Science.gov

Sample records for intestinal tumor burden

  1. The impact of the largest metastasis size on nodal tumor burden in colorectal carcinomas: implications for the sentinel lymph node theory in cancers of the large intestine.

    PubMed

    Bori, Rita; Vinh-Hung, Vincent; Vajda, Kornél; Svébis, Mihály; Cserni, Gábor

    2007-06-15

    Successful sentinel lymph node (SLN) biopsy has been reported in colorectal cancer (CRC), but its results are still controversial. The SLN theory suggests that there is an orderly spread from the primary tumor to the SLNs first, and from the SLNs to further nodes later. This study examines the influence of nodal metastasis size on further nodal involvement. CRC resection specimens with nodal metastasis have been evaluated for the maximum nodal metastasis size for a period of 5 years. All lymph nodes (LNs) were submitted to standard histological examination. Two hundred thirty-five CRC specimens with a single invasive tumor were assessed. The mean numbers of LNs examined and involved were 18 and 4, respectively. The largest metastasis size ranged from 0.14 to 22.1 mm. There was a significant correlation between this parameter and the number or the ratio of LNs involved (Spearman's Rho: 0.517, and 0.382, respectively; P < 0.0001). A cluster analysis identified three relatively distinct groups of low, intermediate, and extensive nodal involvement. The correlation of the largest metastasis size with the number and the ratio of involved nodes may be an indirect proof of the sequential spread from first echelon LNs to further nodes. However, the data suggest a more complex process: with increasing metastasis size, the number of involved nodes and its variability increase more than might be expected. This suggests a recruitment or cascade process, which becomes more unpredictable as nodal tumor burden increases. Copyright 2007 Wiley-Liss, Inc.

  2. Loss of intestinal O-glycans promotes spontaneous duodenal tumors.

    PubMed

    Gao, Nan; Bergstrom, Kirk; Fu, Jianxin; Xie, Biao; Chen, Weichang; Xia, Lijun

    2016-07-01

    Mucin-type O-glycans, primarily core 1- and core 3-derived O-glycans, are the major mucus barrier components throughout the gastrointestinal tract. Previous reports identified the biological role of O-glycans in the stomach and colon. However, the biological function of O-glycans in the small intestine remains unknown. Using mice lacking intestinal core 1- and core 3-derived O-glycans [intestinal epithelial cell C1galt1(-/-);C3GnT(-/-) or double knockout (DKO)], we found that loss of O-glycans predisposes DKO mice to spontaneous duodenal tumorigenesis by ∼1 yr of age. Tumor incidence did not increase with age; however, tumors advanced in aggressiveness by 20 mo. O-glycan deficiency was associated with reduced luminal mucus in DKO mice before tumor development. Altered intestinal epithelial homeostasis with enhanced baseline crypt proliferation characterizes these phenotypes as assayed by Ki67 staining. In addition, fluorescence in situ hybridization analysis reveals a significantly lower bacterial burden in the duodenum compared with the large intestine. This phenotype is not reduced with antibiotic treatment, implying O-glycosylation defects, rather than bacterial-induced inflammation, which causes spontaneous duodenal tumorigenesis. Moreover, inflammatory responses in DKO duodenal mucosa are mild as assayed with histology, quantitative PCR for inflammation-associated cytokines, and immunostaining for immune cells. Importantly, inducible deletion of intestinal O-glycans in adult mice leads to analogous spontaneous duodenal tumors, although with higher incidence and heightened severity compared with mice with O-glycans constitutive deletion. In conclusion, these studies reveal O-glycans within the small intestine are critical determinants of duodenal cancer risk. Future studies will provide insights into the pathogenesis in the general population and those at risk for this rare but deadly cancer.

  3. Quantitative analysis of tumor burden in mouse lung via MRI.

    PubMed

    Tidwell, Vanessa K; Garbow, Joel R; Krupnick, Alexander S; Engelbach, John A; Nehorai, Arye

    2012-02-01

    Lung cancer is the leading cause of cancer death in the United States. Despite recent advances in screening protocols, the majority of patients still present with advanced or disseminated disease. Preclinical rodent models provide a unique opportunity to test novel therapeutic drugs for targeting lung cancer. Respiratory-gated MRI is a key tool for quantitatively measuring lung-tumor burden and monitoring the time-course progression of individual tumors in mouse models of primary and metastatic lung cancer. However, quantitative analysis of lung-tumor burden in mice by MRI presents significant challenges. Herein, a method for measuring tumor burden based upon average lung-image intensity is described and validated. The method requires accurate lung segmentation; its efficiency and throughput would be greatly aided by the ability to automatically segment the lungs. A technique for automated lung segmentation in the presence of varying tumor burden levels is presented. The method includes development of a new, two-dimensional parametric model of the mouse lungs and a multi-faceted cost function to optimally fit the model parameters to each image. Results demonstrate a strong correlation (0.93), comparable with that of fully manual expert segmentation, between the automated method's tumor-burden metric and the tumor burden measured by lung weight.

  4. Rituximab Retreatment for Low-Tumor Burden Follicular Lymphoma

    Cancer.gov

    A summary of results from a randomized clinical trial of patients with low–tumor burden follicular lymphoma that compared maintenance therapy with rituximab versus retreatment with rituximab only when there was evidence of disease progression.

  5. Automatic detection of new tumors and tumor burden evaluation in longitudinal liver CT scan studies.

    PubMed

    Vivanti, R; Szeskin, A; Lev-Cohain, N; Sosna, J; Joskowicz, L

    2017-08-30

    Radiological longitudinal follow-up of liver tumors in CT scans is the standard of care for disease progression assessment and for liver tumor therapy. Finding new tumors in the follow-up scan is essential to determine malignancy, to evaluate the total tumor burden, and to determine treatment efficacy. Since new tumors are typically small, they may be missed by examining radiologists. We describe a new method for the automatic detection and segmentation of new tumors in longitudinal liver CT studies and for liver tumors burden quantification. Its inputs are the baseline and follow-up CT scans, the baseline tumors delineation, and a tumor appearance prior model. Its outputs are the new tumors segmentations in the follow-up scan, the tumor burden quantification in both scans, and the tumor burden change. Our method is the first comprehensive method that is explicitly designed to find new liver tumors. It integrates information from the scans, the baseline known tumors delineations, and a tumor appearance prior model in the form of a global convolutional neural network classifier. Unlike other deep learning-based methods, it does not require large tagged training sets. Our experimental results on 246 tumors, of which 97 were new tumors, from 37 longitudinal liver CT studies with radiologist approved ground-truth segmentations, yields a true positive new tumors detection rate of 86 versus 72% with stand-alone detection, and a tumor burden volume overlap error of 16%. New tumors detection and tumor burden volumetry are important for diagnosis and treatment. Our new method enables a simplified radiologist-friendly workflow that is potentially more accurate and reliable than the existing one by automatically and accurately following known tumors and detecting new tumors in the follow-up scan.

  6. Human Intestinal Parasite Burden and Poor Sanitation in Rural Alabama.

    PubMed

    McKenna, Megan L; McAtee, Shannon; Bryan, Patricia E; Jeun, Rebecca; Ward, Tabitha; Kraus, Jacob; Bottazzi, Maria E; Hotez, Peter J; Flowers, Catherine C; Mejia, Rojelio

    2017-09-05

    Hookworm infection affects 430 million people worldwide, causing iron deficiency, impaired cognitive development, and stunting in children. Because of the environmental conditions needed for the hookworm life-cycle, this parasite is endemic to resource-limited countries. Necator americanus was endemic in the southern United States before improvement of sewage disposal systems and eradication programs. With continued poverty, poor sanitation, and an environment suitable for the hookworm life-cycle in some regions of the southern United States, a current prevalence study using modern molecular diagnostics is warranted. Lowndes County, Alabama, was chosen as the study site given previous high hookworm burdens, degree of poverty, and use of open-sewage systems. Participants were interviewed, and stool, serum, and soil samples were tested for nine intestinal parasites using a multiparallel quantitative real-time PCR (qPCR) and enzyme-linked immunosorbent assays . We found that, among 24 households, 42.4% reported exposure to raw sewage within their home, and from 55 stool samples, 19 (34.5%) tested positive for N. americanus, four (7.3%) for Strongyloides stercoralis, and one (1.8%) for Entamoeba histolytica. Stool tested positive for N. americanus contained low levels of parasite DNA (geometric mean 0.0302 fg/µL). Soil studies detected one (2.9%) Cryptosporidium species, and Toxocara serology assay detected one (5.2%) positive in this population. Individuals living in this high-risk environment within the United States continue to have stool samples positive for N. americanus. Gastrointestinal parasites known to be endemic to developing countries are identifiable in American poverty regions, and areas with lower disease burden are more likely to be identified by using qPCR.

  7. Biomarkers of Renal Tumor Burden and Progression in TSC

    DTIC Science & Technology

    2013-09-01

    AD_________________ Award Number: W81XWH-10- 1 -0433 TITLE: Biomarkers of Renal Tumor Burden and...reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching...ADDRESS. 1 . REPORT DATE September 2013 2. REPORT TYPE Final 3. DATES COVERED 1 September 2010 - 31 August 2013 4. TITLE AND SUBTITLE 5a

  8. Intestinal gastrointestinal stromal tumor in a cat

    PubMed Central

    SUWA, Akihisa; SHIMODA, Tetsuya

    2017-01-01

    A 12-year-old, 3.6-kg, spayed female domestic shorthaired cat had a 2-month history of anorexia and weight loss. Abdominal ultrasonography and computed tomography revealed an exophytic mass originating from the jejunum with very poor central and poor peripheral contrast enhancement. On day 14, surgical resection of the jejunum and mass with 5-cm margins and an end-to-end anastomosis were performed. Histopathological examination revealed the mass was a transmural, invasive cancer showing exophytic growth and originating from the small intestinal muscle layer. Immunohistochemical analysis of tumor cells revealed diffuse positivity for KIT protein and negativity for desmin and S-100. The mass was diagnosed as a gastrointestinal stromal tumor (GIST). Ultrasonographic findings indicated the tumor probably metastasized to the liver and omentum, as seen in humans and dogs. The owner rejected further treatment at the last visit on day 192. To our knowledge, this is the first report of intestinal tumor and metastasis in feline GIST and its imaging features. PMID:28163271

  9. Tumor Burden Talks in Cancer Treatment with PEGylated Liposomal Drugs

    PubMed Central

    Li, Jia-Je; Hwang, Jeng-Jong; Tseng, Yun-Long; Lin, Wuu-Jyh; Lin, Ming-Hsien; Ting, Gann; Wang, Hsin-Ell

    2013-01-01

    Purpose PEGylated liposomes are important drug carriers that can passively target tumor by enhanced permeability and retention (EPR) effect in neoplasm lesions. This study demonstrated that tumor burden determines the tumor uptake, and also the tumor response, in cancer treatment with PEGylated liposomal drugs in a C26/tk-luc colon carcinoma-bearing mouse model. Methods Empty PEGylated liposomes (NanoX) and those encapsulated with VNB (NanoVNB) were labeled with In-111 to obtain InNanoX and InVNBL in high labeling yield and radiochemical purity (all >90%). BALB/c mice bearing either small (58.4±8.0 mm3) or large (102.4±22.0 mm3) C26/tk-luc tumors in the right dorsal flank were intravenously administered with NanoVNB, InNanoX, InVNBL, or NanoX as a control, every 7 days for 3 times. The therapeutic efficacy was evaluated by body weight loss, tumor growth inhibition (using calipers and bioluminescence imaging) and survival fraction. The scintigraphic imaging of tumor mouse was performed during and after treatment. Results The biodistribution study of InVNBL revealed a clear inverse correlation (r2 = 0.9336) between the tumor uptake and the tumor mass ranged from 27.6 to 623.9 mg. All three liposomal drugs showed better therapeutic efficacy in small-tumor mice than in large-tumor mice. Tumor-bearing mice treated with InVNBL (a combination drug) showed the highest tumor growth inhibition rate and survival fraction compared to those treated with NanoVNB (chemodrug only) and InNanoX (radionuclide only). Specific tumor targeting and significantly increased tumor uptake after periodical treatment with InVNBL were evidenced by scintigraphic imaging, especially in mice bearing small tumors. Conclusion The significant differences in the outcomes of cancer treatment and molecular imaging between animals bearing small and large tumors revealed that tumor burden is a critical and discriminative factor in cancer therapy using PEGylated liposomal drugs. PMID:23675454

  10. [Predictive value of Hodgkin's lymphoma tumor burden in present].

    PubMed

    Kulyova, S A; Karitsky, A P

    2014-01-01

    Today approximately 70% of patients with Hodgkin lymphoma can be cured with the combined-modality therapy. Tumor burden, the importance of which was demonstrated 15 years ago for the first time, is a powerful prognostic factor. Data of literature of representations on predictive value of Hodgkin's lymphoma tumor burden are shown in the article. The difficult immunological relations between tumor cells and reactive ones lead to development of the main symptoms. Nevertheless, the collective sign of tumor burden shows the greatest influence on survival and on probability of resistance, which relative risk can be predicted on this variable and treatment program. Patients with bulky disease need escalated therapy with high-dose chemotherapy. Integration into predictive models of the variable will change an expected contribution of clinical and laboratory parameters in the regression analyses constructed on patients with Hodgkin's lymphoma. Today the role of diagnostic functional methods, in particular a positron emission tomography, for metabolic active measurement is conducted which allows excluding a reactive component.

  11. Cables1 is a tumor suppressor gene that regulates intestinal tumor progression in Apc(Min) mice.

    PubMed

    Arnason, Thomas; Pino, Maria S; Yilmaz, Omer; Kirley, Sandra D; Rueda, Bo R; Chung, Daniel C; Zukerberg, Lawrence R

    2013-07-01

    The transformation of colonic mucosal epithelium to adenocarcinoma requires progressive oncogene activation and tumor suppressor gene inactivation. Loss of chromosome 18q is common in colon cancer but not in precancerous adenomas. A few candidate tumor suppressor genes have been identified in this region, including CABLES1 at 18q11.2-12.1. This study investigates the role of CABLES1 in an in vivo mouse model of intestinal adenocarcinoma and in human colon cancer cell culture. Apc(Min/+) mice were crossed with mice harboring targeted inactivation of the Cables1 gene (Cables1(-/-)). The intestinal tumor burden and tumor expression of β-catenin and PCNA was compared in Cables1(+/+)Apc(Min/+) and Cables1(-/-)Apc(Min/+) mice. β-catenin activity in human colon cancer cells with CABLES1 inactivation and intestinal progenitor cell function in Cables1(-/-) mice were assayed in vitro. The mean number of small intestinal tumors per mouse was 3.1 ± 0.6 in Cables1(+/+)Apc(Min/+) mice, compared with 32.4 ± 3.5 in the Cables1(-/-)Apc(Min/+) mice (P < 0.0001). Fewer colonic tumors were observed in Cables1(+/+)Apc(Min/+) mice (mean 0.6 ± 0.1) compared with the Cables1(-/-)Apc(Min/+) mice (mean 1.3 ± 0.3, P = 0.01). Tumors from Cables1(-/-)Apc(Min/+) mice demonstrated increased nuclear expression of β-catenin and an increased number of PCNA-positive cells. In vitro studies revealed that CABLES1 deficiency increased β-catenin dependent transcription and increased intestinal progenitor cell activity. Loss of Cables1 enhances tumor progression in the Apc(Min/+) mouse model and activates the Wnt/β-catenin signaling pathway. Cables1 is a tumor suppressor gene on chromosome 18q in this in vivo mouse model and likely has a similar role in human colon cancer.

  12. Biliary Phospholipids Sustain Enterocyte Proliferation and Intestinal Tumor Progression via Nuclear Receptor Lrh1 in mice

    PubMed Central

    Petruzzelli, Michele; Piccinin, Elena; Pinto, Claudio; Peres, Claudia; Bellafante, Elena; Moschetta, Antonio

    2016-01-01

    The proliferative-crypt compartment of the intestinal epithelium is enriched in phospholipids and accumulation of phospholipids has been described in colorectal tumors. Here we hypothesize that biliary phospholipid flow could directly contribute to the proliferative power of normal and dysplastic enterocytes. We used Abcb4−/− mice which lack biliary phospholipid secretion. We first show that Abcb4−/− mice are protected against intestinal tumorigenesis. At the molecular level, the transcriptional activity of the nuclear receptor Liver Receptor Homolog-1 (Lrh1) is reduced in Abcb4−/− mice and its re-activation re-establishes a tumor burden comparable to control mice. Feeding Abcb4−/− mice a diet supplemented with phospholipids completely overcomes the intestinal tumor protective phenotype, thus corroborating the hypothesis that the absence of biliary phospholipids and not lack of Abcb4 gene per se is responsible for the protection. In turn, phospholipids cannot re-establish intestinal tumorigenesis in Abcb4−/− mice crossed with mice with intestinal specific ablation of Lrh1, a nuclear hormone receptor that is activates by phospholipids. Our data identify the key role of biliary phospholipids in sustaining intestinal mucosa proliferation and tumor progression through the activation of nuclear receptor Lrh1. PMID:27995969

  13. Akkermansia muciniphila and Helicobacter typhlonius modulate intestinal tumor development in mice.

    PubMed

    Dingemanse, Celia; Belzer, Clara; van Hijum, Sacha A F T; Günthel, Marie; Salvatori, Daniela; den Dunnen, Johan T; Kuijper, Ed J; Devilee, Peter; de Vos, Willem M; van Ommen, GertJan B; Robanus-Maandag, Els C

    2015-11-01

    Gastrointestinal tumor growth is thought to be promoted by gastrointestinal bacteria and their inflammatory products. We observed that intestine-specific conditional Apc mutant mice (FabplCre;Apc (15lox/+)) developed many more colorectal tumors under conventional than under pathogen-low housing conditions. Shotgun metagenomic sequencing plus quantitative PCR analysis of feces DNA revealed the presence of two bacterial species in conventional mice, absent from pathogen-low mice. One, Helicobacter typhlonius, has not been associated with cancer in man, nor in immune-competent mice. The other species, mucin-degrading Akkermansia muciniphila, is abundantly present in healthy humans, but reduced in patients with inflammatory gastrointestinal diseases and in obese and type 2 diabetic mice. Eradication of H.typhlonius in young conventional mice by antibiotics decreased the number of intestinal tumors. Additional presence of A.muciniphila prior to the antibiotic treatment reduced the tumor number even further. Colonization of pathogen-low FabplCre;Apc (15lox/+) mice with H.typhlonius or A.muciniphila increased the number of intestinal tumors, the thickness of the intestinal mucus layer and A.muciniphila colonization without H.typhlonius increased the density of mucin-producing goblet cells. However, dual colonization with H.typhlonius and A.muciniphila significantly reduced the number of intestinal tumors, the mucus layer thickness and goblet cell density to that of control mice. By global microbiota composition analysis, we found a positive association of A.muciniphila, and of H.typhlonius, and a negative association of unclassified Clostridiales with increased tumor burden. We conclude that A.muciniphila and H.typhlonius can modulate gut microbiota composition and intestinal tumor development in mice.

  14. Minnelide reduces tumor burden in preclinical models of osteosarcoma

    PubMed Central

    Banerjee, Sulagna; Thayanithy, Venugopal; Sangwan, Veena; Mackenzie, Tiffany N.; Saluja, Ashok K.; Subramanian, Subbaya

    2015-01-01

    Osteosarcoma is the most common bone cancer in children and adolescents with a five-year survival rate of about 70%. In this study, we have evaluated the preclinical therapeutic efficacy of the novel synthetic drug, Minnelide, a prodrug of triptolide on osteosarcoma. Triptolide was effective in significantly inducing apoptosis in all osteosarcoma cell lines tested but had no significant effect on the human osteoblast cells. Notably, Minnelide treatment significantly reduced tumor burden and lung metastasis in the orthotopic and lung colonization models. Triptolide/Minnelide effectively downregulated the levels of pro-survival proteins such as heat shock proteins, cMYC, survivin and targets NF-κB pathway. PMID:23499892

  15. Towards automatic determination of total tumor burden from PET images

    NASA Astrophysics Data System (ADS)

    Renisch, Steffen; Opfer, Roland; Wiemker, Rafael

    2010-03-01

    Quantification of potentially cancerous lesions from imaging modalities, most prominently from CT or PET images, plays a crucial role both in diagnosing and staging of cancer as well as in the assessment of the response of a cancer to a therapy, e.g. for lymphoma or lung cancer. For PET imaging, several quantifications which might bear great discriminating potential (e.g. total tumor burden or total tumor glycolysis) involve the segmentation of the entirety of all of the cancerous lesions. However, this particular task of segmenting the entirety of all cancerous lesions might be very tedious if it has to be done manually, in particular if the disease is scattered or metastasized and thus consists of numerous foci; this is one of the reasons why only few clinical studies on those quantifications are available. In this work, we investigate a way to aid the easy determination of the entirety of cancerous lesions in a PET image of a human. The approach is designed to detect all hot spots within a PET image and rank their probability of being a cancerous lesion. The basis of this component is a modified watershed algorithm; the ranking is performed on a combination of several, primarily morphological measures derived from the individual basins. This component is embedded in a software suite to assess response to a therapy based on PET images. As a preprocessing step, potential lesions are segmented and indicated to the user, who can select the foci which constitute the tumor and discard the false positives. This procedure substantially simplifies the segmentation of the entire tumor burden of a patient. This approach of semi-automatic hot spot detection is evaluated on 17 clinical datasets.

