá, Gabriel

2017-10-01

The clinical spectrum of germline mismatch repair (MMR) gene variants continues increasing, encompassing Lynch syndrome, Constitutional MMR Deficiency (CMMRD), and the recently reported MSH3-associated polyposis. Genetic diagnosis of these hereditary cancer syndromes is often hampered by the presence of variants of unknown significance (VUS) and overlapping phenotypes. Two PMS2 VUS, c.2149G>A (p.V717M) and c.2444C>T (p.S815L), were identified in trans in one individual diagnosed with early-onset colorectal cancer (CRC) who belonged to a family fulfilling clinical criteria for hereditary cancer. Clinico-pathological data, multifactorial likelihood calculations and functional analyses were used to refine their clinical significance. Likelihood analysis based on cosegregation and tumor data classified the c.2444C>T variant as pathogenic, which was supported by impaired MMR activity associated with diminished protein expression in functional assays. Conversely, the c.2149G>A variant displayed MMR proficiency and protein stability. These results, in addition to the conserved PMS2 expression in normal tissues and the absence of germline microsatellite instability (gMSI) in the biallelic carrier ruled out a CMMRD diagnosis. The use of comprehensive strategies, including functional and clinico-pathological information, is mandatory to improve the clinical interpretation of naturally occurring MMR variants. This is critical for appropriate clinical management of cancer syndromes associated to MMR gene mutations.

Benign colonic metaplasia at a previous stoma site in a patient without adenomatous polyposis.

PubMed

Prouty, Megan; Patrawala, Samit; Vogt, Adam; Kelleher, Michael; Lee, Michael; Parker, Douglas C

2016-03-01

There are few reported cases of cutaneous intestinal metaplasia or primary adenocarcinoma arising at the ileostomy site following panproctocolectomy. These complications have been seen almost exclusively in patients with familial adenomatous polyposis and inflammatory bowel disease (IBD). However, benign intraepidermal colonic mucosa at a reversed ileostomy site in a patient without familial adenomatous polyposis or IBD has not been documented. We report a case of a 51-year-old female with a history of colonic adenocarcinoma who presented with pruritic, erythematous, scaly plaques on the right lower abdomen, present since reversal of her ileostomy in 2007. Skin biopsy revealed benign foci of colonic epithelium with no evidence of adenomatous change. Benign intraepidermal colonic mucosa was diagnosed based on histopathologic findings and immunohistochemistry. To our knowledge, this is the first case of intraepidermal benign colonic metaplasia forming in a patient following ostomy reversal. The case emphasizes the importance of patient education and physical examination of the stoma or stoma remnants for detection of unusual or changing lesions due to the risk for malignant transformation. It also demonstrates that benign colonic mucosa should be considered in the differential diagnosis when evaluating lesions near ileostomy sites, regardless of whether the patient has a history of familial adenomatous polyposis or IBD. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Tumor suppressor gene adenomatous polyposis coli downregulates intestinal transport.

PubMed

Rexhepaj, Rexhep; Rotte, Anand; Gu, Shuchen; Michael, Diana; Pasham, Venkanna; Wang, Kan; Kempe, Daniela S; Ackermann, Teresa F; Brücher, Björn; Fend, Falko; Föller, Michael; Lang, Florian

2011-05-01

Loss of function mutations of the tumor suppressor gene adenomatous polyposis coli (APC) underly the familial adenomatous polyposis. Mice carrying an inactivating mutation in the apc gene (apc (Min/+)) similarly develop intestinal polyposis. APC is effective at least in part by degrading β-catenin and lack of APC leads to markedly enhanced cellular β-catenin levels. β-Catenin has most recently been shown to upregulate the Na+/K+ ATPase. The present study, thus, explored the possibility that APC could influence intestinal transport. The abundance and localization of β-catenin were determined utilizing Western blotting and confocal microscopy, the activity of the electrogenic glucose carrier (SGLT1) was estimated from the glucose-induced current in jejunal segments utilizing Ussing chamber experiments and the Na+/H+ exchanger (NHE3) activity from Na+ -dependent re-alkalinization of cytosolic pH (ΔpH(i)) following an ammonium pulse employing BCECF fluorescence. As a result, β-catenin abundance in intestinal tissue was significantly higher in apc (Min/+) mice than in wild-type mice (apc (+/+)). The β-catenin protein was localized in the basolateral membrane. Both, the glucose-induced current and ΔpH(i) were significantly higher in apc (Min/+) mice than in apc (+/+) mice. In conclusion, intestinal electrogenic transport of glucose and intestinal Na+/H+ exchanger activity are both significantly enhanced in apc (Min/+) mice, pointing to a role of APC in the regulation of epithelial transport.

Serum antibodies against frameshift peptides in microsatellite unstable colorectal cancer patients with Lynch syndrome

PubMed Central

Reuschenbach, Miriam; Kloor, Matthias; Morak, Monika; Wentzensen, Nicolas; Germann, Anja; Garbe, Yvette; Tariverdian, Mirjam; Findeisen, Peter; Neumaier, Michael; Holinski-Feder, Elke; Doeberitz, Magnus von Knebel

2014-01-01

High level microsatellite instability (MSI-H) occurs in about 15% of colorectal cancer (CRCs), either as sporadic cancers or in the context of hereditary non-polyposis cancer (HNPCC) or Lynch syndrome. In MSI-H CRC, mismatch repair deficiency leads to insertion/deletion mutations at coding microsatellites (cMS) and thus to the translation of frameshift peptides (FSPs). FSPs are potent inductors of T cell responses in vitro and in vivo. The present study aims at the identification of FSP-specific humoral immune responses in MSI-H CRC and Lynch syndrome. Sera from patients with history of MSI-H CRC (n=69), healthy Lynch syndrome mutation carriers (n=31) and healthy controls (n=52) were analyzed for antibodies against FSPs using peptide ELISA. Reactivities were measured against FSPs derived from genes frequently mutated in MSI-H CRCs, AIM2, TGFBR2, CASP5, TAF1B, ZNF294, and MARCKS. Antibody reactivity against FSPs was significantly higher in MSI-H CRC patients than in healthy controls (p=0.036, Mann-Whitney) and highest in patients with shortest interval between tumor resection and serum sampling. Humoral immune responses in patients were most frequently directed against FSPs derived from mutated TAF1B (11.6%, 8/69) and TGFBR2 (10.1%, 7/69). Low level FSP-specific antibodies were also detected in healthy mutation carriers. Our results show that antibody responses against FSPs are detectable in MSI-H CRC patients and healthy Lynch syndrome mutation carriers. Based on the high number of defined FSP antigens, measuring FSP-specific humoral immune responses is a highly promising tool for future diagnostic application in MSI-H cancer patients. PMID:19957108

Hereditary Gastrointestinal Cancer Syndromes

PubMed Central

Lynch, Jane F.; Shaw, Trudy G.

2011-01-01

ABSTRACT The rapid growth of molecular genetics and its attendant germline mutation discoveries has enabled identification of persons who are at an inordinately high cancer risk and, therefore, ideal candidates for prevention. However, one must fully appreciate the extensive genotypic and phenotypic heterogeneity that exists in hereditary cancer. Once the causative germline mutation has been identified in a patient, high-risk members of the family can be similarly tested and identified and provided highly targeted surveillance and management opportunities. DNA testing can change the individual's presumed risk status and affect decision making by patients and their physicians regarding surveillance and management. Our purpose is to describe familial/hereditary cancers of the gastrointestinal tract, including familial Barrett's esophagus, hereditary diffuse gastric cancer, gastrointestinal stromal tumors, familial adenomatous polyposis and desmoid tumors, Lynch syndrome, small bowel cancer, and familial pancreatic cancer. We use our discussion of Lynch syndrome as a model for diagnostic and clinical translation strategies for all hereditary gastrointestinal tract cancers, which clearly can then be extended to cancer of all anatomic sites. Highly pertinent questions from the patient's perspective include the following: What kind of counseling will be provided to a patient with a Lynch syndrome mutation, and should that counseling be mandatory? Does the proband have the responsibility to inform relatives about the familial mutation, even if the relatives do not want to know whether they carry it? Is the patient is responsible for notifying family members that a parent or sibling has Lynch syndrome? Can notification be forced and, if so, under what circumstances? These questions point out the need for criteria regarding which family members to inform and how to inform them. PMID:22368732

Serum antibodies against frameshift peptides in microsatellite unstable colorectal cancer patients with Lynch syndrome.

PubMed

Reuschenbach, Miriam; Kloor, Matthias; Morak, Monika; Wentzensen, Nicolas; Germann, Anja; Garbe, Yvette; Tariverdian, Mirjam; Findeisen, Peter; Neumaier, Michael; Holinski-Feder, Elke; von Knebel Doeberitz, Magnus

2010-06-01

High level microsatellite instability (MSI-H) occurs in about 15% of colorectal cancer (CRCs), either as sporadic cancers or in the context of hereditary non-polyposis cancer or Lynch syndrome. In MSI-H CRC, mismatch repair deficiency leads to insertion/deletion mutations at coding microsatellites and thus to the translation of frameshift peptides (FSPs). FSPs are potent inductors of T cell responses in vitro and in vivo. The present study aims at the identification of FSP-specific humoral immune responses in MSI-H CRC and Lynch syndrome. Sera from patients with history of MSI-H CRC (n = 69), healthy Lynch syndrome mutation carriers (n = 31) and healthy controls (n = 52) were analyzed for antibodies against FSPs using peptide ELISA. Reactivities were measured against FSPs derived from genes frequently mutated in MSI-H CRCs, AIM2, TGFBR2, CASP5, TAF1B, ZNF294, and MARCKS. Antibody reactivity against FSPs was significantly higher in MSI-H CRC patients than in healthy controls (P = 0.036, Mann-Whitney) and highest in patients with shortest interval between tumor resection and serum sampling. Humoral immune responses in patients were most frequently directed against FSPs derived from mutated TAF1B (11.6%, 8/69) and TGFBR2 (10.1%, 7/69). Low level FSP-specific antibodies were also detected in healthy mutation carriers. Our results show that antibody responses against FSPs are detectable in MSI-H CRC patients and healthy Lynch syndrome mutation carriers. Based on the high number of defined FSP antigens, measuring FSP-specific humoral immune responses is a highly promising tool for future diagnostic application in MSI-H cancer patients.

The gut microbiota in conventional and serrated precursors of colorectal cancer.

PubMed

Peters, Brandilyn A; Dominianni, Christine; Shapiro, Jean A; Church, Timothy R; Wu, Jing; Miller, George; Yuen, Elizabeth; Freiman, Hal; Lustbader, Ian; Salik, James; Friedlander, Charles; Hayes, Richard B; Ahn, Jiyoung

2016-12-30

Colorectal cancer is a heterogeneous disease arising from at least two precursors-the conventional adenoma (CA) and the serrated polyp. We and others have previously shown a relationship between the human gut microbiota and colorectal cancer; however, its relationship to the different early precursors of colorectal cancer is understudied. We tested, for the first time, the relationship of the gut microbiota to specific colorectal polyp types. Gut microbiota were assessed in 540 colonoscopy-screened adults by 16S rRNA gene sequencing of stool samples. Participants were categorized as CA cases (n = 144), serrated polyp cases (n = 73), or polyp-free controls (n = 323). CA cases were further classified as proximal (n = 87) or distal (n = 55) and as non-advanced (n = 121) or advanced (n = 22). Serrated polyp cases were further classified as hyperplastic polyp (HP; n = 40) or sessile serrated adenoma (SSA; n = 33). We compared gut microbiota diversity, overall composition, and normalized taxon abundance among these groups. CA cases had lower species richness in stool than controls (p = 0.03); in particular, this association was strongest for advanced CA cases (p = 0.004). In relation to overall microbiota composition, only distal or advanced CA cases differed significantly from controls (p = 0.02 and p = 0.002). In taxon-based analysis, stool of CA cases was depleted in a network of Clostridia operational taxonomic units from families Ruminococcaceae, Clostridiaceae, and Lachnospiraceae, and enriched in the classes Bacilli and Gammaproteobacteria, order Enterobacteriales, and genera Actinomyces and Streptococcus (all q < 0.10). SSA and HP cases did not differ in diversity or composition from controls, though sample size for these groups was small. Few taxa were differentially abundant between HP cases or SSA cases and controls; among them, class Erysipelotrichi was depleted in SSA cases. Our results indicate that gut microbes may play a role in the early stages of colorectal carcinogenesis through the development of CAs. Findings may have implications for developing colorectal cancer prevention therapies targeting early microbial drivers of colorectal carcinogenesis.

Cilia and Ear.

PubMed

Piatti, Gioia; De Santi, Maria Margherita; Torretta, Sara; Pignataro, Lorenzo; Soi, Daniela; Ambrosetti, Umberto

2017-04-01

To investigate the prevalence of otological complications derived from primary ciliary dyskinesia (PCD) in adulthood. Twenty-three patients with diagnosed PCD underwent medical history aimed at recording the presence of ear, nose, and throat manifestations (ENT) and any surgical treatments. The ENT objectivity was annotated, and then patients were subjected to audiometric test, tympanometry, registration of otoacoustic emission, and vestibular evaluation. Otitis media with chronic middle ear effusion (OME) during childhood was reported in 52% of the subjects, no patient had undergone ear surgery, and only 2 patients had an episode of otitis in the last year. Eleven of 23 patients showed normal hearing, 11 had a conductive hearing impairment, and 1 showed a severe sensorineural hearing loss unrelated to the syndrome. The bilateral stapedial reflex was only found in all cases of normoacusia and type A tympanogram, distortion product otoacoustic emissions (DPOAE) were present in 8 patients, and no patient had vestibular alterations. Our study confirms a very frequent prevalence of OME in PCD during childhood. Careful monitoring of otological complications of the syndrome is always desirable, also given the high presence in adults of other manifestations in the upper airways, such as chronic rhinosinusitis and nasal polyposis.

Roles of miR319 and TCP Transcription Factors in Leaf Development1[OPEN

PubMed Central

2017-01-01

Sophisticated regulation of gene expression, including microRNAs (miRNAs) and their target genes, is required for leaf differentiation, growth, and senescence. The impact of miR319 and its target TEOSINTE BRANCHED1, CYCLOIDEA, and PROLIFERATING CELL NUCLEAR ANTIGEN BINDING FACTOR (TCP) genes on leaf development has been extensively investigated, but the redundancies of these gene families often interfere with the evaluation of their function and regulation in the developmental context. Here, we present the genetic evidence of the involvement of the MIR319 and TCP gene families in Arabidopsis (Arabidopsis thaliana) leaf development. Single mutations in MIR319A and MIR319B genes moderately inhibited the formation of leaf serrations, whereas double mutations increased the extent of this inhibition and resulted in the formation of smooth leaves. Mutations in MIR319 and gain-of-function mutations in the TCP4 gene conferred resistance against miR319 and impaired the cotyledon boundary and leaf serration formation. These mutations functionally associated with CUP-SHAPED COTYLEDON genes, which regulate the cotyledon boundary and leaf serration formation. In contrast, loss-of-function mutations in miR319-targeted and nontargeted TCP genes cooperatively induced the formation of serrated leaves in addition to changes in the levels of their downstream gene transcript. Taken together, these findings demonstrate that the MIR319 and TCP gene families underlie robust and multilayer control of leaf development. This study also provides a framework toward future researches on redundant miRNAs and transcription factors in Arabidopsis and crop plants. PMID:28842549

Roles of miR319 and TCP Transcription Factors in Leaf Development.

PubMed

Koyama, Tomotsugu; Sato, Fumihiko; Ohme-Takagi, Masaru

2017-10-01

Sophisticated regulation of gene expression, including microRNAs (miRNAs) and their target genes, is required for leaf differentiation, growth, and senescence. The impact of miR319 and its target TEOSINTE BRANCHED1 , CYCLOIDEA , and PROLIFERATING CELL NUCLEAR ANTIGEN BINDING FACTOR ( TCP ) genes on leaf development has been extensively investigated, but the redundancies of these gene families often interfere with the evaluation of their function and regulation in the developmental context. Here, we present the genetic evidence of the involvement of the MIR319 and TCP gene families in Arabidopsis ( Arabidopsis thaliana ) leaf development. Single mutations in MIR319A and MIR319B genes moderately inhibited the formation of leaf serrations, whereas double mutations increased the extent of this inhibition and resulted in the formation of smooth leaves. Mutations in MIR319 and gain-of-function mutations in the TCP4 gene conferred resistance against miR319 and impaired the cotyledon boundary and leaf serration formation. These mutations functionally associated with CUP-SHAPED COTYLEDON genes, which regulate the cotyledon boundary and leaf serration formation. In contrast, loss-of-function mutations in miR319-targeted and nontargeted TCP genes cooperatively induced the formation of serrated leaves in addition to changes in the levels of their downstream gene transcript. Taken together, these findings demonstrate that the MIR319 and TCP gene families underlie robust and multilayer control of leaf development. This study also provides a framework toward future researches on redundant miRNAs and transcription factors in Arabidopsis and crop plants. © 2017 American Society of Plant Biologists. All Rights Reserved.

Race and Prevalence of Large Bowel Polyps Among the Low-Income and Uninsured in South Carolina.

PubMed

Wallace, Kristin; Brandt, Heather M; Bearden, James D; Blankenship, Bridgette F; Caldwell, Renay; Dunn, James; Hegedus, Patricia; Hoffman, Brenda J; Marsh, Courtney H; Marsh, William H; Melvin, Cathy L; Seabrook, March E; Sterba, Ronald E; Stinson, Mary Lou; Thibault, Annie; Berger, Franklin G; Alberg, Anthony J

2016-01-01

Compared to whites, blacks have higher colorectal cancer incidence and mortality rates and are at greater risk for early-onset disease. The reasons for this racial disparity are poorly understood, but one contributing factor could be differences in access to high-quality screening and medical care. The present study was carried out to assess whether a racial difference in prevalence of large bowel polyps persists within a poor and uninsured population (n = 233, 124 blacks, 91 whites, 18 other) undergoing screening colonoscopy. Eligible patients were uninsured, asymptomatic, had no personal history of colorectal neoplasia, and were between the ages 45-64 years (blacks) or 50-64 years (whites, other). We examined the prevalence of any adenoma (conventional, serrated) and then difference in adenoma/polyp type by race and age categories. Prevalence for ≥1 adenoma was 37 % (95 % CI 31-43 %) for all races combined and 36 % in blacks <50 years, 38 % in blacks ≥50 years, and 35 % in whites. When stratified by race, blacks had a higher prevalence of large conventional proximal neoplasia (8 %) compared to whites (2 %) (p value = 0.06) but a lower prevalence of any serrated-like (blacks 18 %, whites 32 %; p value = 0.02) and sessile serrated adenomas/polyps (blacks 2 %, whites 8 % Chi-square p value; p = 0.05). Within this uninsured population, the overall prevalence of adenomas was high and nearly equal by race, but the racial differences observed between serrated and conventional polyp types emphasize the importance of taking polyp type into account in future research on this topic.

Computer-assisted recording of tensile tests for the evaluation of serrated flow

DOE Office of Scientific and Technical Information (OSTI.GOV)

Weinhandl, H.; Mitter, F.; Bernt, W.

1994-12-01

In a previous paper the authors pointed out the difficulties which arise in the evaluation of serrated flow curves when the applied tensile strain rates are just above normal''. The recording system of tensile testing machines which were built, say, twenty years ago, are not capable of recording the full size of the load drops due to the inertia of the recording pen. This handicap was then overcome by establishing correction factors which were determined from recording a small number of load drops with an oscilloscope. Modern testing machines are equipped with digital recording. The disadvantage of the common systemmore » is, however, their limited capacity, so that not enough space for data points is available. Consequently, the time intervals between data points are of the order of tenths of seconds. It will become obvious from the present results that such a time interval is too large for recording a correct serration size. This report is concerned with the recording of complete load-extension relations during tensile tests using a computer which is capable of storing the data at sufficiently small time intervals.« less

Creep deformation and mechanisms in Haynes 230 at 800 °C and 900 °C

NASA Astrophysics Data System (ADS)

Pataky, Garrett J.; Sehitoglu, Huseyin; Maier, Hans J.

2013-11-01

Creep was studied in Haynes 230, a material candidate for the very high temperature reactor's intermediate heat exchanger, at 800 °C and 900 °C. This study focused on the differences between the behavior at the two elevated temperature, and using the microstructure, grain boundary serrations and triple junction strain concentrations were quantitatively identified. There was significant damage in the 900 °C samples and the creep was almost entirely tertiary. In contrast, the 800 °C sample exhibited secondary creep. Using an Arrhenius equation, the minimum creep rate exponents were found to be n ≈ 3 and n ≈ 5 for 900 °C and 800 °C, respectively. The creep mechanisms were identified as solute drag for n ≈ 3 and dislocation climb for n ≈ 5. Strain concentrations were identified at triple junctions and grain boundary serrations using high resolution digital image correlation overlaid on the microstructure. The grain boundary serrations restrict grain boundary sliding which may reduce the creep damage at triple junctions and extend the creep life of Haynes 230 at elevated temperatures.

The effects of leading-edge serrations on reducing flow unsteadiness about airfoils, an experimental and analytical investigation

NASA Technical Reports Server (NTRS)

Schwind, R. G.; Allen, H. J.

1973-01-01

High frequency surface pressure measurements were obtained from wind-tunnel tests over the Reynolds number range 1.2 times one million to 6.2 times one million on a rectangular wing of NACA 63-009 airfoil section. Measurements were also obtained with a wide selection of leading-edge serrations added to the basic airfoil. Under a two-dimensional laminar bubble very close to the leading edge of the basic airfoil there is a large apatial peak in rms pressure. Frequency analysis of the pressure signals in this region show a large, high-frequency energy peak which is interpreted as an oscillation in size and position of the bubble. The serrations divide the bubble into segments and reduce the peak rms pressures. A low Reynolds number flow visualization test on a hydrofoil in water was also conducted. A von Karman vortex street was found trailing from the rear of the foil. Its frequency is at a much lower Strouhal number than in the high Reynolds number experiment, and is related to the trailing-edge and boundary-layer thicknesses.

Diagnostic method employing MSH2 nucleic acids

DOEpatents

de la Chapelle, Albert; Vogelstein, Bert; Kinzler, Kenneth W.

1997-01-01

The human MSH2 gene, responsible for hereditary non-polyposis colorectal cancer, was identified by virtue of its homology to the MutS class of genes, which are involved in DNA mismatch repair. The sequence of cDNA clones of the human gene are provided, and the sequence of the gene can be used to demonstrate the existence of germ line mutations in hereditary non-polyposis colorectal cancer (HNPCC) kindreds, as well as in replication error.sup.+ (RER.sup.+) tumor cells.

Diagnostic method employing MSH2 nucleic acids

DOEpatents

Chapelle, A. de la; Vogelstein, B.; Kinzler, K.W.

1997-12-02

The human MSH2 gene, responsible for hereditary non-polyposis colorectal cancer, was identified by virtue of its homology to the MutS class of genes, which are involved in DNA mismatch repair. The sequence of cDNA clones of the human gene are provided, and the sequence of the gene can be used to demonstrate the existence of germ line mutations in hereditary non-polyposis colorectal cancer (HNPCC) kindreds, as well as in replication error{sup +}(RER{sup +}) tumor cells. 19 figs.

Diagnostic method employing MSH2 protein

DOEpatents

Chapelle, A. de la; Vogelstein, B.; Kinzler, K.W.

1998-11-17

The human MSH2 gene, responsible for hereditary non-polyposis colorectal cancer, was identified by virtue of its homology to the MutS class of genes, which are involved in DNA mismatch repair. The sequence of cDNA clones of the human gene are provided, and the sequence of the gene can be used to demonstrate the existence of germ line mutations in hereditary non-polyposis colorectal cancer (HNPCC) kindreds, as well as in replication error{sup +} (RER{sup +}) tumor cells. 19 figs.

WNT Inhibitory Activity of Malus Pumila miller cv Annurca and Malus domestica cv Limoncella Apple Extracts on Human Colon-Rectal Cells Carrying Familial Adenomatous Polyposis Mutations.

PubMed

Riccio, Gennaro; Maisto, Maria; Bottone, Sara; Badolati, Nadia; Rossi, Giovanni Battista; Tenore, Gian Carlo; Stornaiuolo, Mariano; Novellino, Ettore

2017-11-18

Inhibitors of the Wingless-related Integration site (WNT)/β-catenin pathway have recently been under consideration as potential chemopreventive agents against Familial Adenomatous Polyposis (FAP). This autosomal-dominant syndrome is caused by germline mutations in the gene coding for the protein APC and leads to hyperactivation of the WNT/β-catenin signaling pathway, uncontrolled intestinal cell proliferation and formation of adenocarcinomas. The aim of the present work was to: (i) test, on in vitro cultures of cells carrying FAP mutations and on ex vivo biopsies of FAP patients, the WNT inhibitory activity of extracts from two common southern Italian apples, Malus pumila Miller cv. 'Annurca' and Malus domestica cv 'Limoncella'; (ii) identify the mechanisms underpinning their activities and; (iii) evaluate their potency upon gastrointestinal digestion. We here show that both Annurca and Limoncella apple extracts act as WNT inhibitors, mostly thanks to their polyphenolic contents. They inhibit the pathway in colon cells carrying FAP mutations with active dilutions falling in ranges close to consumer-relevant concentrations. Food-grade manufacturing of apple extracts increases their WNT inhibitory activity as result of the conversion of quercetin glycosides into the aglycone quercetin, a potent WNT inhibitor absent in the fresh fruit extract. However, in vitro simulated gastrointestinal digestion severely affected WNT inhibitory activity of apple extracts, as result of a loss of polyphenols. In conclusion, our results show that apple extracts inhibit the WNT pathway in colon cells carrying FAP mutations and represent a potential nutraceutical alternative for the treatment of this pathology. Enteric coating is advisable to preserve the activity of the extracts in the colon-rectal section of the digestive tract.

WNT Inhibitory Activity of Malus Pumila miller cv Annurca and Malus domestica cv Limoncella Apple Extracts on Human Colon-Rectal Cells Carrying Familial Adenomatous Polyposis Mutations

PubMed Central

Maisto, Maria; Bottone, Sara; Badolati, Nadia; Rossi, Giovanni Battista; Novellino, Ettore

2017-01-01

Inhibitors of the Wingless-related Integration site (WNT)/β-catenin pathway have recently been under consideration as potential chemopreventive agents against Familial Adenomatous Polyposis (FAP). This autosomal-dominant syndrome is caused by germline mutations in the gene coding for the protein APC and leads to hyperactivation of the WNT/β-catenin signaling pathway, uncontrolled intestinal cell proliferation and formation of adenocarcinomas. The aim of the present work was to: (i) test, on in vitro cultures of cells carrying FAP mutations and on ex vivo biopsies of FAP patients, the WNT inhibitory activity of extracts from two common southern Italian apples, Malus pumila Miller cv. ‘Annurca’ and Malus domestica cv ‘Limoncella’; (ii) identify the mechanisms underpinning their activities and; (iii) evaluate their potency upon gastrointestinal digestion. We here show that both Annurca and Limoncella apple extracts act as WNT inhibitors, mostly thanks to their polyphenolic contents. They inhibit the pathway in colon cells carrying FAP mutations with active dilutions falling in ranges close to consumer-relevant concentrations. Food-grade manufacturing of apple extracts increases their WNT inhibitory activity as result of the conversion of quercetin glycosides into the aglycone quercetin, a potent WNT inhibitor absent in the fresh fruit extract. However, in vitro simulated gastrointestinal digestion severely affected WNT inhibitory activity of apple extracts, as result of a loss of polyphenols. In conclusion, our results show that apple extracts inhibit the WNT pathway in colon cells carrying FAP mutations and represent a potential nutraceutical alternative for the treatment of this pathology. Enteric coating is advisable to preserve the activity of the extracts in the colon-rectal section of the digestive tract. PMID:29156563

Attitudes to predictive DNA testing in familial adenomatous polyposis.

PubMed Central

Whitelaw, S; Northover, J M; Hodgson, S V

1996-01-01

Attitudes to predictive DNA testing for familial adenomatous polyposis were documented in 62 affected adults. Patient views on prenatal testing and termination of pregnancy for this disorder were sought, as were opinions on the most suitable age to offer predictive testing for at risk children and the most appropriate age to begin screening. While 15 (24%) of those questioned stated that they would proceed to termination of pregnancy if a prenatal test indicated that the unborn baby was affected, in clinical practice no one has yet requested this option. Six (10%) people who had refrained from having children for fear of passing on the polyposis gene felt that the arrival of prenatal testing would enable them to consider planning a family. The majority of patients (93%) said they would like their children tested by DNA analysis at birth or in infancy, but felt that 10 to 12 years was the most appropriate time to discuss the diagnosis with the child. PMID:8818937

145 Rhinitis: Where is the Biofilm?

PubMed Central

Gelardi, Matteo; Quaranta, Nicola; Fiorella, Maria Luisa; Passalacqua, Giovanni

2012-01-01

Background Several ultramicroscopic studies have confirmed the presence of biofilms in ENT diseases, such as chronic rhinosinusitis, nasal polyposis or adenoid hypertrophy. Recently, it has been reported that light microscopy nasal cytology can identify biofilms, which appear as cyan-stained “Infectious Spots.” Methods Subjects suffering from a wide spectrum of nasal disorders, after a detailed clinical history and ENT examination, underwent nasal fibroendoscopy, skin prick test, rhinomanometry and nasal cytology. Results 1410 subjects were studied. The infectious spot was present in 107 of them (7.6%) patients; this percentage reached 55.4% in 193 patients who had clear cytologic signs of infectious rhinitis. Biofilms were largely more frequent in patients with adenoid hypertrophy (57.4%), followed by nasal polyposis (24%), chronic rhinosinusitis (9.5%) and non-allergic “cellular” rhinitis (7.6%). Nasal cytology was normal in the remaining patients, with no infectous spot detectable. Statistical analysis showed that nasal resistances were significantly higher in presence of biofilms in patients affected by adenoid hypertrophy (P = 0.003), nasal polyposis (P < 0.001), chronic rhinosinusitis (P = 0.018) and septal deviation (P = 0.001). Conclusions The results demonstrate that biofilms are not present only in infectious rhinopathies, but also in inflammatory and/or immune-mediateddiseases. Biofilms were more frequent in patients with higher degree of nasal obstruction as assessed by nasal endoscopy (grade III and IV adenoids and stage-3 polyposis) and rhinomanometry. Nasal cytology, by allowing the identification of biofilms represents a useful diagnostic tool with promising research implications.

A novel pathogenic splice acceptor site germline mutation in intron 14 of the APC gene in a Chinese family with familial adenomatous polyposis.

PubMed

Wang, Dan; Liang, Shengyun; Zhang, Zhao; Zhao, Guoru; Hu, Yuan; Liang, Shengran; Zhang, Xipeng; Banerjee, Santasree

2017-03-28

Familial adenomatous polyposis (FAP) is an autosomal dominant precancerous condition, clinically characterized by the presence of multiple colorectal adenomas or polyps. Patients with FAP has a high risk of developing colorectal cancer (CRC) from these colorectal adenomatous polyps by the mean age of diagnosis at 40 years. Germline mutations of the APC gene cause familial adenomatous polyposis (FAP). Colectomy has recommended for the FAP patients with significant polyposis. Here, we present a clinical molecular study of a four generation Chinese family with FAP. Clinical diagnosis of FAP has been done according to the phenotype, family history and medical records. Patient's blood samples were collected and genomic DNA was extracted. In order to identify the pathogenic mutation underlying the disease phenotype targeted next-generation sequencing and confirmatory sanger sequencing has undertaken. Targeted next generation sequencing identified a novel heterozygous splice-acceptor site mutation [c.1744-1G>A] in intron 14 of APC gene, which is co-segregated with the FAP phenotypes in the proband and amongst all the affected family members. This mutation is not present in unaffected family members and in normal healthy controls of same ethnic origin. According to the LOVD database for Chinese colorectal cancer patients, in Chinese population, 60% of the previously reported APC gene mutations causes FAP, are missense mutations. This novel splice-acceptor site mutation causing FAP in this Chinese family expands the germline mutation spectrum of the APC gene in the Chinese population.

Laparoscopic Restorative Total Proctocolectomy With Ileal Pouch Anal Anastomosis for Familial Adenomatous Polyposis

PubMed Central

Palanivelu, C.; Sendhilkumar, K.; Parthasarathi, R.; Senthilnathan, P.; Maheshkumar, G.

2008-01-01

Background: Familial adenomatous polyposis is a hereditary disease characterized by the presence of thousands of colonic adenomas, which, if untreated, invariably undergo malignant transformation. Because this disease manifests at a young age, the laparoscopic approach to perform surgery would be desirable due to its cosmetic benefits. We describe our experience with this procedure and review the literature on the topic. Methods: This is a case series of 15 patients who underwent restorative proctocolectomy with ileo-anal pouch anastomosis for familial adenomatous polyposis between 2000 and 2007. The salient operative steps are described. Results: There were 9 males and 6 females, 32 to 52 years of age, with an average age of 44.8 years. The median body mass index was 21.5 (range, 17 to 28). Rectal cancer was already present in 4 patients at the time of diagnosis. The median operating time was 225 minutes. Mean blood loss was 60mL, with none of the patients requiring perioperative blood transfusion. None of the surgeries required conversion to the open approach. Bowel function resumed on the second postoperative day in 12 patients and on the third postoperative day in 3 patients. The median hospital stay was 8 days. Postoperatively, there was no mortality and no serious morbidity. Conclusion: Laparoscopic restorative proctocolectomy with ileal pouch anal anastomosis is a feasible surgery for familial adenomatous polyposis, and considering its cosmetic benefit, is a desirable option for this group of predominantly young patients. PMID:18765048

Laparoscopic restorative total proctocolectomy with ileal pouch anal anastomosis for familial adenomatous polyposis.

PubMed

Palanivelu, C; Jani, Kalpesh; Sendhilkumar, K; Parthasarathi, R; Senthilnathan, P; Maheshkumar, G

2008-01-01

Familial adenomatous polyposis is a hereditary disease characterized by the presence of thousands of colonic adenomas, which, if untreated, invariably undergo malignant transformation. Because this disease manifests at a young age, the laparoscopic approach to perform surgery would be desirable due to its cosmetic benefits. We describe our experience with this procedure and review the literature on the topic. This is a case series of 15 patients who underwent restorative proctocolectomy with ileo-anal pouch anastomosis for familial adenomatous polyposis between 2000 and 2007. The salient operative steps are described. There were 9 males and 6 females, 32 to 52 years of age, with an average age of 44.8 years. The median body mass index was 21.5 (range, 17 to 28). Rectal cancer was already present in 4 patients at the time of diagnosis. The median operating time was 225 minutes. Mean blood loss was 60 mL, with none of the patients requiring perioperative blood transfusion. None of the surgeries required conversion to the open approach. Bowel function resumed on the second postoperative day in 12 patients and on the third postoperative day in 3 patients. The median hospital stay was 8 days. Postoperatively, there was no mortality and no serious morbidity. Laparoscopic restorative proctocolectomy with ileal pouch anal anastomosis is a feasible surgery for familial adenomatous polyposis, and considering its cosmetic benefit, is a desirable option for this group of predominantly young patients.

Advances in mechanisms of asthma, allergy, and immunology in 2010.