  16. Gastric and small intestine gastrointestinal stromal tumors: Do outcomes differ?

    PubMed

    Giuliano, Katherine; Nagarajan, Neeraja; Canner, Joseph; Najafian, Alireza; Wolfgang, Christopher; Schneider, Eric; Meyer, Christian; Lennon, Anne Marie; Johnston, Fabian M; Ahuja, Nita

    2017-03-01

    Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Previous literature has suggested that small intestine GISTs are more aggressive than gastric GISTs. Our primary objective was to compare the outcomes of gastric and small intestine GISTs in the decade after approval of imatinib for treatment. The SEER database was queried for cases of gastric and small intestine GIST between the years 2002 and 2012, using the ICD-O-3 histology code 8936. Survival analysis was performed using generalized gamma models for time to cause-specific mortality (CSM). CSM was 14.0% for the 3,759 gastric GIST patients and 14.3% for the 1,848 small intestine GIST patients. Five-year survival was 82.2% and 83.3% for gastric and small intestine patients, respectively. The number of diagnosed cases of GIST increased over the course of this study, especially for tumors <5 cm in size and in patients over age 50 years. In this large nation-wide study, we found that patients with gastric and small intestine GISTs had similar outcomes, in contrast to previous reports. The diagnosis of GIST has significantly increased in the last decade, which may reflect the increased recognition of this entity and frequent use of imaging. J. Surg. Oncol. 2017;115:351-357. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  17. Lactonic Sophorolipids Increase Tumor Burden in Apcmin+/- Mice

    PubMed Central

    Callaghan, Breedge; Lydon, Helen; Roelants, Sophie L. K. W.; Van Bogaert, Inge N. A.; Marchant, Roger; Banat, Ibrahim M.; Mitchell, Christopher A.

    2016-01-01

    Sophorolipids (SL) are amphiphilic biosurfactant molecules consisting of a disaccharide sophorose with one fatty acid at the C1 position and optional acetylation at the C6’and C6” positions. They exist in a closed ring lactonic (LSL) or open acidic (ASL) structure Sophorolipids are produced in crude mixtures in economically viable amounts by the yeast Starmerella bombicola and used in a variety of consumer products. Varying levels of anti- proliferative and anti-cancer activity of crude sophorolipid mixtures are described in a number of tumor cell lines in vitro. However, significant inter-study variation exists in the composition of sophorolipid species as well as other biologically active compounds in these mixtures, which makes interpretation of in vitro and in vivo studies difficult. We produced a 96% pure C18:1 lactonic sophorolipid that dose-dependently reduces the viability of colorectal cancer, as well as normal human colonic and lung cell lines in vitro. Oral administration of vehicle-only; or lactonic sophorolipids (50 mg/kg for 70 days), to Apcmin+/- mice resulted in an increase in the number (55.5 ± 3.3 vs 70.50 ± 7.8: p < 0.05) and size (modal size 2mm vs 4mm) of intestinal polyps. Lactonic administration resulted in a systematic effect via reduced hematocrit (49.5 ± 1.0 vs 28.2 ± 2.0 vs: p<0.03) and splenomegaly (0.56 ± 0.03g vs 0.71 ± 0.04g; p<0.01) confirming exacerbation of disease progression in this model. PMID:27271048

  18. [Gastro-intestinal neuroectodermal tumor (GNET): A case report of a small intestine tumor with hepatic metastases].

    PubMed

    Kervarrec, Thibault; Lecointre, Claire; Kerdraon, Rémy; Bens, Guido; Piquard, Arnaud; Michenet, Patrick

    2015-12-01

    The gastro-intestinal neuroectodermal tumor (GNET) is a rare sarcoma of the digestive tract, which was recently recognised. The knowledge of the morphological, immunohistochemical and molecular diagnostic criteria is necessary to not mistake it for the metastasis of a melanoma or for another sarcoma of the digestive tract as the gastro-intestinal clear cells sarcoma or the malignant peripheral nervous system tumor (MPNST). We report the case of a 41-year-old patient with a GNET of the small intestine with hepatic metastasis. The histological examination showed a diffuse proliferation of epithelioid cells, which only express PS100. The presence EWSR1-ATF1 gene fusions with any melanocytic differentiation leads to the diagnosis of GNET.

  19. [Wilms' tumor, multiple intestinal parasitosis and typhoid fever].

    PubMed

    Franco Vega, G; Llausás Vargas, A; Kumate, J

    1977-01-01

    The case was that of a 21-month-old infant who presented a great inoperable Wilm's tumor that was treated with vincristine to the point of practically disappearing. Severe typhoid fever that was complicated by multiple intestinal parasitoses (ascariasis, trichuriasis, giardiasis and strongyloidiasis) appeared. Possibly, tumoral necrosis, salmonellosis and the parasitoses formed a sac that opened to the hepatic angle of the colon. Finally, multiple liver metastases were discovered and confirmed pathologically. The patient died 36 hours after surgical reexamination and liver biopsies, from causes not clearly explained. Comments are made on the diagnostic problems originated by rareness of the association of typhoid fever resistant to chloramphenicol, intestinal parasitoses and a great Wilms' tumor and the possible influence of chemotherapy and radiotherapy in the evolution of the case.

  20. Linking tumor-associated macrophages, inflammation, and intestinal tumorigenesis: role of MCP-1

    PubMed Central

    McClellan, Jamie L.; Davis, J. Mark; Steiner, Jennifer L.; Enos, Reilly T.; Jung, Seung H.; Carson, James A.; Pena, Maria M.; Carnevale, Kevin A.; Berger, Franklin G.

    2012-01-01

    Tumor-associated macrophages are associated with poor prognosis in certain cancers. Monocyte chemoattractant protein 1 (MCP-1) is thought to be the most important chemokine for recruitment of macrophages to the tumor microenvironment. However, its role on tumorigenesis in a genetic mouse model of colon cancer has not been explored. We examined the role of MCP-1 on tumor-associated macrophages, inflammation, and intestinal tumorigenesis. Male ApcMin/+, ApcMin/+/MCP-1−/− or wild-type mice were euthanized at 18 wk of age and intestines were analyzed for polyp burden, apoptosis, proliferation, β-catenin, macrophage number and phenotype, markers for cytotoxic T lymphocytes and regulatory T cells, and inflammatory mediators. MCP-1 deficiency decreased overall polyp number by 20% and specifically large polyp number by 45% (P < 0.05). This was consistent with an increase in apoptotic cells (P < 0.05), but there was no change detected in proliferation or β-catenin. MCP-1 deficiency decreased F4/80-positive cells in both the polyp tissue and surrounding intestinal tissue (P < 0.05) as well as expression of markers associated with M1 (IL-12 and IL-23) and M2 macrophages (IL-13, CD206, TGF-β, and CCL17) (P < 0.05). MCP-1 knockout was also associated with increased cytotoxic T lymphocytes and decreased regulatory T cells (P < 0.05). In addition, MCP-1−/− offset the increased mRNA expression of IL-1β and IL-6 in intestinal tissue and IL-1β and TNF-α in polyp tissue (P < 0.05), and prevented the decrease in SOCS1 expression (P < 0.05). We demonstrate that MCP-1 is an important mediator of tumor growth and immune regulation that may serve as an important biomarker and/or therapeutic target in colon cancer. PMID:23019193

  1. 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.

  2. Individualized Mutation Detection in Circulating Tumor DNA for Monitoring Colorectal Tumor Burden Using a Cancer-Associated Gene Sequencing Panel

    PubMed Central

    Sato, Kei A.; Hachiya, Tsuyoshi; Iwaya, Takeshi; Kume, Kohei; Matsuo, Teppei; Kawasaki, Keisuke; Abiko, Yukito; Akasaka, Risaburo; Matsumoto, Takayuki; Otsuka, Koki; Nishizuka, Satoshi S.

    2016-01-01

    Background Circulating tumor DNA (ctDNA) carries information on tumor burden. However, the mutation spectrum is different among tumors. This study was designed to examine the utility of ctDNA for monitoring tumor burden based on an individual mutation profile. Methodology DNA was extracted from a total of 176 samples, including pre- and post-operational plasma, primary tumors, and peripheral blood mononuclear cells (PBMC), from 44 individuals with colorectal tumor who underwent curative resection of colorectal tumors, as well as nine healthy individuals. Using a panel of 50 cancer-associated genes, tumor-unique mutations were identified by comparing the single nucleotide variants (SNVs) from tumors and PBMCs with an Ion PGM sequencer. A group of the tumor-unique mutations from individual tumors were designated as individual marker mutations (MMs) to trace tumor burden by ctDNA using droplet digital PCR (ddPCR). From these experiments, three major objectives were assessed: (a) Tumor-unique mutations; (b) mutation spectrum of a tumor; and (c) changes in allele frequency of the MMs in ctDNA after curative resection of the tumor. Results A total of 128 gene point mutations were identified in 27 colorectal tumors. Twenty-six genes were mutated in at least 1 sample, while 14 genes were found to be mutated in only 1 sample, respectively. An average of 2.7 genes were mutated per tumor. Subsequently, 24 MMs were selected from SNVs for tumor burden monitoring. Among the MMs found by ddPCR with > 0.1% variant allele frequency in plasma DNA, 100% (8 out of 8) exhibited a decrease in post-operation ctDNA, whereas none of the 16 MMs found by ddPCR with < 0.1% variant allele frequency in plasma DNA showed a decrease. Conclusions This panel of 50 cancer-associated genes appeared to be sufficient to identify individual, tumor-unique, mutated ctDNA markers in cancer patients. The MMs showed the clinical utility in monitoring curatively-treated colorectal tumor burden if the allele

  3. Tailoring Chemotherapy in Early-Stage Breast Cancer: Based on Tumor Biology or Tumor Burden?

    PubMed

    Ribnikar, Domen; Cardoso, Fatima

    2016-01-01

    The question of whether to offer adjuvant chemotherapy to patients with early-stage breast cancer has always been challenging to answer. It is well known that a substantial proportion of patients with early-stage breast cancer are over treated, especially when staging and hormonal and HER2 receptors are solely taken into consideration. The advances in our knowledge of breast cancer biology and its clinical implications were the basis for the discovery of additional reliable prognostic markers to aid decision making for adjuvant treatment. Gene expression profiling is a molecular tool that more precisely defines the intrinsic characteristics of each individual tumor. The application of this technology has led to the development of gene signatures/profiles with relevant prognostic-and some predictive-value that have become important tools in defining which patients with early-stage breast cancer can be safely spared from chemotherapy. However, the exact clinical utility of these tools will only be determined after the results of two large prospective randomized trials, MINDACT and TailorX, evaluating their role become available. Notwithstanding the existence of these genomic tools, tumor burden (defined as tumor size and nodal status) still has independent prognostic value and must be incorporated in decision making. In addition, these gene signatures have limited predictive value, and new biomarkers and new targets are needed. Therefore close collaboration between clinicians and scientists is crucial. Lastly, issues of cost-effectiveness, reimbursement, and availability are crucial and widely variable around the globe.

  4. Dietary effects on liver tumor burden in mice treated with the hepatocellular carcinogen diethylnitrosamine

    PubMed Central

    Healy, Marin E.; Chow, Jenny D.Y.; Byrne, Frances L.; Breen, David S.; Leitinger, Norbert; Li, Chien; Lackner, Carolin; Caldwell, Stephen H.; Hoehn, Kyle L.

    2014-01-01

    Background & Aims Mice exposed to the hepatocellular carcinogen diethylnitrosamine at 2 weeks of age have a high risk of developing primary liver tumors later in life. Previous studies have demonstrated that diethylnitrosamine-treated mice have increased tumor burden when fed an obesigenic “Western” diet rich in lard fat and sugar. However, the role of dietary fats versus sugars in the promotion of liver cancer is poorly understood. The aim of this study was to determine how altering dietary fats versus sugars affects tumor burden in the diethylnitrosamine model. Methods C57BL/6N mice were treated with diethylnitrosamine at 2 weeks of age and, from 6 to 32 weeks of age, fed one of five diets that differed in fat and sugar content including normal chow, ketogenic, and Western diets. Results Mice fed sugar-rich diets had the greatest tumor burden irrespective of dietary fat content. In contrast, mice fed a high-fat low-sugar diet had the least tumor burden despite obesity and glucose intolerance. When evaluated as independent variables, tumor burden was positively correlated with hepatic fat accumulation, postprandial insulin, and liver IL-6, and inversely correlated with serum adiponectin. In contrast, tumor burden did not correlate with adiposity, fasting insulin, or glucose intolerance. Furthermore, mice fed high sugar diets had lower liver expression of p21 and cleaved caspase-3 compared to mice fed low sugar diets. Conclusions These data indicate that dietary sugar intake contributes to liver tumor burden independent of excess adiposity or insulin resistance in mice treated with diethylnitrosamine. PMID:25450719

  5. Dietary effects on liver tumor burden in mice treated with the hepatocellular carcinogen diethylnitrosamine.

    PubMed

    Healy, Marin E; Chow, Jenny D Y; Byrne, Frances L; Breen, David S; Leitinger, Norbert; Li, Chien; Lackner, Carolin; Caldwell, Stephen H; Hoehn, Kyle L

    2015-03-01

    Mice exposed to the hepatocellular carcinogen diethylnitrosamine at 2 weeks of age have a high risk of developing primary liver tumors later in life. Previous studies have demonstrated that diethylnitrosamine-treated mice have increased tumor burden when fed an obesigenic "Western" diet rich in lard fat and sugar. However, the role of dietary fats vs. sugars in the promotion of liver cancer is poorly understood. The aim of this study was to determine how altering dietary fats vs. sugars affects tumor burden in the diethylnitrosamine model. C57BL/6N mice were treated with diethylnitrosamine at 2 weeks of age and, from 6 to 32 weeks of age, fed one of five diets that differed in fat and sugar content, including normal chow, ketogenic, and Western diets. Mice fed sugar-rich diets had the greatest tumor burden irrespective of dietary fat content. In contrast, mice fed a high-fat low-sugar diet had the least tumor burden despite obesity and glucose intolerance. When evaluated as independent variables, tumor burden was positively correlated with hepatic fat accumulation, postprandial insulin, and liver IL-6, and inversely correlated with serum adiponectin. In contrast, tumor burden did not correlate with adiposity, fasting insulin, or glucose intolerance. Furthermore, mice fed high sugar diets had lower liver expression of p21 and cleaved caspase-3 compared to mice fed low sugar diets. These data indicate that dietary sugar intake contributes to liver tumor burden independent of excess adiposity or insulin resistance in mice treated with diethylnitrosamine. Copyright © 2014 European Association for the Study of the Liver. All rights reserved.

  6. Plasma S100β is not a useful biomarker for tumor burden in neurofibromatosis.

    PubMed

    Smith, Miriam J; Esparza, Sonia; Merker, Vanessa L; Muzikansky, Alona; Bredella, Miriam A; Harris, Gordon J; Kassarjian, Ara; Cai, Wenli; Walker, James A; Mautner, Victor F; Plotkin, Scott R

    2013-05-01

    Neurofibromatosis 1 (NF1), NF2, and schwannomatosis are characterized by a predisposition to develop multiple neurofibromas and schwannomas. Currently, there is no blood test to estimate tumor burden in patients with these disorders. We explored whether S100β would act as a biomarker of tumor burden in NF since S100β is a classic immunohistochemical marker of astrocytes, oligodendrocytes and Schwann cells and a small study showed S100β concentrations correlate with the volume of vestibular schwannomas. We calculated whole-body tumor burden in subjects with NF1, NF2, and schwannomatosis using whole-body MRI (WBMRI) and measured the concentration of S100β in plasma using ELISA. We used chi-square tests and Spearman rank correlations to test the relationship between S100β levels and whole-body tumor burden. 127 consecutive patients were enrolled in the study (69 NF1 patients, 28 NF2 patients, and 30 schwannomatosis patients). The median age was 40years, 43% were male, and median whole-body tumor volume was 26.9mL. There was no relationship between the presence of internal tumors and the presence of detectable S100β in blood for the overall group or for individual diagnoses (p>0.05 by chi-square for all comparisons). Similarly, there was no correlation between whole-body tumor volume and S100β concentration for the overall group or for individual diagnoses (p>0.05 by Spearman for all comparisons). Plasma S100β is not a useful biomarker for tumor burden in the neurofibromatoses. Further work is needed to identify a reliable biomarker of tumor burden in NF patients. Copyright © 2012 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

  7. CDC42 inhibition suppresses progression of incipient intestinal tumors

    PubMed Central

    Sakamori, Ryotaro; Yu, Shiyan; Zhang, Xiao; Hoffman, Andrew; Sun, Jiaxin; Das, Soumyashree; Vedula, Pavan; Li, Guangxun; Fu, Jiang; Walker, Francesca; Yang, Chung S.; Yi, Zheng; Hsu, Wei; Yu, Da-Hai; Shen, Lanlan; Rodriguez, Alexis J.; Taketo, Makoto M.; Bonder, Edward M.; Verzi, Michael P.; Gao, Nan

    2014-01-01

    Mutations in the APC or β-catenin genes are well established initiators of colorectal cancer (CRC), yet modifiers that facilitate the survival and progression of nascent tumor cells are not well defined. Using genetic and pharmacological approaches in mouse CRC and human CRC xenograft models, we show that incipient intestinal tumor cells activate CDC42, an APC-interacting small GTPase, as a crucial step in malignant progression. In the mouse, Cdc42 ablation attenuated the tumorigenicity of mutant intestinal cells carrying single APC or β-catenin mutations. Similarly, human CRC with relatively higher levels of CDC42 activity were particularly sensitive to CDC42 blockade. Mechanistic studies suggested that Cdc42 may be activated at different levels, including at the level of transcriptional activation of the stem-cell-enriched Rho family exchange factor Arhgef4. Our results suggest that early-stage mutant intestinal epithelial cells must recruit the pleiotropic functions of Cdc42 for malignant progression, suggesting its relevance as a biomarker and therapeutic target for selective CRC intervention. PMID:25113996

  8. An assessment of the intestinal lumen as a site for intervention in reducing body burdens of organochlorine compounds.

    PubMed

    Jandacek, Ronald J; Genuis, Stephen J

    2013-01-01

    Many individuals maintain a persistent body burden of organochlorine compounds (OCs) as well as other lipophilic compounds, largely as a result of airborne and dietary exposures. Ingested OCs are typically absorbed from the small intestine along with dietary lipids. Once in the body, stored OCs can mobilize from adipose tissue storage sites and, along with circulating OCs, are delivered into the small intestine via hepatic processing and biliary transport. Retained OCs are also transported into both the large and small intestinal lumen via non-biliary mechanisms involving both secretion and desquamation from enterocytes. OCs and some other toxicants can be reabsorbed from the intestine, however, they take part in enterohepatic circulation(EHC). While dietary fat facilitates the absorption of OCs from the small intestine, it has little effect on OCs within the large intestine. Non-absorbable dietary fats and fat absorption inhibitors, however, can reduce the re-absorption of OCs and other lipophiles involved in EHC and may enhance the secretion of these compounds into the large intestine--thereby hastening their elimination. Clinical studies are currently underway to determine the efficacy of using non-absorbable fats and inhibitors of fat absorption in facilitating the elimination of persistent body burdens of OCs and other lipophilic human contaminants.

  9. Extrinsic intestinal denervation modulates tumor development in the small intestine of Apc(Min/+) mice.

    PubMed

    Liu, Verena; Dietrich, Alexandra; Kasparek, Michael S; Benhaqi, Petra; Schneider, Marlon R; Schemann, Michael; Seeliger, Hendrik; Kreis, Martin E

    2015-04-29

    Innervation interacts with enteric immune responses. Chronic intestinal inflammation is associated with increased risk of colorectal cancer. We aimed to study potential extrinsic neuronal modulation of intestinal tumor development in a mouse model. Experiments were performed with male Apc(Min/+) or wild type mice (4 weeks old, body weight approximately 20 g). Subgroups with subdiaphragmatic vagotomy (apcV/wtV), sympathetic denervation of the small intestine (apcS/wtS) or sham operated controls (apcC/wtC) were investigated (n = 6-14 per group). Three months after surgical manipulation, 10 cm of terminal ileum were excised, fixed for 48 h in 4% paraformaldehyde and all tumors were counted and their area determined in mm(2) (mean ± standard error of the mean (SEM)). Whole mounts of the muscularis of terminal ileum and duodenum (internal positive control) were also stained for tyrosine hydroxylase to confirm successful sympathetic denervation. Tumor count in Apc(Min/+) mice was 62 ± 8 (apcC), 46 ± 11 (apcV) and 54 ± 8 (apcS) which was increased compared to wildtype controls with 4 ± 0.5 (wtC), 5 ± 0.5 (wtV) and 5 ± 0.6 (wtS; all p < 0.05). For Apc(Min/+) groups, vagotomized animals showed a trend towards decreased tumor counts compared to sham operated Apc(Min/+) controls while sympathetic denervation was similar to sham Apc(Min/+). Area covered by tumors in Apc(Min/+) mice was 55 ± 10 (apcC), 31 ± 8 (apcV) and 42 ± 8 (apcS) mm(2), which was generally increased compared to wildtype controls with 7 ± 0.6 (wtC), 7 ± 0.4 (wtV) and 7 ± 0.6 (wtS) mm(2) (all p < 0.05). In Apc(Min/+) groups, tumor area was decreased in vagotomized animals compared to sham operated controls (p < 0.05) while sympathetically denervated mice showed a minor trend to decreased tumor area compared to controls. Extrinsic innervation of the small bowel is likely to modulate tumor development in Apc(Min/+) mice

  10. Quantitative Assessment of Whole-Body Tumor Burden in Adult Patients with Neurofibromatosis

    PubMed Central

    Plotkin, Scott R.; Bredella, Miriam A.; Cai, Wenli; Kassarjian, Ara; Harris, Gordon J.; Esparza, Sonia; Merker, Vanessa L.; Munn, Lance L.; Muzikansky, Alona; Askenazi, Manor; Nguyen, Rosa; Wenzel, Ralph; Mautner, Victor F.