PubMed

Broide, David H; Finkelman, Fred; Bochner, Bruce S; Rothenberg, Marc E

2011-03-01

2010 was marked by rapid progress in our understanding of the cellular and molecular mechanisms involved in the pathogenesis of allergic inflammation and asthma. Studies published in the Journal of Allergy and Clinical Immunology described advances in our knowledge of cells associated with allergic inflammation (mast cells, eosinophils, dendritic cells, and T cells), as well as IgE, cytokines, receptors, signaling molecules, and pathways. Studies used animal models, as well as human cells and tissues, to advance our understanding of mechanisms of asthma, eosinophilic esophagitis, food allergy, anaphylaxis and immediate hypersensitivity, mast cells and their disorders, atopic dermatitis, nasal polyposis, and hypereosinophilic syndromes. Additional studies provided novel information about the induction and regulation of allergic inflammation and the genetic contribution to allergic inflammation. Critical features of these studies and their potential effects on human atopic disorders are summarized here. Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Familial Colorectal Cancer: Understanding the Alphabet Soup.

PubMed

Giglia, Matthew D; Chu, Daniel I

2016-09-01

While most colorectal cancers (CRCs) originate from nonhereditary spontaneous mutations, one-third of cases are familial or hereditary. Hereditary CRCs, which account for < 5% of all CRCs, have identifiable germline mutations and phenotypes, such as Lynch syndrome and familial adenomatous polyposis (FAP). Familial CRCs, which account for up to 30% of CRCs, have no identifiable germline mutation or specific pattern of inheritance, but higher-than-expected incidence within a family. Since the discovery that certain genotypes can lead to development of CRC, thousands of mutations have now been implicated in CRC. These new findings have enhanced our ability to identify at-risk patients, initiate better surveillance, and take preventative measures. Given the large number of genes now associated with hereditary and familial CRCs, clinicians should be familiar with the alphabet soup of genes to provide the highest quality of care for patients and families.

Active BRAF-V600E is the key player in generation of a sessile serrated polyp-specific DNA methylation profile

PubMed Central

Dehghanizadeh, Somaye; Khoddami, Vahid; Mosbruger, Timothy L.; Hammoud, Sue S.; Edes, Kornelia; Berry, Therese S.; Done, Michelle; Samowitz, Wade S.; DiSario, James A.; Luba, Daniel G.; Burt, Randall W.

2018-01-01

Background Sessile serrated polyps (SSPs) have emerged as important precursors for a large number of sporadic colorectal cancers. They are difficult to detect during colonoscopy due to their flat shape and the excessive amounts of secreted mucin that cover the polyps. The underlying genetic and epigenetic basis for the emergence of SSPs is largely unknown with existing genetic studies confined to a limited number of oncogenes and tumor suppressors. A full characterization of the genetic and epigenetic landscape of SSPs would provide insight into their origin and potentially offer new biomarkers useful for detection of SSPs in stool samples. Methods We used a combination of genome-wide mutation detection, exome sequencing and DNA methylation profiling (via methyl-array and whole-genome bisulfite sequencing) to analyze multiple samples of sessile serrated polyps and compared these to familial adenomatous polyps. Results Our analysis revealed BRAF-V600E as the sole recurring somatic mutation in SSPs with no additional major genetic mutations detected. The occurrence of BRAF-V600E was coincident with a unique DNA methylation pattern revealing a set of DNA methylation markers showing significant (~3 to 30 fold) increase in their methylation levels, exclusively in SSP samples. These methylation patterns effectively distinguished sessile serrated polys from adenomatous polyps and did so more effectively than parallel gene expression profiles. Conclusions This study provides an important example of a single oncogenic mutation leading to reproducible global DNA methylation changes. These methylated markers are specific to SSPs and could be of important clinical relevance for the early diagnosis of SSPs using non-invasive approaches such as fecal DNA testing. PMID:29590112

Theoretical performance of serrated external occulters for solar coronagraphy. Application to ASPIICS

NASA Astrophysics Data System (ADS)

Rougeot, R.; Aime, C.

2018-04-01

Context. This study is made in the context of the future solar coronagraph ASPIICS of the ESA formation-flying mission Proba-3. Aims: In the context of solar coronagraphy, we provide a comparative study of the theoretical performance of serrated (or toothed) external occulters by varying the number and size of the teeth, which we compare to the sharp-edged and apodized disks. The tooth height is small (a few centimeters), to avoid hindering the observation of the solar corona near the limb. We first analyze the diffraction pattern produced by such occulters. In a second step, we compute the umbra profile by integration over the Sun. Methods: We explored a few methods to compute the diffraction pattern. Two of them were implemented. The first is based on 2D fast Fourier transformation (FFT) routines and a multiplication by the Fresnel filter of the form exp(-iπλzu2). Simple rules were derived and discussed to set the sampling conditions. The Maggi-Rubinowicz representation is then proposed as an alternative method, and is proven to be very efficient for this study. Results: Serrated occulters tend to create a two-level intensity pattern, the inner being the darker, which perfectly matches a previously reported geometrical prediction. The diffraction in this central region is lower by two to four orders of magnitude when compared to the sharp-edged disk. The achieved umbra level at the center ranges from 10-4 to below 10-7, depending on the geometry of the teeth. Conclusions: Our study shows that serrated occulters can achieve a high rejection and can almost reach the performance of the apodized disk when very many teeth are used. We prove that shaped occulters must be preferred to simple disks in solar and stellar coronagraphy.

Taxonomic revision of the Graphipterus serrator (Forskål) group (Coleoptera, Carabidae): an increase from five to 15 valid species

PubMed Central

Renan, Ittai; Assmann, Thorsten; Freidberg, Amnon

2018-01-01

Abstract The south-west Palaearctic Graphipterus serrator group is revised. The systematic concept of the G. serrator group has undergone many changes during the last two centuries, and several different classifications have been published in recent decades. Here, the numerical taxonomy approach is used with the morphological characterization similarity level of the sympatric taxa in order to delimit allopatrically occurring taxa at the species and subspecies level. A key to the species and distribution maps are provided along with analyses of the conservation status and habitat preferences of the taxa. The Graphipterus serrator group currently comprises 16 taxa. Five new species are described: Graphipterus magnus Renan & Assmann, sp. n., Graphipterus mauretensis Renan & Assmann, sp. n., Graphipterus piniamitaii Renan & Freidberg, sp. n., Graphipterus sharonae Renan & Assmann, sp. n., and Graphipterus stagonopsis Renan & Assmann, sp. n. In addition, five taxa are revalidated to full species status: Graphipterus heydeni Kraatz, 1890, stat. rest. (lectotype designated), Graphipterus multiguttatus (Olivier, 1790), stat. rest. (lectotype designated), Graphipterus peletieri Laporte de Castelnau, 1840, stat. rest. (the frequently used name lepeletieri is an error), Graphipterus rotundatus Klug, 1832, stat. rest. (lectotype designated), and Graphipterus valdanii Guérin-Méneville, 1859 stat. rest., and a full species status is proposed for Graphipterus reymondi Antoine, 1953, stat. n. One new synonymy is proposed: Graphipterus kindermanni Chaudoir, 1871, syn. n. of Carabus multiguttatus Olivier, 1790. Lectotype designations were made for Graphipterus heydeni, Graphipterus minutus Dejean, 1822, Graphipterus multiguttatus, and Graphipterus rotundatus. Neotype designations were made for Graphipterus reichei Guérin-Méneville, 1859, Graphipterus intermedius Guérin-Méneville, 1859, and Graphipterus valdanii Guérin-Méneville, 1859. PMID:29731681

Deformation behavior of austenitic stainless steel at deep cryogenic temperatures

NASA Astrophysics Data System (ADS)

Han, Wentuo; Liu, Yuchen; Wan, Farong; Liu, Pingping; Yi, Xiaoou; Zhan, Qian; Morrall, Daniel; Ohnuki, Somei

2018-06-01

The nonmagnetic austenite steels are the jacket materials for low-temperature superconductors of fusion reactors. The present work provides evidences that austenites transform to magnetic martensite when deformation with a high-strain is imposed at 77 K and 4.2 K. The 4.2 K test is characterized by serrated yielding that is related to the specific motion of dislocations and phase transformations. The in-situ transmission electron microscope (TEM) observations in nanoscale reveal that austenites achieve deformation by twinning under low-strain conditions at deep cryogenic temperatures. The generations of twins, martensitic transformations, and serrated yielding are in order of increasing difficulty.

Dynamic Strain Aging of Nickel-Base Alloys 800H and 690

NASA Astrophysics Data System (ADS)

Moss, Tyler E.; Was, Gary S.

2012-10-01

The objective of the current investigation is to characterize the dynamic strain aging (DSA) behavior in alloys 800H and 690. Constant extension rate tests were conducted at strain rates in the range of 10-4 s-1 to 10-7 s-1and temperatures between 295 K and 673 K (22 °C and 400 °C), in an argon atmosphere. Maps for the occurrence of serrated flow as a function of strain rate and temperature were built for both alloys. The enthalpy of serrated flow appearance of alloy 800H was found to be 1.07 ± 0.30 eV.

Investigation of the effect of electric current on serrated deformation and acoustic emission in the aluminum-magnesium alloy 5056

NASA Astrophysics Data System (ADS)

Shibkov, A. A.; Denisov, A. A.; Zheltov, M. A.; Zolotov, A. E.; Gasanov, M. F.; Ivolgin, V. I.

2015-06-01

The effect of direct electric current on the serrated deformation of the aluminum-magnesium alloy 5056 has been studied using the acoustic emission method and high-speed video filming of propagating deformation bands. The phenomenon of the electric current-induced suppression of low-frequency acoustic emission signals has been revealed in the range of 1 Hz-2 kHz, which is connected with the development of Portevin-Le Chatelier deformation bands. The characteristic times of damping and growth of plastic instabilities and acoustic signals caused by them after current turn-on and turn-off, respectively, have been estimated.

Atomic and electronic basis for the serrations of refractory high-entropy alloys

NASA Astrophysics Data System (ADS)

Wang, William Yi; Shang, Shun Li; Wang, Yi; Han, Fengbo; Darling, Kristopher A.; Wu, Yidong; Xie, Xie; Senkov, Oleg N.; Li, Jinshan; Hui, Xi Dong; Dahmen, Karin A.; Liaw, Peter K.; Kecskes, Laszlo J.; Liu, Zi-Kui

2017-06-01

Refractory high-entropy alloys present attractive mechanical properties, i.e., high yield strength and fracture toughness, making them potential candidates for structural applications. Understandings of atomic and electronic interactions are important to reveal the origins for the formation of high-entropy alloys and their structure-dominated mechanical properties, thus enabling the development of a predictive approach for rapidly designing advanced materials. Here, we report the atomic and electronic basis for the valence-electron-concentration-categorized principles and the observed serration behavior in high-entropy alloys and high-entropy metallic glass, including MoNbTaW, MoNbVW, MoTaVW, HfNbTiZr, and Vitreloy-1 MG (Zr41Ti14Cu12.5Ni10Be22.5). We find that the yield strengths of high-entropy alloys and high-entropy metallic glass are a power-law function of the electron-work function, which is dominated by local atomic arrangements. Further, a reliance on the bonding-charge density provides a groundbreaking insight into the nature of loosely bonded spots in materials. The presence of strongly bonded clusters and weakly bonded glue atoms imply a serrated deformation of high-entropy alloys, resulting in intermittent avalanches of defects movement.

Serrated polyps of the colon and rectum: Endoscopic features including image enhanced endoscopy

PubMed Central

Saito, Shoichi; Tajiri, Hisao; Ikegami, Masahiro

2015-01-01

In this review, I outline the characteristic endoscopic findings of serrated lesions of the colorectum based on image enhanced endoscopy (IEE). Histopathologically, lesions with serrated structures are typically classified into the following three types based: hyperplastic polyps (HPs), traditional serrated adenomas (TSAs), and sessile serrated adenoma/polyps (SSA/Ps). Both HP and SSA/P often present as dark-green colors on auto fluorescence imaging (AFI) colonoscopy that are similar to the normal surrounding mucosa. In contrast, TSAs often have elevated shapes and present as magenta colors that are similar to the tubular adenomas. The superficial type of TSA also includes many lesions that present as magenta colors. When SSA/Ps are associated with cytological dysplasia, many lesions present with magenta colors, whereas lesions that are not associated with cytological dysplasia present with dark-green colors. When observed via narrow band imaging (NBI), many SSA/P include lesions with strong mucous adhesions. Because these lesions are observed with reddish mucous adhesions, we refer to them as “red cap sign” and place such signs among the typical findings of SSA/P. Because the dilatation of the pit in SSA/P is observed as a round/oval black dot on magnified observations, we refer to this finding as II-dilatation pit (II-D pit) and also positioned it as a characteristic finding of SSA/P. In contrast, dilatations of the capillary vessels surrounding the glands, such as those that occur in tubular adenoma, are not considered to be useful for differentiating HPs from SSA/Ps. However, in cases in which SSA/P is associated with cytological dysplasia, the dilatation of capillary vessels is observed in the same area. When submucosal layer invasion occurs in the same area, the blood flow presents with irregularities that are similar to those of common colorectal cancer at an early stage and disappears as the invasion proceeds deeply. The surface pattern of invasive cancer that is observed at the tumor surface is also likely to disappear. Based on the above results, we considered that the differentiations between HP and TSA, between TSA and SSA/P, and between HP and SSA/P might become easier due to the concomitant use of white light observation and IEE. We also concluded that AFI and NBI can be useful modalities for SSA/P lesions associated with cytological dysplasia. PMID:26240687

The role of TNF alpha polymorphism and expression in susceptibility to nasal polyposis.

PubMed

Zhang, Guimin; Zhang, Jinmei; Kuang, Manbao; Lin, Peng

2018-05-01

In this study, we first performed a meta-analysis to assess the role of single-nucleotide polymorphism (SNP) within tumor necrosis factor alpha (TNF alpha) gene and TNF alpha expression in the risk of nasal polyposis. STATA 12.0 software was utilized to conduct the Mantel-Haenszel statistics, Cohen statistics, Begg's test, Egger's tests and sensitivity analysis. We systemically carried out the database retrieval and initially identified 486 articles. After screening, 15 articles were included in our meta-analysis. For TNF alpha rs1800629 G/A SNP, compared with control group, an increased risk of nasal polyposis of case group was observed in the models of A vs. G [p (P value of association) = 0.009, OR (odds ratio) = 1.35], GA vs. GG (p = 0.001, OR = 1.69), GA+AA vs. GG (p = 0.010, OR = 1.47). The similar results were observed in Caucasian subgroup (p < 0.05, OR > 1). For TNF alpha rs361525 G/A SNP, no significant difference between control and case group was detected (all p > 0.05). In addition, a significant difference exists between case and control groups in the meta-analyses of TNF alpha expression in nasal mucosal cells, secreted TNF alpha (p < 0.05, OR > 1), but not serum TNF alpha (p = 0.090). The present meta-analysis revealed that TNF alpha rs1800629, increased TNF alpha expression and secretion of nasal mucosal cells were associated with an increased risk of nasal polyposis.

Administering of pregabalin and acetaminophen on management of postoperative pain in patients with nasal polyposis undergoing functional endoscopic sinus surgery.

PubMed

Rezaeian, Ahmad

2017-12-01

Management of postoperative pain is a common problem in endoscopic sinus surgery. The objective of this study is the evaluation of pregabalin and acetaminophen effects on the management of postoperative pain in patients with nasal polyposis undergoing functional endoscopic sinus surgery (FESS). In this clinical trial, double-blinded study, 70 patients with nasal polyposis who have indication of FESS were enrolled to this study. After operation, patients were divided randomly into pregabalin and acetaminophen therapy groups. The pregabalin group (n = 35) was treated under pregabalin 50 mg TDS and the acetaminophen group (n = 35) was treated under tablet acetaminophen 500 mg/6 h. Each group was administered for 3 d. The visual analogue scale (VAS) was measured in onset, 12, 24, 48 and 72 h after surgery. All data were entered into SPSS software (SPSS Inc., Chicago, IL) and appropriate statistical tests were assessed to every relation. In this study, there was no significant difference between two groups according to VAS in onset (p = .37); however, VAS in 12, 24, 48 and 72 h after operation was significantly lower in the pregabalin group compared with the acetaminophen group (p < .0001, for every four). Also in the pregabalin group, adverse effects were significantly lower than the acetaminophen group (p < .03). Pregabalin has more effect, safely and usefully than acetaminophen on the management of postoperative pain in the patients with nasal polyposis undergoing functional endoscopic sinus surgery.

IL-33 activates tumor stroma to promote intestinal polyposis.

PubMed

Maywald, Rebecca L; Doerner, Stephanie K; Pastorelli, Luca; De Salvo, Carlo; Benton, Susan M; Dawson, Emily P; Lanza, Denise G; Berger, Nathan A; Markowitz, Sanford D; Lenz, Heinz-Josef; Nadeau, Joseph H; Pizarro, Theresa T; Heaney, Jason D

2015-05-12

Tumor epithelial cells develop within a microenvironment consisting of extracellular matrix, growth factors, and cytokines produced by nonepithelial stromal cells. In response to paracrine signals from tumor epithelia, stromal cells modify the microenvironment to promote tumor growth and metastasis. Here, we identify interleukin 33 (IL-33) as a regulator of tumor stromal cell activation and mediator of intestinal polyposis. In human colorectal cancer, IL-33 expression was induced in the tumor epithelium of adenomas and carcinomas, and expression of the IL-33 receptor, IL1RL1 (also referred to as IL1-R4 or ST2), localized predominantly to the stroma of adenoma and both the stroma and epithelium of carcinoma. Genetic and antibody abrogation of responsiveness to IL-33 in the Apc(Min/+) mouse model of intestinal tumorigenesis inhibited proliferation, induced apoptosis, and suppressed angiogenesis in adenomatous polyps, which reduced both tumor number and size. Similar to human adenomas, IL-33 expression localized to tumor epithelial cells and expression of IL1RL1 associated with two stromal cell types, subepithelial myofibroblasts and mast cells, in Apc(Min/+) polyps. In vitro, IL-33 stimulation of human subepithelial myofibroblasts induced the expression of extracellular matrix components and growth factors associated with intestinal tumor progression. IL-33 deficiency reduced mast cell accumulation in Apc(Min/+) polyps and suppressed the expression of mast cell-derived proteases and cytokines known to promote polyposis. Based on these findings, we propose that IL-33 derived from the tumor epithelium promotes polyposis through the coordinated activation of stromal cells and the formation of a protumorigenic microenvironment.

[Endocrine-metabolic peculiarities in women of reproductive age with hyperplastic processes of cervix and mammary glands].

PubMed

Kadzhaia, N R; Virsaladze, D K; Tkeshelashvili, B D; Dzhavashvili, L V; Dzhugeli, M K

2006-05-01

The aim of our investigation was the detection of endocrine-metabolic disorders in patients with hyperplastic processes of endomyometrium, uterine cervix and mammary glands. 88 patients of reproductive age with several gynaecological complaints have been investigated. 72 patients with hyperplastic processes in endomyometrium, uterine cervix (hyperplasia, polyposis, myoma) and mammary glands (fibroadenomatosis, adenomatosis) were selected in main group. Control group consisted of 16 patients without any hyperplastic processes of reproductive organs. Metabolic syndrome in main group was revealed in 28% of cases, in control - 18,8% (chi(2)=3,95, p=0,047); insulin resistance - 37,5% and 18,7% (chi(2)=4,59, p=0,033), respectively; obesity - 52,8% and 25,0% (chi(2)=4,05, p=0,045), respectively; dyslipidemia - 52,8% and 0,0%; hypertension - 26,4% and 12,5% (chi(2)=1,88, p=NS), respectively. Blood leptin level in main group was - 13,7+/-10,9 ng/ml, and in control - 5,0+/-2,9 ng/ml (p=0,005). Our results suggest that metabolic syndrome and its components significantly influences the formation of hyperplastic processes of endomyometrium, uterine cervix and mammary glands. Blood leptin level is significantly increased in patients with hyperplastic pathologies.

Identification of five novel modifier loci of ApcMin harbored in the BXH14 recombinant inbred strain

PubMed Central

Siracusa, Linda D.

2012-01-01

Every year thousands of people in the USA are diagnosed with small intestine and colorectal cancers (CRC). Although environmental factors affect disease etiology, uncovering underlying genetic factors is imperative for risk assessment and developing preventative therapies. Familial adenomatous polyposis is a heritable genetic disorder in which individuals carry germ-line mutations in the adenomatous polyposis coli (APC) gene that predisposes them to CRC. The Apc Min mouse model carries a point mutation in the Apc gene and develops polyps along the intestinal tract. Inbred strain background influences polyp phenotypes in Apc Min mice. Several Modifier of Min (Mom) loci that alter tumor phenotypes associated with the Apc Min mutation have been identified to date. We screened BXH recombinant inbred (RI) strains by crossing BXH RI females with C57BL/6J (B6) Apc Min males and quantitating tumor phenotypes in backcross progeny. We found that the BXH14 RI strain harbors five modifier loci that decrease polyp multiplicity. Furthermore, we show that resistance is determined by varying combinations of these modifier loci. Gene interaction network analysis shows that there are multiple networks with proven gene–gene interactions, which contain genes from all five modifier loci. We discuss the implications of this result for studies that define susceptibility loci, namely that multiple networks may be acting concurrently to alter tumor phenotypes. Thus, the significance of this work resides not only with the modifier loci we identified but also with the combinations of loci needed to get maximal protection against polyposis and the impact of this finding on human disease studies. Abbreviations:APCadenomatous polyposis coliGWASgenome-wide association studiesQTLquantitative trait lociSNPsingle-nucleotide polymorphism. PMID:22637734

Genetic and Epigenetic Events Generate Multiple Pathways in Colorectal Cancer Progression

PubMed Central

Pancione, Massimo; Remo, Andrea; Colantuoni, Vittorio

2012-01-01

Colorectal cancer (CRC) is one of the most common causes of death, despite decades of research. Initially considered as a disease due to genetic mutations, it is now viewed as a complex malignancy because of the involvement of epigenetic abnormalities. A functional equivalence between genetic and epigenetic mechanisms has been suggested in CRC initiation and progression. A hallmark of CRC is its pathogenetic heterogeneity attained through at least three distinct pathways: a traditional (adenoma-carcinoma sequence), an alternative, and more recently the so-called serrated pathway. While the alternative pathway is more heterogeneous and less characterized, the traditional and serrated pathways appear to be more homogeneous and clearly distinct. One unsolved question in colon cancer biology concerns the cells of origin and from which crypt compartment the different pathways originate. Based on molecular and pathological evidences, we propose that the traditional and serrated pathways originate from different crypt compartments explaining their genetic/epigenetic and clinicopathological differences. In this paper, we will discuss the current knowledge of CRC pathogenesis and, specifically, summarize the role of genetic/epigenetic changes in the origin and progression of the multiple CRC pathways. Elucidation of the link between the molecular and clinico-pathological aspects of CRC would improve our understanding of its etiology and impact both prevention and treatment. PMID:22888469

Evolution of microstructure of Haynes 230 and Inconel 617 under mechanical testing at high temperatures

NASA Astrophysics Data System (ADS)

Hrutkay, Kyle

Haynes 230 and Inconel 617 are austenitic nickel based superalloys, which are candidate structural materials for next generation high temperature nuclear reactors. High temperature deformation behavior of Haynes 230 and Inconel 617 have been investigated at the microstructural level in order to gain a better understanding of mechanical properties. Tensile tests were performed at strain rates ranging from 10-3-10-5 s -1 at room temperature, 600 °C, 800 °C and 950 °C. Subsequent microstructural analysis, including Scanning Electron Microscopy, Transmission Electron Microscopy, Energy-Dispersive X-ray Spectroscopy, and X-Ray Diffraction were used to relate the microstructural evolution at high temperatures to that of room temperature samples. Grain sizes and precipitate morphologies were used to determine high temperature behavior and fracture mechanics. Serrated flow was observed at intermediate and high temperatures as a result of discontinuous slip and dynamic recrystallization. The amplitude of serration increased with a decrease in the strain rate and increase in the temperature. Dynamic strain ageing was responsible for serrations at intermediate temperatures by means of a locking and unlocking phenomenon between dislocations and solute atoms. Dynamic recrystallization nucleated by grain and twin bulging resulting in a refinement of grain size. Existing models found in the literature were discussed to explain both of these phenomena.

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

PubMed

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

2018-01-01

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

Serrate and Notch specify cell fates in the heart field by suppressing cardiomyogenesis.

PubMed

Rones, M S; McLaughlin, K A; Raffin, M; Mercola, M

2000-09-01

Notch signaling mediates numerous developmental cell fate decisions in organisms ranging from flies to humans, resulting in the generation of multiple cell types from equipotential precursors. In this paper, we present evidence that activation of Notch by its ligand Serrate apportions myogenic and non-myogenic cell fates within the early Xenopus heart field. The crescent-shaped field of heart mesoderm is specified initially as cardiomyogenic. While the ventral region of the field forms the myocardial tube, the dorsolateral portions lose myogenic potency and form the dorsal mesocardium and pericardial roof (Raffin, M., Leong, L. M., Rones, M. S., Sparrow, D., Mohun, T. and Mercola, M. (2000) Dev. Biol., 218, 326-340). The local interactions that establish or maintain the distinct myocardial and non-myocardial domains have never been described. Here we show that Xenopus Notch1 (Xotch) and Serrate1 are expressed in overlapping patterns in the early heart field. Conditional activation or inhibition of the Notch pathway with inducible dominant negative or active forms of the RBP-J/Suppressor of Hairless [Su(H)] transcription factor indicated that activation of Notch feeds back on Serrate1 gene expression to localize transcripts more dorsolaterally than those of Notch1, with overlap in the region of the developing mesocardium. Moreover, Notch pathway activation decreased myocardial gene expression and increased expression of a marker of the mesocardium and pericardial roof, whereas inhibition of Notch signaling had the opposite effect. Activation or inhibition of Notch also regulated contribution of individual cells to the myocardium. Importantly, expression of Nkx2. 5 and Gata4 remained largely unaffected, indicating that Notch signaling functions downstream of heart field specification. We conclude that Notch signaling through Su(H) suppresses cardiomyogenesis and that this activity is essential for the correct specification of myocardial and non-myocardial cell fates.

Epidemiology of goblet cell and microvesicular hyperplastic polyps.

PubMed

Qazi, Taha M; O'Brien, Michael J; Farraye, Francis A; Gould, Ryan W; Chen, Clara A; Schroy, Paul C

2014-12-01

Serrated polyps compromise both typical hyperplastic polyps as well as sessile serrated adenomas and dysplastic serrated polyps. Hyperplastic polyps exhibit two histological patterns: microvesicular hyperplastic polyps (MVHPs) and goblet cell hyperplastic polyps (GCHPs). MVHPs and GCHPs differ in their molecular signature. MVHPs have been frequently found to have the BRAF(V600E) mutation as well as aberrant methylation. In contrast, GCHPs have been associated with the KRAS mutation (KRAS-mut), which are infrequently seen in dysplastic serrated sessile adenomas. The particular risk factors that are associated with development of the types of hyperplastic polyps have not been previously studied. The purpose of this study is to characterize the associations between particular risk factors and the development of goblet cell or microvesicular hyperplastic polyps. We conducted a cross-sectional analysis of 3,543 asymptomatic, mostly average risk patients 50 and 79 years of age undergoing open-access screening colonoscopy between March 2005 and January 2012. Each patient was given a survey regarding 25 reputed risk factors for colorectal neoplasia and the responses were correlated with findings at colonoscopy. Associations between putative risk factors for colorectal neoplasia and MVHPs and GSHPs were examined using multiple logistic regression. MVHPS and GCHPs were identified in 5.3% and 8.7% of patients, respectively. The results of the statistical analysis indicate that a history of smoking greater than 20 years is associated with an increased risk of MVHPs (P<0.005) and GCHPs (P<0.005). An elevated BMI >30 kg/m(2) was also associated with the presence of MVHP at colonoscopy (P<0.005). Blacks and Asians appear to be protected from the development of MVHPs. In contrast, there was a positive association with the presence of GCHP at colonoscopy in blacks. The study suggests that the development of the distinct histological types of hyperplastic polyps are associated with distinct modifiable and non-modifiable lifestyle factors.

Familial polyposis coli: no evidence for increased sensitivity to mitomycin C.

PubMed Central

Mazzullo, H A; Attwood, J; Delhanty, J D

1988-01-01

Spontaneous chromosome instability is well established for the dominantly inherited cancer prone condition, familial polyposis coli (FPC), but conflicting results have been obtained regarding sensitivity to mitomycin C (MMC). We have investigated cell survival in fibroblasts and the induction of sister chromatid exchanges and chromosome damage in lymphocytes and fibroblasts after MMC treatment. We can find no evidence for a differential response of FPC cells as measured by any of these parameters, although individual FPC fibroblast cultures did show an enhanced chromosomal response. Overall, the FPC mutation does not appear to result in defective DNA repair in response to MMC. PMID:2835481

Mismatch repair mRNA and protein expression in intestinal adenocarcinoma in sika deer (Cervus nippon) resembling heritable non-polyposis colorectal cancer in man.

PubMed

Jahns, H; Browne, J A

2015-01-01

Intestinal adenocarcinomas seen in an inbred herd of farmed sika deer (Cervus nippon) morphologically resembled human hereditary non-polyposis colorectal cancer (HNPCC). Features common to both included multiple de novo sites of tumourigenesis in the proximal colon, sessile and non-polyposis mucosal changes, the frequent finding of mucinous type adenocarcinoma, lymphocyte infiltration into the neoplastic tubules and Crohn's-like lymphoid follicles at the deep margin of the tumour. HNPCC is defined by a germline mutation of mismatch repair (MMR) genes resulting in their inactivation and loss of expression. To test the hypothesis that similar MMR gene inactivation occurs in the deer tumours, the expression of the four most important MMR genes, MSH2, MLH1, MSH6 and PMS2, was examined at the mRNA level by reverse transcriptase polymerase chain reaction (n = 12) and at the protein level by immunohistochemistry (n = 40) in tumour and control tissues. All four genes were expressed equally in normal and neoplastic tissues, so MMR gene inactivation could not be implicated in the carcinogenesis of this tumour in sika deer. Copyright © 2014 Elsevier Ltd. All rights reserved.

Berberine potently attenuates intestinal polyps growth in ApcMin mice and familial adenomatous polyposis patients through inhibition of Wnt signalling

PubMed Central

Zhang, Junfang; Cao, Hailong; Zhang, Bing; Cao, Hanwei; Xu, Xiuqin; Ruan, Hang; Yi, Tingting; Tan, Li; Qu, Rui; Song, Gang; Wang, Bangmao; Hu, Tianhui

2013-01-01

As a traditional anti-inflammatory Chinese herbal medicine, Alkaloid berberine has been recently reported to exhibit anti-tumour effects against a wide spectrum of cancer. However, the mechanism was largely unknown. Gene chip array reveals that with berberine treatment, c-Myc, the target gene of Wnt pathway, was down-regulated 5.3-folds, indicating that berberine might inhibit Wnt signalling. TOPflash analysis revealed that Wnt activity was significantly reduced after berberine treatment, and the mechanism of which might be that berberine disrupted β-catenin transfer to nucleus through up-regulating the expression of adenomatous polyposis coli (APC) gene and stabilized APC-β-catenin complex. Berberine administration in ApcMin/+ mice exhibited fewer and smaller polyps in intestine, along with reduction in cyclin D1 and c-Myc expression. In clinical practice, oral administration of berberine also significantly reduced the familial adenomatous polyposis patients' polyp size along with the inhibition of cyclin D1 expression in polyp samples. These observations indicate that berberine inhibits colon tumour formation through inhibition of Wnt/β-catenin signalling and berberine might be a promising drug for the prevention of colon cancer. PMID:24015932

Identification a nonsense mutation of APC gene in Chinese patients with familial adenomatous polyposis.

PubMed

Li, Haishan; Zhang, Lingling; Jiang, Quan; Shi, Zhenwang; Tong, Hanxing

2017-04-01

Familial adenomatous polyposis (FAP; Mendelian of Inherintance in Man ID, 175100) is a rare autosomal dominant disorder characterized by the development of numerous adenomatous polyps throughout the colon and rectum associated with an increased risk of colorectal cancer. FAP is at time accompanied with certain extraintestinal manifestations such as congenital hypertrophy of the retinal pigment epithelium, dental disorders and desmoid tumors. It is caused by mutations in the adenomatous polyposis coli ( APC ) gene. The present study reported on a Chinese family with FAP. Polymerase chain reaction and direct sequencing of the full coding sequence of the APC gene were performed to identify the mutation in this family. A nonsense mutation of the APC gene was identified in this pedigree. It is a heterozygous G>T substitution at position 2,971 in exon 15 of the APC gene, which formed a premature stop codon at amino acid residue 991 (p.Glu991*). The resulting truncated protein lacked 1,853 amino acids. The present study expanded the database on APC gene mutations in FAP and enriched the spectrum of known germline mutations of the APC gene. Prophylactic proctocolectomy may be considered as a possible treatment for carriers of the mutation.

Anaesthesia in aspirin-induced asthma.

PubMed

Celiker, V; Basgül, E

2003-01-01

The triad of bronchial asthma, nasal polyposis, and intolerance to aspirin and aspirin-like chemicals are designated aspirin-induced asthma (AIA) or Samter's syndrome. The exact mechanism of the disease is unknown but it is thought to be a disorder of arachidonic acid metabolism. These patients are frequently referred to allergy clinics for preoperative evaluation for possible anesthetic agent sensitivity, requiring anesthesia for nasal polypectomy or several other reasons. Anesthetists must be aware of their pulmonary dysfunction, because the anesthetic management of asthma requires a specific approach. Marked cross-sensitivity with NSAIDs, which may also precipitate severe bronchospasm and adverse reactions, is the main problem faced by anesthetists in postoperative pain management. This article discusses the relationship between AIA and anesthesia. We also present our experience with 47 patients diagnosed with AIA between 1991 and 2003 in the department of chest diseases and adult allergy unit who underwent surgery requiring general anesthesia. In conclusion, preoperative evaluation of these patients and collaboration between the allergists and anesthesiologists is essential to prevent preoperative, perioperative and postoperative complications.

Histological variations in juvenile polyp phenotype correlate with genetic defect underlying juvenile polyposis

PubMed Central

van Hattem, W. Arnout; Langeveld, Danielle; de Leng, Wendy W. J.; Morsink, Folkert H.; van Diest, Paul J.; Iacobuzio-Donahue, Christine A.; Giardiello, Francis M.; Offerhaus, G. Johan A.; Brosens, Lodewijk A. A.

2011-01-01

Background Juvenile polyps are distinct hamartomatous malformations of the gastrointestinal tract that may occur in the heritable juvenile polyposis syndrome (JPS) or sporadically. Histologically, juvenile polyps are characterised by a marked increase of the stromal cell compartment but, an epithelial phenotype has also been reported. JPS has an increased risk of colorectal cancer but sporadic juvenile polyps do not. In 50–60% of JPS patients a germline mutation of the TGF-β/BMP pathway genes SMAD4 or BMPR1A is found. This study compares the histological phenotype of juvenile polyps with a SMAD4 or BMPR1A germline mutation and sporadic juvenile polyps. Methods H&E slides of 65 JPS polyps and 25 sporadic juvenile polyps were reviewed for histological features and dysplasia. Systematic random crypt and stroma counts were obtained by count stereology and a crypt-stroma ratio was determined. All polyps were subsequently categorised as type A (crypt-stroma ratio <1.00) or type B (crypt-stroma ratio ≥1.00), the latter referring to the epithelial phenotype. Cell cycle activity was assessed using immunohistochemistry of the proliferation marker Ki67, and mutation analysis was conducted for KRAS and APC to determine the involvement of the adenoma-carcinoma sequence. Results Juvenile polyps with a SMAD4 germline mutation were predominantly type B, whereas, type A was more common among juvenile polyps with a BMPR1A germline mutation, but this distinction could not be ascribed to differences in cell cycle activity. Dysplasia was equally common in JPS polyps with either a SMAD4 or BMPR1A germline mutation, where the involvement of the adenoma-carcinoma sequence does not seem to play a distinct role. Conclusion juvenile polyps in the setting of JPS exhibit distinct phenotypes correlating with the underlying genetic defect. PMID:21412070

Three-dimensional finite element analyses of four designs of a high-strength silicon nitride implant.

PubMed

Lin, S; Shi, S; LeGeros, R Z; LeGeros, J P

2000-01-01

The effects of implant shape and size on the stress distribution around high-strength silicon nitride implants under vertical and oblique forces were determined using a three-dimensional finite element analysis. Finite element models were designed using as a basis the serial sections of the mandible. Using Auto-CAD software, the model simulated the placement of implants in the molar region of the left mandible. Results of the analyses demonstrated that mainly the implant root shape and the directions of bite forces influence the stress distributions in the supporting bone around each implant. Implant size is a lesser factor. The serrated implants presented a larger surface area to the bone than either the cylindrical or tapered implants, which resulted in lower compressive stress around the serrated implants. With increasing implant diameter and length, compressive stress decreased. The mean compressive stress distribution on the serrated implants was more flat (platykurtic) than on either the cylindrical or tapered implants. Results of studies on two load directions (vertical and oblique) showed that, in either case, the compressive stress in the cortical bone around the neck of the implant was higher than in the cancellous bone along the length of the implant. The most extreme principal compressive stress was found with oblique force. This study provides the first information on the relationship between shape of the silicon nitride implant and stress on the supporting bone.

Updated Histologic Classification of Adenomas and Carcinomas in the Colon of Carcinogen-treated Sprague-Dawley Rats.

PubMed

Rubio, Carlos A

2017-12-01

Recent studies have disclosed novel histological phenotypes of colon tumours in carcinogen-treated rats. The aim of this study was to update the current histological classification of colonic neoplasias in Sprague-Dawley (SD) rats. Archival sections from 398 SD rats having 408 neoplasias in previous experiments were re-evaluated. Of the 408 colonic neoplasias, 11% (44/408) were adenomas without invasive growth and 89% (364/408) invasive carcinomas. Out of the 44 adenomas, 82% were conventional (tubular or villous), 14% traditional serrated (TSA; with unlocked serrations or with closed microtubules) and 5% gut-associated lymphoid tissue (GALT)-associated adenomas. Out of 364 carcinomas, 57% were conventional carcinomas, 26% GALT carcinomas, 8% undifferentiated, 6% signet-ring cell carcinomas, and 4% traditional serrated carcinomas (TSC). Thus, conventional adenomas, conventional carcinomas and GALT-associated carcinomas predominated (p<0.05). The updated classification of colonic tumours in SD rats includes conventional adenomas, TSA, GALT-associated adenomas, conventional carcinomas, TSC, GALT-associated carcinomas, signet-ring cell carcinomas and undifferentiated carcinomas. Several of the histological phenotypes reported here are not included in any of the current classifications of colonic tumours in rodents. This updated classification fulfils the requirements for an animal model of human disease, inasmuch as similar histological phenotypes of colon neoplasias have been documented in humans. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Features of electrocoagulation syndrome after endoscopic submucosal dissection for colorectal neoplasm.

PubMed

Yamashina, Takeshi; Takeuchi, Yoji; Uedo, Noriya; Hamada, Kenta; Aoi, Kenji; Yamasaki, Yasushi; Matsuura, Noriko; Kanesaka, Takashi; Akasaka, Tomofumi; Yamamoto, Sachiko; Hanaoka, Noboru; Higashino, Koji; Ishihara, Ryu; Iishi, Hiroyasu

2016-03-01

Endoscopic submucosal dissection (ESD) is a promising treatment for large gastrointestinal superficial neoplasms, although it is technically difficult, and perforation and delayed bleeding are well-known adverse events. However, there have been no large studies about electrocoagulation syndrome after colorectal ESD. The aim of this study was to evaluate the incidence and clinical significant risk factors of post-ESD coagulation syndrome (PECS). This was a retrospective cohort study conducted in a referral cancer center. A total of 336 patients with colorectal neoplasms (143 adenomas or serrated lesions and 193 carcinomas) underwent ESD from January 2011 to June 2013. Incidence, outcome, and factors associated with occurrence of PECS were investigated. Occurred in 32 patients (9.5%). The median time until PECS was 15.5 h, and the median period of PECS was 32.5 h. Fever (≥37.6 °C) after ESD was found in 41% of the PECS group and 9% of the non-PECS group (P < 0.001). All PECS cases were managed conservatively. On multivariate analysis, female patients (odds ratio [OR] = 3.2, P = 0.002), lesion location at ascending colon and cecum (OR = 3.5, P = 0.001), and resected specimen ≥40 mm (OR = 2.1, P = 0.05) were independent risk factors for PECS. Occurred in 32 patients (9.5%) with colorectal ESD; however, all cases had a good outcome with conservative management. Female sex, tumor location at the ascending colon and cecum, and resected specimen ≥40 mm were independently significant risk factors for PECS. © 2015 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

Anterior ischaemic optic neuropathy in eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome): a case report and review of the literature.

PubMed

Padovano, Ilaria; Pazzola, Giulia; Pipitone, Nicolò; Cimino, Luca; Salvarani, Carlo

2014-01-01

We report a 62-year-old man with mild fever, headache and acute visual loss in his right eye due to anterior ischaemic optic neuropathy (AION), followed a few days later by pain in the legs and left arm associated with numbness and weakness. Giant cell arteritis complicated by AION was suspected at the beginning and high-dose oral glucocorticoids were started. However, on the basis of the past medical history of nasal polyposis, asthma, and hypereosynophilia as well as of further investigations (biopsy of the nasal mucosa showing granulomatous inflammation with a rich eosinophilic infiltrate, electromyography demonstrating, mononeuritis multiplex and positive p-ANCA), eosinophilic granulomatosis with polyangiitis (EGPA), previously known as Churg-Strauss syndrome, was diagnosed. Because visual acuity in the right eye deteriorated despite glucocorticoid therapy, pulse intravenous cyclophosphamide was started, subsequently replaced by oral azathioprine, while prednisone was slowly tapered. This treatment led to gradual improvement of the neurological symptoms, whereas the right visual impairment remained unchanged. EGPA-related AION is an uncommon lesion that is probably due to vasculitic involvement of posterior ciliary and/or chorioretinal arteries. The prognosis of established AION is poor for the affected eye, even when glucocorticoid treatment is started immediately. However, early recognition of AION and prompt aggressive treatment with high-dose glucocorticoids plus cyclophosphamide can prevent visual loss in the unaffected eye.

Mechanism of action of glucocorticoids in nasal polyposis.

PubMed

Fernandes, Atílio Maximino; Valera, Fabiana Cardoso Pereira; Anselmo-Lima, Wilma T

2008-01-01

Glucocorticoids (GC) are the drugs of choice for the clinical treatment of nasal polyposis, according to the medical literature. Its mechanism of action in the regression of clinical symptoms and polyps, however, is not fully understood. The topical and/or systemic use of glucocorticoids lead to variable expression of cytokines, chemokines and lymphokines, as well as changes in cells. It is known that GC suppresses the expression of pro-inflammatory cytokines, chemokines and adhesion molecules such as ICAM-1 and E-selectin; GC also stimulate the transcription of anti-inflammatory cytokines such as TGF-b. GC suppress pro-fibrotic cytokines related to polyp growth, such as IL-11, the basic fibroblast growth factor (b-FGF), and the vascular endotelial growth factor (VEGF). The action of GC depends fundamentally on their interaction with receptors (GR); certain subjects have a degree of resistance to its effect, which appears to be related with the presence of a b isoform of GR. GC also act variably on the genes involved in immunoglobulin production, presentation, and antigen processing. We present a review of the literature on the mechanisms of GC action in nasal polyosis. Understanding the mechanism of action of GC in nasal polyposis will aid in the development of new, more efficient, drugs.

The role of human papilloma virus and herpes viruses in the etiology of nasal polyposis.

PubMed

Koçoğlu, Mücahide Esra; Mengeloğlu, Fırat Zafer; Apuhan, Tayfun; Özsoy, Şeyda; Yilmaz, Beyhan

2016-02-17

The aim of this study was to investigate the etiological role of human papilloma virus (HPV), herpes simplex virus (HSV), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), and human herpes virus-6 (HHV-6) and -7 (HHV-7) in the occurrence of nasal polyposis. Nasal polyp samples from 30 patients with nasal polyposis and normal nasal mucosa from 10 patients without nasal polyps were obtained. DNA was extracted from tissues. Real-time polymerase chain reaction was performed for all runs. No HSV-1, HSV-2, or VZV was detected in the samples. Among the patient samples, EBV and HHV-7 DNA were detected in 18 (60%), HHV-6 was detected in 20 (66.7%), and HPV was detected in 4 (13.3%) samples. Among the controls, CMV DNA was positive in one (10%). EBV was positive in 5 (50%), HHV-6 and HHV-7 were positive in 7 (70%), and HPV was positive in 2 (20%) samples. No significant difference was found among the groups with any test in terms of positivity. The association of Herpesviridae and HPV with the pathogenesis of nasal polyps was investigated in this study and no relationship was found. Thus, these viruses do not play a significant role in the formation of nasal polyps.

Tsallis q-triplet, intermittent turbulence and Portevin-Le Chatelier effect

NASA Astrophysics Data System (ADS)

Iliopoulos, A. C.; Aifantis, E. C.

2018-05-01

In this paper, we extend a previous study concerning Portevin-LeChatelier (PLC) effect and Tsallis statistics (Iliopoulos et al., 2015). In particular, we estimate Tsallis' q-triplet, namely {qstat, qsens, qrel} for two sets of stress serration time series concerning the deformation of Cu-15%Al alloy corresponding to different deformation temperatures and thus types (A and B) of PLC bands. The results concerning the stress serrations analysis reveal that Tsallis q- triplet attains values different from unity ({qstat, qsens, qrel} ≠ {1,1,1}). In particular, PLC type A bands' serrations were found to follow Tsallis super-q-Gaussian, non-extensive, sub-additive, multifractal statistics indicating that the underlying dynamics are at the edge of chaos, characterized by global long range correlations and power law scaling. For PLC type B bands' serrations, the results revealed a Tsallis sub-q-Gaussian, non-extensive, super-additive, multifractal statistical profile. In addition, our results reveal also significant differences in statistical and dynamical features, indicating important variations of the stress field dynamics in terms of rate of entropy production, relaxation dynamics and non-equilibrium meta-stable stationary states. We also estimate parameters commonly used for characterizing fully developed turbulence, such as structure functions and flatness coefficient (F), in order to provide further information about jerky flow underlying dynamics. Finally, we use two multifractal models developed to describe turbulence, namely Arimitsu and Arimitsu (A&A) [2000, 2001] theoretical model which is based on Tsallis statistics and p-model to estimate theoretical multifractal spectrums f(a). Furthermore, we estimate flatness coefficient (F) using a theoretical formula based on Tsallis statistics. The theoretical results are compared with the experimental ones showing a remarkable agreement between modeling and experiment. Finally, the results of this study verify, as well as, extend previous studies which stated that type B and type A PLC bands underlying dynamics are connected with distinct dynamical behavior, namely chaotic behavior for the first and self-organized critical (SOC) behavior for the latter, while they shed new light concerning the turbulent character of the PLC jerky flow.

Ionizing radiation, inflammation, and their interactions in colon carcinogenesis in Mlh1-deficient mice.

PubMed

Morioka, Takamitsu; Miyoshi-Imamura, Tomoko; Blyth, Benjamin J; Kaminishi, Mutsumi; Kokubo, Toshiaki; Nishimura, Mayumi; Kito, Seiji; Tokairin, Yutaka; Tani, Shusuke; Murakami-Murofushi, Kimiko; Yoshimi, Naoki; Shimada, Yoshiya; Kakinuma, Shizuko

2015-03-01

Genetic, physiological and environmental factors are implicated in colorectal carcinogenesis. Mutations in the mutL homolog 1 (MLH1) gene, one of the DNA mismatch repair genes, are a main cause of hereditary colon cancer syndromes such as Lynch syndrome. Long-term chronic inflammation is also a key risk factor, responsible for colitis-associated colorectal cancer; radiation exposure is also known to increase colorectal cancer risk. Here, we studied the effects of radiation exposure on inflammation-induced colon carcinogenesis in DNA mismatch repair-proficient and repair-deficient mice. Male and female Mlh1(-/-) and Mlh1(+/+) mice were irradiated with 2 Gy X-rays when aged 2 weeks or 7 weeks and/or were treated with 1% dextran sodium sulfate (DSS) in drinking water for 7 days at 10 weeks old to induce mild inflammatory colitis. No colon tumors developed after X-rays and/or DSS treatment in Mlh1(+/+) mice. Colon tumors developed after DSS treatment alone in Mlh1(-/-) mice, and exposure to radiation prior to DSS treatment increased the number of tumors. Histologically, colon tumors in the mice resembled the subtype of well-to-moderately differentiated adenocarcinomas with tumor-infiltrating lymphocytes of human Lynch syndrome. Immunohistochemistry revealed that expression of both p53 and β-catenin and loss of p21 and adenomatosis polyposis coli proteins were observed at the later stages of carcinogenesis, suggesting a course of molecular pathogenesis distinct from typical sporadic or colitis-associated colon cancer in humans. In conclusion, radiation exposure could further increase the risk of colorectal carcinogenesis induced by inflammation under the conditions of Mlh1 deficiency. © 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

Ionizing radiation, inflammation, and their interactions in colon carcinogenesis in Mlh1-deficient mice

PubMed Central

Morioka, Takamitsu; Miyoshi-Imamura, Tomoko; Blyth, Benjamin J; Kaminishi, Mutsumi; Kokubo, Toshiaki; Nishimura, Mayumi; Kito, Seiji; Tokairin, Yutaka; Tani, Shusuke; Murakami-Murofushi, Kimiko; Yoshimi, Naoki; Shimada, Yoshiya; Kakinuma, Shizuko

2015-01-01

Genetic, physiological and environmental factors are implicated in colorectal carcinogenesis. Mutations in the mutL homolog 1 (MLH1) gene, one of the DNA mismatch repair genes, are a main cause of hereditary colon cancer syndromes such as Lynch syndrome. Long-term chronic inflammation is also a key risk factor, responsible for colitis-associated colorectal cancer; radiation exposure is also known to increase colorectal cancer risk. Here, we studied the effects of radiation exposure on inflammation-induced colon carcinogenesis in DNA mismatch repair-proficient and repair-deficient mice. Male and female Mlh1−/− and Mlh1+/+ mice were irradiated with 2 Gy X-rays when aged 2 weeks or 7 weeks and/or were treated with 1% dextran sodium sulfate (DSS) in drinking water for 7 days at 10 weeks old to induce mild inflammatory colitis. No colon tumors developed after X-rays and/or DSS treatment in Mlh1+/+ mice. Colon tumors developed after DSS treatment alone in Mlh1−/− mice, and exposure to radiation prior to DSS treatment increased the number of tumors. Histologically, colon tumors in the mice resembled the subtype of well-to-moderately differentiated adenocarcinomas with tumor-infiltrating lymphocytes of human Lynch syndrome. Immunohistochemistry revealed that expression of both p53 and β-catenin and loss of p21 and adenomatosis polyposis coli proteins were observed at the later stages of carcinogenesis, suggesting a course of molecular pathogenesis distinct from typical sporadic or colitis-associated colon cancer in humans. In conclusion, radiation exposure could further increase the risk of colorectal carcinogenesis induced by inflammation under the conditions of Mlh1 deficiency. PMID:25529563

Severe Gardner syndrome in families with mutations restricted to a specific region of the APC gene

DOE Office of Scientific and Technical Information (OSTI.GOV)

Davies, D.R.; Armstrong, J.G.; Thakker, N.

Familial adenomatous polyposis (FAP) is associated with a number of extraintestinal manifestations, which include osteomas, epidermoid cysts, and desmoid tumors, often referred to as {open_quotes}Gardner syndrome.{close_quotes} Recent studies have suggested that some of the phenotypic features of FAP are dependent on the position of the mutation within the APC gene. In particular, the correlation between congenital hypertrophy of the retinal pigment epithelium (CHRPE) and APC genotype indicates that affected families may be divided into distinct groups. We have investigated the association between the dento-osseous features of GS on dental panoramic radiographs (DPRs) and APC genotype in a regional cohort ofmore » FAP families. DPRs were performed on 84 affected individuals from 36 families, and the dento-osseous features of FAP were quantified by a weighted scoring system. Significant DPR abnormalities were present in 69% of affected individuals. The APC gene mutation was identified in 27 of these families, and for statistical analysis these were subdivided into three groups. Group 1 comprised 18 affected individuals from seven families with mutations 5{prime} of exon 9; these families (except one) did not express CHRPE. Groups 2 comprised 38 individuals from 16 families with mutations between exon 9 and codon 1444, all of whom expressed CHRPE. Group 3 comprised 11 individuals from four families with mutations 3{prime} of codon 1444, none of whom expressed CHRPE. Families with mutations 3{prime} of codon 1444 had significantly more lesions on DPRs (P < .001) and appeared to have a higher incidence of desmoid tumors. These results suggest that severity of some of the features of Gardner syndrome may correlate with genotype in FAP. 32 refs., 2 figs., 2 tabs.« less

Microstructural Evaluations of Baseline HSR/EPM Disk Alloys

NASA Technical Reports Server (NTRS)

Gabb, Timothy P.; Garg, Anita; Ellis, David L.

2004-01-01

Six alloys representing two classes of powder metallurgy nickel-based superalloys were examined by transmission electron microscopy (TEM) and phase extraction. Alloys KM4, CH98, IN-100 and 456 are based on a Ni-18Co-12Cr composition while alloys Rene' 88 DT and SR 3 have lower Al and Co and higher Cr contents. The lambda size distributions were determined from quantitative image analysis of the TEM images. The volume fraction of lambda and carbides and the composition of the phases were determined by a combination of phase extraction and TEM. The results showed many similarities in lambda size distributions, grain boundary serrations, and grain boundary carbide frequencies between alloys KM4, CH98, 456, Rene' 88 DT and SR 3 when heat treated to give an approximate grain size of ASTM 6. The density of grain boundary carbides in KM4 was shown to substantially increase as the grain size increased. IN-100 and 456 subjected to a serration cooling heat treatment had much more complex lambda size distributions with very large intergranular and intragranular secondary lambda as well as finer than average cooling and aging lambda. The grain boundary carbides in IN-100 were similar to the other alloys, but 456 given the serration cooling heat treatment had a more variable density of grain boundary carbides. Examination of the phases extracted from the matrix showed that there were significant differences in the phase chemistries and elemental partitioning ratios between the various alloys.

Contribution of the MLH1 -93G>a promoter polymorphism in modulating susceptibility risk in Malaysian colorectal cancer patients.

PubMed

Nizam, Zahary Mohd; Abdul Aziz, Ahmad Aizat; Kaur, Gurjeet; Abu Hassan, Muhammad Radzi; Mohd Sidek, Ahmad Shanwani; Yeh, Lee Yeong; Mazuwin, Maya; Ankathil, Ravindran

2013-01-01

Colorectal cancer (CRC) exists in a more common sporadic form and less common hereditary forms, associated with the Lynch syndrome, familial adenomatous polyposis (FAP) and other rare syndromes. Sporadic CRC is believed to arise as a result of close interaction between environmental factors, including dietary and lifestyle habits, and genetic predisposition factors. In contrast, hereditary forms such as those related to the Lynch syndrome result from inheritance of germline mutations of mismatch repair (MMR) genes. However, in certain cases, the influence of low penetrance alleles in familial colorectal cancer susceptibility is also undeniable. To investigate the genotype frequencies of MLH1 promoter polymorphism -93G>A and to determine whether it could play any role in modulating familial and sporadic CRC susceptibility risk. A case-control study comprising of 104 histopathologically confirmed CRC patients as cases (52 sporadic CRC and 52 Lynch syndrome patients) and 104 normal healthy individuals as controls was undertaken. DNA was extracted from peripheral blood and the polymorphism was genotyped employing PCR-RFLP methods. The genotypes were categorized into homozygous wild type, heterozygous and homozygous variants. The risk association between these polymorphisms and CRC susceptibility risk was calculated using binary logistic regression analysis and deriving odds ratios (ORs). When risk association was investigated for all CRC patients as a single group, the heterozygous (G/A) genotype showed a significantly higher risk for CRC susceptibility with an OR of 2.273, (95%CI: 1.133-4.558 and p-value=0.021). When analyzed specifically for the 2 types of CRC, the heterozygous (G/A) genotype showed significantly higher risk for sporadic CRC susceptibility with and OR of 3.714, (95%CI: 1.416-9.740 and p-value=0.008). Despite high OR value was observed for Lynch syndrome (OR: 1.600, 95%CI: 0.715-3.581), the risk was not statistically significant (P=0.253). Our results suggest an influence of MLH1 promoter polymorphism -93G>A in modulating susceptibility risk in Malaysian CRC patients, especially those with sporadic disease.

Gel-Sinuplasty for Chronic Rhinosinusitis With and Without Nasal Polyposis

ClinicalTrials.gov

2018-03-13

Chronic Sinusitis, Ethmoidal; Chronic Sinusitis - Ethmoidal Anterior; Chronic Sinusitis; Chronic Sinusitis - Ethmoidal, Posterior; Chronic Sinusitis, Sphenoidal; Chronic Sinusitis - Frontoethmoidal; Nasal Polyps; Nasal Polyp - Posterior

Endoglin (CD105) expression in sinonasal polyposis.

PubMed

Ottaviano, Giancarlo; Cappellesso, Rocco; Mylonakis, Ioannis; Lionello, Marco; Favaretto, Niccolò; Giacomelli, Luciano; Spoladore, Cristiano; Marchese-Ragona, Rosario; Marino, Filippo; Staffieri, Alberto; Martini, Alessandro; Marioni, Gino

2015-11-01

Despite appropriate surgical therapy, 5-10 % of patients with chronic rhinosinusitis (CRS) and nasal polyps (NP) experience disease recurrences. It has been suggested that angiogenesis may relate to the pathogenesis and prognosis of CRS with NP. Endoglin (CD105) is a component of the receptor complex of transforming growth factor-beta, a pleiotropic cytokine that modulates angiogenesis. A series of patients treated surgically for CRS with NP was analyzed to assess the relationship between CD105 expression, main clinicopathological features, and recurrence rate. The immunohistochemical expression of CD105 was assessed in 70 patients consecutively operated for CRS with NP. In the univariate setting, the presence of CD105 (1/0) showed a trend towards a significant association with increasing NP dimensions (p = 0.054). Intensity of CD105 reaction was also significantly associated with NP size (0.04) and with an eosinophilic histology (p = 0.048). In our multivariate setting, only asthma (p = 0.016), hypereosinophilia (p = 0.022), and preoperative polyposis score (p = 0.046) retained their independent prognostic significance in relation to NP recurrence. Further efforts are needed to elucidate the biological, angiogenic and proliferative mechanisms behind recurrent NP. Our preliminary results support the clinical utility of extra postoperative care, in terms of closer follow-ups and medication with oral anti-histamines, topical and/or oral steroids, and antileukotrienes in patients with asthma, advanced nasal polyposis at presentation, and serum hypereosinophilia.

High-resolution melting (HRM) re-analysis of a polyposis patients cohort reveals previously undetected heterozygous and mosaic APC gene mutations.

PubMed

Out, Astrid A; van Minderhout, Ivonne J H M; van der Stoep, Nienke; van Bommel, Lysette S R; Kluijt, Irma; Aalfs, Cora; Voorendt, Marsha; Vossen, Rolf H A M; Nielsen, Maartje; Vasen, Hans F A; Morreau, Hans; Devilee, Peter; Tops, Carli M J; Hes, Frederik J

2015-06-01

Familial adenomatous polyposis is most frequently caused by pathogenic variants in either the APC gene or the MUTYH gene. The detection rate of pathogenic variants depends on the severity of the phenotype and sensitivity of the screening method, including sensitivity for mosaic variants. For 171 patients with multiple colorectal polyps without previously detectable pathogenic variant, APC was reanalyzed in leukocyte DNA by one uniform technique: high-resolution melting (HRM) analysis. Serial dilution of heterozygous DNA resulted in a lowest detectable allelic fraction of 6% for the majority of variants. HRM analysis and subsequent sequencing detected pathogenic fully heterozygous APC variants in 10 (6%) of the patients and pathogenic mosaic variants in 2 (1%). All these variants were previously missed by various conventional scanning methods. In parallel, HRM APC scanning was applied to DNA isolated from polyp tissue of two additional patients with apparently sporadic polyposis and without detectable pathogenic APC variant in leukocyte DNA. In both patients a pathogenic mosaic APC variant was present in multiple polyps. The detection of pathogenic APC variants in 7% of the patients, including mosaics, illustrates the usefulness of a complete APC gene reanalysis of previously tested patients, by a supplementary scanning method. HRM is a sensitive and fast pre-screening method for reliable detection of heterozygous and mosaic variants, which can be applied to leukocyte and polyp derived DNA.

[Rare indication of cephalic duodenopancreatectomy with total gastrectomy--periampullary carcinoma in moderate form of familial adenomatous polyposis].

PubMed

Stănciulea, Oana; Preda, Carmen; Herlea, V; Popa, Monica; Ulmeanu, D; Vasilescu, C

2007-01-01

We present the case of a 52 years old man, with significant familial history, diagnosed with familial adenomatous polyposis-attenuated form, with no clinical and endoscopic surveillance until 2001 when he was admitted for an upper gastrointestinal haemorrhage episode. Upper gastrointestinal scopy revealed duodenal adenomatous polyps and gastric hyperplastic polyps. The patient underwent duodenopancreatectomy with total gastrectomy. The histopathological exam revealed duodenal G2 adenocarcinoma pT3N0, and gastric hyperplastic polyps with no signs of dysplasia. The surgical procedure was followed by chemotherapy. In 2002 the patient was admitted for rectal bleeding and colonoscopy showed 2 sigmoid polyps, appropriate for endoscopic removal and a poly-lobate polyp in the transverse colon. The patient underwent transverse colectomy (the histopathological exam--in situ carcinoma). March 2003--the patient underwent endoscopic removal for a rectal polyp (histopathological exam: moderate dysplasia). In 2005 was noted a pulmonary nodule, located in the postero-apical segment of upper left lobe, for which left superior lobe resection was performed (the histopathological exam: metastatic adenocarcinoma). In May 2006 was performed an exploratory laparotomy. Intraoperatively were noted: peritoneal carcinomatosis and multiple liver metastasis. The surgical procedure recommended in patients with attenuated form of familial adenomatous polyposis and suspect periampullary lesions is duodenopancreatectomy. The particularity of the case is the association of total gastrectomy for gastric hyperplastic polyps.

Co-morbidities in severe asthma: Clinical impact and management.

PubMed

Porsbjerg, Celeste; Menzies-Gow, Andrew

2017-05-01

Patients with severe asthma represent a minority of the total asthma population, but carry a majority of the morbidity and healthcare costs. Achieving better asthma control in this group of patients is therefore of key importance. Systematic assessment of patients with possible severe asthma to identify treatment barriers and triggers of asthma symptoms, including co-morbidities, improves asthma control and reduces healthcare costs and is recommended by international guidelines on management of severe asthma. This review provides the clinician with an overview of the prevalence and clinical impact of the most common co-morbidities in severe asthma, including chronic rhinosinusitis, nasal polyposis, allergic rhinitis, dysfunctional breathing, vocal cord dysfunction, anxiety and depression, obesity, obstructive sleep apnoea syndrome (OSAS), gastroesophageal reflux disease (GERD), bronchiectasis, allergic bronchopulmonary aspergillosis (ABPA) and eosinophilic granulomatous with polyangiitis (EGPA). Furthermore, the review offers a summary of recommended diagnostic and management approaches for each co-morbidity. Finally, the review links co-morbid conditions to specific phenotypes of severe asthma, in order to guide the clinician on which co-morbidities to look for in specific patients. © 2017 Asian Pacific Society of Respirology.

Video capsule endoscopy: Perspectives of a revolutionary technique

PubMed Central

Bouchard, Simon; Ibrahim, Mostafa; Van Gossum, Andre

2014-01-01

Video capsule endoscopy (VCE) was launched in 2000 and has revolutionized direct endoscopic imaging of the gut. VCE is now a first-line procedure for exploring the small bowel in cases of obscure digestive bleeding and is also indicated in some patients with Crohn’s disease, celiac disease, and polyposis syndrome. A video capsule has also been designed for visualizing the esophagus in order to detect Barrett’s esophagus or esophageal varices. Different capsules are now available and differ with regard to dimensions, image acquisition rate, battery life, field of view, and possible optical enhancements. More recently, the use of VCE has been extended to exploring the colon. Within the last 5 years, tremendous developments have been made toward increasing the capabilities of the colon capsule. Although colon capsule cannot be proposed as a first-line colorectal cancer screening procedure, colon capsule may be used in patients with incomplete colonoscopy or in patients who are unwilling to undergo colonoscopy. In the near future, new technological developments will improve the diagnostic yield of VCE and broaden its therapeutic capabilities. PMID:25516644

Apoptosis in neural crest cells by functional loss of APC tumor suppressor gene

PubMed Central

Hasegawa, Sumitaka; Sato, Tomoyuki; Akazawa, Hiroshi; Okada, Hitoshi; Maeno, Akiteru; Ito, Masaki; Sugitani, Yoshinobu; Shibata, Hiroyuki; Miyazaki, Jun-ichi; Katsuki, Motoya; Yamauchi, Yasutaka; Yamamura, Ken-ichi; Katamine, Shigeru; Noda, Tetsuo

2002-01-01

Apc is a gene associated with familial adenomatous polyposis coli (FAP) and its inactivation is a critical step in colorectal tumor formation. The protein product, adenomatous polyposis coli (APC), acts to down-regulate intracellular levels of β-catenin, a key signal transducer in the Wnt signaling. Conditional targeting of Apc in the neural crest of mice caused massive apoptosis of cephalic and cardiac neural crest cells at about 11.5 days post coitum, resulting in craniofacial and cardiac anomalies at birth. Notably, the apoptotic cells localized in the regions where β-catenin had accumulated. In contrast to its role in colorectal epithelial cells, inactivation of APC leads to dysregulation of β-catenin/Wnt signaling with resultant apoptosis in certain tissues including neural crest cells. PMID:11756652

A novel function of adenomatous polyposis coli (APC) in regulating DNA repair

PubMed Central

Jaiswal, Aruna S.; Narayan, Satya

2008-01-01

Prevailing literature suggests diversified cellular functions for the adenomatous polyposis coli (APC) gene. Among them a recently discovered unique role of APC is in DNA repair. The APC gene can modulate the base excision repair (BER) pathway through an interaction with DNA polymerase β (Pol-β) and flap endonuclease 1 (Fen-1). Taken together with the transcriptional activation of APC gene by alkylating agents and modulation of BER activity, APC may play an important role in carcinogenesis and chemotherapy by determining whether cells with DNA damage survive or undergo apoptosis. In this review, we summarize the evidence supporting this novel concept and suggest that these results will have implications for the development of more effective strategies for chemoprevention, prognosis, and chemotherapy of certain types of tumors. PMID:18662849

A metabolic switch controls intestinal differentiation downstream of Adenomatous polyposis coli (APC).

PubMed

Sandoval, Imelda T; Delacruz, Richard Glenn C; Miller, Braden N; Hill, Shauna; Olson, Kristofor A; Gabriel, Ana E; Boyd, Kevin; Satterfield, Christeena; Remmen, Holly Van; Rutter, Jared; Jones, David A

2017-04-11

Elucidating signaling pathways that regulate cellular metabolism is essential for a better understanding of normal development and tumorigenesis. Recent studies have shown that mitochondrial pyruvate carrier 1 (MPC1) , a crucial player in pyruvate metabolism, is downregulated in colon adenocarcinomas. Utilizing zebrafish to examine the genetic relationship between MPC1 and Adenomatous polyposis coli (APC), a key tumor suppressor in colorectal cancer, we found that apc controls the levels of mpc1 and that knock down of mpc1 recapitulates phenotypes of impaired apc function including failed intestinal differentiation. Exogenous human MPC1 RNA rescued failed intestinal differentiation in zebrafish models of apc deficiency. Our data demonstrate a novel role for apc in pyruvate metabolism and that pyruvate metabolism dictates intestinal cell fate and differentiation decisions downstream of apc .

Gastric cancer in FAP: a concerning rise in incidence.

PubMed

Mankaney, Gautam; Leone, Pamela; Cruise, Michael; LaGuardia, Lisa; O'Malley, Margaret; Bhatt, Amit; Church, James; Burke, Carol A

2017-07-01

The highest cancer risks in familial adenomatous polyposis (FAP) include colorectal, duodenal, and thyroid for which surveillance is recommended. Nearly all patients with FAP have gastric fundic gland polyposis (FGP), but gastric cancers are rarely reported with a similar incidence as the general population. We describe a recent, sudden increase in the incidence of gastric cancer in FAP. Seven of the ten cases were diagnosed in the last 20 months. Comparing our population to the SEER database for gastric cancer, the standardized incidence ratio is 140. All cases arose in patients with a carpeting of FGP and associated with large mounds of proximal gastric polyps. Nearly all patients were under upper endoscopic surveillance. This is a concerning observation and reflects a change in the phenotypic presentation of FAP in Western patients.

First description of mutational analysis of MLH1, MSH2 and MSH6 in Algerian families with suspected Lynch syndrome.

PubMed

Ziada-Bouchaar, H; Sifi, K; Filali, T; Hammada, T; Satta, D; Abadi, N

2017-01-01

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant disorder characterized by the early onset of colorectal cancer (CRC) linked to germline defects in Mismatch Repair (MMR) genes. We present here, the first molecular study of the correlation between CRC and mutations occurring in these genes performed in twenty-one unrelated Algerian families. The presence of germline mutations in MMR genes, MLH1, MSH2 and MSH6 genes was tested by sequencing all exons plus adjacent intronic sequences and Multiplex ligand-dependent probe amplification (MLPA) for testing large genomic rearrangements. Pathogenic mutations were identified in 20 % of families with clinical suspicion on HNPCC. Two novel variants described for the first time in Algerian families were identified in MLH1, c.881_884delTCAGinsCATTCCT and a large deletion in MSH6 gene from a young onset of CRC. Moreover, the variants of MSH2 gene: c.942+3A>T, c.1030C>T, the most described ones, were also detected in Algerian families. Furthermore, the families HNPCC caused by MSH6 germline mutation may show an age of onset that is comparable to this of patients with MLH1 and MSH2 mutations. In this study, we confirmed that MSH2, MLH1, and MSH6 contribute to CRC susceptibility. This work represents the implementation of a diagnostic algorithm for the identification of Lynch syndrome patients in Algerian families.