    2012-01-01

    Purpose Patients with neurofibromatosis 1 (NF1), NF2, and schwannomatosis are at risk for multiple nerve sheath tumors and premature mortality. Traditional magnetic resonance imaging (MRI) has limited ability to assess disease burden accurately. The aim of this study was to establish an international cohort of patients with quantified whole-body internal tumor burden and to correlate tumor burden with clinical features of disease. Methods We determined the number, volume, and distribution of internal nerve sheath tumors in patients using whole-body MRI (WBMRI) and three-dimensional computerized volumetry. We quantified the distribution of tumor volume across body regions and used unsupervised cluster analysis to group patients based on tumor distribution. We correlated the presence and volume of internal tumors with disease-related and demographic factors. Results WBMRI identified 1286 tumors in 145/247 patients (59%). Schwannomatosis patients had the highest prevalence of tumors (P = 0.03), but NF1 patients had the highest median tumor volume (P = 0.02). Tumor volume was unevenly distributed across body regions with overrepresentation of the head/neck and pelvis. Risk factors for internal nerve sheath tumors included decreasing numbers of café-au-lait macules in NF1 patients (P = 0.003) and history of skeletal abnormalities in NF2 patients (P = 0.09). Risk factors for higher tumor volume included female gender (P = 0.05) and increasing subcutaneous neurofibromas (P = 0.03) in NF1 patients, absence of cutaneous schwannomas in NF2 patients (P = 0.06), and increasing age in schwannomatosis patients (p = 0.10). Conclusion WBMRI provides a comprehensive phenotype of neurofibromatosis patients, identifies distinct anatomic subgroups, and provides the basis for investigating molecular biomarkers that correlate with unique disease manifestations. PMID:22558206

  11. Quantitative assessment of whole-body tumor burden in adult patients with neurofibromatosis.

    PubMed

    Plotkin, Scott R; Bredella, Miriam A; Cai, Wenli; Kassarjian, Ara; Harris, Gordon J; Esparza, Sonia; Merker, Vanessa L; Munn, Lance L; Muzikansky, Alona; Askenazi, Manor; Nguyen, Rosa; Wenzel, Ralph; Mautner, Victor F

    2012-01-01

    Patients with neurofibromatosis 1 (NF1), NF2, and schwannomatosis are at risk for multiple nerve sheath tumors and premature mortality. Traditional magnetic resonance imaging (MRI) has limited ability to assess disease burden accurately. The aim of this study was to establish an international cohort of patients with quantified whole-body internal tumor burden and to correlate tumor burden with clinical features of disease. We determined the number, volume, and distribution of internal nerve sheath tumors in patients using whole-body MRI (WBMRI) and three-dimensional computerized volumetry. We quantified the distribution of tumor volume across body regions and used unsupervised cluster analysis to group patients based on tumor distribution. We correlated the presence and volume of internal tumors with disease-related and demographic factors. WBMRI identified 1286 tumors in 145/247 patients (59%). Schwannomatosis patients had the highest prevalence of tumors (P = 0.03), but NF1 patients had the highest median tumor volume (P = 0.02). Tumor volume was unevenly distributed across body regions with overrepresentation of the head/neck and pelvis. Risk factors for internal nerve sheath tumors included decreasing numbers of café-au-lait macules in NF1 patients (P = 0.003) and history of skeletal abnormalities in NF2 patients (P = 0.09). Risk factors for higher tumor volume included female gender (P = 0.05) and increasing subcutaneous neurofibromas (P = 0.03) in NF1 patients, absence of cutaneous schwannomas in NF2 patients (P = 0.06), and increasing age in schwannomatosis patients (p = 0.10). WBMRI provides a comprehensive phenotype of neurofibromatosis patients, identifies distinct anatomic subgroups, and provides the basis for investigating molecular biomarkers that correlate with unique disease manifestations.

  12. An Assessment of the Intestinal Lumen as a Site for Intervention in Reducing Body Burdens of Organochlorine Compounds

    PubMed Central

    Jandacek, Ronald J.; Genuis, Stephen J.

    2013-01-01

    Many individuals maintain a persistent body burden of organochlorine compounds (OCs) as well as other lipophilic compounds, largely as a result of airborne and dietary exposures. Ingested OCs are typically absorbed from the small intestine along with dietary lipids. Once in the body, stored OCs can mobilize from adipose tissue storage sites and, along with circulating OCs, are delivered into the small intestine via hepatic processing and biliary transport. Retained OCs are also transported into both the large and small intestinal lumen via non-biliary mechanisms involving both secretion and desquamation from enterocytes. OCs and some other toxicants can be reabsorbed from the intestine, however, they take part in enterohepatic circulation(EHC). While dietary fat facilitates the absorption of OCs from the small intestine, it has little effect on OCs within the large intestine. Non-absorbable dietary fats and fat absorption inhibitors, however, can reduce the re-absorption of OCs and other lipophiles involved in EHC and may enhance the secretion of these compounds into the large intestine—thereby hastening their elimination. Clinical studies are currently underway to determine the efficacy of using non-absorbable fats and inhibitors of fat absorption in facilitating the elimination of persistent body burdens of OCs and other lipophilic human contaminants. PMID:23476122

  13. Taurine drinking attenuates the burden of intestinal adult worms and muscle larvae in mice with Trichinella spiralis infection.

    PubMed

    Yu, Yan-Rong; Liu, Xi-Cheng; Zhang, Jin-Sheng; Ji, Chao-Yue; Qi, Yong-Fen

    2013-10-01

    The parasitic nematode Trichinella spiralis can cause trichinellosis, which leads to pathological processes in the intestine and muscle. The intestinal invasion determines the development, subsequent course, and consequences of the disease. Gastrointestinal nematode infection, including with T. spiralis, is accompanied by a rapid and reversible expansion of mucosal mast cell and goblet cell in the intestinal epithelium, which play important roles in the host immune response to parasite and worm expulsion from the intestine. Taurine and its derivatives have anti-infection and anti-inflammatory properties. We investigated whether taurine supplementation in mice could influence the development and pathological processes of infection with T. spiralis. Supplementing 1% taurine in drinking water in mice infected with T. spiralis could alleviate the burden of intestinal adult worms on days 7 and 10 postinfection (all p < 0.01) and the formation of infective muscle larvae in striated muscle during T. spiralis infection (p < 0.01). As compared with T. spiralis infection alone, taurine treatment increased the number of goblet cells on days 7, 10, and 15 (p < 0.01 and p < 0.05) and alleviated intestinal mucosal mast cell hyperplasia on days 10 and 15 (all p < 0.01). So taurine supplementation in drinking water increased infection-induced intestinal goblet cell hyperplasia and ameliorated mucosal mastocytosis. Thus, taurine can ameliorate the pathological processes of trichinellosis and may be of great value for the treatment and prevention of infection with T. spiralis and other gastrointestinal nematodes.

  14. Pigmentation in the sentinel node correlates with increased sentinel node tumor burden in melanoma patients.

    PubMed

    van Lanschot, Cornelia G F; Koljenović, Senada; Grunhagen, Dirk-Jan; Verhoef, Cornelis; van Akkooi, Alexander C J

    2014-06-01

    The prognosis of sentinel node (SN)-positive melanoma patients is predicted by a number of characteristics such as size and site of the metastases in the SN. The pathway and prognosis of strong pigmentation of melanoma metastases in the SN is unclear. The aim of this study is to evaluate the role of pigmentation and growth pattern of metastases in the SN with respect to survival. A total of 389 patients underwent an SN procedure (1997-2011). Ninety-five patients had a positive SN and material from 75 patients was available for review. The median follow-up time was 75 months (range 6-164). Pigmentation was scored from 0 to 2 using the following scale: 0=absent, 1=slight, and 2=strong. Growth pattern was scored as either eccentric (1) or infiltrative (2). SN tumor burden was measured according to the Rotterdam criteria. The primary melanoma had a median Breslow thickness of 2.90 mm (0.8-12.00 mm). Ulceration was present in 34 patients (45.3%). There was a median SN tumor burden of 0.5 mm (0.05-7.00 mm). In a total of 75 patients, 59 patients (79%) had no pigmentation, 13 patients (17%) had slight pigmentation, and three patients (4%) had strong pigmentation in the SN. Because of the small numbers, the classification was modified to either absent 59 (79%) or present 16 (21%) pigmentation, respectively. The SN tumor burden was significantly higher (P=0.031) for patients with pigmentation. Patients with pigmentation had a 5-year melanoma-specific survival (MSS) of 47% and a 10-year MSS of 33%. Patients without pigmentation had a 5-year MSS of 70% and a 10-year MSS of 59% (P=0.06). There was no difference in MSS for patients with an eccentric or an infiltrative growth pattern, nor did it correlate with other prognostic factors. Multivariate analysis for MSS showed five significant factors associated with worse prognosis: male sex (P=0.036), nodular melanoma (P=0.001), truncal site (P=0.0001), SN tumor burden more than 1.0 mm (P=0.022), and positive completion lymph node

  15. Monitoring and quantitative assessment of tumor burden using in vivo bioluminescence imaging

    NASA Astrophysics Data System (ADS)

    Chen, Chia-Chi; Hwang, Jeng-Jong; Ting, Gann; Tseng, Yun-Long; Wang, Shyh-Jen; Whang-Peng, Jaqueline

    2007-02-01

    In vivo bioluminescence imaging (BLI) is a sensitive imaging modality that is rapid and accessible, and may comprise an ideal tool for evaluating tumor growth. In this study, the kinetic of tumor growth has been assessed in C26 colon carcinoma bearing BALB/c mouse model. The ability of BLI to noninvasively quantitate the growth of subcutaneous tumors transplanted with C26 cells genetically engineered to stably express firefly luciferase and herpes simplex virus type-1 thymidine kinase (C26/ tk-luc). A good correlation ( R2=0.998) of photon emission to the cell number was found in vitro. Tumor burden and tumor volume were monitored in vivo over time by quantitation of photon emission using Xenogen IVIS 50 and standard external caliper measurement, respectively. At various time intervals, tumor-bearing mice were imaged to determine the correlation of in vivo BLI to tumor volume. However, a correlation of BLI to tumor volume was observed when tumor volume was smaller than 1000 mm 3 ( R2=0.907). γ Scintigraphy combined with [ 131I]FIAU was another imaging modality used for verifying the previous results. In conclusion, this study showed that bioluminescence imaging is a powerful and quantitative tool for the direct assay to monitor tumor growth in vivo. The dual reporter genes transfected tumor-bearing animal model can be applied in the evaluation of the efficacy of new developed anti-cancer drugs.

  16. Partial abdominal evisceration and intestinal autotransplantation to resect a mesenteric carcinoid tumor

    PubMed Central

    2011-01-01

    Background Midgut carcinoids are neuroendocrine tumors that commonly metastasize to the intestinal mesentery, where they predispose to intestinal obstruction, ischemia and/or congestion. Because of their location, many mesenteric carcinoid tumors are deemed unresectable due to the risk of uncontrollable bleeding and prolonged intestinal ischemia. Case Presentation We report the case of a 60-year-old male with a mesenteric carcinoid tumor obstructing his superior mesenteric vein, resulting in intestinal varices and severe recurrent GI bleeds. While his tumor was thought to be unresectable by conventional techniques, it was successfully resected using intestinal autotransplantation to safely gain access to the tumor. This case is the first described application of this technique to carcinoid tumors. Conclusions Intestinal autotransplantation can be utilized to safely resect mesenteric carcinoid tumors from patients who were not previously thought to be surgical candidates. We review the literature concerning both carcinoid metastases to the intestinal mesentery and the use of intestinal autotransplantation to treat lesions involving the mesenteric root. PMID:21281518

  17. Plaque burden in HIV-infected patients is associated with serum intestinal microbiota-generated trimethylamine.

    PubMed

    Srinivasa, Suman; Fitch, Kathleen V; Lo, Janet; Kadar, Hanane; Knight, Rachel; Wong, Kimberly; Abbara, Suhny; Gauguier, Dominique; Capeau, Jacqueline; Boccara, Franck; Grinspoon, Steven K

    2015-02-20

    Some intestinal microbiota-generated metabolites of phosphatidylcholine are recognized to be proatherogenic. As the HIV population is vulnerable to cardiovascular disease and can develop intestinal dysbiosis associated with systemic inflammation, we investigated the novel relationship between microbiota-derived metabolites of phosphatidylcholine and coronary atherosclerosis in HIV. One hundred and fifty-five HIV-infected and 67 non-HIV-infected individuals without known history of cardiovascular disease were previously recruited to assess coronary plaque by computed tomography angiography. In the current study, we evaluate whether serum choline, trimethylamine (TMA), or trimethylamine-N-oxide (TMAO) levels are associated with plaque features. Young, asymptomatic HIV-infected patients (age 47 ± 7 years) demonstrated significantly higher prevalence of plaque (53 vs. 35%, P = 0.01) and number of total plaque segments (1.8 ± 2.5 vs. 1.2 ± 2.2, P = 0.03) when compared with well matched noninfected individuals with similar comorbidities. TMA was significantly associated with calcium score (r = 0.22, P = 0.006), number of total (r = 0.20, P = 0.02) and calcified (r = 0.18, P = 0.03) plaque segments, and calcium plaque volume (r = 0.19, P = 0.02) and mass (r = 0.22, P = 0.009) in the HIV cohort only. In multivariate modeling among HIV-infected patients, TMA remained significantly associated with calcium score (P = 0.008), number of total (P = 0.005) and calcified (P = 0.02) plaque segments, and calcium plaque volume (P = 0.01) and mass (P = 0.007), independent of Framingham risk score. In contrast, there was no association of TMAO to coronary plaque features in either cohort. A link between TMA and atherosclerosis has not previously been established. The current study suggests that TMA may be a nontraditional risk factor related to the number of plaque segments and severity of calcified

  18. Tumor Budding in Intestinal Type Gastric Adenocarcinoma is Associated with Nodal Metastasis and Recurrence.

    PubMed

    Olsen, Stephen; Linda, Jin; Fields, Ryan C; Yan, Yan; Nalbantoglu, ILKe

    2017-04-17

    Gastric adenocarcinoma (GAC) is a common cause of cancer-related death worldwide. GAC can be classified as intestinal or diffuse. Intestinal type cancers are common and reported to have a better prognosis compared to diffuse cancers. Studies have shown the presence and amount of tumor budding in intestinal carcinomas of the colon and esophagus to predict nodal metastasis and recurrence. Our aim is to determine if tumor budding in intestinal type GAC correlates with prognostic features. One hundred four patients treated with primary surgical excision between 1999-2013 were identified. Histologic type (intestinal, diffuse, or mixed), tumor grade, T-stage, and lymph node status were evaluated. Tumor bud scores were assigned to all intestinal type cancers using methods previously described for colorectal adenocarcinoma. Scores of <1 were designated as low and ≥1 as high. Tumor characteristics were as follows: 52 intestinal (50%), 36 diffuse (35%) and 16 mixed (15%). Of the 52 cases with intestinal histology, 4 were well (8%), 28 were moderately (54%), and 20 were poorly differentiated (38%). Thirty-three (63%) of the intestinal tumors had high tumor bud scores. Cases with high scores were associated with higher T-stage, N-stage, and grade (P<.001, P<.001, and P=.002). These also had a higher likelihood of recurrence (P=.007). In our cohort, high tumor bud scores in intestinal type GAC have higher T-stage, N-stage, grade, and likelihood of recurrence. Assessment of tumor budding may guide clinical management in a subset of patients. Copyright © 2017. Published by Elsevier Inc.

  19. Obscure Gastrointestinal Bleeding Due to a Small Intestinal Gastrointestinal Stromal Tumor in a Young Adult

    PubMed Central

    Yamamoto, Mami; Yamamoto, Kentaroh; Taketomi, Hirotaka; Yamamoto, Fumio; Yamamoto, Hiroshi

    2016-01-01

    The source of most cases of gastrointestinal bleeding is the upper gastrointestinal tract. Since bleeding from the small intestine is very rare and difficult to diagnose, time is required to identify the source. Among small intestine bleeds, vascular abnormalities account for 70–80%, followed by small intestine tumors that account for 5–10%. The reported peak age of the onset of small intestinal tumors is about 50 years. Furthermore, rare small bowel tumors account for only 1–2% of all gastrointestinal tumors. We describe a 29-year-old man who presented with obscure anemia due to gastrointestinal bleeding and underwent laparotomy. Surgical findings revealed a well-circumscribed lesion measuring 45 × 40 mm in the jejunum that initially appeared similar to diverticulosis with an abscess. However, the postoperative pathological diagnosis was a gastrointestinal stromal tumor with extramural growth. PMID:27920659

  20. Differential effects of peptidoglycan on colorectal tumors and intestinal tissue post-pelvic radiotherapy

    PubMed Central

    Xie, Fang; Wu, Hongya; Gu, Yongping; Chen, Qiu; Zhang, Xueguang

    2016-01-01

    Immediate medical intervention is required after pelvic tumor radiotherapy to protect the radiosensitive intestine and also to mitigate tumor growth. Toll-like receptors (TLRs) have been shown to promote tissue repair processes. Here, we analyzed the effect observed upon combining the TLR2 agonist, peptidoglycan (PGN), with radiation therapy on tumors as well as intestinal tissue, both in vitro and in vivo. In contrast to radiotherapy alone, PGN when combined with ionizing radiation (IR) elicited enhanced antitumor effects and also reduced the IR-induced intestinal damage. Mechanistic studies showed that PGN first induced an IL13 response in the irradiated intestine, but was decreased in tumor cell models screened by Th1/Th2 FlowCytomix assay and validated by the application of IL13 and anti-IL13 neutralizing antibodies. Next, PGN stimulated Akt3, but not Akt1/2, as was verified by AKT1/2/3 plasmid transfection assay and in AKT1/2/3 knockout mice in vivo. Akt3 expression was inhibited in 20 μg/mL PGN-treated tumor cells and in 1.5 mg/kg PGN-treated mouse tumor models. However, Akt3 was raised via IL13 in the irradiated intestine and human intestinal cell line after the same treatment. Finally, PGN activated mTOR via IL13/AKT3 in the intestine and restored intestinal structure and function. As an adjuvant to radiotherapy, PGN inhibited tumorigenesis by suppression of mTOR activity. To summarize, the IL13/AKT3/mTOR pathway was lessened in PGN-treated irradiated tumors but was raised in the normal intestine tissue. This distinct effect of PGN on normal and tumor tissues during pelvic radiotherapy suggests that PGN may be a promising adjuvant therapy to radiation. PMID:27708223

  1. Osteoprotegerin inhibits osteolysis and decreases skeletal tumor burden in syngeneic and nude mouse models of experimental bone metastasis.

    PubMed

    Morony, S; Capparelli, C; Sarosi, I; Lacey, D L; Dunstan, C R; Kostenuik, P J

    2001-06-01

    Certain malignancies, including breast cancer, frequently metastasize to bone, where the tumor cells induce osteoclasts to locally destroy bone. Osteoprotegerin (OPG), a member of the tumor necrosis factor receptor family, is a negative regulator of osteoclast differentiation, activation, and survival. We tested the ability of recombinant OPG to inhibit tumor-induced osteoclastogenesis, osteolysis, and skeletal tumor burden in two animal models. In a syngeneic model, mouse colon adenocarcinoma (Colon-26) cells were injected into the left ventricle of mice. Treatment with OPG dose-dependently decreased the number and area of radiographically evident lytic bone lesions, which, at the highest dose, were undetectable. Histologically, OPG also decreased skeletal tumor burden and tumor-associated osteoclasts. In a nude mouse model, OPG treatment completely prevented radiographic osteolytic lesions caused by human MDA-MB-231 breast cancer cells. Histologically, OPG decreased skeletal tumor burden by 75% and completely eradicated MDA tumor-associated osteoclasts. In both models, OPG had no effect on metastatic tumor burden in a panel of soft tissue organs. These data indicate that OPG may be an effective therapy for preventing osteolysis and decreasing skeletal tumor burden in patients with bone metastasis.

  2. Metabolic Tumor Burden Predicts for Disease Progression and Death in Lung Cancer

    SciTech Connect

    Lee, Percy; Weerasuriya, Dilani K.; Lavori, Philip W.; Quon, Andrew; Hara, Wendy; Maxim, Peter G.; Le, Quynh-Thu; Wakelee, Heather A.; Donington, Jessica S.; Graves, Edward E.; Loo, Billy W.

    2007-10-01

    Purpose: In lung cancer, stage is an important prognostic factor for disease progression and survival. However, stage may be simply a surrogate for underlying tumor burden. Our purpose was to assess the prognostic value of tumor burden measured by {sup 18}F-fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging. Patients and Methods: We identified 19 patients with lung cancer who had staging PET-CT scans before any therapy, and adequate follow-up (complete to time of progression for 18, and death for 15 of 19). Metabolically active tumor regions were segmented on pretreatment PET scans semi-automatically using custom software. We determined the relationship between times to progression (TTP) and death (OS) and two PET parameters: total metabolic tumor volume (MTV), and standardized uptake value (SUV). Results: The estimated median TTP and OS for the cohort were 9.3 months and 14.8 months. On multivariate Cox proportional hazards regression analysis, an increase in MTV of 25 ml (difference between the 75th and 25th percentiles) was associated with increased hazard of progression and of death (5.4-fold and 7.6-fold), statistically significant (p = 0.0014 and p = 0.001) after controlling for stage, treatment intent (definitive or palliative), age, Karnofsky performance status, and weight loss. We did not find a significant relationship between SUV and TTP or OS. Conclusions: In this study, high tumor burden assessed by PET MTV is an independent poor prognostic feature in lung cancer, promising for stratifying patients in randomized trials and ultimately for selecting risk-adapted therapies. These results will need to be validated in larger cohorts with longer follow-up, and evaluated prospectively.

  3. Social isolation dysregulates endocrine and behavioral stress while increasing malignant burden of spontaneous mammary tumors.

    PubMed

    Hermes, Gretchen L; Delgado, Bertha; Tretiakova, Maria; Cavigelli, Sonia A; Krausz, Thomas; Conzen, Suzanne D; McClintock, Martha K

    2009-12-29

    In a life span study, we examined how the social environment regulates naturally occurring tumor development and malignancy in genetically prone Sprague-Dawley rats. We randomly assigned this gregarious species to live either alone or in groups of five female rats. Mammary tumor burden among social isolates increased to 84 times that of age-matched controls, as did malignancy, specifically a 3.3 relative risk for ductal carcinoma in situ and invasive ductal carcinoma, the most common early breast cancers in women. Importantly, isolation did not extend ovarian function in late middle age; in fact, isolated animals were exposed to lower levels of estrogen and progesterone in the middle-age period of mammary tumor growth, with unchanged tumor estrogen and progesterone receptor status. Isolates, however, did develop significant dysregulation of corticosterone responses to everyday stressors manifest in young adulthood, months before tumor development, and persisting into old age. Among isolates, corticosterone response to an acute stressor was enhanced and recovery was markedly delayed, each associated with increased mammary tumor progression. In addition to being stressed and tumor prone, an array of behavioral measures demonstrated that socially isolated females possessed an anxious, fearful, and vigilant phenotype. Our model provides a framework for studying the interaction of social neglect with genetic risk to identify mechanisms whereby psychosocial stressors increase growth and malignancy of breast cancer.