Plastic dynamics of the Al0.5CoCrCuFeNi high entropy alloy at cryogenic temperatures: Jerky flow, stair-like fluctuation, scaling behavior, and non-chaotic state

NASA Astrophysics Data System (ADS)

Guo, Xiaoxiang; Xie, Xie; Ren, Jingli; Laktionova, Marina; Tabachnikova, Elena; Yu, Liping; Cheung, Wing-Sum; Dahmen, Karin A.; Liaw, Peter K.

2017-12-01

This study investigates the plastic behavior of the Al0.5CoCrCuFeNi high-entropy alloy at cryogenic temperatures. The samples are uniaxially compressed at 4.2 K, 7.5 K, and 9 K. A jerky evolution of stress and stair-like fluctuation of strain are observed during plastic deformation. A scaling relationship is detected between the released elastic energy and strain-jump sizes. Furthermore, the dynamical evolution of serrations is characterized by the largest Lyapunov exponent. The largest Lyapunov exponents of the serrations at the three temperatures are all negative, which indicates that the dynamical regime is non-chaotic. This trend reflects an ordered slip process, and this ordered slip process exhibits a more disordered slip process, as the temperature decreases from 9 K to 4.2 K or 7.5 K.

Relationships of environmental contaminants to reproductive success in red-breasted mergansers (Mergus serrator) from Lake Michigan

USGS Publications Warehouse

Heinz, G.H.; Haseltine, S.D.; Reichel, W.L.; Hensler, G.L.

1983-01-01

In 1977 and 1978, we studied red-breasted mergansers Mergus serrator nesting on islands in northwestern Lake Michigan to determine whether environmental contaminants were having effects on reproduction. Seventeen contaminants were measured in randomly chosen eggs from 206 nests under study. Using a variety of statistical approaches, we looked for effects of individual contaminants and combinations of contaminants on reproductive measurements such as nest desertion, failure of eggs to hatch, death of newly hatched ducklings, percentage hatching success, number of ducklings leaving the nest and eggshell thickness. We also looked for relationships between the levels of some contaminants in blood samples of 39 incubating females and reproductive success. A small degree of eggshell thinning was attributed to DDE and a few other statistical tests were significant, but no contaminant or combination of contaminants we measured seemed to have a pronounced effect on the aspects of reproduction we followed.

Mate replacement entails a fitness cost for a socially monogamous seabird.

PubMed

Ismar, Stefanie M H; Daniel, Claire; Stephenson, Brent M; Hauber, Mark E

2010-01-01

Studies of the selective advantages of divorce in socially monogamous bird species have unravelled extensive variation among different lineages with diverse ecologies. We quantified the reproductive correlates of mate retention, mate loss and divorce in a highly philopatric, colonially breeding biparental seabird, the Australasian gannet Morus serrator. Estimates of annual divorce rates varied between 40-43% for M. serrator and were high in comparison with both the closely related Morus bassanus and the range of divorce rates reported across monogamous avian breeding systems. Mate retention across seasons was related to consistently higher reproductive success compared with mate replacement, while divorce per se contributed significantly to lower reproductive output only in one of two breeding seasons. Prior reproductive success was not predictive of mate replacement overall or divorce in particular. These patterns are in accordance with the musical chairs hypothesis of adaptive divorce theory, which operates in systems characterised by asynchronous territorial establishment.

A novel serrated columnar phased array ultrasonic transducer

NASA Astrophysics Data System (ADS)

Zou, Cheng; Sun, Zhenguo; Cai, Dong; Song, Hongwei; Chen, Qiang

2016-02-01

Traditionally, wedges are required to generate transverse waves in a solid specimen and mechanical rotation device is needed for interrogation of a specimen with a hollow bore, such as high speed railway locomotive axles, turbine rotors, etc. In order to eliminate the mechanical rotation process, a novel array pattern of phased array ultrasonic transducers named as serrated columnar phased array ultrasonic transducer (SCPAUT) is designed. The elementary transducers are planar rectangular, located on the outside surface of a cylinder. This layout is aimed to generate electrically rotating transverse waveforms so as to inspect the longitudinal cracks on the outside surface of a specimen which has a hollow bore at the center, such as the high speed railway locomotive axles. The general geometry of the SCPAUT and the inspection system are illustrated. A FEM model and mockup experiment has been carried out. The experiment results are in good agreement with the FEM simulation results.

Larval, pre-juvenile and juvenile development of Diapterus peruvianus (Perciformes: Gerreidae).

PubMed

Jiménez Rosenberg, Sylvia Patricia; González Navarro, Enrique; Saldierna Martínez, Ricardo Javier

2003-06-01

The development of Diapterus peruvianus (Sauvage 1879) is based on 60 larvae collected in superficial tows made in Bahía Concepción, and on 16 pre-juvenile and juvenile organisms collected in Bahía de La Paz, B. C. S., México, using a standard plankton net and a rectangular epibenthonic net, respectively. Larvae of D. peruvianus show three large blotches on the dorsum of the gut that can fuse together and give the appearance of one large continuous blotch. There are two to three pre-anal pigments and 16 post-anal pigments in the ventral midline; cephalic pigments are present from the postflexion stage, as well as a serrated preoperculum. The pre-juvenile and juvenile organisms are distinguished by their body depth, the anal-fin formula, the serrated pre-operculum and the base pigments in the dorsal and anal fins.

Mate replacement entails a fitness cost for a socially monogamous seabird

NASA Astrophysics Data System (ADS)

Ismar, Stefanie M. H.; Daniel, Claire; Stephenson, Brent M.; Hauber, Mark E.

2010-01-01

Studies of the selective advantages of divorce in socially monogamous bird species have unravelled extensive variation among different lineages with diverse ecologies. We quantified the reproductive correlates of mate retention, mate loss and divorce in a highly philopatric, colonially breeding biparental seabird, the Australasian gannet Morus serrator. Estimates of annual divorce rates varied between 40-43% for M. serrator and were high in comparison with both the closely related Morus bassanus and the range of divorce rates reported across monogamous avian breeding systems. Mate retention across seasons was related to consistently higher reproductive success compared with mate replacement, while divorce per se contributed significantly to lower reproductive output only in one of two breeding seasons. Prior reproductive success was not predictive of mate replacement overall or divorce in particular. These patterns are in accordance with the musical chairs hypothesis of adaptive divorce theory, which operates in systems characterised by asynchronous territorial establishment.

Familial Adenomatous Polyposis

MedlinePlus

... these screening recommendations at the Journal of Clinical Oncology . Please note this link takes you to another ... and caregivers, from the American Society of Clinical Oncology (ASCO), the voice of the world’s cancer physicians ...

A novel pit pattern identifies the precursor of colorectal cancer derived from sessile serrated adenoma.

PubMed

Kimura, Tomoaki; Yamamoto, Eiichiro; Yamano, Hiro-O; Suzuki, Hiromu; Kamimae, Seiko; Nojima, Masanori; Sawada, Takeshi; Ashida, Masami; Yoshikawa, Kenjiro; Takagi, Ryo; Kato, Ryusuke; Harada, Taku; Suzuki, Ryo; Maruyama, Reo; Kai, Masahiro; Imai, Kohzoh; Shinomura, Yasuhisa; Sugai, Tamotsu; Toyota, Minoru

2012-03-01

Sessile serrated adenomas (SSAs) are known to be precursors of sporadic colorectal cancers (CRCs) with microsatellite instability (MSI), and to be tightly associated with BRAF mutation and the CpG island methylator phenotype (CIMP). Consequently, colonoscopic identification of SSAs has important implications for preventing CRCs, but accurate endoscopic diagnosis is often difficult. Our aim was to clarify which endoscopic findings are specific to SSAs. The morphological, histological and molecular features of 261 specimens from 226 colorectal tumors were analyzed. Surface microstructures were analyzed using magnifying endoscopy. Mutation in BRAF and KRAS was examined by pyrosequencing. Methylation of p16, IGFBP7, MLH1 and MINT1, -2, -12 and -31 was analyzed using bisulfite pyrosequencing. Through retrospective analysis of a training set (n=145), we identified a novel surface microstructure, the Type II open-shape pit pattern (Type II-O), which was specific to SSAs with BRAF mutation and CIMP. Subsequent prospective analysis of an independent validation set (n=116) confirmed that the Type II-O pattern is highly predictive of SSAs (sensitivity, 65.5%; specificity, 97.3%). BRAF mutation and CIMP occurred with significant frequency in Type II-O-positive serrated lesions. Progression of SSAs to more advanced lesions was associated with further accumulation of aberrant DNA methylation and additional morphological changes, including the Type III, IV and V pit patterns. Our results suggest the Type II-O pit pattern is a useful hallmark of the premalignant stage of CRCs with MSI and CIMP, which could serve to improve the efficacy of colonoscopic surveillance.

Natural Language Processing Accurately Calculates Adenoma and Sessile Serrated Polyp Detection Rates.

PubMed

Nayor, Jennifer; Borges, Lawrence F; Goryachev, Sergey; Gainer, Vivian S; Saltzman, John R

2018-07-01

ADR is a widely used colonoscopy quality indicator. Calculation of ADR is labor-intensive and cumbersome using current electronic medical databases. Natural language processing (NLP) is a method used to extract meaning from unstructured or free text data. (1) To develop and validate an accurate automated process for calculation of adenoma detection rate (ADR) and serrated polyp detection rate (SDR) on data stored in widely used electronic health record systems, specifically Epic electronic health record system, Provation ® endoscopy reporting system, and Sunquest PowerPath pathology reporting system. Screening colonoscopies performed between June 2010 and August 2015 were identified using the Provation ® reporting tool. An NLP pipeline was developed to identify adenomas and sessile serrated polyps (SSPs) on pathology reports corresponding to these colonoscopy reports. The pipeline was validated using a manual search. Precision, recall, and effectiveness of the natural language processing pipeline were calculated. ADR and SDR were then calculated. We identified 8032 screening colonoscopies that were linked to 3821 pathology reports (47.6%). The NLP pipeline had an accuracy of 100% for adenomas and 100% for SSPs. Mean total ADR was 29.3% (range 14.7-53.3%); mean male ADR was 35.7% (range 19.7-62.9%); and mean female ADR was 24.9% (range 9.1-51.0%). Mean total SDR was 4.0% (0-9.6%). We developed and validated an NLP pipeline that accurately and automatically calculates ADRs and SDRs using data stored in Epic, Provation ® and Sunquest PowerPath. This NLP pipeline can be used to evaluate colonoscopy quality parameters at both individual and practice levels.

Mechanism of work hardening in Hadfield manganese steel

NASA Astrophysics Data System (ADS)

Dastur, Y. N.; Leslie, W. C.

1981-05-01

When Hadfield manganese steel in the single-phase austenitic condition was strained in tension, in the temperature range - 25 to 300 °C, it exhibited jerky (serrated) flow, a negative (inverse) strain-rate dependence of flow stress and high work hardening, characteristic of dynamic strain aging. The strain rate-temperature regime of jerky flow was determined and the apparent activation energies for the appearance and disappearance of serrations were found to be 104 kJ/mol and 146 kJ/mol, respectively. The high work hardening cannot be a result of mechanical twinning because at -50 °C numerous twins were produced, but the work hardening was low and no twins were formed above 225 °C even though work hardening was high. The work hardening decreased above 300 °C because of the cessation of dynamic strain aging and increased again above 400 °C because of precipitation of carbides. An apparent activation energy of 138 kJ/mol was measured for static strain aging between 300 and 400 °C, corresponding closely to the activation energies for the disapperance of serrations and for the volume diffusion of carbon in Hadfield steel. Evidence from the present study, together with the known effect of manganese on the activity of carbon in austenite and previous internal friction studies of high-manganese steels, lead to the conclusion that dynamic strain aging, brought about by the reorientation of carbon members of C-Mn couples in the cores of dislocations, is the principal cause of rapid work hardening in Hadfield steel.

Prosthetic Hand Lifts Heavy Loads

NASA Technical Reports Server (NTRS)

Carden, James R.; Norton, William; Belcher, Jewell G.; Vest, Thomas W.

1991-01-01

Prosthetic hand designed to enable amputee to lift diverse heavy objects like rocks and logs. Has simple serrated end effector with no moving parts. Prosthesis held on forearm by system of flexible straps. Features include ruggedness, simplicity, and relatively low cost.

Spontaneous polyploidization in cucumber

USDA-ARS?s Scientific Manuscript database

Cucumber breeders and growers have observed off-type plants in hybrid cultivars with darker green leaves with pronounced serration, shorter stature, and misshaped fruits with non-viable seeds. Field-grown plants were identified with these characteristics and flow cytometry revealed that these plants...

Drug Combo Decreases Colorectal Polyps in People with FAP

Cancer.gov

In people with familial adenomatous polyposis, or FAP, a combination treatment of erlotinib (Tarceva) and sulindac (Aflodac) decreased the number of precancerous colorectal polyps, according to recently published clinical trial results.

Evidence-based management of nasal polyposis by intranasal corticosteroids: from the cause to the clinic.

PubMed

Bachert, Claus

2011-01-01

Nasal polyposis is an inflammatory disorder involving the mucosa of the nose and paranasal sinuses and affecting approximately 2-4% of the general population. A literature search of Medline and Embase was conducted to obtain an overview of the epidemiology, pathophysiology, and current treatment of nasal polyposis, focusing on evidence-based efficacy of intranasal corticosteroids (INSs) as primary and postoperative therapy. Recent research on INSs in nasal polyp treatment, along with notable historic findings, was reviewed. Nasal polyps are mostly characterized by eosinophil infiltration, a complex inflammation of nasal mucosa, and possibly production of polyclonal IgE. Current treatment modalities include INSs, oral corticosteroids, and surgery; surgery is generally limited to those with an insufficient response to medical treatment. Because of their effects on eosinophil-dominated inflammation, INSs and oral corticosteroids are the primary medical treatment strategies. The very low (≤1%) systemic bioavailability of newer INSs minimizes the systemic adverse effects seen with oral corticosteroids. Based on randomized, controlled trials, guidelines recommend INSs as first-line therapy for nasal polyps and for care after polypectomy. Clinical data suggest INSs are effective in reducing polyp size and relieving nasal symptoms. INS treatment has also reduced nasal polyp recurrence in patients undergoing functional endoscopic sinus surgery. Treatment with these mainstay options has been found to improve quality of life, which, along with symptom improvement, is a key factor in disease treatment. Copyright © 2011 S. Karger AG, Basel.

Prevalence of Skin Lesions in Familial Adenomatous Polyposis: A Marker for Presymptomatic Diagnosis?

PubMed Central

Cattani, Nadja; Trueb, Swantje; de Lorenzo, Rosaria; Albertini, Mauro; Bontognali, Emanuele; Itin, Christoph; Schaub, Nathalie; Itin, Peter H.

2011-01-01

Background and Aims. Benign skin tumors such as lipomas, fibromas, and epidermal cysts are among the extracolonic manifestations of familial adenomatous polyposis (FAP). Readily detectable by inspection, they could serve as presymptomatic diagnostic markers to identify FAP patients. We therefore prospectively determined the prevalence of cutaneous lesions in genetically confirmed adenomatous polyposis coli (APC) mutation carriers and assessed their potential usefulness in the identification of FAP patients. Methods. Whole-skin examination was performed in 56 adult APC mutation carriers, compared with a control group (n = 116). In addition, FAP patients were investigated for the presence of congenital hypertrophy of the retinal pigment epithelium (CHRPE), an established clinical marker for FAP, and a detailed review of medical records was performed. Results. Nearly half of all FAP patients (48.2%) had at least one FAP-associated skin lesion, compared with one third (34.5%) of controls. Only multiple lipomas and combined skin lesions were significantly more prevalent in APC mutation carriers. CHRPE was observed in 22 (43.1%) of 51 FAP patients, including 14 (37.8%) of 37 individuals with APC mutations outside the CHRPE-associated region between codons 311 and 1465. Conclusions. Despite a significantly higher prevalence of multiple lipomas, occurring at younger age, and combined skin lesions in APC mutation carriers, the low diagnostic sensitivity of FAP-associated skin lesions precludes their use as markers for FAP in clinical practice. Based on our findings, the common CHRPE-associated region should be extended to APC codons 148-2043. PMID:22135120

The role of mutation analysis of the APC gene in the management of FAP patients. A controversial issue.

PubMed

Dodaro, Concetta; Grifasi, Carlo; Florio, Jole; Santangelo, Michele L; Duraturo, Francesca; De Rosa, Marina; Izzo, Paola; Renda, Andrea

A correlation between the location of mutation in the adenomatous polyposis coli (APC) gene and clinical manifestations of familial adenomatous polyposis (FAP) has repeatedly been reported. Some Authors suggest the use of mutational analysis as a guide to select the best surgical option in FAP patients. However, data coming from studies on large series have raised questions on this issue. The aim of this study is to discuss the role of the genetic tests in the management of FAP. A literature review was performed considering only peer-reviewed articles published between 1991-2015. All the studies examined the role of genetic as a guide for surgical management of FAP. Of 363 articles identified, 21 were selected for full-text review. We found different positions with regard the use of genetic tests to determine surgical management of FAP. In particular, while consistent correlations between the APC mutation site and FAP phenotype were observed in large series, 8 studies reported a wide variation of genotypephenotype correlation in patients with the same mutation and they recommended that decisions regarding surgical strategy should be based not only on genotype but also on the clinical factors and the will of the patient who must be fully informed. The decision on the type and the timing of surgery should be based on the assessment of many factors and genotype assessment should be used in combination with clinical data. Disease severity, Familial adenomatous polyposis, Genetic tests, Genotype-phenotype correlations, Surgical management.

Giant tubular adenoma with malignancy clinical characteristics in a female teenager: Case report and a review of the literature.

PubMed

Mărginean, Cristina Oana; Mărginean, Maria Oana; Simu, Iunius; Horvath, Adrienne; Meliţ, Lorena Elena

2016-10-01

Adenomas of the colon are usually benign tumors which carry a tendency for malignancy. These tumors can be villous, tubular, tubulovillous, or sessile serrated. Those with adenomatous structure can develop malignant characteristics in 1.5% to 9.4% of cases. We present a case report of a 16-year-old female adolescent with an adenoma of the descending colon. History revealed prolonged diarrheic syndrome for the past 6 months, repeated headache, and a weight loss of ∼5 kg in the past month. One week before the admission, the patient presented an episode of inferior digestive hemorrhage. On admission laboratory tests revealed iron deficiency anemia, and a mildly increased erythrocyte sedimentation rate. The abdominal ultrasound revealed an inhomogeneous mass of the descending colon and 2 hyperechoic lesions in the liver. The colonoscopy showed a tumor of the descending colon, a tubular adenoma according to the pathological examination. Additionally, we noted an atypical presentation of the tumor and the signs of mild dysplasia identified at the pathological examination. Weight loss, bowel transit alterations, loss of appetite, and inferior hemorrhage in an adolescent can be symptoms of a benign or malignant tumor of the colon.

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

PubMed

Testa, Ugo; Pelosi, Elvira; Castelli, Germana

2018-04-13

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

MLH1-93 G/a polymorphism is associated with MLH1 promoter methylation and protein loss in dysplastic sessile serrated adenomas with BRAFV600E mutation.

PubMed

Fennell, Lochlan J; Jamieson, Saara; McKeone, Diane; Corish, Tracie; Rohdmann, Megan; Furner, Tori; Bettington, Mark; Liu, Cheng; Kawamata, Futoshi; Bond, Catherine; Van De Pols, Jolieke; Leggett, Barbara; Whitehall, Vicki

2018-01-05

Sessile serrated adenomas with BRAF mutation progress rapidly to cancer following the development of dysplasia (SSAD). Approximately 75% of SSADs methylate the mismatch repair gene MLH1, develop mismatch repair deficiency and the resultant cancers have a good prognosis. The remaining SSADs and BRAF mutant traditional serrated adenomas (TSA) develop into microsatellite stable cancers with a poor prognosis. The reason for this dichotomy is unknown. In this study, we assessed the genotypic frequency of the MLH1-93 polymorphism rs1800734 in SSADs and TSAs to determine if the uncommon variant A allele predisposes to MLH1 promoter hypermethylation. We performed genotyping for the MLH1-93 polymorphism, quantitative methylation specific PCR, and MLH1 immunohistochemistry on 124 SSAD, 128 TSA, 203 BRAF mutant CRCs and 147 control subjects with normal colonoscopy. The minor A allele was significantly associated with a dose dependent increase in methylation at the MLH1 promoter in SSADs (p = 0.022). The AA genotype was only observed in SSADs with MLH1 loss. The A allele was also overrepresented in BRAF mutant cancers with MLH1 loss. Only one of the TSAs showed loss of MLH1 and the overall genotype distribution in TSAs did not differ from controls. The MLH1-93 AA genotype is significantly associated with promoter hypermethylation and MLH1 loss in the context of SSADs. BRAF mutant microsatellite stable colorectal cancers with the AA genotype most likely arise in TSAs since the A allele does not predispose to methylation in this context.

Implementation of an e-learning module improves consistency in the histopathological diagnosis of sessile serrated lesions within a nationwide population screening programme.

PubMed

IJspeert, Joep E G; Madani, Ariana; Overbeek, Lucy I H; Dekker, Evelien; Nagtegaal, Iris D

2017-05-01

Distinguishing premalignant sessile serrated lesions (SSLs) from hyperplastic polyps (HPs) is difficult for pathologists in daily practice. We aimed to evaluate nationwide variability within histopathology laboratories in the frequency of diagnosing an SSL as compared with an HP within the Dutch population-based screening programme for colorectal cancer and to assess the effect of an e-learning module on interlaboratory consistency. Data were retrieved from the Dutch Pathology Registry from the start of the nationwide population screening programme, January 2014, until December 2015. An obligatory e-learning module was implemented among pathologists in October 2014. The ratio between SSL and HP diagnosis was determined per laboratory. Odds ratios (ORs) for the diagnosis of an SSL per laboratory were compared with the laboratory with the median odds (median laboratory), before and after implementation of the e-learning module. In total, 14 997 individuals with 27 879 serrated polyps were included; 6665 (23.9%) were diagnosed as SSLs, and 21 214 as HPs (76.1%). The ratio of diagnosing an SSL ranged from 5% to 47% (median 23%) within 44 laboratories. Half of the laboratories showed a significantly different OR (range 3.47-0.16) for diagnosing an SSL than the median laboratory. Variability decreased after implementation of the e-learning module (P = 0.02). Of all pathology laboratories, 70% became more consistent with the median laboratory after e-learning implementation. We demonstrated substantial interlaboratory variability in the histopathological diagnosis of SSLs, which significantly decreased after implementation of a structured e-learning module. Widespread implementation of education might contribute to more homogeneous practice among pathologists. © 2016 John Wiley & Sons Ltd.

Molecular features of colorectal polyps presenting Kudo’s type II mucosal crypt pattern: are they based on the same mechanism of tumorigenesis?

PubMed Central

Shinmura, Kensuke; Konishi, Kazuo; Yamochi, Toshiko; Kubota, Yutaro; Yano, Yuichiro; Katagiri, Atsushi; Muramoto, Takashi; Kihara, Toshihiro; Tojo, Masayuki; Konda, Kenichi; Tagawa, Teppei; Yanagisawa, Fumito; Kogo, Mari; Makino, Reiko; Takimoto, Masafumi; Yoshida, Hitoshi

2014-01-01

Background and study aims: The molecular features of serrated polyps (SPs) with hyperplastic crypt pattern, also called Kudo’s type II observed by chromoendoscopy, were evaluated. Methods: The clinicopathological and molecular features of 114 SPs with a hyperplastic pit pattern detected under chromoendoscopy (five dysplastic SPs, 63 sessile serrated adenoma/polyps (SSA/Ps), 36 microvesicular hyperplastic polyps (MVHPs), and 10 goblet cell-rich hyperplastic polyps (GCHPs)) were examined. The frequency of KRAS and BRAF mutations and CpG island methylator phenotype (CIMP) were investigated. Results: Dysplastic SPs and SSA/Ps were frequently located in the proximal colon compared to others (SSA/Ps vs. MVHPs or GCHPs, P < 0.0001). No significant difference was found in the frequency of BRAF mutation among SPs apart from GCHP (60 % for dysplastic SPs, 44 % for SSA/Ps, 47 % for MVHPs, and 0 % for GCHPs). The frequency of CIMP was higher in dysplastic SPs or SSA/Ps than in MVHPs or GCHPs (60 % for dysplastic SPs, 56 % for SSA/Ps, 32 % for MVHPs, and 10 % for GCHPs) (SSA/Ps vs. GCHP, P = 0.0068). When serrated neoplasias (SNs) and MVHPs were classified into proximal and distal lesions, the frequency of CIMP was significantly higher in the proximal compared to the distal SNs (64 % vs. 11 %, P = 0.0032). Finally, multivariate analysis showed that proximal location and BRAF mutation were significantly associated with an increased risk of CIMP. Conclusions: Distinct molecular features were observed between proximal and distal SPs with hyperplastic crypt pattern. Proximal MVHPs may develop more frequently through SSA/Ps to CIMP cancers than distal MVHPs. PMID:26134964

Molecular features of colorectal polyps presenting Kudo's type II mucosal crypt pattern: are they based on the same mechanism of tumorigenesis?

PubMed

Shinmura, Kensuke; Konishi, Kazuo; Yamochi, Toshiko; Kubota, Yutaro; Yano, Yuichiro; Katagiri, Atsushi; Muramoto, Takashi; Kihara, Toshihiro; Tojo, Masayuki; Konda, Kenichi; Tagawa, Teppei; Yanagisawa, Fumito; Kogo, Mari; Makino, Reiko; Takimoto, Masafumi; Yoshida, Hitoshi

2014-09-01

The molecular features of serrated polyps (SPs) with hyperplastic crypt pattern, also called Kudo's type II observed by chromoendoscopy, were evaluated. The clinicopathological and molecular features of 114 SPs with a hyperplastic pit pattern detected under chromoendoscopy (five dysplastic SPs, 63 sessile serrated adenoma/polyps (SSA/Ps), 36 microvesicular hyperplastic polyps (MVHPs), and 10 goblet cell-rich hyperplastic polyps (GCHPs)) were examined. The frequency of KRAS and BRAF mutations and CpG island methylator phenotype (CIMP) were investigated. Dysplastic SPs and SSA/Ps were frequently located in the proximal colon compared to others (SSA/Ps vs. MVHPs or GCHPs, P < 0.0001). No significant difference was found in the frequency of BRAF mutation among SPs apart from GCHP (60 % for dysplastic SPs, 44 % for SSA/Ps, 47 % for MVHPs, and 0 % for GCHPs). The frequency of CIMP was higher in dysplastic SPs or SSA/Ps than in MVHPs or GCHPs (60 % for dysplastic SPs, 56 % for SSA/Ps, 32 % for MVHPs, and 10 % for GCHPs) (SSA/Ps vs. GCHP, P = 0.0068). When serrated neoplasias (SNs) and MVHPs were classified into proximal and distal lesions, the frequency of CIMP was significantly higher in the proximal compared to the distal SNs (64 % vs. 11 %, P = 0.0032). Finally, multivariate analysis showed that proximal location and BRAF mutation were significantly associated with an increased risk of CIMP. Distinct molecular features were observed between proximal and distal SPs with hyperplastic crypt pattern. Proximal MVHPs may develop more frequently through SSA/Ps to CIMP cancers than distal MVHPs.

[Serrated polyps and their association with synchronous advanced colorectal neoplasia].

PubMed

Urman, Jesús; Gomez, Marta; Basterra, Marta; Mercado, María Del Rosario; Montes, Marta; Gómez Dorronsoro, Marisa; Garaigorta, Maitane; Fraile, María; Rubio, Eva; Aisa, Gregorio; Galbete, Arkaitz

2016-11-01

Large serrated polyps (SP), proximal SP, SP with dysplasia and the presence of multiple sessile serrated adenomas/polyps (SSA/P), which we refer to as SP with increased risk of metachronous lesions (SPIRML), have been associated with an increased risk of advanced colon lesions on follow-up. It is unclear, however, whether SPIRML are also associated with an increased risk of synchronous advanced colorectal neoplasia (ACN). The aim of this study was to estimate the prevalence of SPIRML and to evaluate the association between SPIRML and synchronous ACN. A cross-sectional population-based study in all patients (1,538) with histological diagnosis of SP obtained from colonoscopies, sigmoidoscopies and colonic surgery performed in Navarra Health Service hospitals (Spain) in 2011. Demographic parameters and synchronous colonic lesions (adenomas, advanced adenomas [AA] and ACN) were analyzed. One fourth of the sample (384 patients) presented SPIRML. These were older patients, with a slight predominance of women, and with no differences in body mass index (BMI) compared to patients without SPIRML. In the univariate analysis, patients with SPIRML showed an increased risk of adenoma, AA and ACN. In the multivariate analysis, the SPIRML group had a higher risk of synchronous AA and ACN (odds ratio [OR]: 2.38 [1.77-3.21] and OR: 2.29 [1.72-3.05], respectively); in the case of ACN, this risk was statistically significant in both locations (proximal or distal), with OR slightly higher for the proximal location. Different subtypes of SPIRML had a higher risk of AA and synchronous NA. SPIRML were common in patients with SP, and their presence was associated with an increased risk of synchronous ACN. Copyright © 2016 Elsevier España, S.L.U. y AEEH y AEG. All rights reserved.

Large bowel resection

MedlinePlus

... blockage in the intestine due to scar tissue Colon cancer Diverticular disease (disease of the large bowel) Other reasons for bowel resection are: Familial polyposis (polyps are growths on the lining of the colon or rectum) Injuries that damage the large bowel ...

Adenomatous polyposis coli protein (APC)-independent regulation of beta-catenin/Tcf-4 mediated transcription in intestinal cells.

PubMed Central

Baulida, J; Batlle, E; García De Herreros, A

1999-01-01

Alterations in the transcriptional activity of the beta-catenin-Tcf complex have been associated with the earlier stages of colonic transformation. We show here that the activation of protein kinase C by the phorbol ester PMA in several intestinal cell lines increases the levels of beta-catenin detected in the nucleus and augments the transcriptional activity mediated by beta-catenin. The response to PMA was not related to modifications in the cytosolic levels of beta-catenin and was observed not only in cells with wild-type adenomatous polyposis coli protein (APC) but also in APC-deficient cells. Binding assays in vitro revealed that PMA facilitates the interaction of the beta-catenin with the nuclear structure. Our results therefore show that beta-catenin-mediated transcription can be regulated independently of the presence of APC. PMID:10567241

Hepatitis B viral X protein interacts with tumor suppressor adenomatous polyposis coli to activate Wnt/β-catenin signaling.

PubMed

Hsieh, Antony; Kim, Hyeon-Seop; Lim, Seung-Oe; Yu, Dae-Yeul; Jung, Guhung

2011-01-28

HBV X protein is a transactivator of several cellular signaling pathways including Wnt which contributes to HBV associated neoplasia. The Wnt/β-catenin pathway is associated with HCC-initiating cells. Here we perform a functional screen for host factors involved in the transactivational properties of HBx. We identify adenomatous polyposis coli (APC) as a binding partner of HBx and further determine that HBx competitively binds APC to displace β-catenin from its degradation complex. This results in β-catenin upregulation in the nucleus and the activation of Wnt signaling. We show that Wnt inhibitors curcumin and quercetin target downstream β-catenin activity and effectively repress HBx-mediated regulation of c-MYC and E-cadherin. Our results provide a pathological mechanism of HBx induced malignant transformation. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Tumour Suppressor Adenomatous Polyposis Coli (APC) localisation is regulated by both Kinesin-1 and Kinesin-2.

PubMed

Ruane, Peter T; Gumy, Laura F; Bola, Becky; Anderson, Beverley; Wozniak, Marcin J; Hoogenraad, Casper C; Allan, Victoria J

2016-06-07

Microtubules and their associated proteins (MAPs) underpin the polarity of specialised cells. Adenomatous polyposis coli (APC) is one such MAP with a multifunctional agenda that requires precise intracellular localisations. Although APC has been found to associate with kinesin-2 subfamily members, the exact mechanism for the peripheral localization of APC remains unclear. Here we show that the heavy chain of kinesin-1 directly interacts with the APC C-terminus, contributing to the peripheral localisation of APC in fibroblasts. In rat hippocampal neurons the kinesin-1 binding domain of APC is required for its axon tip enrichment. Moreover, we demonstrate that APC requires interactions with both kinesin-2 and kinesin-1 for this localisation. Underlining the importance of the kinesin-1 association, neurons expressing APC lacking kinesin-1-binding domain have shorter axons. The identification of this novel kinesin-1-APC interaction highlights the complexity and significance of APC localisation in neurons.

Adenomatous Polyposis Coli-Mediated Accumulation of Abasic DNA Lesions Lead to Cigarette Smoke Condensate-Induced Neoplastic Transformation of Normal Breast Epithelial Cells1

PubMed Central

Jaiswal, Aruna S; Panda, Harekrushna; Pampo, Christine A; Siemann, Dietmar W; Gairola, C Gary; Hromas, Robert; Narayan, Satya

2013-01-01

Adenomatous polyposis coli (APC) is a multifunctional protein having diverse cellular functions including cell migration, cell-cell adhesion, cell cycle control, chromosomal segregation, and apoptosis. Recently, we found a new role of APC in base excision repair (BER) and showed that it interacts with DNA polymerase β and 5′-flap endonuclease 1 and interferes in BER. Previously, we have also reported that cigarette smoke condensate (CSC) increases expression of APC and enhances the growth of normal human breast epithelial (MCF10A) cells in vitro. In the present study, using APC overexpression and knockdown systems, we have examined the molecular mechanisms by which CSC and its major component, Benzo[α]pyrene, enhances APC-mediated accumulation of abasic DNA lesions, which is cytotoxic and mutagenic in nature, leading to enhanced neoplastic transformation of MCF10A cells in an orthotopic xenograft model. PMID:23555190

Selective targeting of mutant adenomatous polyposis coli (APC) in colorectal cancer.

PubMed

Zhang, Lu; Theodoropoulos, Panayotis C; Eskiocak, Ugur; Wang, Wentian; Moon, Young-Ah; Posner, Bruce; Williams, Noelle S; Wright, Woodring E; Kim, Sang Bum; Nijhawan, Deepak; De Brabander, Jef K; Shay, Jerry W

2016-10-19

Mutations in the adenomatous polyposis coli (APC) gene are common in colorectal cancer (CRC), and more than 90% of those mutations generate stable truncated gene products. We describe a chemical screen using normal human colonic epithelial cells (HCECs) and a series of oncogenically progressed HCECs containing a truncated APC protein. With this screen, we identified a small molecule, TASIN-1 (truncated APC selective inhibitor-1), that specifically kills cells with APC truncations but spares normal and cancer cells with wild-type APC. TASIN-1 exerts its cytotoxic effects through inhibition of cholesterol biosynthesis. In vivo administration of TASIN-1 inhibits tumor growth of CRC cells with truncated APC but not APC wild-type CRC cells in xenograft models and in a genetically engineered CRC mouse model with minimal toxicity. TASIN-1 represents a potential therapeutic strategy for prevention and intervention in CRC with mutant APC. Copyright © 2016, American Association for the Advancement of Science.