  4. Dclk1 facilitates intestinal tumor growth via enhancing pluripotency and epithelial mesenchymal transition

    PubMed Central

    Chandrakesan, Parthasarathy; Weygant, Nathaniel; May, Randal; Qu, Dongfeng; Chinthalapally, Harisha R.; Sureban, Sripathi M.; Ali, Naushad; Lightfoot, Stan A.; Umar, Shahid; Houchen, Courtney W.

    2014-01-01

    Doublecortin-like kinase 1 (Dclk1) is overexpressed in many cancers including colorectal cancer (CRC) and it specifically marks intestinal tumor stem cells. However, the role of Dclk1 in intestinal tumorigenesis in Apc mutant conditions is still poorly understood. We demonstrate that Dclk1 expression and Dclk1+ cells are significantly increased in the intestinal epithelium of elderly ApcMin/+ mice compared to young ApcMin/+ mice and wild type mice. Intestinal epithelial cells of ApcMin/+ mice demonstrate increased pluripotency, self-renewing ability, and EMT. Furthermore, miRNAs are dysregulated, expression of onco-miRNAs are significantly increased with decreased tumor suppressor miRNAs. In support of these findings, knockdown of Dclk1 in elderly ApcMin/+ mice attenuates intestinal adenomas and adenocarcinoma by decreasing pluripotency, EMT and onco-miRNAs indicating that Dclk1 overexpression facilitates intestinal tumorigenesis. Knocking down Dclk1 weakens Dclk1-dependent intestinal processes for tumorigenesis. This study demonstrates that Dclk1 is critically involved in facilitating intestinal tumorigenesis by enhancing pluripotency and EMT factors in Apc mutant intestinal tumors and it also provides a potential therapeutic target for the treatment of colorectal cancer. PMID:25211188

  5. A dual-reporter fluorescent imaging approach can be used to estimate sentinel lymph node tumor burden

    NASA Astrophysics Data System (ADS)

    Tichauer, Kenneth M.; Samkoe, Kimberley S.; Gunn, Jason R.; Govindan, Ramesh; Viswanathan, Aravind; Hoopes, P. Jack; Hasan, Tayyaba; Kaufman, Peter A.; Pogue, Brian W.

    2013-03-01

    The presence of metastatic tumor cells in tumor-draining lymph nodes is an important indicator for cancer staging and therapy. Current clinical approaches of assessing lymph node tumor burden require invasive surgery that can be associated with nerve damage and other complications. In this study, a dual-reporter fluorescence molecular imaging approach, previously validated for quantifying targeted reporter binding in various human tumor xenographs, was assessed as a means of quantifying tumor burden in metastatic disease in mice. The utility of the dual-reporter imaging approach to measure tumor burden in sentinel lymph nodes was investigated in a bioluminescent human breast cancer xenograph model in 18 female nude mice. Once the presence of tumor in the lymph node was confirmed by bioluminescent imaging, fluorescently labeled anti-EGFR antibody and an untargeted antibody (labeled with a different fluorophore) were injected intradermally, proximal to the lymph node, and the uptake of the two reporters was imaged simultaneously with a with a flat-panel fluorescent scanner. Preliminary results demonstrated a statistically significant correlation between the dual-reporter measured tumor burden and the bioluminescent measure of tumor burden.

  6. Checkpoint inhibitor is active against large cell neuroendocrine carcinoma with high tumor mutation burden.

    PubMed

    Wang, Victoria E; Urisman, Anatoly; Albacker, Lee; Ali, Siraj; Miller, Vincent; Aggarwal, Rahul; Jablons, David

    2017-09-19

    Large cell neuroendocrine tumor (LCNEC) of the lung is a rare and aggressive tumor similar to small cell lung cancer (SCLC). Thus, it is often treated similarly to SCLC in the front-line setting with a platinum doublet. However, treatment for patients beyond the first line remains undefined. We report the case of a patient with stage IB LCNEC (PD-L1 negative but positive for PD-L1 amplification and tumor mutation burden high) who progressed after adjuvant chemotherapy after surgery and subsequent therapy with an antibody drug conjugate targeting a neuroendocrine-specific cell surface marker but achieved a significant and durable response with pembrolizumab, a humanized IgG4 monoclonal anti-PD-1 antibody. Immunotherapy with checkpoint inhibitors is an effective treatment option for patients with metastatic LCNEC, even if PD-L1 expression is negative.

  7. Chemopreventive effects of berberine on intestinal tumor development in Apcmin/+ mice

    PubMed Central

    2013-01-01

    Background Berberine, an isoquinoline alkaloid, has shown inhibitory effects on growth of several tumor cell lines in vitro. The aim of this study was to investigate chemopreventive effects of berberine on intestinal tumor development in Apcmin/+ mice. Methods Four-week old Apcmin/+ mice were treated with 0.05% or 0.1% berberine in drinking water for twelve weeks. The number and the size of tumors were measured to evaluate intestinal tumor development. Tissue sections were prepared for PCNA and Ki-67 immunostaining to detect cell proliferation, and TUNEL assay and cleaved caspase-3 immunostaining for apoptosis. Western blot analysis and immunostaining were performed to detect the activation of Wnt and epidermal growth factor receptor (EGFR) signaling pathways and COX-2 expression in the intestinal tumor cells. The prostaglandin E2 level in the small intestine was detected using ELISA. Results Compared with untreated Apcmin/+ mice, the total numbers of tumors in the small intestine and the colon were reduced by 39.6% and 62.5% in 0.05% and 0.1% berberine-treated mice, respectively. The numbers of tumors in proximal, middle, and distal segments of the small intestine in 0.1% berberine-treated mice were significantly reduced by 53.7%, 55.3%, and 76.5% respectively. Berberine treatment also decreased the numbers of all sizes of tumors (>2 mm, 1–2 mm, and <1 mm) in the small intestine. Berberine suppressed tumor cell proliferation and increased apoptosis. Furthermore, berberine decreased the activation levels of Wnt and EGFR signaling pathways, and down-regulated COX-2 expression in intestinal tumor cells and prostaglandin E2 production in the small intestine. Conclusions Berberine inhibits intestinal tumor development, which is correlated with its activity to suppress tumor cell proliferation and increase apoptosis in Apcmin/+ mice. Down-regulation of Wnt and EGFR signaling pathways and COX-2 expression by berberine may be involved in its anti-tumorigenic effects

  8. Percutaneous biliary drainage catheter insertion in patients with extensive hepatic metastatic tumor burden

    PubMed Central

    Langman, Eun L.; Suhocki, Paul V.; Hurwitz, Herbert I.; Morse, Michael A.; Burbridge, Rebecca A.; Smith, Tony P.

    2016-01-01

    Background Patients with metastatic disease of the liver can have hyperbilirubinemia due to a number of reasons, including biliary obstruction. The purpose of this study was to analyze patient outcomes after percutaneous biliary drainage (PBD) catheter insertion in patients with extensive hepatic metastatic tumor burden. Methods Out of 746 PBD insertions, 44 patients (24 males, 20 females, mean age 57.4 years, range, 34–80 years) had metastatic malignancy with a hepatic tumor burden of greater than 20% parenchymal volume based on pre-procedure computed tomography (CT) or magnetic resonance imaging (MRI). Laboratory data before and after PBD insertion were compared. Survival and outcomes analysis performed. A subanalysis was performed on patients with CT-demonstrated catheter traversal of tumoral tissue. Results A PBD catheter was successfully inserted in all patients. The mean serum bilirubin level decreased significantly from 10.9±6.4 mg/dL immediately prior to PBD insertion to 7.1±5.6 mg/dL (P<0.001) within one month post PBD insertion. Four patients (11%) demonstrated normalization of bilirubin levels to less than 1.6 mg/dL. Of the 14 patients with a post-procedure CT or MRI, the PBD catheter traversed a tumor in 11 (79%). One of these patients required a transfusion after the procedure and one had recurrent catheter exchanges due to pericatheter leakage. The 30-day overall survival was 41% with a median survival of 19 days. The percentage decrease in serum bilirubin after PBD insertion and pre-procedure international normalized ratio (INR) were correlated with improved survival (OR =3.7, P=0.010 and OR =4.9, P=0.028 respectively). The PBD-associated major complication rate was 16%. Conclusions In patients with hyperbilirubinemia and extensive hepatic metastatic disease burden, survival was dismal after PBD catheter insertion. Serum bilirubin level normalization occurred rarely. PMID:28078111

  9. Growth Hormone Protects the Intestine Preserving Radiotherapy Efficacy on Tumors: A Short-Term Study.

    PubMed

    Caz, Victor; Elvira, Marcos; Tabernero, Maria; Grande, Antonio G; Lopez-Plaza, Bricia; de Miguel, Enrique; Largo, Carlota; Santamaria, Monica

    2015-01-01

    The efficacy of radiotherapy on tumors is hampered by its devastating adverse effects on healthy tissue, particularly that of the gastrointestinal tract. These effects cause acute symptoms that are so disruptive to patients that they can lead to interruption of the radiotherapy program. These adverse effects could limit the intensity of radiation received by the patient, resulting in a sublethal dose to the tumor, thus increasing the risk of tumor resistance. The lack of an effective treatment to protect the bowel during radiation therapy to allow higher radiation doses that are lethal to the tumor has become a barrier to implementing effective therapy. In this study, we present a comparative analysis of both intestinal and tumor tissue in regard to the efficacy and the preventive impact of a short-term growth hormone (GH) treatment in tumor-bearing rats as a protective agent during radiotherapy. Our data show that the exogenous administration of GH improved intestinal recovery after radiation treatment while preserving the therapeutic effect against the tumor. GH significantly increased proliferation in the irradiated intestine but not in the irradiated tumors, as assessed by Positron Emission Tomography and the proliferative markers Ki67, cyclin D3, and Proliferating Cell Nuclear Antigen. This proliferative effect was consistent with a significant increase in irradiated intestinal villi and crypt length. Furthermore, GH significantly decreased caspase-3 activity in the intestine, whereas GH did not produce this effect in the irradiated tumors. In conclusion, short-term GH treatment protects the bowel, inducing proliferation while reducing apoptosis in healthy intestinal tissue and preserving radiotherapy efficacy on tumors.

  10. Growth Hormone Protects the Intestine Preserving Radiotherapy Efficacy on Tumors: A Short-Term Study

    PubMed Central

    Caz, Victor; Elvira, Marcos; Tabernero, Maria; Grande, Antonio G.; Lopez-Plaza, Bricia; de Miguel, Enrique; Largo, Carlota; Santamaria, Monica

    2015-01-01

    The efficacy of radiotherapy on tumors is hampered by its devastating adverse effects on healthy tissue, particularly that of the gastrointestinal tract. These effects cause acute symptoms that are so disruptive to patients that they can lead to interruption of the radiotherapy program. These adverse effects could limit the intensity of radiation received by the patient, resulting in a sublethal dose to the tumor, thus increasing the risk of tumor resistance. The lack of an effective treatment to protect the bowel during radiation therapy to allow higher radiation doses that are lethal to the tumor has become a barrier to implementing effective therapy. In this study, we present a comparative analysis of both intestinal and tumor tissue in regard to the efficacy and the preventive impact of a short-term growth hormone (GH) treatment in tumor-bearing rats as a protective agent during radiotherapy. Our data show that the exogenous administration of GH improved intestinal recovery after radiation treatment while preserving the therapeutic effect against the tumor. GH significantly increased proliferation in the irradiated intestine but not in the irradiated tumors, as assessed by Positron Emission Tomography and the proliferative markers Ki67, cyclin D3, and Proliferating Cell Nuclear Antigen. This proliferative effect was consistent with a significant increase in irradiated intestinal villi and crypt length. Furthermore, GH significantly decreased caspase-3 activity in the intestine, whereas GH did not produce this effect in the irradiated tumors. In conclusion, short-term GH treatment protects the bowel, inducing proliferation while reducing apoptosis in healthy intestinal tissue and preserving radiotherapy efficacy on tumors. PMID:26670463

  11. SGI-110 and entinostat therapy reduces lung tumor burden and reprograms the epigenome.

    PubMed

    Tellez, Carmen S; Grimes, Marcie J; Picchi, Maria A; Liu, Yushi; March, Thomas H; Reed, Matthew D; Oganesian, Aram; Taverna, Pietro; Belinsky, Steven A

    2014-11-01

    The DNA methyltransferase (DNMT) inhibitor vidaza (5-Azacytidine) in combination with the histone deacetylase inhibitor entinostat has shown promise in treating lung cancer and this has been replicated in our orthotopic lung cancer model. However, the effectiveness of DNMT inhibitors against solid tumors is likely impacted by their limited stability and rapid inactivation by cytidine deaminase (CDA) in the liver. These studies were initiated to test the efficacy of SGI-110, a dinucleotide containing decitabine that is resistant to deamination by CDA, as a single agent and in combination with entinostat. Evaluation of in vivo plasma concentrations and pharmacokinetic properties of SGI-110 showed rapid conversion to decitabine and a plasma half-life of 4 hr. SGI-110 alone or in combination with entinostat reduced tumor burden of a K-ras/p53 mutant lung adenocarcinoma cell line (Calu6) engrafted orthotopically in nude rats by 35% and 56%, respectively. SGI-110 caused widespread demethylation of more than 300 gene promoters and microarray analysis revealed expression changes for 212 and 592 genes with SGI-110 alone or in combination with entinostat. Epigenetic therapy also induced demethylation and expression of cancer testis antigen genes that could sensitize tumor cells to subsequent immunotherapy. In the orthotopically growing tumors, highly significant gene expression changes were seen in key cancer regulatory pathways including induction of p21 and the apoptotic gene BIK. Moreover, SGI-110 in combination with entinostat caused widespread epigenetic reprogramming of EZH2-target genes. These preclinical in vivo findings demonstrate the clinical potential of SGI-110 for reducing lung tumor burden through reprogramming the epigenome.

  12. Development of a circulating miRNA assay to monitor tumor burden: From mouse to man.

    PubMed

    Greystoke, Alastair; Ayub, Mahmood; Rothwell, Dominic G; Morris, Dan; Burt, Deborah; Hodgkinson, Cassandra L; Morrow, Christopher J; Smith, Nigel; Aung, Kyaw; Valle, Juan; Carter, Louise; Blackhall, Fiona; Dive, Caroline; Brady, Ged

    2016-02-01

    Circulating miRNA stability suggests potential utility of miRNA based biomarkers to monitor tumor burden and/or progression, particularly in cancer types where serial biopsy is impractical. Assessment of miRNA specificity and sensitivity is challenging within the clinical setting. To address this, circulating miRNAs were examined in mice bearing human SCLC tumor xenografts and SCLC patient derived circulating tumor cell explant models (CDX). We identified 49 miRNAs using human TaqMan Low Density Arrays readily detectable in 10 μl tail vein plasma from mice carrying H526 SCLC xenografts that were low or undetectable in non-tumor bearing controls. Circulating miR-95 measured serially in mice bearing CDX was detected with tumor volumes as low as 10 mm(3) and faithfully reported subsequent tumor growth. Having established assay sensitivity in mouse models, we identified 26 miRNAs that were elevated in a stage dependent manner in a pilot study of plasma from SCLC patients (n = 16) compared to healthy controls (n = 11) that were also elevated in the mouse models. We selected a smaller panel of 10 previously reported miRNAs (miRs 95, 141, 200a, 200b, 200c, 210, 335#, 375, 429) that were consistently elevated in SCLC, some of which are reported to be elevated in other cancer types. Using a multiplex qPCR assay, elevated levels of miRNAs across the panel were also observed in a further 66 patients with non-small cell lung, colorectal or pancreatic cancers. The utility of this circulating miRNA panel as an early warning of tumor progression across several tumor types merits further evaluation in larger studies.

  13. Targeting geranylgeranylation reduces adrenal gland tumor burden in a murine model of prostate cancer metastasis

    PubMed Central

    Reilly, Jacqueline E; Neighbors, Jeffrey D; Tong, Huaxiang; Henry, Michael D; Hohl, Raymond J

    2016-01-01

    The isoprenoid biosynthetic pathway (IBP) is critical for providing substrates for the post-translational modification of proteins key in regulating malignant cell properties, including proliferation, invasion, and migration. Inhibitors of the IBP, including statins and nitrogenous bisphosphonates, are used clinically for the treatment of hypercholesterolemia and bone disease respectively. The statins work predominantly in the liver, while the nitrogenous bisphosphonates are highly sequestered to bone. Inhibition of the entire IBP is limited by organ specificity and side effects resulting from depletion of all isoprenoids. We have developed a novel compound, disodium [(6Z,11E,15E)-9-[bis(sodiooxy)phosphoryl]-17-hydroxy-2,6,12,16-tetramethyheptadeca-2,6,11,15-tetraen-9-yl]phosphonate (GGOHBP), which selectively targets geranylgeranyl diphosphate synthase (GGDPS), reducing post-translational protein geranylgeranylation. Intracardiac injection of luciferase-expressing human-derived 22Rv1 PCa cells into SCID mice resulted in tumor development in bone (100%), adrenal glands (72%), mesentery (22%), liver (17%), and the thoracic cavity (6%). Three weeks after tumor inoculation, daily subcutaneous (SQ) injections of 1.5 mg/kg GGOHBP or the vehicle were given for one month. Dissected tumors revealed areduction in adrenal gland tumors corresponding to a 54% (P < 0.005) reduction in total adrenal gland tumor weight of the treated mice as compared to vehicle-treated controls. Western blot analysis of the harvested tissues showed a reduction in Rap1A geranylgeranylation in adrenal glands and mesenteric tumors of the treated mice while non-tumorous tissues and control mice showed no Rap1A alteration. Our findings detail a novel bisphosphonate compound capable of preferentially altering the IBP in tumor-burdened adrenal glands of a murine model of PCa metastasis. PMID:26070429

  14. Targeting geranylgeranylation reduces adrenal gland tumor burden in a murine model of prostate cancer metastasis.

    PubMed

    Reilly, Jacqueline E; Neighbors, Jeffrey D; Tong, Huaxiang; Henry, Michael D; Hohl, Raymond J

    2015-08-01

    The isoprenoid biosynthetic pathway (IBP) is critical for providing substrates for the post-translational modification of proteins key in regulating malignant cell properties, including proliferation, invasion, and migration. Inhibitors of the IBP, including statins and nitrogenous bisphosphonates, are used clinically for the treatment of hypercholesterolemia and bone disease respectively. The statins work predominantly in the liver, while the nitrogenous bisphosphonates are highly sequestered to bone. Inhibition of the entire IBP is limited by organ specificity and side effects resulting from depletion of all isoprenoids. We have developed a novel compound, disodium [(6Z,11E,15E)-9-[bis(sodiooxy)phosphoryl]-17-hydroxy-2,6,12,16-tetramethyheptadeca-2,6,11,15-tetraen-9-yl]phosphonate (GGOHBP), which selectively targets geranylgeranyl diphosphate synthase, reducing post-translational protein geranylgeranylation. Intracardiac injection of luciferase-expressing human-derived 22Rv1 PCa cells into SCID mice resulted in tumor development in bone (100 %), adrenal glands (72 %), mesentery (22 %), liver (17 %), and the thoracic cavity (6 %). Three weeks after tumor inoculation, daily subcutaneous (SQ) injections of 1.5 mg/kg GGOHBP or the vehicle were given for one month. Dissected tumors revealed a reduction in adrenal gland tumors corresponding to a 54 % (P < 0.005) reduction in total adrenal gland tumor weight of the treated mice as compared to vehicle-treated controls. Western blot analysis of the harvested tissues showed a reduction in Rap1A geranylgeranylation in adrenal glands and mesenteric tumors of the treated mice while non-tumorous tissues and control mice showed no Rap1A alteration. Our findings detail a novel bisphosphonate compound capable of preferentially altering the IBP in tumor-burdened adrenal glands of a murine model of PCa metastasis.

  15. Quality of life and brain tumors: what beyond the clinical burden?

    PubMed

    Giovagnoli, Anna Rita; Meneses, Rute Flávia; Silvani, Antonio; Milanesi, Ida; Fariselli, Laura; Salmaggi, Andrea; Boiardi, Amerigo

    2014-05-01

    This study analyzed the subjective facets of quality of life (QoL) and their relation to the type of brain tumor (BT) and phase of disease. Two hundred and ninety-one patients with pinealoblastoma, medulloblastoma, low-grade glioma, anaplastic astrocytoma, or glioblastoma were evaluated. With respect to 110 healthy controls, patients in the phases of radiotherapy/chemotherapy, stable disease, or tumor recurrence were significantly more anxious and depressed compared with patients in the early postoperative period. All patients were impaired in mental flexibility and memory, with preservation of abstract reasoning. The Functional Living Index-Cancer (FLIC), previously validated in cancer and BT patients, yielded six subjective factors (disease perception, affective well-being, role and leisure, personal base, nausea, sharing). None of the FLIC factors were predicted by tumor type, which only related to the physical and cognitive performances and mood scores. Affective well-being, role and leisure, and sharing were predicted by the phase of disease. Personal base, including self-perception and confidence, was independent on tumor progression and treatment. To conclude, QoL encompasses different subjective aspects, which vary in relation to the phase of disease and clinical burden. However, some person-related facets appear independent on tumor progression and treatment, indicating individual resources. Knowing this may guide tailored interventions supporting QoL.