Multiscale Modeling of Deformation Twinning Based on Field Theory of Multiscale Plasticity (FTMP)

DTIC Science & Technology

2013-09-01

of the deformation twinning: nucleation, growth (into, e.g., lenticular shapes), lattice rotation (satisfying the mirror symmetry), the attendant...Nucleation and subsequent growth into lenticular shapes is realistically captured. • Stress-strain responses accompanied by serration and overall softening

Developmental and evolutionary novelty in the serrated teeth of theropod dinosaurs.

PubMed

Brink, K S; Reisz, R R; LeBlanc, A R H; Chang, R S; Lee, Y C; Chiang, C C; Huang, T; Evans, D C

2015-07-28

Tooth morphology and development can provide valuable insights into the feeding behaviour and evolution of extinct organisms. The teeth of Theropoda, the only clade of predominantly predatory dinosaurs, are characterized by ziphodonty, the presence of serrations (denticles) on their cutting edges. Known today only in varanid lizards, ziphodonty is much more pervasive in the fossil record. Here we present the first model for the development of ziphodont teeth in theropods through histological, SEM, and SR-FTIR analyses, revealing that structures previously hypothesized to prevent tooth breakage instead first evolved to shape and maintain the characteristic denticles through the life of the tooth. We show that this novel complex of dental morphology and tissues characterizes Theropoda, with the exception of species with modified feeding behaviours, suggesting that these characters are important for facilitating the hypercarnivorous diet of most theropods. This adaptation may have played an important role in the initial radiation and subsequent success of theropods as terrestrial apex predators.

Dynamic strain aging and plastic instabilities

NASA Astrophysics Data System (ADS)

Mesarovic, Sinisa Dj.

1995-05-01

A constitutive model proposed by McCormick [(1988) Theory of flow localization due to dynamic strain ageing. Acta. Metall.36, 3061-3067] based on dislocation-solute interaction and describing dynamic strain aging behavior, is analyzed for the simple loading case of uniaxial tension. The model is rate dependent and includes a time-varying state variable, representing the local concentration of the impurity atoms at dislocations. Stability of the system and its post-instability behavior are considered. The methods used include analytical and numerical stability and bifurcation analysis with a numerical continuation technique. Yield point behavior and serrated yielding are found to result for well defined intervals of temperature and strain rate. Serrated yielding emerges as a branch of periodic solutions of the relaxation oscillation type, similar to frictional stick-slip. The distinction between the temporal and spatial (loss of homogeneity of strain) instability is emphasized. It is found that a critical machine stiffness exists above which a purely temporal instability cannot occur. The results are compared to the available experimental data.

Tuned critical avalanche scaling in bulk metallic glasses

DOE PAGES

Antonaglia, James; Xie, Xie; Schwarz, Gregory; ...

2014-03-17

In this study, ingots of the bulk metallic glass (BMG), Zr 64.13Cu 15.75Ni 10.12Al 10 in atomic percent (at. %), are compressed at slow strain rates. The deformation behavior is characterized by discrete, jerky stress-drop bursts (serrations). Here we present a quantitative theory for the serration behavior of BMGs, which is a critical issue for the understanding of the deformation characteristics of BMGs. The mean-field interaction model predicts the scaling behavior of the distribution, D(S), of avalanche sizes, S, in the experiments. D(S) follows a power law multiplied by an exponentially-decaying scaling function. The size of the largest observed avalanchemore » depends on experimental tuning-parameters, such as either imposed strain rate or stress. Similar to crystalline materials, the plasticity of BMGs reflects tuned criticality showing remarkable quantitative agreement with the slip statistics of slowly-compressed nanocrystals. The results imply that material-evaluation methods based on slip statistics apply to both crystalline and BMG materials.« less

LMI1-like genes involved in leaf margin development of Brassica napus.

PubMed

Ni, Xiyuan; Liu, Han; Huang, Jixiang; Zhao, Jianyi

2017-06-01

In rapeseed (Brassica napus L.), leaf margins are variable and can be entire, serrate, or lobed. In our previous study, the lobed-leaf gene (LOBED-LEAF 1, BnLL1) was mapped to a 32.1 kb section of B. napus A10. Two LMI1-like genes, BnaA10g26320D and BnaA10g26330D, were considered the potential genes that controlled the lobed-leaf trait in rapeseed. In the present study, these two genes and another homologous gene (BnaC04g00850D) were transformed into Arabidopsis thaliana (L.) Heynh. plants to identify their functions. All three LMI1-like genes of B. napus produced serrate leaf margins. The expression analysis indicated that the expression level of BnaA10g26320D determined the difference between lobed- and entire-leaved lines in rapeseed. Therefore, it is likely that BnaA10g26320D corresponds to BnLL1.

Correlation of the Jurassic through Oligocene Stratigraphic Units of Trinidad and Northeastern Venezuela

DOE Office of Scientific and Technical Information (OSTI.GOV)

Algar, S.; Erikson, J.P.

1995-04-01

The Jurassic through Oligocene stratigraphies of Trinidad and the Serrenia del Interior of eastern Venezuela exhibit many similarities because of their proximity on the passive continental margins of northeastern South America. A slightly later subsidence in eastern Venezuela, and the generally deeper-water sedimentation in Trinidad, is interpreted to be the result of a serration of the original rift margin, producing an eastern Venezuela promontory and Trinidadian re-entrant. We interpret these serrations to be the result of oblique (NW-SE) spreading of North and South America during Middle and late Jurassic time. The stratigraphies of northeastern Venezuela and Trinidad contrast in themore » Hauterivan-Albian interval, with dynamic shallow shelf environments prevailing in the Serrenia del Interior and deeper marine submarine-fan deposition in Trinidad. Both areas develop middle to Upper Cretaceous source rocks during a time of eustatic sea level high and widespread oceanic anoxia. 15 refs., 4 fig.« less

Developmental and evolutionary novelty in the serrated teeth of theropod dinosaurs

PubMed Central

Brink, K. S.; Reisz, R. R.; LeBlanc, A. R. H.; Chang, R. S.; Lee, Y. C.; Chiang, C. C.; Huang, T.; Evans, D. C.

2015-01-01

Tooth morphology and development can provide valuable insights into the feeding behaviour and evolution of extinct organisms. The teeth of Theropoda, the only clade of predominantly predatory dinosaurs, are characterized by ziphodonty, the presence of serrations (denticles) on their cutting edges. Known today only in varanid lizards, ziphodonty is much more pervasive in the fossil record. Here we present the first model for the development of ziphodont teeth in theropods through histological, SEM, and SR-FTIR analyses, revealing that structures previously hypothesized to prevent tooth breakage instead first evolved to shape and maintain the characteristic denticles through the life of the tooth. We show that this novel complex of dental morphology and tissues characterizes Theropoda, with the exception of species with modified feeding behaviours, suggesting that these characters are important for facilitating the hypercarnivorous diet of most theropods. This adaptation may have played an important role in the initial radiation and subsequent success of theropods as terrestrial apex predators. PMID:26216577

A homozygote splice site PMS2 mutation as cause of Turcot syndrome gives rise to two different abnormal transcripts.

PubMed

Sjursen, Wenche; Bjørnevoll, Inga; Engebretsen, Lars F; Fjelland, Kristine; Halvorsen, Tore; Myrvold, Helge E

2009-01-01

Turcot syndrome is a rare, inherited disease predisposing of tumours in the central nerve system and in the colorectal system. This report describes a Turcot patient with an extraordinary clinical history. The patient is still alive at the age of 43. She was operated at the age of 10 by brain tumour and at the age of 16 by colorectal cancer. She has since then been treated for multiple cancers (gastrointestinal, endometrial, basal cell carcinomas), and removal of adenomatous polyps at several occasions. The aim of this work was to investigate if there was any specific genotype that explains her remarkable clinical history. Microsatellite instability and immunohistochemistry analysis for four DNA mismatch repair proteins were performed. DNA mutation analysis was done for genes involved in polyposis and mismatch repair by denaturing high performance liquid chromatography and sequencing. cDNA analysis was carried out for the mismatch repair gene PMS2. The patients genotype was found to be a homozygous splice site mutation in the PMS2 gene, c.989-1G

The national comparative audit of surgery for nasal polyposis and chronic rhinosinusitis.

PubMed

Hopkins, C; Browne, J P; Slack, R; Lund, V; Topham, J; Reeves, B; Copley, L; Brown, P; van der Meulen, J

2006-10-01

This study summarises the results of a National Audit of sino-nasal surgery carried out in England and Wales. It describes patient and operative characteristics as well as patient outcomes up to 36 months after surgery. Prospective cohort study. NHS hospitals in England and Wales. Consecutive patients undergoing surgery for nasal polyposis and/or chronic rhinosinusitis. The total score derived from a 22-item version of the Sino-Nasal Outcome Test (SNOT-22). Lower scores represent better health-related quality of life. A total of 3128 consecutive patients at 87 NHS hospitals were enrolled. There is a large improvement in SNOT-22 scores from the pre-operative period (mean = 42.0) to 3 months after surgery (mean = 25.5). The scores for patients undergoing nasal polypectomy improved from 41.0 before surgery to 23.1 at 3 months after surgery, while the scores for patients undergoing surgery for chronic rhinosinusitis alone improved from 44.2 to 31.2. The SNOT-22 scores reported at 12 and 36 months after surgery were similar to those reported at 3 months. Excessive bleeding occurred in 5% of patients during the operation and in 1% of patients after the operation. Intra-orbital complications were reported in 0.2%. Of those patients undergoing primary surgery for bilateral grade I or II polyposis, 18% had not received a pre-operative course of steroid treatment. At the 36-month follow-up, 11.4% of patients had undergone revision surgery. The audit confirms that sino-nasal surgery is generally safe and effective. There is some evidence that patient selection for surgery could be improved.

Assessing barriers to a rational chemoprevention trial design in young patients with familial adenomatous polyposis.

PubMed

Wood, Joanna P; Howells, Lynne M; Brown, Karen; Thomas, Anne L

2017-07-01

Familial adenomatous polyposis coli (FAP) is an autosomal dominant condition caused by a germline mutation in the adenomatous polyposis coli gene. Colonic adenomas form and almost all patients will develop colorectal cancer if they are not managed at an early stage. The safest preventive strategy is surgical resection of the colon, most commonly performed in late teenage years. There is a paucity of trials investigating the use of primary chemoprevention to delay polyp formation in paediatric FAP. There are extensive preclinical and early clinical data demonstrating that curcumin may be a safe and effective chemotherapeutic agent in reducing the polyp burden in this disease. We ultimately proposed to design and conduct a clinical study to assess whether curcumin treatment delays the need for surgery and/or prevents cancer in young patients with FAP. Research into clinical trial protocols has demonstrated that assessing patients' perceptions at the initial stage leads to better outcomes. We therefore conducted a questionnaire study of patients and parents of children affected by FAP to gain information to aid the protocol design. Results demonstrated that there are some FAP patients for whom this study is relevant and desirable. Those with a personal history of curcumin use reported that it was well tolerated. However, the response rate was poor (25%), indicating that there are potential difficulties ensuring adequate recruitment to the proposed trial. This report draws on lessons learnt from prior trials and the findings from the questionnaire to outline the challenges faced in designing such a study.

Congenital hypertrophy of retinal pigment epithelium (CHRPE) in patients with familial adenomatous polyposis (FAP); a polyposis registry experience.

PubMed

Nusliha, Anwer; Dalpatadu, Ushantha; Amarasinghe, Binara; Chandrasinghe, Pramodh Chitral; Deen, Kemal Ismail

2014-10-18

Familial Adenomatous Polyposis (FAP) is an autosomal dominant condition giving rise to multiple adenomatous polyps in the colon which invariably become malignant by the fourth decade. Congenital hypertrophy of retinal pigment epithelium (CHRPE) is one of its extra intestinal manifestations early in childhood seen, present in 90% of FAP population and is easy to detect. Patients diagnosed with FAP and at risk first degree family members were screened for CHRPE using a slit lamp and indirect ophthalmoscopy. The retina of 17 diagnosed FAP patients and 13 individuals at risk were examined. The site and size of CHRPE lesions were documented. Thirteen (76%) of 17 FAP patients (male-10, female - 7, median age - 30 years; range 15-55 years) had CHRPE lesions; seven (54%) had bilateral CHRPE lesions and six (46%) had unilateral lesions. A single lesion was detected in 6 (46%) while 7 (54%) patients had multiple lesions. Of 13 at risk individuals (7- male, female-6 ; median age 34; range 16-52 years), one was positive for CHRPE and 12 were free of retinal lesions. The sensitivity of the presence of a CHRPE lesion in association with colonic polyps in FAP was 76%, specificity 92%, positive predictive value 93%, and negative predictive value 75%. This study found a high sensitivity and specificity for a CHRPE lesion to be associated with colonic polyps of FAP and hence a useful screening method in a burdened health-care system. The method is minimally invasive and simple and would be of particular value in screening children at risk for FAP.

Our experience of treatment of cribriform morular variant of papillary thyroid carcinoma; difference in clinicopathological features of FAP-associated and sporadic patients.

PubMed

Ito, Yasuhiro; Miyauchi, Akira; Ishikawa, Hideki; Hirokawa, Mitsuhiro; Kudo, Takumi; Tomoda, Chisato; Miya, Akihiro

2011-01-01

Cribriform-morular variant (CMV) is a comparably rare histological subtype of papillary thyroid carcinoma (PTC). This can be associated with familial adenomatous polyposis (FAP) due to APC gene mutations. In this study, we investigated the difference in the biological characteristics between FAP-associated and sporadic CMV. Between 1991 and 2010, 32 patients with CMV were treated in Kuma Hospital. Thirty-one of these underwent initial surgery for CMV in Kuma Hospital. Twelve patients were FAP-associated and the remaining 19 were sporadic CMV. All patients were female. Tumors of FAP-associated CMV were more frequently multiple than those of sporadic CMV. Patient age and tumor size did not differ between the two groups. Of 12 FAP-associated CMV, 5 were detected by thyroid nodule (thyroid precedent group) and 7 were detected by FAP (polyposis precedent group) as an initial manifestation. Patient age was younger and tumor size was smaller in the polyposis group than in the thyroid nodule group. All patients lacked extrathyroid extension on intraoperative finding and were node-negative on pathological examination. To date, two patients with FAP-associated CMV who initially underwent hemithyroidectomy (one in Kuma Hospital and one in another hospital) showed recurrence to the remnant thyroid during follow-up. None of the patients showed recurrence to other regions or died of carcinoma. Taken together, CMV is considered an indolent disease in our series. FAP-associated CMV showed multiple tumors more frequently than sporadic CMV. Total thyroidectomy is recommended for FAP-associated CMV, but extensive lymph node dissection is not necessary.

Continuing difficulties in interpreting CNV data: lessons from a genome-wide CNV association study of Australian HNPCC/lynch syndrome patients.

PubMed

Talseth-Palmer, Bente A; Holliday, Elizabeth G; Evans, Tiffany-Jane; McEvoy, Mark; Attia, John; Grice, Desma M; Masson, Amy L; Meldrum, Cliff; Spigelman, Allan; Scott, Rodney J

2013-03-26

Hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome (LS) is a cancer syndrome characterised by early-onset epithelial cancers, especially colorectal cancer (CRC) and endometrial cancer. The aim of the current study was to use SNP-array technology to identify genomic aberrations which could contribute to the increased risk of cancer in HNPCC/LS patients. Individuals diagnosed with HNPCC/LS (100) and healthy controls (384) were genotyped using the Illumina Human610-Quad SNP-arrays. Copy number variation (CNV) calling and association analyses were performed using Nexus software, with significant results validated using QuantiSNP. TaqMan Copy-Number assays were used for verification of CNVs showing significant association with HNPCC/LS identified by both software programs. We detected copy number (CN) gains associated with HNPCC/LS status on chromosome 7q11.21 (28% cases and 0% controls, Nexus; p =3.60E-20 and QuantiSNP; p < 1.00E-16) and 16p11.2 (46% in cases, while a CN loss was observed in 23% of controls, Nexus; p = 4.93E-21 and QuantiSNP; p = 5.00E-06) via in silico analyses. TaqMan Copy-Number assay was used for validation of CNVs showing significant association with HNPCC/LS. In addition, CNV burden (total CNV length, average CNV length and number of observed CNV events) was significantly greater in cases compared to controls. A greater CNV burden was identified in HNPCC/LS cases compared to controls supporting the notion of higher genomic instability in these patients. One intergenic locus on chromosome 7q11.21 is possibly associated with HNPCC/LS and deserves further investigation. The results from this study highlight the complexities of fluorescent based CNV analyses. The inefficiency of both CNV detection methods to reproducibly detect observed CNVs demonstrates the need for sequence data to be considered alongside intensity data to avoid false positive results.

Correlation between mutations and mRNA expression of APC and MUTYH genes: new insight into hereditary colorectal polyposis predisposition.

PubMed

Aceto, Gitana Maria; Fantini, Fabiana; De Iure, Sabrina; Di Nicola, Marta; Palka, Giandomenico; Valanzano, Rosa; Di Gregorio, Patrizia; Stigliano, Vittoria; Genuardi, Maurizio; Battista, Pasquale; Cama, Alessandro; Curia, Maria Cristina

2015-10-28

Transcript dosage imbalance may influence the transcriptome. To gain insight into the role of altered gene expression in hereditary colorectal polyposis predisposition, in the present study we analyzed absolute and allele-specific expression (ASE) of adenomatous polyposis coli (APC) and mutY Homolog (MUTYH) genes. We analyzed DNA and RNA extracted from peripheral blood mononuclear cells (PBMC) of 49 familial polyposis patients and 42 healthy blood donors selected according similar gender and age. Patients were studied for germline alterations in both genes using dHPLC, MLPA and automated sequencing. APC and MUTYH mRNA expression levels were investigated by quantitative Real-Time PCR (qRT-PCR) analysis using TaqMan assay and by ASE assays using dHPLC-based primer extension. Twenty out of 49 patients showed germline mutations: 14 in APC gene and six in MUTYH gene. Twenty-nine patients did not show mutations in both genes. Results from qRT-PCR indicated that gene expression of both APC and MUTYH was reduced in patients analyzed. In particular, a significant reduction in APC expression was observed in patients without APC germline mutation vs control group (P < 0.05) while APC expression in the mutation carrier patients, although lower compared to control individuals, did not show statistical significance. On the other hand a significant reduced MUTYH expression was detected in patients with MUTYH mutations vs control group (P < 0.05). Altered ASE of APC was detected in four out of eight APC mutation carriers. In particular one case showed a complete loss of one allele. Among APC mutation negative cases, 4 out of 13 showed a moderate ASE. ASE of MUTYH did not show any altered expression in the cases analyzed. Spearman's Rho Test analysis showed a positive and significant correlation between APC and MUTYH genes both in cases and in controls (P = 0.020 and P < 0.001). APC and MUTYH showed a reduced germline expression, not always corresponding to gene mutation. Expression of APC is decreased in mutation negative cases and this appears to be a promising indicator of FAP predisposition, while for MUTYH gene, mutation is associated to reduced mRNA expression. This study could improve the predictive genetic diagnosis of at-risk individuals belonging to families with reduced mRNA expression regardless of presence of mutation.

Surgical Instrument Decontamination Unit

DTIC Science & Technology

1989-02-15

0.54 Aspergillus niger 8.55 1.32 Candida parapsilosa 18.30 3.44 note 1: As reported by Turner, 1975. note 2: Contamination level = 7x105 organisms...Serrat’a marcescens and two of the fungi. Although Aspergillus nrger andCandida parapsilosis were more resistant, lenses were completely disinfected

Development of a model for the ice scraping process.

DOT National Transportation Integrated Search

1996-10-01

A laboratory study has been conducted with two aims in mind. The first goal was : to develop a description of how a cutting edge scrapes ice from the road surface. The : second goal was to investigate the extent, if any, to which serrated blades were...

A Specific Mutational Signature Associated with DNA 8-Oxoguanine Persistence in MUTYH-defective Colorectal Cancer

DOE PAGES

Viel, Alessandra; Bruselles, Alessandro; Meccia, Ettore; ...

2017-04-13

8-Oxoguanine, a common mutagenic DNA lesion, generates G:C > T:A transversions via mispairing with adenine during DNA replication. When operating normally, the MUTYH DNA glycosylase prevents 8-oxoguanine-related mutagenesis by excising the incorporated adenine. Biallelic MUTYH mutations impair this enzymatic function and are associated with colorectal cancer (CRC) in MUTYH-Associated Polyposis (MAP) syndrome. Here in this paper, we perform whole-exome sequencing that reveals a modest mutator phenotype in MAP CRCs compared to sporadic CRC stem cell lines or bulk tumours. The excess G:C > T:A transversion mutations in MAP CRCs exhibits a novel mutational signature, termed Signature 36, with a strongmore » sequence dependence. The MUTYH mutational signature reflecting persistent 8-oxoG:A mismatches occurs frequently in the APC, KRAS, PIK3CA, FAT4, TP53, FAT1, AMER1, KDM6A, SMAD4 and SMAD2 genes that are associated with CRC. In conclusion, the occurrence of Signature 36 in other types of human cancer indicates that DNA 8-oxoguanine-related mutations might contribute to the development of cancer in other organs.« less

Novel LOVD databases for hereditary breast cancer and colorectal cancer genes in the Chinese population.

PubMed

Pan, Min; Cong, Peikuan; Wang, Yue; Lin, Changsong; Yuan, Ying; Dong, Jian; Banerjee, Santasree; Zhang, Tao; Chen, Yanling; Zhang, Ting; Chen, Mingqing; Hu, Peter; Zheng, Shu; Zhang, Jin; Qi, Ming

2011-12-01

The Human Variome Project (HVP) is an international consortium of clinicians, geneticists, and researchers from over 30 countries, aiming to facilitate the establishment and maintenance of standards, systems, and infrastructure for the worldwide collection and sharing of all genetic variations effecting human disease. The HVP-China Node will build new and supplement existing databases of genetic diseases. As the first effort, we have created a novel variant database of BRCA1 and BRCA2, mismatch repair genes (MMR), and APC genes for breast cancer, Lynch syndrome, and familial adenomatous polyposis (FAP), respectively, in the Chinese population using the Leiden Open Variation Database (LOVD) format. We searched PubMed and some Chinese search engines to collect all the variants of these genes in the Chinese population that have already been detected and reported. There are some differences in the gene variants between the Chinese population and that of other ethnicities. The database is available online at http://www.genomed.org/LOVD/. Our database will appear to users who survey other LOVD databases (e.g., by Google search, or by NCBI GeneTests search). Remote submissions are accepted, and the information is updated monthly. © 2011 Wiley Periodicals, Inc.

Predicting adaptation to presymptomatic DNA testing for late onset disorders: who will experience distress? Rotterdam Leiden Genetics Workgroup.

PubMed Central

DudokdeWit, A C; Tibben, A; Duivenvoorden, H J; Niermeijer, M F; Passchier, J

1998-01-01

The first comparative study on predicting post-test distress (conceptualised by intrusion and avoidance, measured with the Impact of Event Scale) after presymptomatic genetic testing for Huntington's disease (HD, n=25), cancer syndromes (familial adenomatous polyposis (FAP, n=23)), and hereditary breast and ovarian cancer (HBOC, n=10) is reported. The variables with the highest predictive potential of post-test distress are presented. Participants who were depressed before the test were more distressed after testing, but we found that those who were anxious before the test were less distressed, that is, had less intrusive thoughts post-test. Other factors associated with a higher level of post-test intrusion were gender (being a woman), having children, and pre-test intrusion. Religion and being at risk for HBOC were associated with less post-test intrusion. Participants who showed avoidance behaviour before the test and those who had many people available for support showed more avoidance behaviour post-test. The test result did not additionally contribute to post-test distress. The prima facie simple notion that the test result, as such, determines the distress experienced seems to be a misrepresentation of the complex reality. PMID:9733033

The Pleiotropic Phenotype of Apc Mutations in the Mouse: Allele Specificity and Effects of the Genetic Background

PubMed Central

Halberg, Richard B.; Chen, Xiaodi; Amos-Landgraf, James M.; White, Alanna; Rasmussen, Kristin; Clipson, Linda; Pasch, Cheri; Sullivan, Ruth; Pitot, Henry C.; Dove, William F.

2008-01-01

Familial adenomatous polyposis (FAP) is a human cancer syndrome characterized by the development of hundreds to thousands of colonic polyps and extracolonic lesions including desmoid fibromas, osteomas, epidermoid cysts, and congenital hypertrophy of the pigmented retinal epithelium. Afflicted individuals are heterozygous for mutations in the APC gene. Detailed investigations of mice heterozygous for mutations in the ortholog Apc have shown that other genetic factors strongly influence the phenotype. Here we report qualitative and quantitative modifications of the phenotype of Apc mutants as a function of three genetic variables: Apc allele, p53 allele, and genetic background. We have found major differences between the Apc alleles Min and 1638N in multiplicity and regionality of intestinal tumors, as well as in incidence of extracolonic lesions. By contrast, Min mice homozygous for either of two different knockout alleles of p53 show similar phenotypic effects. These studies illustrate the classic principle that functional genetics is enriched by assessing penetrance and expressivity with allelic series. The mouse permits study of an allelic gene series on multiple genetic backgrounds, thereby leading to a better understanding of gene action in a range of biological processes. PMID:18723878

The pleiotropic phenotype of Apc mutations in the mouse: allele specificity and effects of the genetic background.

PubMed

Halberg, Richard B; Chen, Xiaodi; Amos-Landgraf, James M; White, Alanna; Rasmussen, Kristin; Clipson, Linda; Pasch, Cheri; Sullivan, Ruth; Pitot, Henry C; Dove, William F

2008-09-01

Familial adenomatous polyposis (FAP) is a human cancer syndrome characterized by the development of hundreds to thousands of colonic polyps and extracolonic lesions including desmoid fibromas, osteomas, epidermoid cysts, and congenital hypertrophy of the pigmented retinal epithelium. Afflicted individuals are heterozygous for mutations in the APC gene. Detailed investigations of mice heterozygous for mutations in the ortholog Apc have shown that other genetic factors strongly influence the phenotype. Here we report qualitative and quantitative modifications of the phenotype of Apc mutants as a function of three genetic variables: Apc allele, p53 allele, and genetic background. We have found major differences between the Apc alleles Min and 1638N in multiplicity and regionality of intestinal tumors, as well as in incidence of extracolonic lesions. By contrast, Min mice homozygous for either of two different knockout alleles of p53 show similar phenotypic effects. These studies illustrate the classic principle that functional genetics is enriched by assessing penetrance and expressivity with allelic series. The mouse permits study of an allelic gene series on multiple genetic backgrounds, thereby leading to a better understanding of gene action in a range of biological processes.

Colorectal Carcinoma: Why Is There a Lower Incidence in Nigerians When Compared to Caucasians?

PubMed Central

Irabor, David Omoareghan

2011-01-01

Carcinoma of the colon and rectum is the 2nd commonest cancer in the United States; the leading cancer being lung cancer. It has been estimated that 130,200 new cases of colorectal cancer will be diagnosed annually while 56,300 sufferers will die from the disease (Murphy et al., 2000). In developing countries especially West Africa, the rate has not yet reached such magnitude. This suggests that there may be factors either anthropomorphic or environmental which may be responsible for this. The paper acknowledges the reduced incidence of colorectal cancer in native West Africans living in Africa and endeavours to highlight the various factors that produce this observation in medical literature. A diligent search through available literature on the aetiology, epidemiology and comparative anthropology of colorectal cancer was done. Internet search using Pubmed, British library online and Google scholar was also utilized. The rarity of adenomatous polyposis syndromes in the native West African contributes to the reduced incidence of colorectal cancer. Cancer prevention and cancer-protective factors are deemed to lie in the starchy, high-fiber, spicy, peppery foodstuff low in animal protein which many West African nations consume. PMID:22253627

[CAS in rhino-surgical procedures in the growing age].

PubMed

Schipper, J; Maier, W; Gellrich, N-C; Arapakis, I; Hochmuth, A; Laszig, R

2005-01-01

Rhinosurgery in children and adolescents meets special requirements: Limited cooperation and reduced limits for the organ dose for ionizing radiological examinations aggravate diagnostics. On the other side, bone sutures and bone growth areas have to be respected intraoperatively, and regions of bones not yet calcified have to be distinguished from possible tumor infiltration. Computer assisted surgery (CAS) can help to identify these areas safely. 5 patients, from the first to the 20 (th) year of life, suffering from tumors, malformation syndromes or therapy resistant nasal polyposis were treated with CAS in rhinosurgery. In addition to radiological diagnostics, we performed 3D computed tomography of the skull for CAS. CAS enabled us to intraoperatively respect possible areas of bone growth, to identify regions with thin, not bonily developed cranial vault and to safely distinguish bone sutures from ethmoidal cells. CAS helped the surgeon to navigate in the not yet developed paranasal sinus system. CAS is a useful complementary method in rhinosurgery of the developing skull of the child. In spite of the additional 3D computed tomography, the calculated organ dose of the ocular lense amounted to 5 millisievert, so a recommended maximal organ dose for the ocular lense of 15 millisievert was not exceeded.

Unregulated smooth-muscle myosin in human intestinal neoplasia.

PubMed

Alhopuro, Pia; Phichith, Denis; Tuupanen, Sari; Sammalkorpi, Heli; Nybondas, Miranda; Saharinen, Juha; Robinson, James P; Yang, Zhaohui; Chen, Li-Qiong; Orntoft, Torben; Mecklin, Jukka-Pekka; Järvinen, Heikki; Eng, Charis; Moeslein, Gabriela; Shibata, Darryl; Houlston, Richard S; Lucassen, Anneke; Tomlinson, Ian P M; Launonen, Virpi; Ristimäki, Ari; Arango, Diego; Karhu, Auli; Sweeney, H Lee; Aaltonen, Lauri A

2008-04-08

A recent study described a recessive ATPase activating germ-line mutation in smooth-muscle myosin (smmhc/myh11) underlying the zebrafish meltdown (mlt) phenotype. The mlt zebrafish develops intestinal abnormalities reminiscent of human Peutz-Jeghers syndrome (PJS) and juvenile polyposis (JP). To examine the role of MYH11 in human intestinal neoplasia, we searched for MYH11 mutations in patients with colorectal cancer (CRC), PJS and JP. We found somatic protein-elongating frameshift mutations in 55% of CRCs displaying microsatellite instability and in the germ-line of one individual with PJS. Additionally, two somatic missense mutations were found in one microsatellite stable CRC. These two missense mutations, R501L and K1044N, and the frameshift mutations were functionally evaluated. All mutations resulted in unregulated molecules displaying constitutive motor activity, similar to the mutant myosin underlying mlt. Thus, MYH11 mutations appear to contribute also to human intestinal neoplasia. Unregulated MYH11 may affect the cellular energy balance or disturb cell lineage decisions in tumor progenitor cells. These data challenge our view on MYH11 as a passive differentiation marker functioning in muscle contraction and add to our understanding of intestinal neoplasia.

A Specific Mutational Signature Associated with DNA 8-Oxoguanine Persistence in MUTYH-defective Colorectal Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Viel, Alessandra; Bruselles, Alessandro; Meccia, Ettore

8-Oxoguanine, a common mutagenic DNA lesion, generates G:C > T:A transversions via mispairing with adenine during DNA replication. When operating normally, the MUTYH DNA glycosylase prevents 8-oxoguanine-related mutagenesis by excising the incorporated adenine. Biallelic MUTYH mutations impair this enzymatic function and are associated with colorectal cancer (CRC) in MUTYH-Associated Polyposis (MAP) syndrome. Here in this paper, we perform whole-exome sequencing that reveals a modest mutator phenotype in MAP CRCs compared to sporadic CRC stem cell lines or bulk tumours. The excess G:C > T:A transversion mutations in MAP CRCs exhibits a novel mutational signature, termed Signature 36, with a strongmore » sequence dependence. The MUTYH mutational signature reflecting persistent 8-oxoG:A mismatches occurs frequently in the APC, KRAS, PIK3CA, FAT4, TP53, FAT1, AMER1, KDM6A, SMAD4 and SMAD2 genes that are associated with CRC. In conclusion, the occurrence of Signature 36 in other types of human cancer indicates that DNA 8-oxoguanine-related mutations might contribute to the development of cancer in other organs.« less

Different surgical strategies in the treatment of familial adenomatous polyposis: what's the role of the ileal pouch-anal anastomosis?

PubMed

Leonard, D; Wolthuis, A; D'Hoore, A; Bruyninx, L; Van De Stadt, J; Van Cutsem, E; Kartheuser, A

2011-09-01

Restorative coloproctectomy (RCP) with ileal pouch-anal anastomosis (IPAA), is one of the surgical responses to the crucial question of prophylactic treatment in familial adenomatous polyposis (FAP). No consensus has been reached, until now, to choose between IPAA and ileo-rectal anastomosis (IRA), the rectal sparing prophylactic colectomy. This paper aims to review the latest issues related to IPAA and highlights its specificities compared to IRA. PubMed database was searched using the following search items: familial adenomatous polyposis, surgery, ileal pouch-anal anastomosis, ileo-rectal anastomosis. Papers published between 1978 and 2010 were selected. Absence of mortality, acceptable morbidity and good functional results combined to high quality of life have promoted the IPAA technique. New technical issues such as the double stapled technique, mesenteric lengthening, omission of temporary protective stoma can be addressed almost systematically for these patients. A laparoscopic approach, lessening the body image impact, has proven to be as effective and safe as the open approach to perform IPAA. Further advantages of laparoscopic IPAA rely on the lower adhesion formation resulting in less small bowel occlusion. Sexuality, fertility and childbirth are important functional issues often cited as threatened by the pelvic manoeuvres of the IPAA technique which can be prevented by close rectal wall dissection and a laparoscopic approach. IPAA offers the best available prophylaxis in FAP patients. Technical enhancements in IPAA will most probably decrease the functional risks. Thus IPAA remains the alternative to IRA for the prophylactic treatment of FAP.Nevertheless, based on the latest evidence, the choice between both procedures is still matter of debate.

Adenomatous Polyposis Coli Mutation Leads to Myopia Development in Mice

PubMed Central

Li, Jing; Zhu, Zhenzhen; Yang, Wenzhao; Zhou, Xiangtian; An, Jianhong; Huang, Furong; Wang, Qiongsi; Reinach, Peter S.; Li, Wei; Chen, Wensheng; Liu, Zuguo

2015-01-01

Myopia incidence in China is rapidly becoming a very serious sight compromising problem in a large segment of the general population. Therefore, delineating the underlying mechanisms leading to myopia will markedly lessen the likelihood of other sight compromising complications. In this regard, there is some evidence that patients afflicted with familial adenomatous polyposis (FAP), havean adenomatous polyposis coli (APC) mutation and a higher incidence of myopia. To clarify this possible association, we determined whether the changes in pertinent biometric and biochemical parameters underlying postnatal refractive error development in APCMin mice are relevant for gaining insight into the pathogenesis of this disease in humans. The refraction and biometrics in APCMin mice and age-matched wild-type (WT) littermates between postnatal days P28 and P84 were examined with eccentric infrared photorefraction (EIR) and customized optical coherence tomography (OCT). Compared with WT littermates, the APCMin mutated mice developed myopia (average -4.64 D) on P84 which was associated with increased vitreous chamber depth (VCD). Furthermore, retinal and scleral changes appear in these mice along with: 1) axial length shortening; 2) increased retinal cell proliferation; 3) and decreased tyrosine hydroxylase (TH) expression, the rate-limiting enzyme of DA synthesis. Scleral collagen fibril diameters became heterogeneous and irregularly organized in the APCMin mice. Western blot analysis showed that scleral alpha-1 type I collagen (col1α1) expression also decreased whereas MMP2 and MMP9 mRNA expression was invariant. These results indicate that defective APC gene function promotes refractive error development. By characterizing in APCMin mice ocular developmental changes, this approach provides novel insight into underlying pathophysiological mechanisms contributing to human myopia development. PMID:26495845

Loss of single immunoglobulin interlukin-1 receptor-related molecule leads to enhanced colonic polyposis in Apc(min) mice.