  16. Structure of the gut microbiome following colonization with human feces determines colonic tumor burden.

    PubMed

    Baxter, Nielson T; Zackular, Joseph P; Chen, Grace Y; Schloss, Patrick D

    2014-01-01

    A growing body of evidence indicates that the gut microbiome plays a role in the development of colorectal cancer (CRC). Patients with CRC harbor gut microbiomes that are structurally distinct from those of healthy individuals; however, without the ability to track individuals during disease progression, it has not been possible to observe changes in the microbiome over the course of tumorigenesis. Mouse models have demonstrated that these changes can further promote colonic tumorigenesis. However, these models have relied upon mouse-adapted bacterial populations and so it remains unclear which human-adapted bacterial populations are responsible for modulating tumorigenesis. We transplanted fecal microbiota from three CRC patients and three healthy individuals into germ-free mice, resulting in six structurally distinct microbial communities. Subjecting these mice to a chemically induced model of CRC resulted in different levels of tumorigenesis between mice. Differences in the number of tumors were strongly associated with the baseline microbiome structure in mice, but not with the cancer status of the human donors. Partitioning of baseline communities into enterotypes by Dirichlet multinomial mixture modeling resulted in three enterotypes that corresponded with tumor burden. The taxa most strongly positively correlated with increased tumor burden were members of the Bacteroides, Parabacteroides, Alistipes, and Akkermansia, all of which are Gram-negative. Members of the Gram-positive Clostridiales, including multiple members of Clostridium Group XIVa, were strongly negatively correlated with tumors. Analysis of the inferred metagenome of each community revealed a negative correlation between tumor count and the potential for butyrate production, and a positive correlation between tumor count and the capacity for host glycan degradation. Despite harboring distinct gut communities, all mice underwent conserved structural changes over the course of the model. The

  17. Soluble AXL: a possible circulating biomarker for neurofibromatosis type 1 related tumor burden.

    PubMed

    Johansson, Gunnar; Peng, Po-Chun; Huang, Po-Yuan; Chien, Hsiung-Fei; Hua, Kuo-Tai; Kuo, Min-Liang; Chen, Chin-Tin; Lee, Ming-Jen

    2014-01-01

    Neurofibromatosis type 1 (NF1) is the most common tumor predisposition disorder affecting 1/3500 worldwide. Patients are at risk of developing benign (neurofibromas) and malignant peripheral nerve sheath tumors (MPNST). The AXL receptor tyrosine kinase has been implicated in several kinds of cancers, but so far no studies have investigated the role of AXL in NF1 related tumorigenesis. Recently, the soluble fraction from the extracellular domain of AXL (sAXL) has been found in human plasma, and its level was correlated to poor prognosis in patients with renal cancer. Compared to normal human Schwann cells, a significantly high expression level of AXL was found in three of the four MPNST cell lines and two of the three primary MPNST tissues. Similarly, the level of sAXL in conditioned media corresponded to the protein and mRNA levels of AXL in the MPNST cell lines. Furthermore, in two different human MPNST xenograft models, the human sAXL could be detected in the mouse plasma. Its level was proportionate to the size of the xenograft tumors, while no human sAXL was detect prior to the formation of the tumors. Treatment with a newly developed photodynamic therapy, prevented further tumor growth and resulted in drastically reduced the levels of sAXL compared to that of the control group. Finally, the level of sAXL was significantly increased in patients with plexiform tumors compared to patients with only dermal neurofibromas, further supporting the role of sAXL as a marker for NF1 related tumor burden.

  18. Elp3 drives Wnt-dependent tumor initiation and regeneration in the intestine.

    PubMed

    Ladang, Aurélie; Rapino, Francesca; Heukamp, Lukas C; Tharun, Lars; Shostak, Kateryna; Hermand, Damien; Delaunay, Sylvain; Klevernic, Iva; Jiang, Zheshen; Jacques, Nicolas; Jamart, Diane; Migeot, Valérie; Florin, Alexandra; Göktuna, Serkan; Malgrange, Brigitte; Sansom, Owen J; Nguyen, Laurent; Büttner, Reinhard; Close, Pierre; Chariot, Alain

    2015-11-16

    Tumor initiation in the intestine can rapidly occur from Lgr5(+) crypt columnar stem cells. Dclk1 is a marker of differentiated Tuft cells and, when coexpressed with Lgr5, also marks intestinal cancer stem cells. Here, we show that Elp3, the catalytic subunit of the Elongator complex, is required for Wnt-driven intestinal tumor initiation and radiation-induced regeneration by maintaining a subpool of Lgr5(+)/Dclk1(+)/Sox9(+) cells. Elp3 deficiency dramatically delayed tumor appearance in Apc-mutated intestinal epithelia and greatly prolonged mice survival without affecting the normal epithelium. Specific ablation of Elp3 in Lgr5(+) cells resulted in marked reduction of polyp formation upon Apc inactivation, in part due to a decreased number of Lgr5(+)/Dclk1(+)/Sox9(+) cells. Mechanistically, Elp3 is induced by Wnt signaling and promotes Sox9 translation, which is needed to maintain the subpool of Lgr5(+)/Dclk1(+) cancer stem cells. Consequently, Elp3 or Sox9 depletion led to similar defects in Dclk1(+) cancer stem cells in ex vivo organoids. Finally, Elp3 deficiency strongly impaired radiation-induced intestinal regeneration, in part because of decreased Sox9 protein levels. Together, our data demonstrate the crucial role of Elp3 in maintaining a subpopulation of Lgr5-derived and Sox9-expressing cells needed to trigger Wnt-driven tumor initiation in the intestine.

  19. Effect of Indomethacin on Intestinal Tumors Induced in Rats by the Acetate Derivative of Dimethylnitrosamine

    NASA Astrophysics Data System (ADS)

    Pollard, Morris; Luckert, Phyllis H.

    1981-10-01

    Over the course of 20 weeks, Sprague-Dawley rats developed intestinal tumors in response to an intraperitoneal injection of the acetate derivative of dimethylnitrosamine. The same agent did not induce tumors in Lobund-Wistar rats. The number of tumors was significantly smaller in rats given drinking water containing indomethacin (beginning 14 days after the injections) than in control rats given drug-free water.

  20. Detection of coding microsatellite frameshift mutations in DNA mismatch repair-deficient mouse intestinal tumors.

    PubMed

    Woerner, Stefan M; Tosti, Elena; Yuan, Yan P; Kloor, Matthias; Bork, Peer; Edelmann, Winfried; Gebert, Johannes

    2015-11-01

    Different DNA mismatch repair (MMR)-deficient mouse strains have been developed as models for the inherited cancer predisposing Lynch syndrome. It is completely unresolved, whether coding mononucleotide repeat (cMNR) gene mutations in these mice can contribute to intestinal tumorigenesis and whether MMR-deficient mice are a suitable molecular model of human microsatellite instability (MSI)-associated intestinal tumorigenesis. A proof-of-principle study was performed to identify mouse cMNR-harboring genes affected by insertion/deletion mutations in MSI murine intestinal tumors. Bioinformatic algorithms were developed to establish a database of mouse cMNR-harboring genes. A panel of five mouse noncoding mononucleotide markers was used for MSI classification of intestinal matched normal/tumor tissues from MMR-deficient (Mlh1(-/-) , Msh2(-/-) , Msh2(LoxP/LoxP) ) mice. cMNR frameshift mutations of candidate genes were determined by DNA fragment analysis. Murine MSI intestinal tumors but not normal tissues from MMR-deficient mice showed cMNR frameshift mutations in six candidate genes (Elavl3, Tmem107, Glis2, Sdccag1, Senp6, Rfc3). cMNRs of mouse Rfc3 and Elavl3 are conserved in type and length in their human orthologs that are known to be mutated in human MSI colorectal, endometrial and gastric cancer. We provide evidence for the utility of a mononucleotide marker panel for detection of MSI in murine tumors, the existence of cMNR instability in MSI murine tumors, the utility of mouse subspecies DNA for identification of polymorphic repeats, and repeat conservation among some orthologous human/mouse genes, two of them showing instability in human and mouse MSI intestinal tumors. MMR-deficient mice hence are a useful molecular model system for analyzing MSI intestinal carcinogenesis.

  1. CFTR is a tumor suppressor gene in murine and human intestinal cancer

    PubMed Central

    Than, BLN; Linnekamp, JF; Starr, TK; Largaespada, DA; Rod, A; Zhang, Y; Bruner, V; Abrahante, J; Schumann, A; Luczak, T; Niemczyk, A; O’Sullivan, MG; Medema, JP; Fijneman, RJA; Meijer, GA; Van den Broek, E; Hodges, CA; Scott, PM; Vermeulen, L; Cormier, RT

    2016-01-01

    CFTR, the cystic fibrosis (CF) gene, encodes for the CFTR protein that plays an essential role in anion regulation and tissue homeostasis of various epithelia. In the gastrointestinal (GI) tract CFTR promotes chloride and bicarbonate secretion, playing an essential role in ion and acid–base homeostasis. Cftr has been identified as a candidate driver gene for colorectal cancer (CRC) in several Sleeping Beauty DNA transposon-based forward genetic screens in mice. Further, recent epidemiological and clinical studies indicate that CF patients are at high risk for developing tumors in the colon. To investigate the effects of CFTR dysregulation on GI cancer, we generated ApcMin mice that carried an intestinal-specific knockout of Cftr. Our results indicate that Cftr is a tumor suppressor gene in the intestinal tract as Cftr mutant mice developed significantly more tumors in the colon and the entire small intestine. In Apc+/+ mice aged to ~ 1 year, Cftr deficiency alone caused the development of intestinal tumors in >60% of mice. Colon organoid formation was significantly increased in organoids created from Cftr mutant mice compared with wild-type controls, suggesting a potential role of Cftr in regulating the intestinal stem cell compartment. Microarray data from the Cftr-deficient colon and the small intestine identified dysregulated genes that belong to groups of immune response, ion channel, intestinal stem cell and other growth signaling regulators. These associated clusters of genes were confirmed by pathway analysis using Ingenuity Pathway Analysis and gene set enrichment analysis (GSEA). We also conducted RNA Seq analysis of tumors from Apc+/+ Cftr knockout mice and identified sets of genes dysregulated in tumors including altered Wnt β-catenin target genes. Finally we analyzed expression of CFTR in early stage human CRC patients stratified by risk of recurrence and found that loss of expression of CFTR was significantly associated with poor disease

  2. CFTR is a tumor suppressor gene in murine and human intestinal cancer.

    PubMed

    Than, B L N; Linnekamp, J F; Starr, T K; Largaespada, D A; Rod, A; Zhang, Y; Bruner, V; Abrahante, J; Schumann, A; Luczak, T; Niemczyk, A; O'Sullivan, M G; Medema, J P; Fijneman, R J A; Meijer, G A; Van den Broek, E; Hodges, C A; Scott, P M; Vermeulen, L; Cormier, R T

    2016-08-11

    CFTR, the cystic fibrosis (CF) gene, encodes for the CFTR protein that plays an essential role in anion regulation and tissue homeostasis of various epithelia. In the gastrointestinal (GI) tract CFTR promotes chloride and bicarbonate secretion, playing an essential role in ion and acid-base homeostasis. Cftr has been identified as a candidate driver gene for colorectal cancer (CRC) in several Sleeping Beauty DNA transposon-based forward genetic screens in mice. Further, recent epidemiological and clinical studies indicate that CF patients are at high risk for developing tumors in the colon. To investigate the effects of CFTR dysregulation on GI cancer, we generated Apc(Min) mice that carried an intestinal-specific knockout of Cftr. Our results indicate that Cftr is a tumor suppressor gene in the intestinal tract as Cftr mutant mice developed significantly more tumors in the colon and the entire small intestine. In Apc(+/+) mice aged to ~1 year, Cftr deficiency alone caused the development of intestinal tumors in >60% of mice. Colon organoid formation was significantly increased in organoids created from Cftr mutant mice compared with wild-type controls, suggesting a potential role of Cftr in regulating the intestinal stem cell compartment. Microarray data from the Cftr-deficient colon and the small intestine identified dysregulated genes that belong to groups of immune response, ion channel, intestinal stem cell and other growth signaling regulators. These associated clusters of genes were confirmed by pathway analysis using Ingenuity Pathway Analysis and gene set enrichment analysis (GSEA). We also conducted RNA Seq analysis of tumors from Apc(+/+) Cftr knockout mice and identified sets of genes dysregulated in tumors including altered Wnt β-catenin target genes. Finally we analyzed expression of CFTR in early stage human CRC patients stratified by risk of recurrence and found that loss of expression of CFTR was significantly associated with poor disease

  3. Alternative Polyadenylation of Tumor Suppressor Genes in Small Intestinal Neuroendocrine Tumors

    PubMed Central

    Rehfeld, Anders; Plass, Mireya; Døssing, Kristina; Knigge, Ulrich; Kjær, Andreas; Krogh, Anders; Friis-Hansen, Lennart

    2014-01-01

    The tumorigenesis of small intestinal neuroendocrine tumors (SI-NETs) is poorly understood. Recent studies have associated alternative polyadenylation (APA) with proliferation, cell transformation, and cancer. Polyadenylation is the process in which the pre-messenger RNA is cleaved at a polyA site and a polyA tail is added. Genes with two or more polyA sites can undergo APA. This produces two or more distinct mRNA isoforms with different 3′ untranslated regions. Additionally, APA can also produce mRNAs containing different 3′-terminal coding regions. Therefore, APA alters both the repertoire and the expression level of proteins. Here, we used high-throughput sequencing data to map polyA sites and characterize polyadenylation genome-wide in three SI-NETs and a reference sample. In the tumors, 16 genes showed significant changes of APA pattern, which lead to either the 3′ truncation of mRNA coding regions or 3′ untranslated regions. Among these, 11 genes had been previously associated with cancer, with 4 genes being known tumor suppressors: DCC, PDZD2, MAGI1, and DACT2. We validated the APA in three out of three cases with quantitative real-time-PCR. Our findings suggest that changes of APA pattern in these 16 genes could be involved in the tumorigenesis of SI-NETs. Furthermore, they also point to APA as a new target for both diagnostic and treatment of SI-NETs. The identified genes with APA specific to the SI-NETs could be further tested as diagnostic markers and drug targets for disease prevention and treatment. PMID:24782827

  4. Protective effect of genistein on radiation-induced intestinal injury in tumor bearing mice

    PubMed Central

    2013-01-01

    Background Radiation therapy is the most widely used treatment for cancer, but it causes the side effect of mucositis due to intestinal damage. We examined the protective effect of genistein in tumor-bearing mice after abdominal irradiation by evaluation of apoptosis and intestinal morphological changes. Methods Mouse colon cancer CT26 cells were subcutaneously injected at the flank of BALB/c mice to generate tumors. The tumor-bearing mice were treated with abdominal radiation at 5 and 10 Gy, and with genistein at 200 mg/kg body weight per day for 1 d before radiation. The changes in intestinal histology were evaluated 12 h and 3.5 d after irradiation. To assess the effect of the combination treatment on the cancer growth, the tumor volume was determined at sacrifice before tumor overgrowth occurred. Results Genistein significantly decreased the number of apoptotic nuclei compared with that in the irradiation group 12 h after 5 Gy irradiation. Evaluation of histological changes showed that genistein ameliorated intestinal morphological changes such as decreased crypt survival, villus shortening, and increased length of the basal lamina 3.5 d after 10 Gy irradiation. Moreover, the genistein-treated group exhibited more Ki-67-positive proliferating cells in the jejunum than the irradiated control group, and crypt depths were greater in the genistein-treated group than in the irradiated control group. The mean weight of the CT26 tumors was reduced in the group treated with genistein and radiation compared with the control group. Conclusion Genistein had a protective effect on intestinal damage induced by irradiation and delayed tumor growth. These results suggest that genistein is a useful candidate for preventing radiotherapy-induced intestinal damage in cancer patients. PMID:23672582

  5. Generation and analysis of mouse intestinal tumors and organoids harboring APC and K-Ras mutations.

    PubMed

    van Es, Johan H; Clevers, Hans

    2015-01-01

    Genetically engineered mouse models of intestinal cancer are experimental systems in which mice are genetically manipulated to develop malignancies in the gastrointestinal tract. These models enable researchers to study the mechanisms of onset, progression, and metastasis of the disease. They also provide a valuable biological system which is suitable for testing (novel) drugs in vivo. Recently, an in vitro culture model has been established in which intestinal epithelial stem cells can grow into three-dimensional, ever-expanding epithelial organoids that retain their original organ identity and genetic stability. This culture system has been applied to diseased epithelia, such as adenoma, adenocarcinoma, and Barrett's epithelium. These organoids can be particularly useful for studying the mechanisms of intestinal tumors and to test (novel) drugs in vitro. Here, we describe our current laboratory protocols to generate and analyze intestinal tumors and organoids harboring APC and K-Ras double mutations.

  6. Dclk1, a tumor stem cell marker, regulates pro-survival signaling and self-renewal of intestinal tumor cells.

    PubMed

    Chandrakesan, Parthasarathy; Yao, Jiannan; Qu, Dongfeng; May, Randal; Weygant, Nathaniel; Ge, Yang; Ali, Naushad; Sureban, Sripathi M; Gude, Modhi; Vega, Kenneth; Bannerman-Menson, Eddie; Xia, Lijun; Bronze, Michael; An, Guangyu; Houchen, Courtney W

    2017-02-01

    More than 80% of intestinal neoplasia is associated with the adenomatous polyposis coli (APC) mutation. Doublecortin-like kinase 1 (Dclk1), a kinase protein, is overexpressed in colorectal cancer and specifically marks tumor stem cells (TSCs) that self-renew and increased the tumor progeny in Apc (Min/+) mice. However, the role of Dclk1 expression and its contribution to regulating pro-survival signaling for tumor progression in Apc mutant cancer is poorly understood. We analyzed DCLK1 and pro-survival signaling gene expression datasets of 329 specimens from TCGA Colon Adenocarcinoma Cancer Data. The network of DCLK1 and pro-survival signaling was analyzed utilizing the GeneMANIA database. We examined the expression levels of Dclk1 and other stem cell-associated markers, pro-survival signaling pathways, cell self-renewal in the isolated intestinal epithelial cells of Apc (Min/+) mice with high-grade dysplasia and adenocarcinoma. To determine the functional role of Dclk1 for tumor progression, we knocked down Dclk1 and determined the pro-survival signaling pathways and stemness. We used siRNA technology to gene silence pro-survival signaling in colon cancer cells in vitro. We utilized FACS, IHC, western blot, RT-PCR, and clonogenic (self-renewal) assays. We found a correlation between DCLK1 and pro-survival signaling expression. The expression of Dclk1 and stem cell-associated markers Lgr5, Bmi1, and Musashi1 were significantly higher in the intestinal epithelial cells of Apc (Min/+) mice than in wild-type controls. Intestinal epithelial cells of Apc (Min/+) mice showed increased expression of pro-survival signaling, pluripotency and self-renewal ability. Furthermore, the enteroids formed from the intestinal Dclk1(+) cells of Apc (Min/+) mice display higher pluripotency and pro-survival signaling. Dclk1 knockdown in Apc (Min/+) mice attenuates intestinal adenomas and adenocarcinoma, and decreases pro-survival signaling and self-renewal. Knocking down RELA and NOTCH1

  7. Transformation of epithelial cells through recruitment leads to polyclonal intestinal tumors

    PubMed Central

    Thliveris, Andrew T.; Schwefel, Brittany; Clipson, Linda; Plesh, Lauren; Zahm, Christopher D.; Leystra, Alyssa A.; Washington, Mary Kay; Sullivan, Ruth; Deming, Dustin A.; Newton, Michael A.; Halberg, Richard B.

    2013-01-01

    Intestinal tumors from mice and humans can have a polyclonal origin. Statistical analyses indicate that the best explanation for this source of intratumoral heterogeneity is the presence of interactions among multiple progenitors. We sought to better understand the nature of these interactions. An initial progenitor could recruit others by facilitating the transformation of one or more neighboring cells. Alternatively, two progenitors that are independently initiated could simply cooperate to form a single tumor. These possibilities were tested by analyzing tumors from aggregation chimeras that were generated by fusing together embryos with unequal predispositions to tumor development. Strikingly, numerous polyclonal tumors were observed even when one genetic component was highly, if not completely, resistant to spontaneous tumorigenesis in the intestine. Moreover, the observed number of polyclonal tumors could be explained by the facilitated transformation of a single neighbor within 144 μm of an initial progenitor. These findings strongly support recruitment instead of cooperation. Thus, it is conceivable that these interactions are necessary for tumors to thrive, so blocking them might be a highly effective method for preventing the formation of tumors in the intestine and other tissues. PMID:23798428

  8. Intestinal Kaposi's sarcoma may mimic gastrointestinal stromal tumor in HIV infection.

    PubMed

    Zoufaly, A; Schmiedel, S; Lohse, A W; van Lunzen, J

    2007-09-07

    Diffuse intestinal Kaposi's sarcoma shares macroscopic and histopathologic features with gastrointestinal stromal tumors. Correct diagnosis may pose a clinical challenge. We describe the case of a young HIV-1-infected African lady without advanced immunodeficiency, who presented with a diffuse spindle cell tumor of the gut. Initial diagnosis was of a gastrointestinal stromal tumor, based on endoscopy and histopathology. Further evaluation revealed evidence for human herpesvirus 8 (HHV8) and the diagnosis had to be changed to diffuse intestinal Kaposi's sarcoma. Antiretroviral triple therapy together with chemotherapy was commenced, and has led to the rapid remission of intestinal lesions. With a background of HIV infection, the presence of HHV8 as the causative agent of Kaposi's sarcoma should be determined, as distinct treatment is indicated.

  9. Intestinal and peri-tumoral lymphatic endothelial cells are resistant to radiation-induced apoptosis

    SciTech Connect

    Sung, Hoon Ki; Morisada, Tohru; Cho, Chung-Hyun; Oike, Yuichi; Lee, Jayhun; Sung, Eon Ki; Chung, Jae Hoon; Suda, Toshio; Koh, Gou Young . E-mail: gykoh@kaist.ac.kr

    2006-06-30

    Radiation therapy is a widely used cancer treatment, but it is unable to completely block cancer metastasis. The lymphatic vasculature serves as the primary route for metastatic spread, but little is known about how lymphatic endothelial cells respond to radiation. Here, we show that lymphatic endothelial cells in the small intestine and peri-tumor areas are highly resistant to radiation injury, while blood vessel endothelial cells in the small intestine are relatively sensitive. Our results suggest the need for alternative therapeutic modalities that can block lymphatic endothelial cell survival, and thus disrupt the integrity of lymphatic vessels in peri-tumor areas.

  10. Patient-Reported Experience of Diagnosis, Management, and Burden of Neuroendocrine Tumors

    PubMed Central

    Wolin, Edward M.; Leyden, John; Goldstein, Grace; Kolarova, Teodora; Hollander, Ron; Warner, Richard R.P.