PubMed

Xiao, Hui; Yin, Weiguo; Khan, Mohammed A; Gulen, Muhammet F; Zhou, Hang; Sham, Ho Pan; Jacobson, Kevan; Vallance, Bruce A; Li, Xiaoxia

2010-08-01

Commensal bacteria can activate signaling by the Toll-like and interleukin-1 receptors (TLR and IL-1R) to mediate pathogenesis of inflammatory bowel diseases and colitis-associated cancer. We investigated the role of the single immunoglobulin IL-1 receptor-related (SIGIRR) molecule, a negative regulator of TLR and IL-1R signaling, as a tumor suppressor to determine whether SIGIRR controls cell-cycle progression, genetic instability, and colon tumor initiation by modulating commensal TLR signaling in the gastrointestinal tract. We analyzed adenomatous polyposis coli (Apc)min/+/Sigirr-/- mice for polyps, microadenomas, and anaphase bridge index. Commensal bacteria were depleted from mice with antibiotics. Akt, mammalian target of rapamycin (mTOR), and beta-catenin pathways were examined by immunoblotting and immunohistochemistry. Loss of heterozygosity of Apc and expression of cytokines and proinflammatory mediators were measured by nonquantitative or quantitative polymerase chain reaction. Apcmin/+/Sigirr-/- mice had increased loss of heterozygosity of Apc and microadenoma formation, resulting in spontaneous colonic polyposis, compared with Apcmin/+/Sigirr+/+ mice. The increased colonic tumorigenesis that occurred in the Apcmin/+/Sigirr-/- mice depended on the presence of commensal bacteria in the gastrointestinal tract. Cell proliferation and chromosomal instability increased in colon crypt cells of the Apcmin/+/Sigirr-/- mice. Akt, mTOR, and their substrates were hyperactivated in colon epithelium of Apcmin/+/Sigirr-/- mice in response to TLR or IL-1R ligands. Inhibition of the mTOR pathway by rapamycin reduced formation of microadenomas and polyps in the Apcmin/+/Sigirr-/- mice. SIGIRR acts as a tumor suppressor in the colon by inhibiting TLR-induced, mTOR-mediated cell-cycle progression and genetic instability. Copyright (c) 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

Prevalence of human papilloma virus and human herpes virus types 1-7 in human nasal polyposis.

PubMed

Zaravinos, Apostolos; Bizakis, John; Spandidos, Demetrios A

2009-09-01

This study aimed to investigate the prevalence of human papilloma virus (HPV), herpes simplex virus-1/-2 (HSV-1/-2), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), and human herpes virus-6/-7 (HHV-6/-7) in 23 human nasal polyps by applying PCR. Two types of control tissues were used: adjacent inferior/middle turbinates from the patients and inferior/middle turbinates from 13 patients undergoing nasal corrective surgery. EBV was the virus most frequently detected (35%), followed by HPV (13%), HSV-1 (9%), and CMV (4%). The CMV-positive polyp was simultaneously positive for HSV-1. HPV was also detected in the adjacent turbinates (4%) and the adjacent middle turbinate (4%) of one of the HPV-positive patients. EBV, HSV, and CMV were not detected in the adjacent turbinates of the EBV-, HSV- or CMV-positive patients. All mucosae were negative for the VZV, HHV-6, and HHV-7. This is the first study to deal with the involvement of a comparable group of viruses in human nasal polyposis. The findings support the theory that the presence of viral EBV markedly influences the pathogenesis of these benign nasal tumors. The low incidence of HPV detected confirms the hypothesis that HPV is correlated with infectious mucosal lesions to a lesser extent than it is with proliferative lesions, such as inverted papilloma. The low incidence of HSV-1 and CMV confirms that these two herpes viruses may play a minor role in the development of nasal polyposis. Double infection with HSV-1 and CMV may also play a minor, though causative, role in nasal polyp development. VZV and HHV-6/-7 do not appear to be involved in the pathogenesis of these mucosal lesions.

Neurotensin receptor 1 gene activation by the Tcf/beta-catenin pathway is an early event in human colonic adenomas.

PubMed

Souazé, Frédérique; Viardot-Foucault, Véronique; Roullet, Nicolas; Toy-Miou-Leong, Mireille; Gompel, Anne; Bruyneel, Erik; Comperat, Eva; Faux, Maree C; Mareel, Marc; Rostène, William; Fléjou, Jean-François; Gespach, Christian; Forgez, Patricia

2006-04-01

Alterations in the Wnt/APC (adenomatous polyposis coli) signalling pathway, resulting in beta-catenin/T cell factor (Tcf)-dependent transcriptional gene activation, are frequently detected in familial and sporadic colon cancers. The neuropeptide neurotensin (NT) is widely distributed in the gastrointestinal tract. Its proliferative and survival effects are mediated by a G-protein coupled receptor, the NT1 receptor. NT1 receptor is not expressed in normal colon epithelial cells, but is over expressed in a number of cancer cells and tissues suggesting a link to the outgrowth of human colon cancer. Our results demonstrate that the upregulation of NT1 receptor occurring in colon cancer is the result of Wnt/APC signalling pathway activation. We first established the functionality of the Tcf response element within the NT1 receptor promoter. Consequently, we observed the activation of NT1 receptor gene by agents causing beta-catenin cytosolic accumulation, as well as a strong decline of endogenous receptor when wt-APC was restored. At the cellular level, the re-establishment of wt-APC phenotype resulted in the impaired functionality of NT1 receptor, like the breakdown in NT-induced intracellular calcium mobilization and the loss of NT pro-invasive effect. We corroborated the Wnt/APC signalling pathway on the NT1 receptor promoter activation with human colon carcinogenesis, and showed that NT1 receptor gene activation was perfectly correlated with nuclear or cytoplasmic beta-catenin localization while NT1 receptor was absent when beta-catenin was localized at the cell-cell junction in early adenomas of patients with familial adenomatous polyposis, hereditary non-polyposis colorectal cancer and loss of heterozygosity tumours. In this report we establish a novel link in vitro between the Tcf/beta-catenin pathway and NT1 receptor promoter activation.

Transforming activity and therapeutic targeting of C-terminal-binding protein 2 in Apc-mutated neoplasia.

PubMed

Sumner, E T; Chawla, A T; Cororaton, A D; Koblinski, J E; Kovi, R C; Love, I M; Szomju, B B; Korwar, S; Ellis, K C; Grossman, S R

2017-08-17

Overexpression of the transcriptional coregulators C-terminal binding proteins 1 and 2 (CtBP1 and 2) occurs in many human solid tumors and is associated with poor prognosis. CtBP modulates oncogenic gene expression programs and is an emerging drug target, but its oncogenic role is unclear. Consistent with this oncogenic potential, exogenous CtBP2 transformed primary mouse and human cells to anchorage independence similarly to mutant H-Ras. To investigate CtBP's contribution to in vivo tumorigenesis, Apc min/+ mice, which succumb to massive intestinal polyposis, were bred to Ctbp2 +/- mice. CtBP interacts with adenomatous polyposis coli (APC) protein, and is stabilized in both APC-mutated human colon cancers and Apc min/+ intestinal polyps. Ctbp2 heterozygosity increased the median survival of Apc min/+ mice from 21 to 48 weeks, and reduced polyp formation by 90%, with Ctbp2 +/- polyps exhibiting reduced levels of β-catenin and its oncogenic transcriptional target, cyclin D1. CtBP's potential as a therapeutic target was studied by treating Apc min/+ mice with the CtBP small-molecule inhibitors 4-methylthio-2-oxobutyric acid and 2-hydroxy-imino phenylpyruvic acid, both of which reduced polyposis by more than half compared with vehicle treatment. Phenocopying Ctbp2 deletion, both Ctbp inhibitors caused substantial decreases in the protein level of Ctbp2, as well its oncogenic partner β-catenin, and the effects of the inhibitors on CtBP and β-catenin levels could be modeled in an APC-mutated human colon cancer cell line. CtBP2 is thus a druggable transforming oncoprotein critical for the evolution of neoplasia driven by Apc mutation.

The genetics of familial adenomatous polyposis (FAP) and MutYH-associated polyposis (MAP).

PubMed

Claes, Kathleen; Dahan, Karin; Tejpar, S; De Paepe, Anne; Bonduelle, Maryse; Abramowicz, Marc; Verellen, Christine; Franchimont, Denis; Van Cutsem, Eric; Kartheuser, Alex

2011-09-01

FAP is characterized by 100-1000s of adenomatous polyps in colon and rectum, and is in 70% of the patients associated with extracolonic manifestations. Attenuated FAP (AFAP) is a less severe form of FAP, marked by the presence of < 100 polyps and a later onset of colorectal cancer (CRC). (A)FAP is caused by autosomal dominantly inherited mutations in the APC (Adenomatous polyposis coli) gene, a tumour suppressor gene that controls beta-catenin turnover in the Wnt pathway. De novo occurrence is reported in 30-40% of the patients. Mutations are detected in 85% of classical FAP families, while only 20%-30% of AFAP cases will exhibit a germline APC mutation. MUTYH is the second (A)FAP-related gene and is involved with base-excision repair of DNA damaged by oxidative stress. MUTYH mutations are inherited in an autosomal recessive way and account for 10%-20% of classical FAP cases without an APC mutation and for 30% of AFAP cases. Genotype-phenotype correlations exist for mutations in the APC gene, however, contradictions in the literature caution against the sole use of the genotype for decisions regarding clinical management. Once the family's specific APC mutation is identified in the proband, predictive testing for first degree relatives is possible from the age of 10 to 12 years on. For AFAP, relatives are tested at age 18 and older. Opinions about the appropriate ages at which to initiate genetic testing may vary. Physicians must have a discussion about prenatal testing with patients in childbearing age. They may either opt for conventional prenatal diagnosis (amniocentesis or chorionic villous sampling) or for preimplantation genetic diagnosis (PGD).

Spectrum of APC and MUTYH germ-line mutations in Russian patients with colorectal malignancies.

PubMed

Yanus, G A; Akhapkina, T A; Ivantsov, A O; Preobrazhenskaya, E V; Aleksakhina, S N; Bizin, I V; Sokolenko, A P; Mitiushkina, N V; Kuligina, E Sh; Suspitsin, E N; Venina, A R; Holmatov, M M; Zaitseva, O A; Yatsuk, O S; Pashkov, D V; Belyaev, A M; Togo, A V; Imyanitov, E N; Iyevleva, A G

2018-05-01

Distribution of cancer-predisposing mutations demonstrates significant interethnic variations. This study aimed to evaluate patterns of APC and MUTYH germ-line mutations in Russian patients with colorectal malignancies. APC gene defects were identified in 26/38 (68%) subjects with colon polyposis; 8/26 (31%) APC mutations were associated with 2 known mutational hotspots (p.E1309Dfs*4 [n = 5] and p.Q1062fs* [n = 3]), while 6/26 (23%) mutations were novel (p.K73Nfs*6, p.S254Hfs*12, p.S1072Kfs*9, p.E1547Kfs*11, p.L1564X and p.C1263Wfs*22). Biallelic mutations in MUTYH gene were detected in 3/12 (25%) remaining subjects with polyposis and in 6/90 (6.7%) patients with colorectal cancer (CRC) carrying KRAS p.G12C substitution, but not in 231 early-onset CRC cases negative for KRAS p.G12C allele. In addition to known European founder alleles p.Y179C and p.G396D, this study revealed a recurrent character of MUTYH p.R245H germ-line mutation. Besides that, 3 novel pathogenic MUTYH alleles (p.L111P, p.R245S and p.Q293X) were found. Targeted next-generation sequencing of 7 APC/MUTYH mutation-negative DNA samples identified novel potentially pathogenic POLD1 variant (p.L460R) in 1 patient and known low-penetrant cancer-associated allele CHEK2 p.I157T in 3 patients. The analysis of 1120 healthy subjects revealed 15 heterozygous carriers of recurrent MUTYH mutations, thus the expected incidence of MUTYH-associated polyposis in Russia is likely to be 1:23 000. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Causality Assessment of Olfactory and Gustatory Dysfunction Associated with Intranasal Fluticasone Propionate: Application of the Bradford Hill Criteria.

PubMed

Muganurmath, Chandrashekhar S; Curry, Amy L; Schindzielorz, Andrew H

2018-02-01

Causality assessment is crucial to post-marketing pharmacovigilance and helps optimize safe and appropriate use of medicines by patients in the real world. Self-reported olfactory and gustatory dysfunction are common in the general population as well as in patients with allergic rhinitis and nasal polyposis. Intranasal corticosteroids, including intranasal fluticasone propionate (INFP), are amongst the most effective drugs indicated in the treatment of allergic rhinitis and nasal polyposis. While intranasal corticosteroids are associated with olfactory and gustatory dysfunction and are currently labeled for these adverse events, causality assessment has not been performed to date. Although there is no single widely accepted method to assess causality in pharmacovigilance, the Bradford Hill criteria offer a robust and comprehensive approach because nine distinct aspects of an observed potential drug-event association are assessed. In this literature-based narrative review, Hill's criteria were applied to determine causal inference between INFP and olfactory and gustatory dysfunction.

Tumour Suppressor Adenomatous Polyposis Coli (APC) localisation is regulated by both Kinesin-1 and Kinesin-2

PubMed Central

Ruane, Peter T.; Gumy, Laura F.; Bola, Becky; Anderson, Beverley; Wozniak, Marcin J.; Hoogenraad, Casper C.; Allan, Victoria J.

2016-01-01

Microtubules and their associated proteins (MAPs) underpin the polarity of specialised cells. Adenomatous polyposis coli (APC) is one such MAP with a multifunctional agenda that requires precise intracellular localisations. Although APC has been found to associate with kinesin-2 subfamily members, the exact mechanism for the peripheral localization of APC remains unclear. Here we show that the heavy chain of kinesin-1 directly interacts with the APC C-terminus, contributing to the peripheral localisation of APC in fibroblasts. In rat hippocampal neurons the kinesin-1 binding domain of APC is required for its axon tip enrichment. Moreover, we demonstrate that APC requires interactions with both kinesin-2 and kinesin-1 for this localisation. Underlining the importance of the kinesin-1 association, neurons expressing APC lacking kinesin-1-binding domain have shorter axons. The identification of this novel kinesin-1-APC interaction highlights the complexity and significance of APC localisation in neurons. PMID:27272132

[Informed Treatment Consent and Refusal in Advanced Endonasal Surgery: The Ethical Dilemma of Olfaction Sacrifice in Surgery for Chronic Rhinosinusitis with Polyposis].

PubMed

Subtil, João; Araújo, João Pedro; Saraiva, José; Santos, Alberto; Vera-Cruz, Paulo; Paço, João; Pais, Diogo

2015-01-01

Olfaction is frequently affected in chronic rhino-sinusitis with polyposis and has been recognised to have important impact on quality of life. Surgical resolution on cases of maximal medical therapy failure is an option to relieve symptoms, with debates as to how extensive surgery should be. A more radical approach will achieve better disease control with less relapse, but can also compromise olfaction. This decision about a more radical surgical approach should be shared with the patient. Thorough informed consent regarding disease control and hyposmia should be taken. Literature review and consultation with a board of experts. We propose some elements to be included in the informed consent discussion, in order to broadly address the surgical limitations regarding anosmia as a frequent complaint, as well as the different options and their associated consequences. Radical surgery decision making should be shared with the patient and the informed consent should be as thorough as possible regarding disease control and hyposmia resolution.

PLK1 has tumor-suppressive potential in APC-truncated colon cancer cells.

PubMed

Raab, Monika; Sanhaji, Mourad; Matthess, Yves; Hörlin, Albrecht; Lorenz, Ioana; Dötsch, Christina; Habbe, Nils; Waidmann, Oliver; Kurunci-Csacsko, Elisabeth; Firestein, Ron; Becker, Sven; Strebhardt, Klaus

2018-03-16

The spindle assembly checkpoint (SAC) acts as a molecular safeguard in ensuring faithful chromosome transmission during mitosis, which is regulated by a complex interplay between phosphatases and kinases including PLK1. Adenomatous polyposis coli (APC) germline mutations cause aneuploidy and are responsible for familial adenomatous polyposis (FAP). Here we study the role of PLK1 in colon cancer cells with chromosomal instability promoted by APC truncation (APC-ΔC). The expression of APC-ΔC in colon cells reduces the accumulation of mitotic cells upon PLK1 inhibition, accelerates mitotic exit and increases the survival of cells with enhanced chromosomal abnormalities. The inhibition of PLK1 in mitotic, APC-∆C-expressing cells reduces the kinetochore levels of Aurora B and hampers the recruitment of SAC component suggesting a compromised mitotic checkpoint. Furthermore, Plk1 inhibition (RNAi, pharmacological compounds) promotes the development of adenomatous polyps in two independent Apc Min/+ mouse models. High PLK1 expression increases the survival of colon cancer patients expressing a truncated APC significantly.

GENERAL VIEW OF CHAPEL (smaller than church; to right of ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

GENERAL VIEW OF CHAPEL (smaller than church; to right of church). NOTE SERRATED PARAPET AND THE FAMOUS "ROSE WINDOW" IN CENTER. ALSO NOTE BUTTRESSES. SOUTH SIDE. Duplicate color view of HABS TX-333-B-1 - Mission San Jose y San Miguel de Aguayo, Chapel, 6539 San Jose Road, San Antonio, Bexar County, TX

Graptemys gibbonsi Lovich and McCoy -- Pascagoula Map Turtle

USGS Publications Warehouse

Lovich, Jeffrey E.; Ennen, Joshua R.

2014-01-01

Hatchling pigmentation patterns resemble those of adults, but with more conspicuous patterns on the pleural scutes. Similarly, the plastron of hatchlings commonly has more dark pigmentation along the seams than adults. The shell is highly serrated along the edge of the carapace and the vertebral keel is more pronounced than in adults.

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

DTIC Science & Technology

2017-08-01

mouse and human colon epithelium; Aim 2.) Perform genome editing using CRISPR /Cas9 on immortalized human colon epithelial cells to introduce CRC...relevant gene mutations; Aim 3.) Use CRISPR /Cas9 genome editing in colon organoid cultures to introduce CRC relevant gene mutations into primary colon cells

Numerical analysis on interactions between fluid flow and structure deformation in plate-fin heat exchanger by Galerkin method

NASA Astrophysics Data System (ADS)

Liu, Jing-cheng; Wei, Xiu-ting; Zhou, Zhi-yong; Wei, Zhen-wen

2018-03-01

The fluid-structure interaction performance of plate-fin heat exchanger (PFHE) with serrated fins in large scale air-separation equipment was investigated in this paper. The stress and deformation of fins were analyzed, besides, the interaction equations were deduced by Galerkin method. The governing equations of fluid flow and heat transfer in PFHE were deduced by finite volume method (FVM). The distribution of strain and stress were calculated in large scale air separation equipment and the coupling situation of serrated fins under laminar situation was analyzed. The results indicated that the interactions between fins and fluid flow in the exchanger have significant impacts on heat transfer enhancement, meanwhile, the strain and stress of fins includes dynamic pressure of the sealing head and flow impact with the increase of flow velocity. The impacts are especially significant at the conjunction of two fins because of the non-alignment fins. It can be concluded that the soldering process and channel width led to structure deformation of fins in the exchanger, and degraded heat transfer efficiency.

Spherical shock-wave propagation in three-dimensional granular packings.

PubMed

Xue, Kun; Bai, Chun-Hua

2011-02-01

We investigate numerically the spherical shock-wave propagation in an open dense granular packing perturbed by the sudden expansion of a spherical intruder in the interior of the pack, focusing on the correlation between geometrical fabrics and propagating properties. The measurements of the temporal and spatial variations in a variety of propagating properties define a consistent serrated wave substructure with characteristic length on the orders of particle diameters. Further inspection of particle packing reveals a well-defined particle layering that persists several particle diameters away from the intruder, although its dominant effects are only within one to two diameters. This interface-induced layering not only exactly coincides with the serrated wave profile, but also highlights the competition between two energy transmission mechanisms involving distinct transport speeds. The alternating dominances between these two mechanisms contribute to the nonlinear wave propagation on the particle scale. Moreover, the proliferation of intricate three-dimensional contact force networks suggests the anisotropic stress transmission, which is found to also arise from the localized packing structure in the vicinity of the intruder.

A standardized method to create peripheral nerve injury in dogs using an automatic non-serrated forceps★

PubMed Central

Wang, Xuhui; Wan, Liang; Li, Xinyuan; Meng, Youqiang; Zhu, Ningxi; Yang, Min; Feng, Baohui; Zhang, Wenchuan; Zhu, Shugan; Li, Shiting

2012-01-01

This study describes a method that not only generates an automatic and standardized crush injury in the skull base, but also provides investigators with the option to choose from a range of varying pressure levels. We designed an automatic, non-serrated forceps that exerts a varying force of 0 to 100 g and lasts for a defined period of 0 to 60 seconds. This device was then used to generate a crush injury to the right oculomotor nerve of dogs with a force of 10 g for 15 seconds, resulting in a deficit in the pupil-light reflex and ptosis. Further testing of our model with Toluidine-blue staining demonstrated that, at 2 weeks post-surgery disordered oculomotor nerve fibers, axonal loss, and a thinner than normal myelin sheath were visible. Electrophysiological examination showed occasional spontaneous potentials. Together, these data verified that the model for oculomotor nerve injury was successful, and that the forceps we designed can be used to establish standard mechanical injury models of peripheral nerves. PMID:25337103

LES tests on airfoil trailing edge serration

NASA Astrophysics Data System (ADS)

Zhu, Wei Jun; Shen, Wen Zhong

2016-09-01

In the present study, a large number of acoustic simulations are carried out for a low noise airfoil with different Trailing Edge Serrations (TES). The Ffowcs Williams-Hawkings (FWH) acoustic analogy is used for noise prediction at trailing edge. The acoustic solver is running on the platform of our in-house incompressible flow solver EllipSys3D. The flow solution is first obtained from the Large Eddy Simulation (LES), the acoustic part is then carried out based on the instantaneous hydrodynamic pressure and velocity field. To obtain the time history data of sound pressure, the flow quantities are integrated around the airfoil surface through the FWH approach. For all the simulations, the chord based Reynolds number is around 1.5x106. In the test matrix, the effects from angle of attack, the TE flap angle, the length/width of the TES are investigated. Even though the airfoil under investigation is already optimized for low noise emission, most numerical simulations and wind tunnel experiments show that the noise level is further decreased by adding the TES device.

Ultrafast Plasmonic Control of Second Harmonic Generation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Davidson, Roderick B.; Yanchenko, Anna; Ziegler, Jed I.

Efficient frequency conversion techniques are crucial to the development of plasmonic metasurfaces for information processing and signal modulation. In principle, nanoscale electric-field confinement in nonlinear materials enables higher harmonic conversion efficiencies per unit volume than those attainable in bulk materials. Here we demonstrate efficient second-harmonic generation (SHG) in a serrated nanogap plasmonic geometry that generates steep electric field gradients on a dielectric metasurface. An ultrafast control pulse is used to control plasmon-induced electric fields in a thin-film material with inversion symmetry that, without plasmonic enhancement, does not exhibit an even-order nonlinear optical response. The temporal evolution of the plasmonic near-fieldmore » is characterized with ~100 as resolution using a novel nonlinear interferometric technique. The serrated nanogap is a unique platform in which to investigate optically controlled, plasmonically enhanced harmonic generation in dielectric materials on an ultrafast time scale. Lastly, this metamaterial geometry can also be readily extended to all-optical control of other nonlinear phenomena, such as four-wave mixing and sum- and difference-frequency generation, in a wide variety of dielectric materials.« less

Ultrafast Plasmonic Control of Second Harmonic Generation

DOE PAGES

Davidson, Roderick B.; Yanchenko, Anna; Ziegler, Jed I.; ...

2016-06-01

Efficient frequency conversion techniques are crucial to the development of plasmonic metasurfaces for information processing and signal modulation. In principle, nanoscale electric-field confinement in nonlinear materials enables higher harmonic conversion efficiencies per unit volume than those attainable in bulk materials. Here we demonstrate efficient second-harmonic generation (SHG) in a serrated nanogap plasmonic geometry that generates steep electric field gradients on a dielectric metasurface. An ultrafast control pulse is used to control plasmon-induced electric fields in a thin-film material with inversion symmetry that, without plasmonic enhancement, does not exhibit an even-order nonlinear optical response. The temporal evolution of the plasmonic near-fieldmore » is characterized with ~100 as resolution using a novel nonlinear interferometric technique. The serrated nanogap is a unique platform in which to investigate optically controlled, plasmonically enhanced harmonic generation in dielectric materials on an ultrafast time scale. Lastly, this metamaterial geometry can also be readily extended to all-optical control of other nonlinear phenomena, such as four-wave mixing and sum- and difference-frequency generation, in a wide variety of dielectric materials.« less

Self-Similar Random Process and Chaotic Behavior In Serrated Flow of High Entropy Alloys

PubMed Central

Chen, Shuying; Yu, Liping; Ren, Jingli; Xie, Xie; Li, Xueping; Xu, Ying; Zhao, Guangfeng; Li, Peizhen; Yang, Fuqian; Ren, Yang; Liaw, Peter K.

2016-01-01

The statistical and dynamic analyses of the serrated-flow behavior in the nanoindentation of a high-entropy alloy, Al0.5CoCrCuFeNi, at various holding times and temperatures, are performed to reveal the hidden order associated with the seemingly-irregular intermittent flow. Two distinct types of dynamics are identified in the high-entropy alloy, which are based on the chaotic time-series, approximate entropy, fractal dimension, and Hurst exponent. The dynamic plastic behavior at both room temperature and 200 °C exhibits a positive Lyapunov exponent, suggesting that the underlying dynamics is chaotic. The fractal dimension of the indentation depth increases with the increase of temperature, and there is an inflection at the holding time of 10 s at the same temperature. A large fractal dimension suggests the concurrent nucleation of a large number of slip bands. In particular, for the indentation with the holding time of 10 s at room temperature, the slip process evolves as a self-similar random process with a weak negative correlation similar to a random walk. PMID:27435922

Dynamic strain-aging effect on fracture toughness of vessel steels

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kang, S.S.; Kim, I.S.

1992-03-01

In this paper the effect of dynamic strain aging (DSA) on fracture is investigated on the quenched and tempered specimens of American Society of Mechanical Engineers (ASME) standard SA508 class 3 nuclear pressure vessel steel. Serrated flow by DSA is observed between 180 and 340{degrees}C at a tensile strain rate of 2.08 {times} 10{sup {minus}4}/s and 1.25 {times} 10{sup {minus}3}/s. The DSA causes a sharp rise in the ultimate tensile strength and a marked decrease in ductility. The DSA range shifts to higher temperatures with increased strain rates. The temperature and strain rate dependence of the onset of serrations yieldsmore » an activation energy of 16.2 kcal/mol, which suggests that the process is controlled by interstitial diffusion of carbon and nitrogen in ferrite. The J{sub i} value obtained from the direct current potential drop (DCPD) method, for true crack initiation, is lowered by DSA. The drop in J{sub i} at elevated temperatures may be because of the interaction of the interstitial impurities with dislocations at the crack front.« less

Peculiar macrophagous adaptations in a new Cretaceous pliosaurid

PubMed Central

Arkhangelsky, Maxim S.; Stenshin, Ilya M.; Uspensky, Gleb N.; Zverkov, Nikolay G.

2015-01-01

During the Middle and Late Jurassic, pliosaurid plesiosaurs evolved gigantic body size and a series of craniodental adaptations that have been linked to the occupation of an apex predator niche. Cretaceous pliosaurids (i.e. Brachaucheninae) depart from this morphology, being slightly smaller and lacking the macrophagous adaptations seen in earlier forms. However, the fossil record of Early Cretaceous pliosaurids is poor, concealing the evolution and ecological diversity of the group. Here, we report a new pliosaurid from the Late Hauterivian (Early Cretaceous) of Russia. Phylogenetic analyses using reduced consensus methods recover it as the basalmost brachauchenine. This pliosaurid is smaller than other derived pliosaurids, has tooth alveoli clustered in pairs and possesses trihedral teeth with complex serrated carinae. Maximum-likelihood ancestral state reconstruction suggests early brachauchenines retained trihedral teeth from their ancestors, but modified this feature in a unique way, convergent with macrophagous archosaurs or sphenacodontoids. Our findings indicate that Early Cretaceous marine reptile teeth with serrated carinae cannot be unequivocally assigned to metriorhynchoid crocodylomorphs. Furthermore, they extend the known diversity of dental adaptations seen in Sauropterygia, the longest lived clade of marine tetrapods. PMID:27019740

Self-similar random process and chaotic behavior in serrated flow of high entropy alloys

DOE PAGES

Chen, Shuying; Yu, Liping; Ren, Jingli; ...

2016-07-20

Here, the statistical and dynamic analyses of the serrated-flow behavior in the nanoindentation of a high-entropy alloy, Al 0.5CoCrCuFeNi, at various holding times and temperatures, are performed to reveal the hidden order associated with the seemingly-irregular intermittent flow. Two distinct types of dynamics are identified in the high-entropy alloy, which are based on the chaotic time-series, approximate entropy, fractal dimension, and Hurst exponent. The dynamic plastic behavior at both room temperature and 200 °C exhibits a positive Lyapunov exponent, suggesting that the underlying dynamics is chaotic. The fractal dimension of the indentation depth increases with the increase of temperature, andmore » there is an inflection at the holding time of 10 s at the same temperature. A large fractal dimension suggests the concurrent nucleation of a large number of slip bands. In particular, for the indentation with the holding time of 10 s at room temperature, the slip process evolves as a self-similar random process with a weak negative correlation similar to a random walk.« less

Self-Similar Random Process and Chaotic Behavior In Serrated Flow of High Entropy Alloys.

PubMed

Chen, Shuying; Yu, Liping; Ren, Jingli; Xie, Xie; Li, Xueping; Xu, Ying; Zhao, Guangfeng; Li, Peizhen; Yang, Fuqian; Ren, Yang; Liaw, Peter K

2016-07-20

The statistical and dynamic analyses of the serrated-flow behavior in the nanoindentation of a high-entropy alloy, Al0.5CoCrCuFeNi, at various holding times and temperatures, are performed to reveal the hidden order associated with the seemingly-irregular intermittent flow. Two distinct types of dynamics are identified in the high-entropy alloy, which are based on the chaotic time-series, approximate entropy, fractal dimension, and Hurst exponent. The dynamic plastic behavior at both room temperature and 200 °C exhibits a positive Lyapunov exponent, suggesting that the underlying dynamics is chaotic. The fractal dimension of the indentation depth increases with the increase of temperature, and there is an inflection at the holding time of 10 s at the same temperature. A large fractal dimension suggests the concurrent nucleation of a large number of slip bands. In particular, for the indentation with the holding time of 10 s at room temperature, the slip process evolves as a self-similar random process with a weak negative correlation similar to a random walk.

Endoscopic ultrasound evaluation in the surgical treatment of duodenal and peri-ampullary adenomas.

PubMed

Azih, Lilian C; Broussard, Brett L; Phadnis, Milind A; Heslin, Martin J; Eloubeidi, Mohamad A; Varadarajulu, Shayam; Arnoletti, Juan Pablo

2013-01-28

To investigate endoscopic ultrasound (EUS) for predicting depth of mucosal invasion and to analyze outcomes following endoscopic and transduodenal resection. Records of 111 patients seen at our institution from November 1999 to July 2011 with the post-operative pathological diagnosis of benign ampullary and duodenal adenomas were reviewed. Records of patients who underwent preoperative EUS for diagnostic purposes were identified. The accuracy of EUS in predicting the absence of muscular invasion was assessed by comparing EUS reports to the final surgical pathological results. In addition, the incidence of the post-operative complications over a period of 30 d and the subsequent long-term outcome (recurrence) over a period of 30 mo associated with endoscopic and transduodenal surgical resection was recorded, compared and analyzed. Among 111 patients with benign ampullary and duodenal adenomas, 47 underwent preoperative EUS for 29 peri-ampullary lesions and 18 duodenal lesions. In addition, computed tomography was performed in 18 patients, endoscopic retrograde cholangio-pancreatography in 10 patients and esophagogastroduodenoscopy in 22 patients. There were 43 patients with sporadic adenomas and 4 patients with familial adenomatous polyposis (FAP)/other polyposis syndromes. In 38 (81%, P < 0.05) patients, EUS reliably identified absence of submucosal and muscularis invasion. In 4 cases, EUS underestimated submucosal invasion that was proven by pathology. In the other 5 patients, EUS predicted muscularis invasion which could not be demonstrated in the resected specimen. EUS predicted tumor muscularis invasion with a specificity of 88% and negative predictive value of 90% (P < 0.05). Types of resection performed included endoscopic resection in 22 cases, partial duodenectomy in 9 cases, transduodenal ampullectomy with sphincteroplasty in 10 cases and pancreaticoduodenectomy in 6 cases. The main post-operative final pathological results included villous adenoma (n = 5), adenoma (n = 8), tubulovillous adenoma (n = 10), tubular adenoma (n = 20) and hyperplastic polyp (n = 2). Among the 47 patients who underwent resection, 8 (17%, 5 of which corresponded to surgical resection) developed post-procedural complications which included retroperitoneal hematoma, intra-abdominal abscess, wound infection, delayed gastric emptying and prolonged ileus. After median follow-up of 20 mo there were 6 local recurrences (13%, median follow-up = 20 mo) 4 of which were in patients with FAP. EUS accurately predicts the depth of mucosal invasion in suspected benign ampullary and duodenal adenomas. These patients can safely undergo endoscopic or local resection.

Clinical and Genetic Heterogeneity, Overlap with Other Tumor Syndromes, and Atypical Glucocorticoid Hormone Secretion in Adrenocorticotropin-Independent Macronodular Adrenal Hyperplasia Compared with Other Adrenocortical Tumors

PubMed Central

Hsiao, Hui-Pin; Kirschner, Lawrence S.; Bourdeau, Isabelle; Keil, Margaret F.; Boikos, Sosipatros A.; Verma, Somya; Robinson-White, Audrey J.; Nesterova, Maria; Lacroix, André; Stratakis, Constantine A.