    2017-01-01

    Objectives The aim of this survey was to examine the experience of patients with neuroendocrine tumors (NETs) to raise awareness of the NET-related burden and identify unmet needs. Here, we report data from patients in the United States. Methods Patients with NETs participated in a 25-minute anonymous survey, conducted primarily online from February to May 2014. Survey questions captured information on sociodemographics, clinical characteristics, NET diagnostic experience, disease impact/management, interaction with medical teams, and NETs knowledge/awareness. Results Of 1928 patients who participated globally, the largest percentage was from the United States (39%). Approximately 50% of US patients reported being diagnosed with other conditions before receiving their NET diagnosis, which for 34% took 5 years or more. Patients experienced many symptoms on a daily basis as a result of NETs, which had a substantial negative impact on their work and daily lives. Numerous improvements were suggested by patients, including better access to NET-specific treatments and medical teams/centers and better education for the management of disease-related and treatment-related symptoms. Conclusions This survey demonstrated the significant burden of NETs on patients' lives and identified key areas for improvement in diagnosis and long-term management, including better access to NET-specific treatments and specialist medical teams/centers. PMID:28328615

  11. Capillary blood flow in murine tumors, feet, and intestines during localized hyperthermia

    SciTech Connect

    Peck, J.W.; Gibbs, F.A. Jr.

    1983-10-01

    Changes in capillary blood flow were determined by serial measurements of xenon-133 (/sup 133/Xe) washout rates from Slow-line C/sub 3/H-mouse mammary carcinomas transplanted onto the flank or hindfoot, from non-tumor-bearing hindfeet, and from the lumen of a short portion of the proximal jejunum. Immersion in a 44/sup 0/C bath immediately doubled washout rates not only from the immersed tumor, but also from a contralatreral tumor that was not heated. This result and behavioral observations were consistent with an arousal-induced increase in cardiac output to the tumors that increased the capillary blood flow in them. In contrast, washout rates from the hindfeet or intestinal lumen did not increase unless the foot or intestine in question was itself heated, which is consistent with normal tissues having intrinsic mechanisms for regulating their own capillary blood flow that the Slow-line tumor lacks. This lack could complicate the design and interpretation of hyperthermia experiments in vivo. Immersion of Slow-line tumors in a 44/sup 0/C bath for 20 min did no microvascular damage detectable from /sup 133/Xe washout rates during the heating or for 1 hr subsequently. Washout rates from both foot and flank tumors had dropped by one-half after 41 to 43 min in the 44/sup 0/C bath. Equivalent declines had occurred after 60 min for the intestine and 100 min for the hindfeet.

  12. Use of Cancer-Specific Genomic Rearrangements to Quantify Disease Burden in Plasma from Patients with Solid Tumors

    PubMed Central

    McBride, David J.; Orpana, Arto K.; Sotiriou, Christos; Joensuu, Heikki; Stephens, Philip J.; Mudie, Laura J.; Hämälaïnen, Eija; Stebbings, Lucy A.; Andersson, Leif C.; Flanagan, Adrienne M.; Durbecq, Virginie; Ignatiadis, Michail; Kallioniemi, Olli; Heckman, Caroline A.; Alitalo, Kari; Edgren, Henrik; Futreal, P. Andrew; Stratton, Michael R.; Campbell, Peter J.

    2011-01-01

    Detection of recurrent somatic rearrangements routinely allows monitoring of residual disease burden in leukemias, but is not used for most solid tumors. However, next-generation sequencing now allows rapid identification of patient-specific rearrangements in solid tumors. We mapped genomic rearrangements in three cancers and showed that PCR assays for rearrangements could detect a single copy of the tumor genome in plasma without false positives. Disease status, drug responsiveness, and incipient relapse could be serially assessed. In future, this strategy could be readily established in diagnostic laboratories, with major impact on monitoring of disease status and personalizing treatment of solid tumors. PMID:20725990

  13. Use of cancer-specific genomic rearrangements to quantify disease burden in plasma from patients with solid tumors.

    PubMed

    McBride, David J; Orpana, Arto K; Sotiriou, Christos; Joensuu, Heikki; Stephens, Philip J; Mudie, Laura J; Hämäläinen, Eija; Stebbings, Lucy A; Andersson, Leif C; Flanagan, Adrienne M; Durbecq, Virginie; Ignatiadis, Michail; Kallioniemi, Olli; Heckman, Caroline A; Alitalo, Kari; Edgren, Henrik; Futreal, P Andrew; Stratton, Michael R; Campbell, Peter J

    2010-11-01

    Detection of recurrent somatic rearrangements routinely allows monitoring of residual disease burden in leukemias, but is not used for most solid tumors. However, next-generation sequencing now allows rapid identification of patient-specific rearrangements in solid tumors. We mapped genomic rearrangements in three cancers and showed that PCR assays for rearrangements could detect a single copy of the tumor genome in plasma without false positives. Disease status, drug responsiveness, and incipient relapse could be serially assessed. In future, this strategy could be readily established in diagnostic laboratories, with major impact on monitoring of disease status and personalizing treatment of solid tumors.

  14. Liver Metastases of Small Intestine Neuroendocrine Tumors: Ki67 heterogeneity and WHO grade discordance with primary tumors

    PubMed Central

    Shi, Chanjuan; Gonzalez, Raul S.; Zhao, Zhiguo; Koyama, Tatsuki; Cornish, Toby C; Hande, Kenneth R; Walker, Ronald; Sandler, Martin; Berlin, Jordan; Liu, Eric H

    2015-01-01

    Objective We examined Ki67 heterogeneity within single and between synchronous liver metastases of small intestine neuroendocrine tumors. Methods There were 27 patients (10 males and 17 females) with ≥2 liver metastases. Ki67 index was used to classify the tumors into WHO grade 1, 2, or 3. Association between Ki67 heterogeneity and tumor size of liver metastases were analyzed. Correlation of tumor grade with patient survival was also evaluated. Results Primary tumors from 20 patients were graded, including 17 grade 1 and 3 grade 2. A total of 188 liver metastases were resected, including 122 (65%) grade 1, 47 (25%) grade 2, and 19 (10%) grade 3. The highest tumor grade was grade 1 in10 (37%), grade 2 in 9 (33%), and grade 3 in 8 (30%) patients. Patients with ≥1 grade 3 liver lesions were associated with a shorter progression-free survival compared to those with grade 1/2 tumors (p<0.001). A positive association was found between tumor size and Ki67 index (p=0.04) as well as between tumor size and intratumoral Ki67 heterogeneity (p<0.001). Conclusions Intratumoral and intertumoral Ki67 heterogeneity is common and is positively correlated with tumor size. The presence of ≥1 grade 3 liver lesions predicts a worse prognosis. PMID:25696798

  15. Chromosomes and causation of human cancer and leukemia. XXX. Banding studies of primary intestinal tumors.

    PubMed

    Sonta, S; Sandberg, A A

    1978-01-01

    The chromosomes of 15 primary intestinal tumors were analyzed with a banding technique. Of the 15 tumors, 12 had some chromosomal abnormalities (8 with numerical changes and 4 with both numerical and structural abnormalities) and in the remaining three no karyotypic abnormalities were found. No common marker chromosomes were seen among the various tumors and no two tumors with chromosomal changes and identical karyotypes, though some chromosomes were involved more often than others. Excessive chromosomes in the primary tumors were usually due to extra chromosomes in the following groups (numbers of tumors involved are shown in parenthesis): No. 8 (7), No. 13 (4), No. 15 (4), No. 17 (6) and No. 21 (6). On the other hand, chromosomes losses, though much less frequent, involved chromosomes No. 5, No. 6, No. 7, No. 10 and No. 16. Most of the tumor cells with chromosomal changes were hyperdiploid and usually contained less than 60 chromosomes. Only one tumor contained hypodiploid cells. The cytogenetic data presented on primary intestinal tumors indicate that they consist primarily of numerical changes, relative infrequency (when compared to metastases) and small number (1-4) of markers.

  16. Global microRNA profiling of well-differentiated small intestinal neuroendocrine tumors

    PubMed Central

    Li, Su-Chen; Essaghir, Ahmed; Martijn, Cécile; Lloyd, Ricardo V; Demoulin, Jean-Baptiste; Öberg, Kjell; Giandomenico, Valeria

    2013-01-01

    Well-differentiated small intestinal neuroendocrine tumors are rare malignancies. They arise from enterochromaffin cells and very little is known about differential microRNA (miRNA) expression. The aim of this study was to identify the miRNA profile of well-differentiated small intestinal neuroendocrine tumors, which may have a critical role in tumor development, progression and potentially develop miRNAs as novel clinical biomarkers. Specimens from two test groups, 24 small intestinal neuroendocrine tumor specimens at different stages of malignancy, are included in this study. Total RNA from the first test group, five primary tumors, five mesentery metastases and five liver metastases was hybridized onto the Affymetrix Genechip miRNA arrays to perform a genome-wide profile. The results were validated by using quantitative real-time PCR (QRT-PCR) and northern blot analyses. We then expanded the investigation to laser capture microdissected small intestinal neuroendocrine tumor cells and immuno-laser capture microdissected normal enterochromaffin cells of the first test group. Furthermore, a second test group, three primary tumors, three mesentery metastases and three liver metastases, was included in the study. Thus, two independent test groups validated the data by QRT-PCR. Moreover, we characterized nine miRNAs, five (miR-96, -182, -183, -196a and -200a), which are upregulated during tumor progression, whereas four (miR-31, -129-5p, -133a and -215) are downregulated. Several online software programs were used to predict potential miRNA target genes to map a number of putative target genes for the aberrantly regulated miRNAs, through an advanced and novel bioinformatics analysis. Our findings provide information about pivotal miRNAs, which may lead to further insights into tumorigenesis, progression mechanisms and novel therapeutic targets recognition. PMID:23328977

  17. CDC42 inhibition suppresses progression of incipient intestinal tumors

    USDA-ARS?s Scientific Manuscript database

    Mutations in the APC or Beta-catenin genes are well-established initiators of colorectal cancer, yet modifiers that facilitate the survival and progression of nascent tumor cells are not well defined. Using genetic and pharmacologic approaches in mouse colorectal cancer and human colorectal cancer x...

  18. Wip1 abrogation decreases intestinal tumor frequency in APC(Min/+) mice irrespective of radiation quality.

    PubMed

    Suman, Shubhankar; Moon, Bo-Hyun; Thakor, Hemang; Fornace, Albert J; Datta, Kamal

    2014-09-01

    Low-linear energy transfer (low-LET) γ-ray exposure is a risk factor for colorectal cancer (CRC). Due to their high-LET nature, energetic iron ions found in space are expected to pose greater CRC risks to astronauts undertaking long-duration space missions beyond low Earth orbit. Wild-type p53-induced phosphatase 1 (Wip1) is important for cellular DNA damage response and its abrogation has been shown to inhibit spontaneous intestinal tumorigenesis in APC(Min/+) mice, a well-studied mouse model of human CRC. However, the relationship of Wip1 to radiation-induced intestinal tumorigenesis, especially by energetic iron ions, has not been investigated in APC(Min/+) mice. We have previously reported that there is a greater intestinal tumorigenic potential of iron-ion radiation relative to (137)Cs γ rays, so the purpose of the current study was to investigate whether Wip1 abrogation could influence high-LET dependent intestinal tumorigenesis in APC(Min/+) mice. Intestinal tumor frequency and grade were assessed in APC(Min/+)/Wip1(-/-) mice and results were compared to those in APC(Min/+)/Wip1(+/+) mice after exposure to a mean absorbed dose of 2 Gy from (137)Cs γ rays or 1.6 Gy from 1 GeV/n iron ions. Cellular differentiation and proliferation were also assessed in the intestinal tumors of sham-irradiated and irradiated mice. Decreased tumor frequency and lower tumor grade were observed in APC(Min/+)/Wip1(-/-) relative to APC(Min/+)/Wip1(+/+) mice. Notably, a similar decrease (∼6-fold in both groups) in tumor number was observed in sham-irradiated and γ-irradiated APC(Min/+)/Wip1(-/-) relative to APC(Min/+)/Wip1(+/+) mice. However, tumorigenesis in the energetic iron-ion exposed group was reduced ∼8-fold in APC(Min/+)/Wip1(-/-) relative to APC(Min/+)/Wip1(+/+) mice. A significantly lower proliferation/differentiation index in tumors of iron-ion exposed APC(Min/+)/Wip1(-/-) relative to APC(Min/+)/Wip1(+/+) mice suggests that reduced proliferation and enhanced

  19. Intestine.

    PubMed

    Smith, J M; Skeans, M A; Horslen, S P; Edwards, E B; Harper, A M; Snyder, J J; Israni, A K; Kasiske, B L

    2016-01-01

    Intestine and intestine-liver transplant plays an important role in the treatment of intestinal failure, despite decreased morbidity associated with parenteral nutrition. In 2014, 210 new patients were added to the intestine transplant waiting list. Among prevalent patients on the list at the end of 2014, 65% were waiting for an intestine transplant and 35% were waiting for an intestine-liver transplant. The pretransplant mortality rate decreased dramatically over time for all age groups. Pretransplant mortality was highest for adult candidates, at 22.1 per 100 waitlist years compared with less than 3 per 100 waitlist years for pediatric candidates, and notably higher for candidates for intestine-liver transplant than for candidates for intestine transplant without a liver. Numbers of intestine transplants without a liver increased from a low of 51 in 2013 to 67 in 2014. Intestine-liver transplants increased from a low of 44 in 2012 to 72 in 2014. Short-gut syndrome (congenital and other) was the main cause of disease leading to both intestine and intestine-liver transplant. Graft survival improved over the past decade. Patient survival was lowest for adult intestine-liver recipients and highest for pediatric intestine recipients. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

  20. Apc, but not obesity, synergizes with PTEN to drive intestinal stem cell tumors.

    PubMed

    Tabrizian, Tahmineh; Wang, Donghai; Guan, Fangxia; Hu, Zunju; Beck, Amanda; Delahaye, Fabien; Huffman, Derek M

    2017-03-28

    Obesity is a major risk factor for colorectal cancer and can accelerate Lgr5+ intestinal stem cell (ISC)-derived tumorigenesis following inactivation of Apc. However, whether non-canonical pathways involving PI3K-Akt signaling in ISCs can lead to tumor formation, and if this can be further exacerbated by obesity is unknown. Despite the synergy between Pten and Apc inactivation in epithelial cells on intestinal tumor formation, their combined role in Lgr5+-ISCs, which are the most rapidly dividing ISC population in the intestine, is unknown. Lgr5+-GFP mice were provided low-fat diet (LFD) or high-fat diet (HFD) for 8 mo and the transcriptome was evaluated in Lgr5+-ISCs. For tumor studies, Lgr5+-GFP and Lgr5+-GFP Ptenflox/flox mice were tamoxifen treated to inactivate Pten in ISCs and provided LFD or HFD until 14-15 mo of age. Finally, various combinations of Lgr5+-ISC specific, Apc and Pten-deleted mice were generated, and evaluated for histopathology and survival. HFD did not overtly alter Akt signaling in ISCs, but did increase other metabolic pathways. Pten deficiency, but not HFD, increased BrdU positive cells in the small intestine (P<0.05). However, combining Pten and Apc deficiency synergistically increased proliferative markers, tumor pathology and mortality, in a dose-dependent fashion (P<0.05). In summary, we show that HFD alone fails to drive Akt signaling in ISCs and that Pten deficiency, is dispensable as a tumor suppressor in Lgr5+-ISCs. However, combining Pten and Apc deficiency in ISCs synergistically increases proliferation, tumor formation, and mortality. Thus, aberrant Wnt/β-catenin, rather than PI3K-Akt signaling, is requisite for obesity to drive Lgr5+ISC-derived tumorigenesis.

  1. Intestinal cancer stem cells marked by Bmi1 or Lgr5 expression contribute to tumor propagation via clonal expansion

    PubMed Central

    Yanai, Hirotsugu; Atsumi, Naho; Tanaka, Toshihiro; Nakamura, Naohiro; Komai, Yoshihiro; Omachi, Taichi; Tanaka, Kiyomichi; Ishigaki, Kazuhiko; Saiga, Kazuho; Ohsugi, Haruyuki; Tokuyama, Yoko; Imahashi, Yuki; Ohe, Shuichi; Hisha, Hiroko; Yoshida, Naoko; Kumano, Keiki; Kon, Masanori; Ueno, Hiroo

    2017-01-01

    Although the existence of cancer stem cells in intestine tumors has been suggested, direct evidence has not been yet provided. Here, we showed, using the multicolor lineage-tracing method and mouse models of intestinal adenocarcinoma and adenoma that Bmi1- or Lgr5- positive tumorigenic cells clonally expanded in proliferating tumors. At tumor initiation and during tumor propagation in the colon, the descendants of Lgr5-positive cells clonally proliferated to form clusters. Clonal analysis using ubiquitous multicolor lineage tracing revealed that colon tumors derived from Lgr5-positive cells were monoclonal in origin but eventually merged with neighboring tumors, producing polyclonal tumors at the later stage. In contrast, the origin of small intestine tumors was likely polyclonal, and during cancer progression some clones were eliminated, resulting in the formation of monoclonal tumors, which could merge similar to colon tumors. These results suggest that in proliferating intestinal neoplasms, Bmi1- or Lgr5-positive cells represent a population of cancer stem cells, whereas Lgr5-positive cells also function as cells-of-origin for intestinal tumors. PMID:28176811

  2. Disease kinetics but not disease burden is relevant for survival in melanoma of unknown primary tumor.

    PubMed

    Heppt, Markus V; Tietze, Julia K; Reinholz, Markus; Rahimi, Farnaz; Jung, Andreas; Kirchner, Thomas; Ruzicka, Thomas; Flaig, Michael J; Berking, Carola

    2015-10-01

    Melanoma of unknown primary (MUP) is a type of metastatic melanoma with no evidence of a primary tumor. Recent evidence suggested better survival in MUP as compared to melanoma with a known primary site (MKP). However, prognostic markers that reliably predict overall survival in MUP are lacking. The primary objective of this study was to analyze the mutational status of the BRAF, NRAS, and KIT oncogenes and to investigate if the genotype or other clinical parameters were associated with overall survival. We retrospectively analyzed the genotype and the clinical course of 40 patients with MUP. Mutations of BRAF and NRAS were determined with pyrosequencing. Mutations of KIT were investigated with a nested PCR approach followed by Sanger sequencing. Survival fractions were calculated applying the Kaplan-Meier model. Mutations in the BRAF (50.0%), NRAS (17.5%), and KIT genes (5.0%) were found frequently, but had no major impact on overall survival (p=0.62). The AJCC stage was a strong prognostic factor with a hazard ratio for death of 0.17 (stage III vs. IV; p=0.04). All patients diagnosed with stage III disease survived the median follow-up period of 23 months (p=0.03). The survival rates of patients with stage IV were significantly associated with rapid disease progression but not with metastatic tumor load at primary diagnosis (p=0.01). Altogether, AJCC stage and time to disease progression were important prognostic parameters. We propose that the kinetics of the disease but not the initial metastatic burden nor the mutational status is relevant for survival in advanced MUP.

  3. Relationship between whole-body tumor burden, clinical phenotype, and quality of life in patients with neurofibromatosis.

    PubMed

    Merker, Vanessa L; Bredella, Miriam A; Cai, Wenli; Kassarjian, Ara; Harris, Gordon J; Muzikansky, Alona; Nguyen, Rosa; Mautner, Victor F; Plotkin, Scott R

    2014-06-01

    Patients with neurofibromatosis 1 (NF1), NF2, and schwannomatosis share a predisposition to develop multiple nerve sheath tumors. Previous studies have demonstrated that patients with NF1 and NF2 have reduced quality of life (QOL), but no studies have examined the relationship between whole-body tumor burden and QOL in these patients. We administered a QOL questionnaire (the SF-36) and a visual analog pain scale (VAS) to a previously described cohort of adult neurofibromatosis patients undergoing whole-body MRI. One-sample t-tests were used to compare norm-based SF-36 scores to weighted population means. Spearman correlation coefficients and multiple linear regression analyses controlling for demographic and disease-specific clinical variable were used to relate whole-body tumor volume to QOL scales. Two hundred forty-five patients (142 NF1, 53 NF2, 50 schwannomatosis) completed the study. Subjects showed deficits in selected subscales of the SF-36 compared to adjusted general population means. In bivariate analysis, increased tumor volume was significantly associated with pain in schwannomatosis patients, as measured by the SF-36 bodily pain subscale (rho = -0.287, P = 0.04) and VAS (rho = 0.34, P = 0.02). Regression models for NF2 patients showed a positive relationship between tumor burden and increased pain, as measured by the SF-36 (P = 0.008). Patients with NF1, NF2, and schwannomatosis suffer from reduced QOL, although only pain shows a clear relationship to patient's overall tumor burden. These findings suggest that internal tumor volume is not a primary contributor to QOL and emphasize the need for comprehensive treatment approaches that go beyond tumor-focused therapies such as surgery by including psychosocial interventions. © 2014 Wiley Periodicals, Inc.

  4. Baseline Metabolic Tumor Volume Predicts Outcome in High-Tumor-Burden Follicular Lymphoma: A Pooled Analysis of Three Multicenter Studies.

    PubMed

    Meignan, Michel; Cottereau, Anne Ségolène; Versari, Annibale; Chartier, Loïc; Dupuis, Jehan; Boussetta, Sami; Grassi, Ilaria; Casasnovas, René-Olivier; Haioun, Corinne; Tilly, Hervé; Tarantino, Vittoria; Dubreuil, Julien; Federico, Massimo; Salles, Gilles; Luminari, Stefano; Trotman, Judith

    2016-08-22

    Identifying patients at high risk of progression and early death among those with high-tumor-burden follicular lymphoma (FL) is unsatisfactory with current prognostic models. This study aimed to determine the prognostic impact of the total metabolic tumor volume (TMTV) measured at baseline with [(18)F]fluorodeoxyglucose/positron emission tomography-computed tomography ([(18)F]FDG/PET-CT) scans and its added value to these models. A pooled analysis was performed by using patient data and centrally reviewed baseline PET-CT scans for 185 patients with FL who were receiving immunochemotherapy within three prospective trials. TMTV was computed by using the 41% maximum standardized uptake value thresholding method, and the optimal cutoff for survival prediction was determined. Median age was 55 years, 92% of patients had stage III to IV disease, 37% had a Follicular Lymphoma International Prognostic Index (FLIPI) score of 3 to 5, and 31% had a FLIPI2 score of 3 to 5. With a median follow-up of 64 months, overall 5-year progression-free survival (PFS) was 55% and overall survival (OS) was 92%. Median TMTV was 297 cm(3) (quartile 1 through quartile 3, 135 to 567 cm(3)). The optimal cutoff identified was 510 cm(3), with a markedly inferior survival in the 29% of patients with TMTV > 510 cm(3). Five-year PFS was 33% versus 65% (hazard ratio [HR], 2.90; P < .001), and 5-year OS was 85% versus 95% (HR, 3.45; P = .010). On multivariable analysis, TMTV (HR, 2.3; P = .002) and FLIPI2 score (HR, 2.2; P = .002) were independent predictors of PFS. In combination, they identify three risk groups: high TMTV and intermediate-to-high FLIPI2 score with 5-year PFS of 20% (HR, 5.0; P < .001), high TMTV or intermediate-to-high FLIPI2 score with 5-year PFS of 46% (HR, 2.1; P = .007), and low TMTV and low FLIP2 with 5-year PFS of 69%. Baseline TMTV is a strong independent predictor of outcome in FL. In combination with FLIPI2 score, it identifies patients at high risk of early progression. It

  5. Inhibition of DNA Methylation Suppresses Intestinal Tumor Organoids by Inducing an Anti-Viral Response.

    PubMed

    Saito, Yoshimasa; Nakaoka, Toshiaki; Sakai, Kasumi; Muramatsu, Toshihide; Toshimitsu, Kohta; Kimura, Masaki; Kanai, Takanori; Sato, Toshiro; Saito, Hidetsugu

    2016-05-04

    Recent studies have proposed that the major anti-tumor effect of DNA methylation inhibitors is induction of interferon-responsive genes via dsRNAs-containing endogenous retroviruses. Recently, a 3D culture system for stem cells known as organoid culture has been developed. Lgr5-positive stem cells form organoids that closely recapitulate the properties of original tissues. To investigate the effect of DNA demethylation on tumor organoids, we have established organoids from intestinal tumors of Apc(Min/+) (Min) mice and subjected them to 5-aza-2'-deoxycytidine (5-Aza-CdR) treatment and Dnmt1 knockdown. DNA demethylation induced by 5-Aza-CdR treatment and Dnmt1 knockdown significantly reduced the cell proliferation of the tumor organoids. Microarray analyses of the tumor organoids after 5-Aza-CdR treatment and Dnmt1 knockdown revealed that interferon-responsive genes were activated by DNA demethylation. Gene ontology and pathway analyses clearly demonstrated that these genes activated by DNA demethylation are involved in the anti-viral response. These findings indicate that DNA demethylation suppresses the proliferation of intestinal tumor organoids by inducing an anti-viral response including activation of interferon-responsive genes. Treatment with DNA methylation inhibitors to activate a growth-inhibiting immune response may be an effective therapeutic approach for colon cancers.

  6. 755 nm alexandrite laser for the reduction of tumor burden in basal cell Nevus syndrome.

    PubMed

    Ibrahimi, Omar A; Sakamoto, Fernanda H; Tannous, Zeina; Anderson, R Rox

    2011-02-01

    Basal Cell Nevus syndrome (BCNS) is characterized by numerous basal cell carcinomas (BCCs). Multiple treatments with the pulsed dye laser (PDL) have been shown, in small studies, to be effective for the treatment of superficial and nodular BCCs. Like PDL, the alexandrite laser can be vessel-selective, but has the added advantage of deeper tissue penetration. We evaluated the utility of the alexandrite laser in reducing the tumor burden in BCNS with a single treatment. A case report and review of the literature are presented. A 45-year-old man with BCNS and a history of radiation therapy presented with an extraordinarily high tumor burden (>250 BCCs). As a compassionate measure to reduce the tumor burden, we investigated the utility of a single treatment of the long-pulsed 755 nm alexandrite laser to several BCC lesions. The treated lesions were evaluated at 2-month and 7-month clinical follow-up. Histopathologic analysis of a treated lesion was performed at 7-month clinical follow-up. At 2-month, and 7-month clinical follow-up, 15 of 18 treated lesions or about 83% of the alexandrite laser treated lesions showed a complete clinical response and appeared as hypopigmented areas with scarring. Histopathologic analysis of a treated lesion at 7-month clinical follow-up showed no evidence of residual tumor. The long-pulsed alexandrite laser may be helpful in significantly reducing tumor burden in difficult to manage BCNS patients with a single treatment. This provides a facile and practical treatment alternative for the management of challenging cases of BCNS. The limitation of this study is that it is a single case observation. Larger, prospective studies are needed to confirm these observations. Copyright © 2011 Wiley-Liss, Inc.

  7. Osteopontin Deficiency Suppresses Intestinal Tumor Development in Apc-Deficient Min Mice.

    PubMed

    Ishigamori, Rikako; Komiya, Masami; Takasu, Shinji; Mutoh, Michihiro; Imai, Toshio; Takahashi, Mami

    2017-05-14

    Osteopontin (OPN) is a secreted phosphoglycoprotein, and is a transcriptional target of aberrant Wnt signaling. OPN is upregulated in human colon cancers, and is suggested to enhance cancer progression. In this study, the effect of deficiency of OPN on intestinal tumor development in Apc-deficient Min mice was investigated. At 16 weeks of age, the number of small intestinal polyps in Min/OPN(+/-) and Min/OPN(-/-) mice was lower than that of Min/OPN(+/+) mice. Colorectal tumor incidences and multiplicities in Min/OPN(+/-) and Min/OPN(-/-) mice were significantly lower than those in Min/OPN(+/+) mice, being 48% and 0.6 ± 0.8, 50% and 0.8 ± 0.9 vs. 80% and 1.6 ± 1.7, respectively. OPN expression in colorectal tumors was strongly upregulated in Min/OPN(+/+) compared to adjacent non-tumor parts, but was decreased in Min/OPN(+/-) and not detected in Min/OPN(-/-). Targets of OPN, matrix metalloproteinases (MMPs)-3, -9, and -13 were lowered by OPN deficiency. Macrophage marker F4/80 in colorectal tumors was also lowered by OPN deficiency. MMP-9 expression was observed in tumor cells and tumor-infiltrating neutrophils. These results indicate that induction of OPN by aberrant Wnt signaling could enhance colorectal tumor development in part by upregulation of MMP-3, -9, and -13 and infiltration of macrophage and neutrophils. Suppression of OPN expression could contribute to tumor prevention, but complete deficiency of OPN may cause some adverse effects.

  8. Paternal B Vitamin Intake Is a Determinant of Growth, Hepatic Lipid Metabolism and Intestinal Tumor Volume in Female Apc1638N Mouse Offspring

    PubMed Central

    Sabet, Julia A.; Park, Lara K.; Iyer, Lakshmanan K.; Tai, Albert K.; Koh, Gar Yee; Pfalzer, Anna C.; Parnell, Laurence D.; Mason, Joel B.; Liu, Zhenhua; Byun, Alexander J.; Crott, Jimmy W.

    2016-01-01

    Background The importance of maternal nutrition to offspring health and risk of disease is well established. Emerging evidence suggests paternal diet may affect offspring health as well. Objective In the current study we sought to determine whether modulating pre-conception paternal B vitamin intake alters intestinal tumor formation in offspring. Additionally, we sought to identify potential mechanisms for the observed weight differential among offspring by profiling hepatic gene expression and lipid content. Methods Male Apc1638N mice (prone to intestinal tumor formation) were fed diets containing replete (control, CTRL), mildly deficient (DEF), or supplemental (SUPP) quantities of vitamins B2, B6, B12, and folate for 8 weeks before mating with control-fed wild type females. Wild type offspring were euthanized at weaning and hepatic gene expression profiled. Apc1638N offspring were fed a replete diet and euthanized at 28 weeks of age to assess tumor burden. Results No differences in intestinal tumor incidence or burden were found between male Apc1638N offspring of different paternal diet groups. Although in female Apc1638N offspring there were no differences in tumor incidence or multiplicity, a stepwise increase in tumor volume with increasing paternal B vitamin intake was observed. Interestingly, female offspring of SUPP and DEF fathers had a significantly lower body weight than those of CTRL fed fathers. Moreover, hepatic trigylcerides and cholesterol were elevated 3-fold in adult female offspring of SUPP fathers. Weanling offspring of the same fathers displayed altered expression of several key lipid-metabolism genes. Hundreds of differentially methylated regions were identified in the paternal sperm in response to DEF and SUPP diets. Aside from a few genes including Igf2, there was a striking lack of overlap between these genes differentially methylated in sperm and differentially expressed in offspring. Conclusions In this animal model, modulation of

  9. Paternal B Vitamin Intake Is a Determinant of Growth, Hepatic Lipid Metabolism and Intestinal Tumor Volume in Female Apc1638N Mouse Offspring.

    PubMed

    Sabet, Julia A; Park, Lara K; Iyer, Lakshmanan K; Tai, Albert K; Koh, Gar Yee; Pfalzer, Anna C; Parnell, Laurence D; Mason, Joel B; Liu, Zhenhua; Byun, Alexander J; Crott, Jimmy W

    2016-01-01

    The importance of maternal nutrition to offspring health and risk of disease is well established. Emerging evidence suggests paternal diet may affect offspring health as well. In the current study we sought to determine whether modulating pre-conception paternal B vitamin intake alters intestinal tumor formation in offspring. Additionally, we sought to identify potential mechanisms for the observed weight differential among offspring by profiling hepatic gene expression and lipid content. Male Apc1638N mice (prone to intestinal tumor formation) were fed diets containing replete (control, CTRL), mildly deficient (DEF), or supplemental (SUPP) quantities of vitamins B2, B6, B12, and folate for 8 weeks before mating with control-fed wild type females. Wild type offspring were euthanized at weaning and hepatic gene expression profiled. Apc1638N offspring were fed a replete diet and euthanized at 28 weeks of age to assess tumor burden. No differences in intestinal tumor incidence or burden were found between male Apc1638N offspring of different paternal diet groups. Although in female Apc1638N offspring there were no differences in tumor incidence or multiplicity, a stepwise increase in tumor volume with increasing paternal B vitamin intake was observed. Interestingly, female offspring of SUPP and DEF fathers had a significantly lower body weight than those of CTRL fed fathers. Moreover, hepatic trigylcerides and cholesterol were elevated 3-fold in adult female offspring of SUPP fathers. Weanling offspring of the same fathers displayed altered expression of several key lipid-metabolism genes. Hundreds of differentially methylated regions were identified in the paternal sperm in response to DEF and SUPP diets. Aside from a few genes including Igf2, there was a striking lack of overlap between these genes differentially methylated in sperm and differentially expressed in offspring. In this animal model, modulation of paternal B vitamin intake prior to mating alters

  10. Intestinal ischaemia associated with carcinoid tumor: a case report with review of the pathogenesis.

    PubMed

    Yener, O

    2013-01-01

    Carcinoid tumors are rare, slow-growing neuroendocrine neoplasms that are often indolent and may not become clinically apparent until there is a metastatic spread or evidence of carcinoid syndrome. A 44-year-old man presented to our clinic department with a history of previous left colon cancer operation, chronic crampy left lower quadrant pain, mass and severe anemia. A MR scan was obtained which demonstrated a calcified mesenteric mass 12×8×10 cm diameter with surrounding left colon mesenteric infiltration. The liver was normal. A case of ischaemic ileal necrosis is reported. It was associated with elastic vascular sclerosis produced by mesenteric metastases of an ileal carcinoid tumor. It is postulated that intestinal ischaemia may be of more importance in the production of abdominal pain by carcinoid tumors than has been generally accepted, and that it is the result of functional and structural changes in and around the mesenteric blood vessels, caused by substances secreted by the carcinoid tumor.

  11. Inhibitor of Apoptosis Protein-1 Regulates Tumor Necrosis Factor-Mediated Destruction of Intestinal Epithelial Cells.

    PubMed

    Grabinger, Thomas; Bode, Konstantin J; Demgenski, Janine; Seitz, Carina; Delgado, M Eugenia; Kostadinova, Feodora; Reinhold, Cindy; Etemadi, Nima; Wilhelm, Sabine; Schweinlin, Matthias; Hänggi, Kay; Knop, Janin; Hauck, Christof; Walles, Heike; Silke, John; Wajant, Harald; Nachbur, Ueli; W Wei-Lynn, Wong; Brunner, Thomas

    2017-03-01

    Tumor necrosis factor (TNF) is a cytokine that promotes inflammation and contributes to pathogenesis of inflammatory bowel diseases. Unlike other cells and tissues, intestinal epithelial cells undergo rapid cell death upon exposure to TNF, by unclear mechanisms. We investigated the roles of inhibitor of apoptosis proteins (IAPs) in the regulation of TNF-induced cell death in the intestinal epithelium of mice and intestinal organoids. RNA from cell lines and tissues was analyzed by quantitative polymerase chain reaction, protein levels were analyzed by immunoblot assays. BIRC2 (also called cIAP1) was expressed upon induction from lentiviral vectors in young adult mouse colon (YAMC) cells. YAMC cells, the mouse colon carcinoma cell line MC38, the mouse macrophage cell line RAW 264.7, or mouse and human organoids were incubated with second mitochondrial activator of caspases (Smac)-mimetic compound LCL161 or recombinant TNF-like weak inducer of apoptosis (TNFSF12) along with TNF, and cell death was quantified. C57BL/6 mice with disruption of Xiap, Birc2 (encodes cIAP1), Birc3 (encodes cIAP2), Tnfrsf1a, or Tnfrsf1b (Tnfrsf1a and b encode TNF receptors) were injected with TNF or saline (control); liver and intestinal tissues were collected and analyzed for apoptosis induction by cleaved caspase 3 immunohistochemistry. We also measured levels of TNF and alanine aminotransferase in serum from mice. YAMC cells, and mouse and human intestinal organoids, died rapidly in response to TNF. YAMC and intestinal crypts expressed lower levels of XIAP, cIAP1, cIAP2, and cFLIP than liver tissue. Smac-mimetics reduced levels of cIAP1 and XIAP in MC38 and YAMC cells, and Smac-mimetics and TNF-related weak inducer of apoptosis increased TNF-induced cell death in YAMC cells and organoids-most likely by sequestering and degrading cIAP1. Injection of TNF greatly increased levels of cell death in intestinal tissue of cIAP1-null mice, compared with wild-type C57BL/6 mice, cIAP2-null mice, or

  12. Endoscopic tattooing of early colon carcinoma enhances detection of lymph nodes most prone to harbor tumor burden.

    PubMed

    Aldecoa, Iban; Montironi, Carla; Planell, Nuria; Pellise, Maria; Fernandez-Esparrach, Gloria; Gines, Angels; Delgado, Salvadora; Momblan, Dulce; Moreira, Leticia; Lopez-Ceron, Maria; Rakislova, Natalia; Martinez-Palli, Graciela; Balust, Jaume; Bombi, Josep Antoni; de Lacy, Antonio; Castells, Antoni; Balaguer, Francesc; Cuatrecasas, Miriam

    2017-02-01

    Colorectal cancer (CRC) screening programs result in the detection of early-stage asymptomatic carcinomas suitable to be surgically cured. Lymph nodes (LN) from early CRC are usually small and may be difficult to collect. Still, at least 12 LNs should be analyzed from colectomies, to ensure a reliable pN0 stage. Presurgical endoscopic tattooing improves LN procurement. In addition, molecular detection of occult LN tumor burden in histologically pN0 CRC patients is associated with a decreased survival rate. We aimed to study the impact of presurgical endoscopic tattooing on the molecular detection of LN tumor burden in early colon neoplasms. A prospective cohort study from a CRC screening-based population was performed at a tertiary academic hospital. LNs from colectomies with and without preoperative endoscopic tattooing were assessed by two methods, hematoxylin and eosin (HE), and RT-LAMP, to detect tumor cytokeratin 19 (CK19) mRNA. We compared the amount of tumor burden and LN yields from tattooed and non-tattooed specimens. HE and RT-LAMP analyses of 936 LNs were performed from 71 colectomies containing early carcinomas and endoscopically unresectable adenomas (8 pT0, 17 pTis, 27 pT1, 19 pT2); 47 out of 71 (66.2 %) were tattooed. Molecular positivity correlated with the presence of tattoo in LN [p < 0.001; OR 3.1 (95 % CI 1.7-5.5)]. A significantly higher number of LNs were obtained in tattooed specimens (median 17 LN vs. 14.5 LN; p = 0.019). Endoscopic tattooing enables the analysis of those LNs most prone to harbor tumor cells and improves the number of LN harvested.

  13. Vasoactive intestinal peptide receptor-based imaging and treatment of tumors (Review).

    PubMed

    Tang, Bo; Yong, Xin; Xie, Rui; Li, Qian-Wei; Yang, Shi-Ming

    2014-04-01

    Vasoactive intestinal peptide receptors (VIPRs) are members of the G-protein-coupled receptor superfamily. These receptors are overexpressed in many common malignant tumors and play a major role in the progression and angiogenesis of a number of malignancies. Therefore, VIPRs may be a valuable target for the molecular imaging of tumors and therapeutic interventions. The specific natural ligand or its analogs can be labeled with a radionuclide and used for tumor receptor imaging, which could be used to visualize VIPR-related surface protein expression in vivo and to monitor the in vivo effects of molecular drugs on tumors. Moreover, the involvement of VIPRs in malignant transformation and angiogenesis renders them potential therapeutic targets for cancer treatment. A variety of VIP antagonists and cytotoxic VIP conjugates have been synthesized and evaluated for VIPR-targeted molecular therapy. The importance of VIPRs in tumor biology and the ability to predict responses to targeted therapy and monitor drug interventions suggest that VIP receptor-based imaging and treatment will be critical for the early diagnosis and management of cancer. Here, we review the current literature regarding VIPRs and their natural ligands and the involvement of VIPRs in tumor growth and angiogenesis, with an emphasis on the present use of VIPRs for the molecular imaging of tumors and therapies targeting VIPRs.

  14. Brush border Myosin Ia has tumor suppressor activity in the intestine

    PubMed Central

    Mazzolini, Rocco; Dopeso, Higinio; Mateo-Lozano, Silvia; Chang, Wakam; Rodrigues, Paulo; Bazzocco, Sarah; Alazzouzi, Hafid; Landolfi, Stefania; Hernández-Losa, Javier; Andretta, Elena; Alhopuro, Pia; Espín, Eloy; Armengol, Manel; Tabernero, Josep; Ramón y Cajal, Santiago; Kloor, Matthias; Gebert, Johannes; Mariadason, John M.; Schwartz, Simo; Aaltonen, Lauri A.; Mooseker, Mark S.; Arango, Diego

    2012-01-01

    The loss of the epithelial architecture and cell polarity/differentiation is known to be important during the tumorigenic process. Here we demonstrate that the brush border protein Myosin Ia (MYO1A) is important for polarization and differentiation of colon cancer cells and is frequently inactivated in colorectal tumors by genetic and epigenetic mechanisms. MYO1A frame-shift mutations were observed in 32% (37 of 116) of the colorectal tumors with microsatellite instability analyzed, and evidence of promoter methylation was observed in a significant proportion of colon cancer cell lines and primary colorectal tumors. The loss of polarization/differentiation resulting from MYO1A inactivation is associated with higher tumor growth in soft agar and in a xenograft model. In addition, the progression of genetically and carcinogen-initiated intestinal tumors was significantly accelerated in Myo1a knockout mice compared with Myo1a wild-type animals. Moreover, MYO1A tumor expression was found to be an independent prognostic factor for colorectal cancer patients. Patients with low MYO1A tumor protein levels had significantly shorter disease-free and overall survival compared with patients with high tumoral MYO1A (logrank test P = 0.004 and P = 0.009, respectively). The median time-to-disease recurrence in patients with low MYO1A was 1 y, compared with >9 y in the group of patients with high MYO1A. These results identify MYO1A as a unique tumor-suppressor gene in colorectal cancer and demonstrate that the loss of structural brush border proteins involved in cell polarity are important for tumor development. PMID:22307608

  15. Serotonin-producing enterochromaffin cell tumors of the pancreas: clinicopathologic study of 15 cases and comparison with intestinal enterochromaffin cell tumors.

    PubMed

    La Rosa, Stefano; Franzi, Francesca; Albarello, Luca; Schmitt, Anja; Bernasconi, Barbara; Tibiletti, Maria Grazia; Finzi, Giovanna; Placidi, Claudia; Perren, Aurel; Capella, Carlo

    2011-08-01

    Serotonin-producing tumors of the pancreas are rare endocrine neoplasms composed of enterochromaffin (EC) cells that have been mainly described in the literature as case reports. This study analyzes the clinicopathologic features of a series of pancreatic EC cell neoplasms and their similarities to and differences from intestinal EC cell tumors. The morphological, immunohistochemical, ultrastructural, and fluorescent in situ hybridization features of 15 pancreatic and 20 intestinal serotonin-producing neoplasms were compared. In addition, we reviewed the literature on pancreatic serotonin-producing tumors to better understand the clinicopathologic features of this rare tumor type. The lack of substance P and acidic fibroblast growth factor immunoreactivity; the low immunohistochemical expression of CDX2, vesicular monoamine transporter 1, connective tissue growth factor, and prostatic acid phosphatase; the lack of S100-positive sustentacular cells; the strong expression of vesicular monoamine transporter 2; and peculiar ultrastructural features characterize pancreatic EC cell tumors and differentiate them from intestinal ones, although both categories show similar chromosome 18 cytogenetic alterations. The review of the literature indicates that pancreatic functioning tumors associated with the carcinoid syndrome arise in younger patients and are larger, more frequently malignant, and more aggressive neoplasms than pancreatic nonfunctioning ones. Pancreatic EC cell tumors show several different morphological features compared with related intestinal tumors despite similar cytogenetic alterations on chromosome 18.