2009-01-01

Objective: ACTH-independent macronodular adrenal hyperplasia (AIMAH) is often associated with subclinical cortisol secretion or atypical Cushing’s syndrome (CS). We characterized a large series of patients of AIMAH and compared them with patients with other adrenocortical tumors. Design and Patients: We recruited 82 subjects with: 1) AIMAH (n = 16); 2) adrenocortical cortisol-producing adenoma with CS (n = 15); 3) aldosterone-producing adenoma (n = 19); and 4) single adenomas with clinically nonsignificant cortisol secretion (n = 32). Methods: Urinary free cortisol (UFC) and 17-hydroxycorticosteroid (17OHS) were collected at baseline and during dexamethasone testing; aberrant receptor responses was also sought by clinical testing and confirmed molecularly. Peripheral and/or tumor DNA was sequenced for candidate genes. Results: AIMAH patients had the highest 17OHS excretion, even when UFCs were within or close to the normal range. Aberrant receptor expression was highly prevalent. Histology showed at least two subtypes of AIMAH. For three patients with AIMAH, there was family history of CS; germline mutations were identified in three other patients in the genes for menin (one), fumarate hydratase (one), and adenomatosis polyposis coli (APC) (one); a PDE11A gene variant was found in another. One patient had a GNAS mutation in adrenal nodules only. There were no mutations in any of the tested genes in the patients of the other groups. Conclusions: AIMAH is a clinically and genetically heterogeneous disorder that can be associated with various genetic defects and aberrant hormone receptors. It is frequently associated with atypical CS and increased 17OHS; UFCs and other measures of adrenocortical activity can be misleadingly normal. PMID:19509103

Cronkhite-Canada syndrome associated with rib fractures: a case report.

PubMed

Yuan, Bosi; Jin, Xinxin; Zhu, Renmin; Zhang, Xiaohua; Liu, Jiong; Wan, Haijun; Lu, Heng; Shen, Yunzhu; Wang, Fangyu

2010-10-18

Cronkhite-Canada syndrome (CCS) is a rare multiple gastrointestinal polyposis. Up till now, many complications of CCS have been reported in the literature, but rib fracture is not included. We report a case of a 58-year-old man who was admitted to our hospital with a 6-month history of frequent diarrhea, intermittent hematochezia and a weight loss of 13 kg. On admission, physical examination revealed alopecia of the scalp, hyperpigmentation of the hands and soles, and dystrophy of the fingernails. Laboratory data revealed hypocalcaemia and hypoproteinemia. Esophagogastroduodenoscopy, video capsule endoscopy and colonoscopy revealed various sizes of generalized gastrointestinal polyps. Histological examination of the biopsy specimens obtained from the stomach and the colon showed adenomatous polyp and inflammatory polyp respectively. Thus, a diagnosis of CCS was made. After treatment with corticosteroids for 24 days and nutritional support for two months, his clinical condition improved. Two months later, he was admitted to our hospital for the second time with frequent diarrhea and weight loss. The chest radiography revealed fractures of the left sixth and seventh ribs. Examinations, including emission computed tomography, bone densitometry test, and other serum parameters, were performed, but could not identify the definite etiology of the rib fractures. One month later, the patient suffered from aggravating multiple rib fractures due to the ineffective treatment, persistent hypocalcaemia and malnutrition. This is the first case of a CCS patient with multiple rib fractures. Although the association between CCS and multiple rib fractures in this case remains uncertain, we presume that persistent hypocalcaemia and malnutrition contribute to this situation, or at least aggravate this rare complication. Besides, since prolonged corticosteroid therapy will result in an increased risk of osteoporotic fracture, CCS patients who accept corticosteroid therapy could be potential victims of rib fracture.

Impact of fair bowel preparation quality on adenoma and serrated polyp detection: data from the New Hampshire colonoscopy registry by using a standardized preparation-quality rating.

PubMed

Anderson, Joseph C; Butterly, Lynn F; Robinson, Christina M; Goodrich, Martha; Weiss, Julia E

2014-09-01

The effect of colon preparation quality on adenoma detection rates (ADRs) is unclear, partly because of lack of uniform colon preparation ratings in prior studies. The New Hampshire Colonoscopy Registry collects detailed data from colonoscopies statewide, by using a uniform preparation quality scale after the endoscopist has cleaned the mucosa. To compare the overall and proximal ADR and serrated polyp detection rates (SDR) in colonoscopies with differing levels of colon preparation quality. Cross-sectional. New Hampshire statewide registry. Patients undergoing colonoscopy. We examined colon preparation quality for 13,022 colonoscopies, graded by using specific descriptions provided to endoscopists. ADR and SDR are the number of colonoscopies with at least 1 adenoma or serrated polyp (excluding those in the rectum and/or sigmoid colon) detected divided by the total number of colonoscopies, for the preparation categories: optimal (excellent and/or good), fair, and poor. Overall/proximal ADR/SDR. The overall detection rates in examinations with fair colon preparation quality (SDR 8.9%; 95% confidence interval [CI], 7.4-10.7, ADR 27.1%; 95% CI, 24.6-30.0) were similar to rates observed in colonoscopies with optimal preparation quality (SDR 8.8%; 95% CI, 8.3-9.4, ADR 26.3%; 95% CI, 25.6-27.2). This finding also was observed for rates in the proximal colon. A logistic regression model (including withdrawal time) found that proximal ADR was statistically lower in the poor preparation category (odds ratio 0.45; 95% CI, 0.24-0.84; P < .01) than in adequately prepared colons. Homogeneous population. In our sample, there was no significant difference in overall or proximal ADR or SDR between colonoscopies with fair versus optimal colon preparation quality. Poor colon preparation quality may reduce the proximal ADR. Published by Mosby, Inc.

Associations between colorectal cancer molecular markers and pathways with clinicopathologic features in older women.

PubMed

Samadder, N Jewel; Vierkant, Robert A; Tillmans, Lori S; Wang, Alice H; Weisenberger, Daniel J; Laird, Peter W; Lynch, Charles F; Anderson, Kristin E; French, Amy J; Haile, Robert W; Potter, John D; Slager, Susan L; Smyrk, Thomas C; Thibodeau, Stephen N; Cerhan, James R; Limburg, Paul J

2013-08-01

Colorectal tumors have a large degree of molecular heterogeneity. Three integrated pathways of carcinogenesis (ie, traditional, alternate, and serrated) have been proposed, based on specific combinations of microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and mutations in BRAF and KRAS. We used resources from the population-based Iowa Women's Health Study (n = 41,836) to associate markers of colorectal tumors, integrated pathways, and clinical and pathology characteristics, including survival times. We assessed archived specimens from 732 incident colorectal tumors and characterized them as microsatellite stable (MSS), MSI high or MSI low, CIMP high or CIMP low, CIMP negative, and positive or negative for BRAF and/or KRAS mutations. Informative marker data were collected from 563 tumors (77%), which were assigned to the following integrated pathways: traditional (MSS, CIMP negative, BRAF mutation negative, and KRAS mutation negative; n = 170), alternate (MSS, CIMP low, BRAF mutation negative, and KRAS mutation positive; n = 58), serrated (any MSI, CIMP high, BRAF mutation positive, and KRAS mutation negative; n = 142), or unassigned (n = 193). Multivariable-adjusted Cox proportional hazards regression models were used to assess the associations of interest. Patients' mean age (P = .03) and tumors' anatomic subsite (P = .0001) and grade (P = .0001) were significantly associated with integrated pathway assignment. Colorectal cancer (CRC) mortality was not associated with the traditional, alternate, or serrated pathways, but was associated with a subset of pathway-unassigned tumors (MSS or MSI low, CIMP negative, BRAF mutation negative, and KRAS mutation positive) (n = 96 cases; relative risk = 1.76; 95% confidence interval, 1.07-2.89, compared with the traditional pathway). We identified clinical and pathology features associated with molecularly defined CRC subtypes. However, additional studies are needed to determine how these features might influence prognosis. Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

Arabidopsis Type II Phosphatidylinositol 4-Kinase PI4Kγ5 Regulates Auxin Biosynthesis and Leaf Margin Development through Interacting with Membrane-Bound Transcription Factor ANAC078

PubMed Central

Tan, Shu-Tang; Xue, Hong-Wei

2016-01-01

Normal leaf margin development is important for leaf morphogenesis and contributes to diverse leaf shapes in higher plants. We here show the crucial roles of an atypical type II phosphatidylinositol 4-kinase, PI4Kγ5, in Arabidopsis leaf margin development. PI4Kγ5 presents a dynamics expression pattern along with leaf development and a T-DNA mutant lacking PI4Kγ5, pi4kγ5–1, presents serrated leaves, which is resulted from the accelerated cell division and increased auxin concentration at serration tips. Studies revealed that PI4Kγ5 interacts with and phosphorylates a membrane-bound NAC transcription factor, ANAC078. Previous studies demonstrated that membrane-bound transcription factors regulate gene transcription by undergoing proteolytic process to translocate into nucleus, and ANAC078 undergoes proteolysis by cleaving off the transmembrane region and carboxyl terminal. Western blot analysis indeed showed that ANAC078 deleting of carboxyl terminal is significantly reduced in pi4kγ5–1, indicating that PI4Kγ5 is important for the cleavage of ANAC078. This is consistent with the subcellular localization observation showing that fluorescence by GFP-ANAC078 is detected at plasma membrane but not nucleus in pi4kγ5–1 mutant and that expression of ANAC078 deleting of carboxyl terminal, driven by PI4Kγ5 promoter, could rescue the leaf serration defects of pi4kγ5–1. Further analysis showed that ANAC078 suppresses the auxin synthesis by directly binding and regulating the expression of auxin synthesis-related genes. These results indicate that PI4Kγ5 interacts with ANAC078 to negatively regulate auxin synthesis and hence influences cell proliferation and leaf development, providing informative clues for the regulation of in situ auxin synthesis and cell division, as well as the cleavage and functional mechanism of membrane-bound transcription factors. PMID:27529511

A study of oral contrast coating on the surface of polyps: an implication for computer-aided detection and classification of polyps

NASA Astrophysics Data System (ADS)

Singh, Harmanpreet; Li, Lihong C.; Pomeroy, Marc; Pickhardt, Perry J.; Barish, Matthew A.; Harrington, Donald P.; Liang, Zhengrong

2017-03-01

Accurate identification of polyps is the ultimate goal of Computed Tomography Colonography (CTC). While oral contrast agents were originally used to tag stool and fluid for the ultimate goal of CTC, recently their effect on coating the surface of polyps has been observed. This study aims to evaluate (1) the frequency at which the oral contrast adhered to polyp surfaces and (2) if there was a difference in contrast adherence with respect to diverse polyp types. To eliminate gravity as a factor in this study, the polyps in contact with tagged fluid pools, particularly on the bottom of the colon wall were excluded. A total of 150 polyps were selected under the above condition from a CTC database and screened for any adherent contrast on the luminal edge. Among the total, 53% of the screened polyps had adherent contrast. Serrated adenomas and hyperplastic polyps had a higher tagging percentage, 77.80% and 62.50% respectively, than tubular adenomas and tubulovillous adenomas, 44.40% and 43% respectively. Other factors that were analyzed for the effect on coating include size and location of the polyps. The higher tagging percentage of serrated adenomas and hyperplastic polyps may be due to their similar cellular features. The average size of the polyps was 8.9 mm. When the polyps were separated by size into small (5-9mm) and large (10-26mm) groups, the large group had a higher tagging percentage. The polyp types were also classified by location with the major findings being: 1) Tubular adenomas were present in all segments of the colon and 2) that serrated adenomas were present at a higher percentage in the proximal colon. These findings shall facilitate characterizing tagging agents and improve computer aided detection and classification of polyps via CTC.

More than two decades of Apc modeling in rodents

PubMed Central

Zeineldin, Maged; Neufeld, Kristi L.

2013-01-01

Mutation of tumor suppressor gene Adenomatous polyposis coli (APC) is an initiating step in most colon cancers. This review summarizes Apc models in mice and rats, with particular concentration on those most recently developed, phenotypic variation among different models, and genotype/ phenotype correlations. PMID:23333833

The biochemical adaptations of spotted wing drosophila (Diptera: Drosophilidae) to fresh fruits reduced fructose concentrations and glutathione-S transferase activities

USDA-ARS?s Scientific Manuscript database

Spotted wing drosophila (SWD), Drosophila suzukii, is an invasive and economically damaging pest in Europe and North America, because the females have a serrated ovipositor enabling them to infest ripening almost all small fruits before harvest. Also flies are strongly attracted to fresh fruits rath...

Exome sequencing reveals a de novo POLD1 mutation causing phenotypic variability in mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL).

PubMed

Elouej, Sahar; Beleza-Meireles, Ana; Caswell, Richard; Colclough, Kevin; Ellard, Sian; Desvignes, Jean Pierre; Béroud, Christophe; Lévy, Nicolas; Mohammed, Shehla; De Sandre-Giovannoli, Annachiara

2017-06-01

Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL) is an autosomal dominant systemic disorder characterized by prominent loss of subcutaneous fat, a characteristic facial appearance and metabolic abnormalities. This syndrome is caused by heterozygous de novo mutations in the POLD1 gene. To date, 19 patients with MDPL have been reported in the literature and among them 14 patients have been characterized at the molecular level. Twelve unrelated patients carried a recurrent in-frame deletion of a single codon (p.Ser605del) and two other patients carried a novel heterozygous mutation in exon 13 (p.Arg507Cys). Additionally and interestingly, germline mutations of the same gene have been involved in familial polyposis and colorectal cancer (CRC) predisposition. We describe a male and a female patient with MDPL respectively affected with mild and severe phenotypes. Both of them showed mandibular hypoplasia, a beaked nose with bird-like facies, prominent eyes, a small mouth, growth retardation, muscle and skin atrophy, but the female patient showed such a severe and early phenotype that a first working diagnosis of Hutchinson-Gilford Progeria was made. The exploration was performed by direct sequencing of POLD1 gene exon 15 in the male patient with a classical MDPL phenotype and by whole exome sequencing in the female patient and her unaffected parents. Exome sequencing identified in the latter patient a de novo heterozygous undescribed mutation in the POLD1 gene (NM_002691.3: c.3209T>A), predicted to cause the missense change p.Ile1070Asn in the ZnF2 (Zinc Finger 2) domain of the protein. This mutation was not reported in the 1000 Genome Project, dbSNP and Exome sequencing databases. Furthermore, the Isoleucine1070 residue of POLD1 is highly conserved among various species, suggesting that this substitution may cause a major impairment of POLD1 activity. For the second patient, affected with a typical MDPL phenotype, direct sequencing of POLD1 exon 15 revealed the recurrent in-frame deletion (c.1812_1814del, p.S605del). Our work highlights that mutations in different POLD1 domains can lead to phenotypic variability, ranging from dominantly inherited cancer predisposition syndromes, to mild MDPL phenotypes without lifespan reduction, to very severe MDPL syndromes with major premature aging features. These results also suggest that POLD1 gene testing should be considered in patients presenting with severe progeroid features. Copyright © 2017 Elsevier Inc. All rights reserved.

DNA mismatch repair deficiency and hereditary syndromes in Latino patients with colorectal cancer.

PubMed

Ricker, Charité N; Hanna, Diana L; Peng, Cheng; Nguyen, Nathalie T; Stern, Mariana C; Schmit, Stephanie L; Idos, Greg E; Patel, Ravi; Tsai, Steven; Ramirez, Veronica; Lin, Sonia; Shamasunadara, Vinay; Barzi, Afsaneh; Lenz, Heinz-Josef; Figueiredo, Jane C

2017-10-01

The landscape of hereditary syndromes and clinicopathologic characteristics among US Latino/Hispanic individuals with colorectal cancer (CRC) remains poorly understood. A total of 265 patients with CRC who were enrolled in the Hispanic Colorectal Cancer Study were included in the current study. Information regarding CRC risk factors was elicited through interviews, and treatment and survival data were abstracted from clinical charts. Tumor studies and germline genetic testing results were collected from medical records or performed using standard molecular methods. The mean age of the patients at the time of diagnosis was 53.7 years (standard deviation, 10.3 years), and 48.3% were female. Overall, 21.2% of patients reported a first-degree or second-degree relative with CRC; 3.4% met Amsterdam I/II criteria. With respect to Bethesda guidelines, 38.5% of patients met at least 1 criterion. Of the 161 individuals who had immunohistochemistry and/or microsatellite instability testing performed, 21 (13.0%) had mismatch repair (MMR)-deficient (dMMR) tumors. dMMR tumors were associated with female sex (61.9%), earlier age at the time of diagnosis (50.4 ± 12.4 years), proximal location (61.9%), and first-degree (23.8%) or second-degree (9.5%) family history of CRC. Among individuals with dMMR tumors, 13 (61.9%) had a germline MMR mutation (MutL homolog 1 [MLH1] in 6 patients; MutS homolog 2 [MSH2] in 4 patients; MutS homolog 6 [MHS6] in 2 patients; and PMS1 homolog 2, mismatch repair system component [PMS2] in 1 patient). The authors identified 2 additional MLH1 mutation carriers by genetic testing who had not received immunohistochemistry/microsatellite instability testing. In total, 5.7% of the entire cohort were confirmed to have Lynch syndrome. In addition, 6 individuals (2.3%) had a polyposis phenotype. The percentage of dMMR tumors noted among Latino individuals (13%) is similar to estimates in non-Hispanic white individuals. In the current study, the majority of individuals with dMMR tumors were confirmed to have Lynch syndrome. Cancer 2017. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. Cancer 2017;123:3732-3743. © 2017 American Cancer Society. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

Radiation promotes colorectal cancer initiation and progression by inducing senescence-associated inflammatory responses.

PubMed

Kim, S B; Bozeman, R G; Kaisani, A; Kim, W; Zhang, L; Richardson, J A; Wright, W E; Shay, J W

2016-06-30

Proton radiotherapy is becoming more common as protons induce more precise DNA damage at the tumor site with reduced side effects to adjacent normal tissues. However, the long-term biological effects of proton irradiation in cancer initiation compared with conventional photon irradiation are poorly characterized. In this study, using a human familial adenomatous polyposis syndrome susceptible mouse model, we show that whole-body irradiation with protons are more effective in inducing senescence-associated inflammatory responses (SIRs), which are involved in colon cancer initiation and progression. After proton irradiation, a subset of SIR genes (Troy, Sox17, Opg, Faim2, Lpo, Tlr2 and Ptges) and a gene known to be involved in invasiveness (Plat), along with the senescence-associated gene (P19Arf), are markedly increased. Following these changes, loss of Casein kinase Iα and induction of chronic DNA damage and TP53 mutations are increased compared with X-ray irradiation. Proton irradiation also increases the number of colonic polyps, carcinomas and invasive adenocarcinomas. Pretreatment with the non-steroidal anti-inflammatory drug, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid-ethyl amide (CDDO-EA), reduces proton irradiation-associated SIR and tumorigenesis. Thus exposure to proton irradiation elicits significant changes in colorectal cancer initiation and progression that can be mitigated using CDDO-EA.

BMP suppresses PTEN expression via RAS/ERK signaling.

PubMed

Beck, Stayce E; Carethers, John M

2007-08-01

Bone morphogenetic protein (BMP), a member of the transforming growth factor beta family, classically utilizes the SMAD signaling pathway for its growth suppressive effects,and loss of this signaling cascade may accelerate cell growth. In the colon cancer predisposition syndrome Juvenile Polyposis, as well as in the late progression stages of nonsyndromic colorectal cancers, SMAD4 function is typically abrogated. Here, we utilized the SMAD4-null SW480 colon cancer cell line to examine BMPs effect on a potential target gene, PTEN, and how its expression might be regulated. Initial treatment of the SMAD4-null cells with BMP resulted in mild growth suppression, but with prolonged exposure to BMP, the cells become growth stimulatory, which coincided with observed decreases in transcription and translation of PTEN, and with corresponding increases in phospho-AKT protein levels. BMP-induced PTEN suppression was mediated via the RAS/ERK pathway, as pharmacologic inhibition of RAS/ERK, or interference with protein function in the cytosol by DN-RAS prevented BMP-induced growth promotion and changes in PTEN levels, as did treatment with noggin, a BMP ligand inhibitor. Thus, BMP downregulates PTEN via RAS/ERK in a SMAD4-null environment that contributes to cell growth, and constitutes a SMAD4-independent but BMP-responsive signaling pathway.

FAP Associated Papillary Thyroid Carcinoma: A Peculiar Subtype of Familial Nonmedullary Thyroid Cancer.

PubMed

Cetta, Francesco

2015-01-01

Familial Nonmedullary Thyroid Carcinoma (FNMTC) makes up to 5-10% of all thyroid cancers, also including those FNMTC occurring as a minor component of familial cancer syndromes, such as Familial Adenomatous Polyposis (FAP). We give evidence that this extracolonic manifestation of FAP is determined by the same germline mutation of the APC gene responsible for colonic polyps and cancer but also shows some unusual features (F : M ratio = 80 : 1, absence of LOH for APC in the thyroid tumoral tissue, and indolent biological behaviour, despite frequent multicentricity and lymph nodal involvement), suggesting that the APC gene confers only a generic susceptibility to thyroid cancer, but perhaps other factors, namely, modifier genes, sex-related factors, or environmental factors, are also required for its phenotypic expression. This great variability is against the possibility of classifying all FNMTC as a single entity, not only with a unique or prevalent causative genetic factor, but also with a unique or common biological behavior and a commonly dismal prognosis. A new paradigm is also suggested that could be useful (1) for a proper classification of FAP associated PTC within the larger group of FNMTC and (2) for making inferences to sporadic carcinogenesis, based on the lesson from FAP.

The Italian National External quality assessment program in molecular genetic testing: results of the VII round (2010-2011).

PubMed

Censi, F; Tosto, F; Floridia, G; Marra, M; Salvatore, M; Baffico, A M; Grasso, M; Melis, M A; Pelo, E; Radice, P; Ravani, A; Rosatelli, C; Resta, N; Russo, S; Seia, M; Varesco, L; Falbo, V; Taruscio, D

2013-01-01

Since 2001 the Istituto Superiore di Sanità established a quality assurance programme for molecular genetic testing that covers four pathologies: Cystic Fibrosis (CF), Beta Thalassemia (BT), Fragile X Syndrome (FX), and Familial Adenomatous Polyposis Coli (APC). Since 2009 this activity is an institutional activity and participation is open to both public and private laboratories. Seven rounds have been performed until now and the eighth is in progress. Laboratories receive 4 DNA samples with mock clinical indications. They analyze the samples using their routine procedures. A panel of assessors review the raw data and the reports; all data are managed through a web utility. In 2010 the number of participants was 43, 17, 15, 5 for CF, BT, FX, APC schemes respectively. Genotyping results were correct in 96%, 98.5%, 100%, and 100% of CF, BT, FX, and APC samples, respectively. Interpretation was correct in 74%, 91%, 88%, and 60% of CF, BT, FX, and APC reports, respectively; however in most of them it was not complete but a referral to genetic counseling was given. Reports were satisfactory in more than 60% of samples in all schemes. This work presents the 2010 results in detail comparing our data with those from other European schemes.

Adenomatous polyposis coli nucleates actin assembly to drive cell migration and microtubule-induced focal adhesion turnover

PubMed Central

Eskin, Julian A.; Jaiswal, Richa

2017-01-01

Cell motility depends on tight coordination between the microtubule (MT) and actin cytoskeletons, but the mechanisms underlying this MT–actin cross talk have remained poorly understood. Here, we show that the tumor suppressor protein adenomatous polyposis coli (APC), which is a known MT-associated protein, directly nucleates actin assembly to promote directed cell migration. By changing only two residues in APC, we generated a separation-of-function mutant, APC (m4), that abolishes actin nucleation activity without affecting MT interactions. Expression of full-length APC carrying the m4 mutation (APC (m4)) rescued cellular defects in MT organization, MT dynamics, and mitochondrial distribution caused by depletion of endogenous APC but failed to restore cell migration. Wild-type APC and APC (m4) localized to focal adhesions (FAs), and APC (m4) was defective in promoting actin assembly at FAs to facilitate MT-induced FA turnover. These results provide the first direct evidence for APC-mediated actin assembly in vivo and establish a role for APC in coordinating MTs and actin at FAs to direct cell migration. PMID:28663347

Childbirth after surgery for familial adenomatous polyposis in Japan.

PubMed

Kobayashi, Hirotoshi; Ishida, Hideyuki; Ueno, Hideki; Hinoi, Takao; Inoue, Yasuhiro; Ishida, Fumio; Kanemitsu, Yukihide; Konishi, Tsuyoshi; Yamaguchi, Tatsuro; Tomita, Naohiro; Matsubara, Nagahide; Watanabe, Toshiaki; Sugihara, Kenichi

2017-02-01

Familial adenomatous polyposis (FAP) is a genetic disorder. Some female patients with FAP can become pregnant. However, the current state of childbirth after surgery for FAP is unclear in Japan. The study investigated 303 patients (147 female) who had undergone surgery for FAP at the 23 institutions between 2000 and 2012. Eighty female patients had information available on childbirth after surgery for FAP. Eight patients (10 %) gave birth after surgery. The mean age at surgery for FAP was 27 (range 20-41) years and 37 years in patients with and without childbirth after surgery, respectively (P = 0.044). The rate of childbirth after surgery was 17 % in women ≤30 years of age and 13 % in those ≤40 years of age. Although only one patient with invasive cancer (2.9 %) gave childbirth after surgery, seven patients without cancer (15.6 %) gave birth (P = 0.045). This study clarified the current state of childbirth after surgery for FAP in Japan. It is important to use these data to determine the best therapeutic approach for female FAP patients.

[Comparison of the sensibility and specificity between single-stranded conformation polymorphism and denaturing high-performance liquid chromatography in screening hMSH2 and hMLH1 gene mutations in hereditary non-polyposis colorectal cancer].

PubMed

Wei, Guang-hui; Zhao, Bo; Wang, Zhen-jun

2008-09-01

To compare the sensibility and specificity between single-stranded conformation polymorphism (SSCP) and denaturing high-performance liquid chromatography (DHPLC) in screening hMSH2 and hMLH1 gene mutations for the diagnosis of hereditary non-polyposis colorectal cancer (HNPCC). Seven Chinese HNPCC kindreds were collected. PCR-SSCP and DHPLC were used to screen the coding regions of hMSH2 and hMLH1 genes and the abnormal profiles were sequenced by a 377 DNA sequencer. Seven gene sequence variations of hMSH2 or hMLH1 were found. Among them, 4 variations were not found by SSCP, but by DHPLC. The sensibility of SSCP and DHPLC were 51.6% and 100% respectively, and the specificity were 66.6% and 93.3% respectively. DHPLC has better sensibility and specificity in screening hMSH2 and hMLH1 gene mutation as compared to SSCP. DHPLC is an ideal method in the diagnosis of HNPCC.

Adenomatous Polyposis Coli Interacts with Flap Endonuclease 1 to Block Its Nuclear Entry and Function1

PubMed Central

Jaiswal, Aruna S; Armas, Melissa L; Izumi, Tadahide; Strauss, Phyllis R; Narayan, Satya

2012-01-01

In previous studies, we found that adenomatous polyposis coli (APC) blocks the base excision repair (BER) pathway by interacting with 5′-flap endonuclease 1 (Fen1). In this study, we identify the molecular features that contribute to the formation and/or stabilization of the APC/Fen1 complex that determines the extent of BER inhibition, and the subsequent accumulation of DNA damage creates mutagenic lesions leading to transformation susceptibility. We show here that APC binds to the nuclear localization sequence of Fen1 (Lys365Lys366Lys367), which prevents entry of Fen1 into the nucleus and participation in Pol-β-directed long-patch BER. We also show that levels of the APC/Fen1 complex are higher in breast tumors than in the surrounding normal tissues. These studies demonstrate a novel role for APC in the suppression of Fen1 activity in the BER pathway and a new biomarker profile to be explored to identify individuals who may be susceptible to the development of mammary and other tumors. PMID:22787431

Immunopurification of adenomatous polyposis coli (APC) proteins

PubMed Central

2013-01-01

Background The adenomatous polyposis coli (APC) tumour suppressor gene encodes a 2843 residue (310 kDa) protein. APC is a multifunctional protein involved in the regulation of β-catenin/Wnt signalling, cytoskeletal dynamics and cell adhesion. APC mutations occur in most colorectal cancers and typically result in truncation of the C-terminal half of the protein. Results In order to investigate the biophysical properties of APC, we have generated a set of monoclonal antibodies which enable purification of recombinant forms of APC. Here we describe the characterisation of these anti-APC monoclonal antibodies (APC-NT) that specifically recognise endogenous APC both in solution and in fixed cells. Full-length APC(1–2843) and cancer-associated, truncated APC proteins, APC(1–1638) and APC(1–1311) were produced in Sf9 insect cells. Conclusions Recombinant APC proteins were purified using a two-step affinity approach using our APC-NT antibodies. The purification of APC proteins provides the basis for detailed structure/function analyses of full-length, cancer-truncated and endogenous forms of the protein. PMID:24156781

Detection of familial adenomatous polyposis with polarized spectroscopic imaging and oral vascular density

NASA Astrophysics Data System (ADS)

Basiri, Ali; Edelstein, Daniel L.; Giardiello, Francis M.; Ramella-Roman, J. C.

2011-03-01

Familial Adenomatous Polyposis (FAP) is an autosomal dominant disease characterized by the development of multiple colonic polyps at younger age with a near 100% lifetime risk of colorectal cancer in later years. The determination of FAP is made after extensive clinical evaluation and genetic testing of at risk individuals. Genetic testing is expensive and in some cases deleterious mutations are not found in all patients with a clinical diagnosis of FAP. As such, the early identification of affected individuals could substantially eliminate associated morbidity and mortality. We investigated a novel spectro-polarimetric imaging system to capture images of the oral mucosa at different wavelengths in an attempt to distinguish patients with FAP from controls. Total diffused oral mucosal reflectance (OMR) and oral mucosal vascular density (OMVD) were calculated from spectral data collected from 33 patients with gene positive FAP, 5 patients who tested negative for FAP, and 45 controls. A statistically significant difference in OMVD (p < 0.001) was observed between individuals with FAP and controls. Analysis of OMR showed no significant difference between the two subject groups.

[A Case of Metachronous Multiple Thyroid Papillary Carcinoma with FAP].

PubMed

Tajima, Yusuke; Kumamoto, Kensuke; Yamamoto, Azusa; Chika, Noriyasu; Watanabe, Yuichiro; Matsuzawa, Takeaki; Ishibashi, Keiichiro; Mochiki, Erito; Iwama, Takeo; Akagi, Kiwamu; Ishida, Hideyuki

2015-11-01

Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited disorder, the result of a germ line mutation in the adenomatous polyposis coli (APC) gene. FAP can be associated with various extracolonic lesions, including thyroid cancer, which frequently occurs in women. We report the case of a 36-year-old woman diagnosed as having FAP with multiple metachronous thyroid papillary carcinomas. She underwent left thyroidectomy at the age of 19 years without a diagnosis of FAP. Multiple polyps in her stomach were detected by medical examination and more than 100 polyps in the colon were found by colonoscopy. She was referred to our hospital after a diagnosis of non-profuse FAP. Multiple tumors with a maximum diameter of 10mm were detected in the right lobe of the thyroid gland during the preoperative examination. Papillary carcinoma was suspected based on fine-needle aspiration cytology. We performed a right thyroidectomy after prophylactic colectomy. Pathological findings revealed a cribriform-morula variant of papillary thyroid carcinoma. The patient remains well after 2 year 6 months with no recurrence.

Continuing difficulties in interpreting CNV data: lessons from a genome-wide CNV association study of Australian HNPCC/lynch syndrome patients

PubMed Central

2013-01-01

Background Hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome (LS) is a cancer syndrome characterised by early-onset epithelial cancers, especially colorectal cancer (CRC) and endometrial cancer. The aim of the current study was to use SNP-array technology to identify genomic aberrations which could contribute to the increased risk of cancer in HNPCC/LS patients. Methods Individuals diagnosed with HNPCC/LS (100) and healthy controls (384) were genotyped using the Illumina Human610-Quad SNP-arrays. Copy number variation (CNV) calling and association analyses were performed using Nexus software, with significant results validated using QuantiSNP. TaqMan Copy-Number assays were used for verification of CNVs showing significant association with HNPCC/LS identified by both software programs. Results We detected copy number (CN) gains associated with HNPCC/LS status on chromosome 7q11.21 (28% cases and 0% controls, Nexus; p = 3.60E-20 and QuantiSNP; p < 1.00E-16) and 16p11.2 (46% in cases, while a CN loss was observed in 23% of controls, Nexus; p = 4.93E-21 and QuantiSNP; p = 5.00E-06) via in silico analyses. TaqMan Copy-Number assay was used for validation of CNVs showing significant association with HNPCC/LS. In addition, CNV burden (total CNV length, average CNV length and number of observed CNV events) was significantly greater in cases compared to controls. Conclusion A greater CNV burden was identified in HNPCC/LS cases compared to controls supporting the notion of higher genomic instability in these patients. One intergenic locus on chromosome 7q11.21 is possibly associated with HNPCC/LS and deserves further investigation. The results from this study highlight the complexities of fluorescent based CNV analyses. The inefficiency of both CNV detection methods to reproducibly detect observed CNVs demonstrates the need for sequence data to be considered alongside intensity data to avoid false positive results. PMID:23531357

FUEL ROD ASSEMBLY

DOEpatents

Hutter, E.

1959-09-01

A cluster of nuclear fuel rods aod a tubular casing through which a coolant flows in heat-change contact with the ruel rods are described. The casting is of trefoil section and carries the fuel rods, each of which has two fin engaging the serrated fins of the other two fuel rods, whereby the fuel rods are held in the casing and are interlocked against relative longitudinal movement.

Surgical Tooth Implants, Combat and Field.

DTIC Science & Technology

1982-07-15

design. The serrated root portion is alumina ceramic. The upper two parts of the implant (post and core and crown) are conventional dental materials...ceramic. The upper two parts of the implant (post and core and crown) are conventional dental materials, usually gold. Roots are produced by grinding...I1 Clinical Examples of Baboon Dental Implants . . . .. . . . .. 12 Clinical Chemistry and Hematology Results in Baboons. . . . . . . 20

Design and Analysis of Bionic Cutting Blades Using Finite Element Method.

PubMed

Li, Mo; Yang, Yuwang; Guo, Li; Chen, Donghui; Sun, Hongliang; Tong, Jin

2015-01-01

Praying mantis is one of the most efficient predators in insect world, which has a pair of powerful tools, two sharp and strong forelegs. Its femur and tibia are both armed with a double row of strong spines along their posterior edges which can firmly grasp the prey, when the femur and tibia fold on each other in capturing. These spines are so sharp that they can easily and quickly cut into the prey. The geometrical characteristic of the praying mantis's foreleg, especially its tibia, has important reference value for the design of agricultural soil-cutting tools. Learning from the profile and arrangement of these spines, cutting blades with tooth profile were designed in this work. Two different sizes of tooth structure and arrangement were utilized in the design on the cutting edge. A conventional smooth-edge blade was used to compare with the bionic serrate-edge blades. To compare the working efficiency of conventional blade and bionic blades, 3D finite element simulation analysis and experimental measurement were operated in present work. Both the simulation and experimental results indicated that the bionic serrate-edge blades showed better performance in cutting efficiency.

Design and Analysis of Bionic Cutting Blades Using Finite Element Method

PubMed Central

Li, Mo; Yang, Yuwang; Guo, Li; Chen, Donghui; Sun, Hongliang; Tong, Jin

2015-01-01

Praying mantis is one of the most efficient predators in insect world, which has a pair of powerful tools, two sharp and strong forelegs. Its femur and tibia are both armed with a double row of strong spines along their posterior edges which can firmly grasp the prey, when the femur and tibia fold on each other in capturing. These spines are so sharp that they can easily and quickly cut into the prey. The geometrical characteristic of the praying mantis's foreleg, especially its tibia, has important reference value for the design of agricultural soil-cutting tools. Learning from the profile and arrangement of these spines, cutting blades with tooth profile were designed in this work. Two different sizes of tooth structure and arrangement were utilized in the design on the cutting edge. A conventional smooth-edge blade was used to compare with the bionic serrate-edge blades. To compare the working efficiency of conventional blade and bionic blades, 3D finite element simulation analysis and experimental measurement were operated in present work. Both the simulation and experimental results indicated that the bionic serrate-edge blades showed better performance in cutting efficiency. PMID:27019583

Features of owl wings that promote silent flight

PubMed Central

Weger, Matthias; Klaas, Michael; Schröder, Wolfgang

2017-01-01

Owls are an order of birds of prey that are known for the development of a silent flight. We review here the morphological adaptations of owls leading to silent flight and discuss also aerodynamic properties of owl wings. We start with early observations (until 2005), and then turn to recent advances. The large wings of these birds, resulting in low wing loading and a low aspect ratio, contribute to noise reduction by allowing slow flight. The serrations on the leading edge of the wing and the velvet-like surface have an effect on noise reduction and also lead to an improvement of aerodynamic performance. The fringes at the inner feather vanes reduce noise by gliding into the grooves at the lower wing surface that are formed by barb shafts. The fringed trailing edge of the wing has been shown to reduce trailing edge noise. These adaptations to silent flight have been an inspiration for biologists and engineers for the development of devices with reduced noise production. Today several biomimetic applications such as a serrated pantograph or a fringed ventilator are available. Finally, we discuss unresolved questions and possible future directions. PMID:28163870

Regulation of Compound Leaf Development by PHANTASTICA in Medicago truncatula1[C][W][OPEN

PubMed Central

Ge, Liangfa; Peng, Jianling; Berbel, Ana; Madueño, Francisco; Chen, Rujin

2014-01-01

Plant leaves, simple or compound, initiate as peg-like structures from the peripheral zone of the shoot apical meristem, which requires class I KNOTTED-LIKE HOMEOBOXI (KNOXI) transcription factors to maintain its activity. The MYB domain protein encoded by the ASYMMETRIC LEAVES1/ROUGH SHEATH2/PHANTASTICA (ARP) gene, together with other factors, excludes KNOXI gene expression from incipient leaf primordia to initiate leaves and specify leaf adaxial identity. However, the regulatory relationship between ARP and KNOXI is more complex in compound-leafed species. Here, we investigated the role of ARP and KNOXI genes in compound leaf development in Medicago truncatula. We show that the M. truncatula phantastica mutant exhibited severe compound leaf defects, including curling and deep serration of leaf margins, shortened petioles, increased rachises, petioles acquiring motor organ characteristics, and ectopic development of petiolules. On the other hand, the M. truncatula brevipedicellus mutant did not exhibit visible compound leaf defects. Our analyses show that the altered petiole development requires ectopic expression of ELONGATED PETIOLULE1, which encodes a lateral organ boundary domain protein, and that the distal margin serration requires the auxin efflux protein M. truncatula PIN-FORMED10 in the M. truncatula phantastica mutant. PMID:24218492

Clinical features of cytotoxic CD8+ T-lymphocyte deficiency in chronic rhinosinusitis patients: a demographic and functional study.

PubMed

Gabra, Nathalie; Alromaih, Saud; Endam, Leandra Mfuna; Brito, Rose Marie; Larivière, Françoise; Al-Mot, Sawsan; LeDeist, Françoise; Desrosiers, Martin

2014-06-01

Identification of Staphylococcus aureus intracellularly in chronic rhinosinusitis (CRS) suggests an underlying cellular immunodeficiency. Supporting this, we have previously reported low CD8+ (cytotoxic) T-lymphocyte levels in a subpopulation of CRS patients and identified polymorphisms in the CD8A gene associated with CRS. In order to better understand the role of low CD8+ in CRS, we wished to determine the phenotype for CRS/Low CD8+ in comparison to that of conventional CRS. Sixty-seven low CD8+ CRS patients identified during investigation of CRS were compared for demographics, disease evolution, and bacteriology on endoscopic culture were compared with an existing population of 480 patients with CRS with nasal polyposis previously recruited for genetic association studies. Mean level of CD8+ in the CRS/Low CD8+ population was 0.15 × 10(9)/L (range, 0.20-1.5 × 10(9)/L). There was no difference between both groups in terms of history of allergy, asthma, eczema, acetylsalicylic acid (ASA) intolerance or smoking. The bacteriology was similar between both groups (S. aureus: CRS/Low CD8+: 35%; CRS 32%, p = 0.643). Evolution of disease was somewhat milder in CRS/Low CD8+, with fewer patients requiring surgery, and first surgery performed at a more advanced age. However, antibiotic use was higher in CRS/Low CD8+. Subgroup analysis restricted to CRS with nasal polyposis (CRSwNP)/Low CD8 or CRS without nasal polyposis (CRSsNP)/Low CD8 phenotypes did not substantially alter these results. Low CD8+ levels are often identified in CRS patients; however, these patients have disease remarkably similar to those with conventional CRS. This suggests that immune deficiency, whether systemic or locally mediated, is well tolerated and may be present in other forms in CRS. CRS patients with low CD8+ levels may possibly require antibacterial therapies as part of ongoing management. © 2014 ARS-AAOA, LLC.

Tissue-Specific Effects of Reduced β-catenin Expression on Adenomatous Polyposis Coli Mutation-Instigated Tumorigenesis in Mouse Colon and Ovarian Epithelium

PubMed Central

Feng, Ying; Sakamoto, Naoya; Wu, Rong; Liu, Jie-yu; Wiese, Alexandra; Green, Maranne E.; Green, Megan; Akyol, Aytekin; Roy, Badal C.; Zhai, Yali; Cho, Kathleen R.; Fearon, Eric R.

2015-01-01

Adenomatous polyposis coli (APC) inactivating mutations are present in most human colorectal cancers and some other cancers. The APC protein regulates the β-catenin protein pool that functions as a co-activator of T cell factor (TCF)-regulated transcription in Wnt pathway signaling. We studied effects of reduced dosage of the Ctnnb1 gene encoding β-catenin in Apc-mutation-induced colon and ovarian mouse tumorigenesis and cell culture models. Concurrent somatic inactivation of one Ctnnb1 allele, dramatically inhibited Apc mutation-induced colon polyposis and greatly extended Apc-mutant mouse survival. Ctnnb1 hemizygous dose markedly inhibited increases in β-catenin levels in the cytoplasm and nucleus following Apc inactivation in colon epithelium, with attenuated expression of key β-catenin/TCF-regulated target genes, including those encoding the EphB2/B3 receptors, the stem cell marker Lgr5, and Myc, leading to maintenance of crypt compartmentalization and restriction of stem and proliferating cells to the crypt base. A critical threshold for β-catenin levels in TCF-regulated transcription was uncovered for Apc mutation-induced effects in colon epithelium, along with evidence of a feed-forward role for β-catenin in Ctnnb1 gene expression and CTNNB1 transcription. The active β-catenin protein pool was highly sensitive to CTNNB1 transcript levels in colon cancer cells. In mouse ovarian endometrioid adenocarcinomas (OEAs) arising from Apc- and Pten-inactivation, while Ctnnb1 hemizygous dose affected β-catenin levels and some β-catenin/TCF target genes, Myc induction was retained and OEAs arose in a fashion akin to that seen with intact Ctnnb1 gene dose. Our findings indicate Ctnnb1 gene dose exerts tissue-specific differences in Apc mutation-instigated tumorigenesis. Differential expression of selected β-catenin/TCF-regulated genes, such as Myc, likely underlies context-dependent effects of Ctnnb1 gene dosage in tumorigenesis. PMID:26528816

The TLR3/TICAM-1 signal constitutively controls spontaneous polyposis through suppression of c-Myc in Apc Min/+ mice.

PubMed

Ono, Junya; Shime, Hiroaki; Takaki, Hiromi; Takashima, Ken; Funami, Kenji; Yoshida, Sumito; Takeda, Yohei; Matsumoto, Misako; Kasahara, Masanori; Seya, Tsukasa

2017-10-17

Intestinal tumorigenesis is promoted by myeloid differentiation primary response gene 88 (MyD88) activation in response to the components of microbiota in Apc Min/+ mice. Microbiota also contains double-stranded RNA (dsRNA), a ligand for TLR3, which activates the toll-like receptor adaptor molecule 1 (TICAM-1, also known as TRIF) pathway. We established Apc Min/+ Ticam1 -/- mice and their survival was compared to survival of Apc Min/+ Myd88 -/- and wild-type (WT) mice. The properties of polyps were investigated using immunofluorescence staining and RT-PCR analysis. We demonstrate that TICAM-1 is essential for suppression of polyp formation in Apc Min/+ mice. TICAM-1 knockout resulted in shorter survival of mice compared to WT mice or mice with knockout of MyD88 in the Apc Min/+ background. Polyps were more frequently formed in the distal intestine of Apc Min/+ Ticam1 -/- mice than in Apc Min/+ mice. Infiltration of immune cells such as CD11b + and CD8α + cells into the polyps was detected histologically. CD11b and CD8α mRNAs were increased in polyps of Apc Min/+ Ticam1 -/- mice compared to Apc Min/+ mice. Gene expression of inducible nitric oxide synthase (iNOS), interferon (IFN)-γ, CXCL9 and IL-12p40 was increased in polyps of Apc Min/+ Ticam1 -/- mice. mRNA and protein expression of c-Myc, a critical transcription factor for inflammation-associated polyposis, were increased in polyps of Apc Min/+ Ticam1 -/- mice. A Lactobacillus strain producing dsRNA was detected in feces of Apc Min/+ mice. These results imply that the TLR3/TICAM-1 pathway inhibits polyposis through suppression of c-Myc expression and supports long survival in Apc Min/+ mice.

Aspirin augments the expression of Adenomatous Polyposis Coli protein by suppression of IKKβ

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ashida, Noboru, E-mail: nashida@kuhp.kyoto-u.ac.jp; Kishihata, Masako; Tien, Dat Nguyen

Highlights: • Clinical studies revealed aspirin inhibits cancer, but the mechanism is not known. • Adenomatous Polyposis Coli (APC) is a well-known tumor-suppressing gene. • We found aspirin up-regulates the protein of APC. • Aspirin suppressed the expression of IKKβ, an essential kinase in NFκB activation. • The deletion of IKKβ significantly increases the expression of APC protein. - Abstract: Aspirin has been widely used as analgesic, antipyretic and anti-inflammatory medicine for long. In addition to these traditional effects, clinical studies suggest that aspirin can protect against cancer, but its mechanism has not been explored. To unveil it, we identifiedmore » the proteins up- or down-regulated after incubation with aspirin by using proteomics analysis with Nano-flow LC/MALDI-TOF system. Interestingly, the analysis identified the protein of Adenomatous Polyposis Coli (APC) as one of the most up-regulated protein. APC regulates cell proliferation or angiogenesis, and is widely known as a tumor-suppressing gene which can cause colorectal cancer when it is mutated. Western blots confirmed this result, and real-time PCR indicated it is transcriptionally regulated. We further tried to elucidate the molecular mechanism with focusing on IKKβ. IKKβ is the essential kinase in activation of nuclear factor-kappa B (NF-κB), major transcriptional factors that regulate genes responsible for inflammation or immune response. Previous reports indicated that aspirin specifically inhibits IKKβ activity, and constitutively active form of IKKβ accelerates APC loss. We found that aspirin suppressed the expression of IKKβ, and the deletion of IKKβ by siRNA increases the expression of APC in HEK294 cells. Finally, we observed similar effects of aspirin in human umbilical vein endothelial cells. Taken together, these results reveal that aspirin up-regulates the expression of APC via the suppression of IKKβ. This can be a mechanism how aspirin prevents cancer at least in part, and a novel link between inflammatory NF-κB signaling and cancer.« less

Effect of Subcutaneous Dupilumab on Nasal Polyp Burden in Patients With Chronic Sinusitis and Nasal Polyposis: A Randomized Clinical Trial.

PubMed

Bachert, Claus; Mannent, Leda; Naclerio, Robert M; Mullol, Joaquim; Ferguson, Berrylin J; Gevaert, Philippe; Hellings, Peter; Jiao, Lixia; Wang, Lin; Evans, Robert R; Pirozzi, Gianluca; Graham, Neil M; Swanson, Brian; Hamilton, Jennifer D; Radin, Allen; Gandhi, Namita A; Stahl, Neil; Yancopoulos, George D; Sutherland, E Rand

2016-02-02

Dupilumab has demonstrated efficacy in patients with asthma and atopic dermatitis, which are both type 2 helper T-cell-mediated diseases. To assess inhibition of interleukins 4 and 13 with dupilumab in patients with chronic sinusitis and nasal polyposis. A randomized, double-blind, placebo-controlled parallel-group study conducted at 13 sites in the United States and Europe between August 2013 and August 2014 in 60 adults with chronic sinusitis and nasal polyposis refractory to intranasal corticosteroids with 16 weeks of follow-up. Subcutaneous dupilumab (a 600 mg loading dose followed by 300 mg weekly; n = 30) or placebo (n = 30) plus mometasone furoate nasal spray for 16 weeks. Change in endoscopic nasal polyp score (range, 0-8; higher scores indicate worse status) at 16 weeks (primary end point). Secondary end points included Lund-Mackay computed tomography (CT) score (range, 0-24; higher scores indicate worse status), 22-item SinoNasal Outcome Test score (range, 0-110; higher scores indicating worse quality of life; minimal clinically important difference ≥8.90), sense of smell assessed using the University of Pennsylvania Smell Identification Test (UPSIT) score (range, 0-40; higher scores indicate better status), symptoms, and safety. Among the 60 patients who were randomized (mean [SD] age, 48.4 years [9.4 years]; 34 men [56.7%]; 35 with comorbid asthma), 51 completed the study. The least squares (LS) mean change in nasal polyp score was -0.3 (95% CI, -1.0 to 0.4) with placebo and -1.9 (95% CI, -2.5 to -1.2) with dupilumab (LS mean difference, -1.6 [95% CI, -2.4 to -0.7]; P < .001). The LS mean difference between the 2 groups for the Lund-Mackay CT total score was -8.8 (95% CI, -11.1 to -6.6; P < .001). Significant improvements with dupilumab were also observed for the 22-item SinoNasal Outcome Test (LS mean difference between groups, -18.1 [95% CI, -25.6 to -10.6]; P < .001) and sense of smell assessed by UPSIT (LS mean difference, 14.8 [95% CI, 10.9 to 18.7]; P < .001). The most common adverse events were nasopharyngitis (33% in the placebo group vs 47% in the dupilumab group), injection site reactions (7% vs 40%, respectively), and headache (17% vs 20%). Among adults with symptomatic chronic sinusitis and nasal polyposis refractory to intranasal corticosteroids, the addition of subcutaneous dupilumab to mometasone furoate nasal spray compared with mometasone alone reduced endoscopic nasal polyp burden after 16 weeks. Further studies are needed to assess longer treatment duration, larger samples, and direct comparison with other medications. clinicaltrials.gov Identifier: NCT01920893.

Microbial networking in cancer: when two toxins collide.

PubMed

Tomkovich, Sarah; Jobin, Christian

2018-05-01

A recent study by Dejea et al. has demonstrated that two enterotoxigenic bacteria frequently associated with sporadic colorectal cancer, Bacteroides fragilis and pks+ Escherichia coli, are found together in biofilms on tissue from patients with familial adenomatous polyposis. In preclinical mouse models, these two bacteria and their corresponding toxins work synergistically to promote colon cancer.

Sudhir Srivastava, PhD, MPH | Division of Cancer Prevention

Cancer.gov

Dr. Sudhir Srivastava has been Chief of the Cancer Biomarkers Research Group since 2000. His efforts focus on molecular biology of malignancies, early malignancies, risk assessment, and informatics, providing leadership in the areas of molecular screening and early detection. He is one of the principal authors of the Bethesda Guidelines for diagnosing Hereditary non-polyposis

miRNA863-3p sequentially targets negative regulators—atypical receptor-like Pseudokinases—and serrate, a positive regulator of plant immunity upon infection

USDA-ARS?s Scientific Manuscript database

Plant small RNAs (sRNAs) play important roles in regulating gene expression during pathogen infection. We identified miR863-3p, which is specifically induced by the avirulent bacterial pathogen Pseudomonas syringae pv. tomato DC3000 carrying the effector avrRpt2. During early infection stages, miR86...

Surgical Tooth Implants, Combat and Field.

DTIC Science & Technology

1985-11-15

development of dental implantology must not be overlooked. The early stages of this project clearly defined that rigid fixation of an implant device...block number) .-... This report summarizes progress on a long-ter implant study of a serrated ceramic dental implant designed for fresh extraction...implant, post and core and crown, are conventional metal materials, A series of graded dental implants have been produced to provide an interference fit

Controlled laboratory testing of arthroscopic shaver systems: do blades, contact pressure, and speed influence their performance?

PubMed

Wieser, Karl; Erschbamer, Matthias; Neuhofer, Stefan; Ek, Eugene T; Gerber, Christian; Meyer, Dominik C

2012-10-01

The purposes of this study were (1) to establish a reproducible, standardized testing protocol to evaluate the performance of different shaver systems and blades in a controlled, laboratory setting, and (2) to determine the optimal use of different blades with respect to the influence of contact pressure and speed of blade rotation. A holding device was developed for reproducible testing of soft-tissue (tendon and meniscal) resection performance in a submerged environment, after loading of the shaver with interchangeable weights. The Karl Storz Powershaver S2 (Karl Storz, Tuttlingen, Germany), the Stryker Power Shaver System (Stryker, Kalamazoo, MI), and the Dyonics Power Shaver System (Smith & Nephew, Andover, MA) were tested, with different 5.5-mm shaver blades and varied contact pressure and rotation speed. For quality testing, serrated shaver blades were evaluated at 40× image magnification. Overall, more than 150 test cycles were performed. No significant differences could be detected between comparable blade types from different manufacturers. Shavers with a serrated inner blade and smooth outer blade performed significantly better than the standard smooth resectors (P < .001). Teeth on the outer layer of the blade did not lead to any further improvement of resection (P = .482). Optimal contact pressure ranged between 6 and 8 N, and optimal speed was found to be 2,000 to 2,500 rpm. Minimal blunting of the shaver blades occurred after soft-tissue resection; however, with bone resection, progressive blunting of the shaver blades was observed. Arthroscopic shavers can be tested in a controlled setting. The performance of the tested shaver types appears to be fairly independent of the manufacturer. For tendon resection, a smooth outer blade and serrated inner blade were optimal. This is one of the first established independent and quantitative assessments of arthroscopic shaver systems and blades. We believe that this study will assist the surgeon in choosing the optimal tool for the desired effect. Copyright © 2012 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.

Endoscopic ultrasound evaluation in the surgical treatment of duodenal and peri-ampullary adenomas

PubMed Central

Azih, Lilian C; Broussard, Brett L; Phadnis, Milind A; Heslin, Martin J; Eloubeidi, Mohamad A; Varadarajulu, Shayam; Arnoletti, Juan Pablo

2013-01-01

AIM: To investigate endoscopic ultrasound (EUS) for predicting depth of mucosal invasion and to analyze outcomes following endoscopic and transduodenal resection. METHODS: Records of 111 patients seen at our institution from November 1999 to July 2011 with the post-operative pathological diagnosis of benign ampullary and duodenal adenomas were reviewed. Records of patients who underwent preoperative EUS for diagnostic purposes were identified. The accuracy of EUS in predicting the absence of muscular invasion was assessed by comparing EUS reports to the final surgical pathological results. In addition, the incidence of the post-operative complications over a period of 30 d and the subsequent long-term outcome (recurrence) over a period of 30 mo associated with endoscopic and transduodenal surgical resection was recorded, compared and analyzed. RESULTS: Among 111 patients with benign ampullary and duodenal adenomas, 47 underwent preoperative EUS for 29 peri-ampullary lesions and 18 duodenal lesions. In addition, computed tomography was performed in 18 patients, endoscopic retrograde cholangio-pancreatography in 10 patients and esophagogastroduodenoscopy in 22 patients. There were 43 patients with sporadic adenomas and 4 patients with familial adenomatous polyposis (FAP)/other polyposis syndromes. In 38 (81%, P < 0.05) patients, EUS reliably identified absence of submucosal and muscularis invasion. In 4 cases, EUS underestimated submucosal invasion that was proven by pathology. In the other 5 patients, EUS predicted muscularis invasion which could not be demonstrated in the resected specimen. EUS predicted tumor muscularis invasion with a specificity of 88% and negative predictive value of 90% (P < 0.05). Types of resection performed included endoscopic resection in 22 cases, partial duodenectomy in 9 cases, transduodenal ampullectomy with sphincteroplasty in 10 cases and pancreaticoduodenectomy in 6 cases. The main post-operative final pathological results included villous adenoma (n = 5), adenoma (n = 8), tubulovillous adenoma (n = 10), tubular adenoma (n = 20) and hyperplastic polyp (n = 2). Among the 47 patients who underwent resection, 8 (17%, 5 of which corresponded to surgical resection) developed post-procedural complications which included retroperitoneal hematoma, intra-abdominal abscess, wound infection, delayed gastric emptying and prolonged ileus. After median follow-up of 20 mo there were 6 local recurrences (13%, median follow-up = 20 mo) 4 of which were in patients with FAP. CONCLUSION: EUS accurately predicts the depth of mucosal invasion in suspected benign ampullary and duodenal adenomas. These patients can safely undergo endoscopic or local resection. PMID:23382629

Surgical Tooth Implants, Combat and Field.

DTIC Science & Technology

1984-07-15

and identify by block number) --- This Annual Report summarizes progress to date on a long-term implant study of a serrated ceramic dental implant...upper two parts of the implant, post and core and crown, are conventional metaT materials. A series of graded dental implants have been produced to...throughout the experimental period. Periodic radio- graphic analyses of dental implants verify this observation. Gross and microscopic patho- logic analyses

Surgical Tooth Implants, Combat and Field.

DTIC Science & Technology

1985-11-15

project in the development of dental implantology must not be overlooked. The early stages of this project clearly defined that rigid fixation of an...a long-term implant study of a serrated ceramic dental implant designed for fresh extraction sites. The baboon study was successfully completed last...materials. A series of graded dental implants have been produce’ to provide an interference fit in any fresh extraction site. The long-term implant

Reevaluation of Chalcophora angulicollis (LeConte) and Chalcophora virginiensis (Drury) with a review and key to the North American species of Chalcophora DeJean (Coleoptera: Buprestidae)

Treesearch

Crystal A. Maier; Michael A. Ivie

2013-01-01

Chalcophora angulicollis (LeConte) and Chalcophora virginiensis (Drury) are shown to be valid allopatric species in the western and eastern forests of North America, respectively. The historic uncertainty regarding their status is reviewed, and new characters of the aedeagus, penultimate maxillary palpomere, and elytral serrations are utilized for their identification...

[Aggressive fibromatosis of the nasal sinuses].

PubMed

Artazkoz del Toro, J J; Pons Rocher, F; Dalmau Galofré, J; Mompó Romero, L; Guallart Domènech, F; Serrano Badía, E

1994-01-01

A case report of a feminine patient who complained of nasal ventilatory obstruction and nasosinusal polyposis is presented. She underwent surgery and the pathological study revealed the existence of an aggressive fibromatosis. The AA. review the literature dealing with this illness and explain an update state of the clinical features, treatment and the course of this rare entity, closely related to fibrosarcoma.

Microstructural Characteristics and Mechanical Properties of Friction Stir Welded Thick 5083 Aluminum Alloy

NASA Astrophysics Data System (ADS)

Imam, Murshid; Sun, Yufeng; Fujii, Hidetoshi; Ma, Ninshu; Tsutsumi, Seiichiro; Murakawa, Hidekazu

2017-01-01

Joining thick sections of aluminum alloys by friction stir welding (FSW) in a single pass needs to overcome many challenges before it comes to full-scale industrial use. Important parameters controlling the structure-properties relationships both across weld cross-section and through thickness direction were investigated through mechanical testing, electron backscatter diffraction technique, transmission electron microscopy, and occurrence of serrated plastic flow. The evolution of the properties in the weld cross-section shows that the presence of undissolved and fragmented Al_6MnFe particles cause discrepancies in establishing the Hall-Petch relationship, and derive the strengthening from the Orowan strengthening mechanism. A `stop action' friction stir weld has been prepared to understand the role of geometrical features of the tool probe in the development of the final microstructure after complete weld. Sectioning through the `stop action' weld with the probe in situ displays the individual effect of thread and flat on the grain structure formation. The material at the thread surface experiences more severe deformation than the material at flat surface. Both the high-angle boundaries and mean grain size are found to be higher at the thread surface. The strain hardening capacity, stress serration amplitude, and frequency are observed to be higher in the stir zone than other weld regions.

Migratory patterns and population structure among breeding and wintering red-breasted mergansers (Mergus serrator) and common mergansers (M. merganser)

USGS Publications Warehouse

Pearce, J.M.; McCracken, K.G.; Christensen, Thomas K.; Zhuravlev, Y.N.

2009-01-01

Philopatry has long been assumed to structure populations of waterfowl and other species of birds genetically, especially via maternally transmitted mitochondrial DNA (mtDNA), yet other migratory behaviors and nesting ecology (use of ground vs. cavity sites) may also contribute to population genetic structure. We investigated the effects of migration and nesting ecology on the population genetic structure of two Holarctic waterfowl, the Red-breasted Merganser (Mergus serrator) and Common Merganser (M. merganser), using mtDNA control-region sequence data. Red-breasted Mergansers (a ground-nesting species) exhibited lower levels of population differentiation across their North American range, possibly as a result of post-Pleistocene range expansion and population growth. By contrast, Common Mergansers (a cavity-nesting species) breeding in western and eastern North America were strongly differentiated, as were continental groups in North America and Europe. Our hypothesis that population differentiation of breeding female Common Mergansers results from limited migration during non-breeding periods was not supported, in that equally heterogeneous mtDNA lineages were observed in males and females on several wintering areas. The interspecific differences in mtDNA patterns for these two closely related species may have resulted from factors related to nesting ecology (ground vs. cavity nesting) and responses to historical climate change.

Dilatancy induced ductile-brittle transition of shear band in metallic glasses.

PubMed

Zeng, F; Jiang, M Q; Dai, L H

2018-04-01

Dilatancy-generated structural disordering, an inherent feature of metallic glasses (MGs), has been widely accepted as the physical mechanism for the primary origin and structural evolution of shear banding, as well as the resultant shear failure. However, it remains a great challenge to determine, to what degree of dilatation, a shear banding will evolve into a runaway shear failure. In this work, using in situ acoustic emission monitoring, we probe the dilatancy evolution at the different stages of individual shear band in MGs that underwent severely plastic deformation by the controlled cutting technology. A scaling law is revealed that the dilatancy in a shear band is linearly related to its evolution degree. A transition from ductile-to-brittle shear bands is observed, where the formers dominate stable serrated flow, and the latter lead to a runaway instability (catastrophe failure) of serrated flow. To uncover the underlying mechanics, we develop a theoretical model of shear-band evolution dynamics taking into account an atomic-scale deformation process. Our theoretical results agree with the experimental observations, and demonstrate that the atomic-scale volume expansion arises from an intrinsic shear-band evolution dynamics. Importantly, the onset of the ductile-brittle transition of shear banding is controlled by a critical dilatation.

Association of meat intake and meat-derived mutagen exposure with the risk of colorectal polyps by histologic type

PubMed Central

Fu, Zhenming; Shrubsole, Martha J.; Smalley, Walter E.; Wu, Huiyun; Chen, Zhi; Shyr, Yu; Ness, Reid M.; Zheng, Wei

2011-01-01

Background The association of meat intake and meat-derived mutagens with colorectal tumor risk remains unclear. We evaluated this hypothesis in a large colonoscopy-based case-control study. Methods Included in the study were 2,543 polyp patients [(1,881 with adenomas, and 622 with hyperplastic polyp (HPP)] and 3,764 polyp-free controls. Surveys obtained information about meat intake by cooking methods and doneness levels plus other suspected or known risk factors for colorectal tumors. Unconditional logistic regression was used to derive odds ratios (ORs) after adjusting for potential confounders. Results High intake of red meat and processed meat (P-trend < 0.05), particularly red meat cooked using high-temperature cooking methods (P-trend ≤ 0.01), was associated with an elevated risk for colorectal polyps. A significant positive association between exposures to meat-derived heterocyclic amines and risk of polyps was found for both adenomas and hyperplastic polyps. Furthermore, the positive association with red-meat intake and heterocyclic amine exposure was stronger for multiple adenomas than single adenoma and serrated than non-serrated adenomas. Conclusion This study supports a role for red meat and meat-derived mutagen exposure in the development of colorectal tumor. PMID:21803984

Hyperplastic polyps of the colon and rectum - reclassification, BRAF and KRAS status in index polyps and subsequent colorectal carcinoma.

PubMed

Janjua, Huma Gul Rehana; Høgdall, Estrid; Linnemann, Dorte

2015-04-01

Hyperplastic polyps (HP) of the colon and rectum were previously considered benign. Newer studies have suggested that colorectal HP are different entities. The aim of this study was to reclassify lesions from a 5-year period previously classified as colorectal HP into traditional hyperplastic polyp (THP), sessile serrated lesions (SSL), and other lesions. All patients were confirmed in the Danish National Pathology Database for the occurrence of metachronous polyps/adenomas, colorectal cancer (CRC), and other gastrointestinal malignancies. Molecular pathology of the CRC were characterized and correlated with the index lesion. In total, 591 HP biopsy specimens were obtained from 480 patients. The lesions were reclassified as: 358 THP, 109 SSL, 35 TA, 81 unspecified non-neoplastic lesions, four traditional serrated adenoma, and 4 SSL with cytological dysplasia. Seven patients developed CRC in the follow-up period (1 patient had SSL, 4 had THP, and 2 had unspecified non-neoplastic lesions). Ten patients developed other gastrointestinal malignancies. The patient with SSL as index lesions who developed CRC harbored V600E BRAF mutation in both index lesion and the carcinoma. Sixteen percent of patients with SSL subsequently developed a neoplastic lesion. Further studies are needed to clarify the cancer risk of SSL. © 2015 APMIS. Published by John Wiley & Sons Ltd.

Dilatancy induced ductile-brittle transition of shear band in metallic glasses

NASA Astrophysics Data System (ADS)

Zeng, F.; Jiang, M. Q.; Dai, L. H.

2018-04-01

Dilatancy-generated structural disordering, an inherent feature of metallic glasses (MGs), has been widely accepted as the physical mechanism for the primary origin and structural evolution of shear banding, as well as the resultant shear failure. However, it remains a great challenge to determine, to what degree of dilatation, a shear banding will evolve into a runaway shear failure. In this work, using in situ acoustic emission monitoring, we probe the dilatancy evolution at the different stages of individual shear band in MGs that underwent severely plastic deformation by the controlled cutting technology. A scaling law is revealed that the dilatancy in a shear band is linearly related to its evolution degree. A transition from ductile-to-brittle shear bands is observed, where the formers dominate stable serrated flow, and the latter lead to a runaway instability (catastrophe failure) of serrated flow. To uncover the underlying mechanics, we develop a theoretical model of shear-band evolution dynamics taking into account an atomic-scale deformation process. Our theoretical results agree with the experimental observations, and demonstrate that the atomic-scale volume expansion arises from an intrinsic shear-band evolution dynamics. Importantly, the onset of the ductile-brittle transition of shear banding is controlled by a critical dilatation.

Influences of Cutting Speed and Material Mechanical Properties on Chip Deformation and Fracture during High-Speed Cutting of Inconel 718.

PubMed

Wang, Bing; Liu, Zhanqiang; Hou, Xin; Zhao, Jinfu

2018-03-21

The paper aims to investigate the influences of material constitutive and fracture parameters in addition to cutting speed on chip formation during high-speed cutting of Inconel 718. Finite element analyses for chip formation are conducted with Johnson-Cook constitutive and fracture models. Meanwhile, experiments of high-speed orthogonal cutting are performed to verify the simulation results with cutting speeds ranging from 50 m/min to 7000 m/min. The research indicates that the chip morphology transforms from serrated to fragmented at the cutting speed of 7000 m/min due to embrittlement of the workpiece material under ultra-high cutting speeds. The parameter of shear localization sensitivity is put forward to describe the influences of material mechanical properties on serrated chip formation. The results demonstrate that the effects of initial yield stress and thermal softening coefficient on chip shear localization are much more remarkable than the other constitutive parameters. For the material fracture parameters, the effects of initial fracture strain and exponential factor of stress state on chip shear localization are more much prominent. This paper provides guidance for controlling chip formation through the adjustment of material mechanical properties and the selection of appropriate cutting parameters.

Influences of Cutting Speed and Material Mechanical Properties on Chip Deformation and Fracture during High-Speed Cutting of Inconel 718

PubMed Central

Hou, Xin; Zhao, Jinfu

2018-01-01

The paper aims to investigate the influences of material constitutive and fracture parameters in addition to cutting speed on chip formation during high-speed cutting of Inconel 718. Finite element analyses for chip formation are conducted with Johnson–Cook constitutive and fracture models. Meanwhile, experiments of high-speed orthogonal cutting are performed to verify the simulation results with cutting speeds ranging from 50 m/min to 7000 m/min. The research indicates that the chip morphology transforms from serrated to fragmented at the cutting speed of 7000 m/min due to embrittlement of the workpiece material under ultra-high cutting speeds. The parameter of shear localization sensitivity is put forward to describe the influences of material mechanical properties on serrated chip formation. The results demonstrate that the effects of initial yield stress and thermal softening coefficient on chip shear localization are much more remarkable than the other constitutive parameters. For the material fracture parameters, the effects of initial fracture strain and exponential factor of stress state on chip shear localization are more much prominent. This paper provides guidance for controlling chip formation through the adjustment of material mechanical properties and the selection of appropriate cutting parameters. PMID:29561770

Study on Dynamic Strain Aging and Low-Cycle Fatigue of Stainless Steel in Ultra-Supercritical Unit

NASA Astrophysics Data System (ADS)

Hongwei, Zhou; Yizhu, He; Jizu, Lv; Sixian, Rao

Dynamic strain aging (DSA) and low-cycle fatigue (LCF) behavior of TP347H stainless steel in ultra-supercritical unit were investigated at 550-650 °C. All the LCF tests were carried out under a fully-reversed, total axial strain control mode at the total strain amplitude from ±0.2% to ±1.0%. The effects of DSA in cyclic stress response, microstructure evolution and fatigue fracture surfaces and fatigue life were investigated in detail. The results show that DSA occurs during tensile, which is manifested as serrated flow in tensile stress-strain curves. The apparent activation energy for appearing of serrations in tensile stress-strain curves was 270 kJ/mol. Pipe diffusion of substitutional solutes such as Cr and Nb along the dislocation core, and strong interactions between segregated solutes and dislocations are considered as the mechanism of DSA. DSA partly restricts dislocation cross-slip, and dislocation cross-slip and planar-slip happen simultaneously during LCF. A lot of planar structures form, which is due to dislocation gliding on the special plane. This localized deformation structures result in many crack initiation sites. Meanwhile, DSA hardening increases cyclic stress response, accelerating crack propagation, which reduces high temperature strain fatigue life of steel.