  16. COX-2 inhibitor prevents tumor induced down regulation of classical DC lineage specific transcription factor Zbtb46 resulting in immunocompetent DC and decreased tumor burden.

    PubMed

    Pandey, Vipul K; Amin, Prayag J; Shankar, Bhavani S

    2017-04-01

    The interaction between the immune and tumor cells in the microenvironment is an important factor deciding the progression of cancer. Though many of the soluble mediators in the microenvironment that mediate immunosuppression are known, the mechanism by which the tumor affects the distal progenitors is not known. We report that the tumor derived prostanoids down regulated classical dendritic cells DC (cDC) lineage specific transcription factor Zbtb46 in the progenitor cells which affects its differentiation. Prostanoids also induced ERK/CREB/IL-10 signaling pathway in DC that is more important for maturation of DC. This was observed under in vitro as well as in vivo conditions leading to phenotypic and functional impairment of DC. siRNA mediated knockdown of Zbtb46 and not exogenous IL-10 mimicked the effects of tumor conditioned medium (TCM) on suppression of maturation markers. Treatment of tumor cells with COX-2 inhibitor NS-398 averted TCM induced phenotypic impairment of DC in vitro. Treatment of tumor bearing mice with NS-398 prevented tumor induced down regulation of Zbtb46 resulting in immunocompetent DC which in turn led to a decrease in tumor burden. The effects of NS-398 was indeed through immunomodulation was corroborated by no such response in SCID mice. Our study provides novel insight into the distal regulation of progenitor cells by tumor and the importance of Zbtb46 expression in anti-tumor immunity. These results identify Zbtb46 expression as an indicator of immunocompetent DC in tumor and also highlights that COX-2 inhibitors could be useful in cancer immunotherapy. Copyright © 2017 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

  17. IKKβ acts as a tumor suppressor in cancer-associated fibroblasts during intestinal tumorigenesis

    PubMed Central

    Pallangyo, Charles K.; Ziegler, Paul K.

    2015-01-01

    Cancer-associated fibroblasts (CAFs) comprise one of the most important cell types in the tumor microenvironment. A proinflammatory NF-κB gene signature in CAFs has been suggested to promote tumorigenesis in models of pancreatic and mammary skin cancer. Using an autochthonous model of colitis-associated cancer (CAC) and sporadic cancer, we now provide evidence for a tumor-suppressive function of IKKβ/NF-κB in CAFs. Fibroblast-restricted deletion of Ikkβ stimulates intestinal epithelial cell proliferation, suppresses tumor cell death, enhances accumulation of CD4+Foxp3+ regulatory T cells, and induces angiogenesis, ultimately promoting colonic tumor growth. In Ikkβ-deficient fibroblasts, transcription of negative regulators of TGFβ signaling, including Smad7 and Smurf1, is impaired, causing up-regulation of a TGFβ gene signature and elevated hepatocyte growth factor (HGF) secretion. Overexpression of Smad7 in Ikkβ-deficient fibroblasts prevents HGF secretion, and pharmacological inhibition of Met during the CAC model confirms that enhanced tumor promotion is dependent on HGF–Met signaling in mucosa of Ikkβ-mutant animals. Collectively, these results highlight an unexpected tumor suppressive function of IKKβ/NF-κB in CAFs linked to HGF release and raise potential concerns about the use of IKK inhibitors in colorectal cancer patients. PMID:26621452

  18. Point of care assessment of melanoma tumor signaling and metastatic burden from μNMR analysis of tumor fine needle aspirates and peripheral blood.

    PubMed

    Gee, Michael S; Ghazani, Arezou A; Haq, Rizwan; Wargo, Jennifer A; Sebas, Matthew; Sullivan, Ryan J; Lee, Hakho; Weissleder, Ralph

    2017-04-01

    This study evaluates μNMR technology for molecular profiling of tumor fine needle aspirates and peripheral blood of melanoma patients. In vitro assessment of melanocyte (MART-1, HMB45) and MAP kinase signaling (pERK, pS6K) molecule expression was performed in human cell lines, while clinical validation was performed in an IRB-approved study of melanoma patients undergoing biopsy and blood sampling. Tumor FNA and blood specimens were compared with BRAF genetic analysis and cross-sectional imaging. μNMR in vitro analysis showed increased expression of melanocyte markers in melanoma cells as well as increased expression of phosphorylated MAP kinase targets in BRAF-mutant melanoma cells. Melanoma patient FNA samples showed increased pERK and pS6K levels in BRAF mutant compared with BRAF WT melanomas, with μNMR blood circulating tumor cell level increased with higher metastatic burden visible on imaging. These results indicate that μNMR technology provides minimally invasive point-of-care evaluation of tumor signaling and metastatic burden in melanoma patients. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. The role of Pygo2 for Wnt/ß-catenin signaling activity during intestinal tumor initiation and progression

    PubMed Central

    Talla, Suranand B.; Brembeck, Felix H.

    2016-01-01

    Pygo2 acts as a co-activator of Wnt signaling in a nuclear complex with ß-catenin/BCL9/BCL9-2 to increase target gene transcription. Previous studies showed that Pygo2 is upregulated in murine intestinal tumors and human colon cancer, but is apparently dispensable for normal intestinal homeostasis. Here, we have evaluated the in vivo role of Pygo2 during intestinal tumorigenesis using Pygo2 deficient mice. We analyzed chemically induced colon tumor development and conditional intestine specific mouse models harboring either Apc loss-of-function (LOF) or Ctnnb1 gain-of-function (ß-catenin GOF). Remarkably, the number and size of chemically induced tumors was significantly reduced in Pygo2 deficient mice, suggesting that Pygo2 has a tumor promoting function. Furthermore, loss of Pygo2 rescued early tumorigenesis of Ctnnb1 GOF mutants. In contrast, Pygo2 ablation was not sufficient to prevent tumor development of Apc LOF mice. The effect on tumor formation by Pygo2 knockout was linked to the repression of specific deregulated Wnt target genes, in particular of c-Myc. Moreover, the role of Pygo2 appears to be associated with the signaling output of deregulated Wnt signaling in the different tumor models. Thus, targeting Pygo2 might provide a novel strategy to suppress tumor formation in a context dependent manner. PMID:27811361

  20. Tumor necrosis factor-α mediates JNK activation response to intestinal ischemia-reperfusion injury

    PubMed Central

    Yang, Qi; Zheng, Feng-Ping; Zhan, Ya-Shi; Tao, Jin; Tan, Si-Wei; Liu, Hui-Ling; Wu, Bin

    2013-01-01

    AIM: To investigate whether tumor necrosis factor-α (TNF-α) mediates ischemia-reperfusion (I/R)-induced intestinal mucosal injury through c-Jun N-terminal kinase (JNK) activation. METHODS: In this study, intestinal I/R was induced by 60-min occlusion of the superior mesenteric artery in rats followed by 60-min reperfusion, and the rats were pretreated with a TNF-α inhibitor, pentoxifylline, or the TNF-α antibody infliximab. After surgery, part of the intestine was collected for histological analysis. The mucosal layer was harvested for RNA and protein extraction, which were used for further real-time polymerase chain reaction, enzyme-linked immunosorbent assay and Western blotting analyses. The TNF-α expression, intestinal mucosal injury, cell apoptosis, activation of apoptotic protein and JNK signaling pathway were analyzed. RESULTS: I/R significantly enhanced expression of mucosal TNF-α at both the mRNA and protein levels, induced severe mucosal injury and cell apoptosis, activated caspase-9/caspase-3, and activated the JNK signaling pathway. Pretreatment with pentoxifylline markedly downregulated TNF-α at both the mRNA and protein levels, whereas infliximab pretreatment did not affect the expression of TNF-α induced by I/R. However, pretreatment with pentoxifylline or infliximab dramatically suppressed I/R-induced mucosal injury and cell apoptosis and significantly inhibited the activation of caspase-9/3 and JNK signaling. CONCLUSION: The results indicate there was a TNF-α-mediated JNK activation response to intestinal I/R injury. PMID:23946597

  1. In liver metastases from small intestinal neuroendocrine tumors, SSTR2A expression is heterogeneous.

    PubMed

    Charoenpitakchai, Mongkon; Liu, Eric; Zhao, Zhiguo; Koyama, Tatsuki; Huh, Won Jae; Berlin, Jordan; Hande, Kenneth; Walker, Ronald; Shi, Chanjuan

    2017-02-17

    We examined somatostatin receptor type 2A (SSTR2A) expression in primary and metastatic small intestinal neuroendocrine tumors (SI-NETs). We retrieved 156 liver metastases from 26 patients (10 males, 16 females) who had two or more liver lesions resected. A representative formalin-fixed paraffin-embedded section of tumor tissue from each liver metastasis and from the primary tumor, when available, were immunohistochemically stained for SSTR2A. SSTR2A expression was evaluated by the Her2/neu-scoring system and the scoring system proposed by Volante et al. Based on the Her2/neu-scoring system, moderate to strong SSTR2A expression was observed in 121 of 156 (78%) liver metastases. In 15 (58%) subjects, all liver metastases showed moderate to strong SSTR2A expression, whereas in 11 (42%) one or more liver tumors had weak or no expression. Of the 16 stained primaries, 11 (69%) showed heterogeneous SSTR2A expression. The corresponding liver metastases showed only weak to no expression in one, moderate to strong in five, and both weak to no and moderate to strong expression in five of the 11 cases. Using the Volante scoring system, no tumor was scored 0 (0%), two were scored 1 (1%), 38 were scored 2 (24%), and 116 were scored 3 (74%). No statistically significant association was observed between SSTR2A expression and Ki67 index (p = 0.56). Fifteen of 18 (83%) metastatic tumors with a Ki67 index >20% showed moderate to strong SSTR2A. Most liver tumors with weak SSTR2A expression or an IHC score of 2 were detected by OctreoScan. SSTR2A expression in liver metastases of SI-NETs can be variable, even between lesions in the same patient. Expression in metastatic lesions is not always similar to that in the primary tumor. SSTR2A expression is not associated with the Ki67 index.

  2. Salmonella Bacterial Monotherapy Reduces Autochthonous Prostate Tumor Burden in the TRAMP Mouse Model

    PubMed Central

    Kazmierczak, Robert A.; Gentry, Bettina; Mumm, Tyler; Schatten, Heide; Eisenstark, Abraham

    2016-01-01

    Attenuated Salmonella typhimurium injected in the circulatory system of mammals selectively targets tumors. Using weekly intraperitoneal injections of attenuated Salmonella strain CRC2631, we tested for regression and/or inhibition of tumor development in the TRAMP prostate tumor mouse model, which utilizes SV40 early region expression for autochthonous formation of prostate tumors that progress into metastatic, poorly differentiated prostatic carcinomas in an immunocompetent murine model. Thirteen weekly intraperitoneal administrations of 105–107 CFU CRC2631 into 10 week old mice were well tolerated by the TRAMP model. Sacrifice and histological analysis of TRAMP prostates at 22 weeks indicated that Salmonella monotherapy at administrated levels decrease visible tumor size (>29%) but did not significantly inhibit previously described SV40 expression-driven TRAMP tumor progression to undifferentiated carcinomas when histologically examined. In conclusion, this work demonstrates baseline results for CRC2631 Salmonella monotherapy using the immunocompetent TRAMP prostate tumor model in preparation for study of combination therapies that resolve autochthonously generated TRAMP prostate tumors, further reduce tumor size, or inhibit prostate tumor progression. PMID:27504973

  3. Human intestinal Vdelta1+ lymphocytes recognize tumor cells of epithelial origin

    PubMed Central

    1996-01-01

    gammadelta T cells can be grouped into discrete subsets based upon their expression of T cell receptor (TCR) variable (V) region families, their tissue distribution, and their specificity. Vdelta2+ T cells constitute the majority of gammadelta T cells in peripheral blood whereas Vdelta1+T cells reside preferentially in skin epithelium and in the intestine. gammadelta T cells are envisioned as first line host defense mechanisms capable of providing a source of immune effector T cells and immunomodulating cytokines such as interleukin (IL) 4 or interferon (IFN) gamma. We describe here the fine specificity of three distinct gammadelta+ tumor-infiltrating lymphocytes (TIL) obtained from patients with primary or metastatic colorectal cancer, that could be readily expanded in vitro in the presence of IL-1beta and IL-7. Irrespective of donor, these individual gammadelta T cells exhibited a similar pattern of reactivity defined by recognition of autologous and allogeneic colorectal cancer cells, renal cell cancer, pancreatic cancer, and a freshly isolated explant from human intestine as measured by cytolytic T cell responses and by IFN-gamma release. In contrast, tumors of alternate histologies were not lysed, including lung cancer, squamous cell cancer, as well as the natural/lymphocyte-activated killer cell-sensitive hematopoietic cell lines T2, C1R, or Daudi. The cell line K562 was only poorly lysed when compared with colorectal cancer targets. Target cell reactivity mediated by Vdelta1+ T cells was partially blocked with Abs directed against the TCR, the beta2 or beta7 integrin chains, or fibronectin receptor. Marker analysis using flow cytometry revealed that all three gammadelta T cell lines exhibit a similar phenotype. Analysis of the gammadelta TCR junctional suggested exclusive usage of the Vdelta1/Ddelta3/Jdelta1 TCR segments with extensive (< or = 29 bp) N/P region diversity. T cell recognition of target cells did not appear to be a major histocompatibility

  4. Downregulation of Sp1 by Minnelide leads to decrease in HSP70 and decrease in tumor burden of gastric cancer.

    PubMed

    Arora, Nivedita; Alsaied, Osama; Dauer, Patricia; Majumder, Kaustav; Modi, Shrey; Giri, Bhuwan; Dudeja, Vikas; Banerjee, Sulagna; Von Hoff, Daniel; Saluja, Ashok

    2017-01-01

    Gastric cancer is the third leading cause of cancer related mortality worldwide with poor survival rates. Even though a number of chemotherapeutic compounds have been used against this disease, stomach cancer has not been particularly sensitive to these drugs. In this study we have evaluated the effect of triptolide, a naturally derived diterpene triepoxide and its water soluble pro-drug Minnelide on several gastric adenocarcinoma cell lines both as monotherapy and in combination with CPT-11. Gastric cancer cell lines MKN28 and MKN45 were treated with varying doses of triptolide in vitro. Cell viability was measured using MTT based assay kit. Apoptotic cell death was assayed by measuring caspase activity. Effect of the triptolide pro-drug, Minnelide, was evaluated by implanting the gastric cancer cells subcutaneously in athymic nude mice. Gastric cancer cell lines MKN28 and MKN45 cells exhibited decreased cell viability and increased apoptosis when treated with varying doses of triptolide in vitro. When implanted in athymic nude mice, treatment with Minnelide reduced tumor burden in both MKN28 derived tumors as well as MKN45 derived tumors. Additionally, we also evaluated Minnelide as a single agent and in combination with CPT-11 in the NCI-N87 human gastric tumor xenograft model. Our results indicated that the combination of Minnelide with CPT-11 resulted in significantly smaller tumors compared to control. These studies are extremely encouraging as Minnelide is currently undergoing phase 1 clinical trials for gastrointestinal cancers.

  5. Downregulation of Sp1 by Minnelide leads to decrease in HSP70 and decrease in tumor burden of gastric cancer

    PubMed Central

    Arora, Nivedita; Alsaied, Osama; Dauer, Patricia; Majumder, Kaustav; Modi, Shrey; Giri, Bhuwan; Dudeja, Vikas; Banerjee, Sulagna; Von Hoff, Daniel; Saluja, Ashok

    2017-01-01

    Background Gastric cancer is the third leading cause of cancer related mortality worldwide with poor survival rates. Even though a number of chemotherapeutic compounds have been used against this disease, stomach cancer has not been particularly sensitive to these drugs. In this study we have evaluated the effect of triptolide, a naturally derived diterpene triepoxide and its water soluble pro-drug Minnelide on several gastric adenocarcinoma cell lines both as monotherapy and in combination with CPT-11. Methods Gastric cancer cell lines MKN28 and MKN45 were treated with varying doses of triptolide in vitro. Cell viability was measured using MTT based assay kit. Apoptotic cell death was assayed by measuring caspase activity. Effect of the triptolide pro-drug, Minnelide, was evaluated by implanting the gastric cancer cells subcutaneously in athymic nude mice. Results Gastric cancer cell lines MKN28 and MKN45 cells exhibited decreased cell viability and increased apoptosis when treated with varying doses of triptolide in vitro. When implanted in athymic nude mice, treatment with Minnelide reduced tumor burden in both MKN28 derived tumors as well as MKN45 derived tumors. Additionally, we also evaluated Minnelide as a single agent and in combination with CPT-11 in the NCI-N87 human gastric tumor xenograft model. Conclusion Our results indicated that the combination of Minnelide with CPT-11 resulted in significantly smaller tumors compared to control. These studies are extremely encouraging as Minnelide is currently undergoing phase 1 clinical trials for gastrointestinal cancers. PMID:28192510

  6. Multifocal Carcinoid Tumor of Small Intestine: A Rare Cause of Chronic Obscure Gastrointestinal Bleeding, Suspected on Capsule Endoscopy and Diagnosed on Double Balloon Enteroscopy

    PubMed Central

    Hernandez, Jose C.; Rojas, Juan; Gurudu, Suryakanth R.

    2011-01-01

    We reported a case of multifocal carcinoid tumor of small intestine causing chronic obscure gastrointestinal bleeding, suspected on capsule endoscopy and diagnosed on double balloon enteroscopy. PMID:27942327

  7. Treg-cell depletion promotes chemokine production and accumulation of CXCR3(+) conventional T cells in intestinal tumors.

    PubMed

    Akeus, Paulina; Langenes, Veronica; Kristensen, Jonas; von Mentzer, Astrid; Sparwasser, Tim; Raghavan, Sukanya; Quiding-Järbrink, Marianne

    2015-06-01

    Colorectal cancer (CRC) is one of the most prevalent tumor types worldwide and tumor-infiltrating T cells are crucial for anti-tumor immunity. We previously demonstrated that Treg cells from CRC patients inhibit transendothelial migration of conventional T cells. However, it remains unclear if local Treg cells affect lymphocyte migration into colonic tumors. By breeding APC(Min/+) mice with depletion of regulatory T cells mice, expressing the diphtheria toxin receptor under the control of the FoxP3 promoter, we were able to selectively deplete Treg cells in tumor-bearing mice, and investigate the impact of these cells on the infiltration of conventional T cells into intestinal tumors. Short-term Treg-cell depletion led to a substantial increase in the frequencies of T cells in the tumors, attributed by both increased infiltration and proliferation of T cells in the Treg-cell-depleted tumors. We also demonstrate a selective increase of the chemokines CXCL9 and CXCL10 in Treg-cell-depleted tumors, which were accompanied by accumulation of CXCR3(+) T cells, and increased IFN-γ mRNA expression. In conclusion, Treg-cell depletion increases the accumulation of conventional T cells in intestinal tumors, and targeting Treg cells could be a possible anti-tumor immunotherapy, which not only affects T-cell effector functions, but also their recruitment to tumors.

  8. The symptom burden of primary brain tumors: evidence for a core set of tumor- and treatment-related symptoms.

    PubMed

    Armstrong, Terri S; Vera-Bolanos, Elizabeth; Acquaye, Alvina A; Gilbert, Mark R; Ladha, Harshad; Mendoza, Tito

    2016-02-01

    A set of symptoms common across cancers has been proposed to enhance quality of care and clinical research in solid tumor patients. Using data from several clinical studies, this study evaluated these symptoms in primary brain tumor patients. Symptom report data using the MD Anderson Symptom Instrument -Brain Tumor (MDASI-BT) from 621 patients enrolled in 8 clinical studies was used. The prevalence and severity of symptoms were reported as they relate to tumor grade, treatment stage and KPS. The sample was primarily white (82.5%) males (59%) with high-grade gliomas (75%). More than 50% of patients reported at least 10 concurrent symptoms, and 40% of patients reporting having at least 3 moderate-to-severe symptoms. Fatigue, drowsiness, difficulty remembering, disturbed sleep, and distress were the most severe symptoms reported by all tumor grades. Functional interference of symptoms with ability to work, perform activities, walk, and enjoy life was reported by more than 25% of patients. These results support a core set of symptoms, common in other solid tumor patients, that may impact clinical care and assessment of treatment benefit. Although only 5 of the Center for Medical Technology Policy list of proposed core symptoms met criteria for inclusion in this sample, 5 of the other proposed core symptoms were also reported in similar frequency as reported in the other cancer populations. This primary brain tumor population differed from other solid tumor patients in that other symptoms, which could be disease related, were more prevalent and thus should also be collected for these patients. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  9. The symptom burden of primary brain tumors: evidence for a core set of tumor- and treatment-related symptoms

    PubMed Central

    Armstrong, Terri S.; Vera-Bolanos, Elizabeth; Acquaye, Alvina A.; Gilbert, Mark R.; Ladha, Harshad; Mendoza, Tito

    2016-01-01

    Background A set of symptoms common across cancers has been proposed to enhance quality of care and clinical research in solid tumor patients. Using data from several clinical studies, this study evaluated these symptoms in primary brain tumor patients. Methods Symptom report data using the MD Anderson Symptom Instrument -Brain Tumor (MDASI-BT) from 621 patients enrolled in 8 clinical studies was used. The prevalence and severity of symptoms were reported as they relate to tumor grade, treatment stage and KPS. Results The sample was primarily white (82.5%) males (59%) with high-grade gliomas (75%). More than 50% of patients reported at least 10 concurrent symptoms, and 40% of patients reporting having at least 3 moderate-to-severe symptoms. Fatigue, drowsiness, difficulty remembering, disturbed sleep, and distress were the most severe symptoms reported by all tumor grades. Functional interference of symptoms with ability to work, perform activities, walk, and enjoy life was reported by more than 25% of patients. Conclusions These results support a core set of symptoms, common in other solid tumor patients, that may impact clinical care and assessment of treatment benefit. Although only 5 of the Center for Medical Technology Policy list of proposed core symptoms met criteria for inclusion in this sample, 5 of the other proposed core symptoms were also reported in similar frequency as reported in the other cancer populations. This primary brain tumor population differed from other solid tumor patients in that other symptoms, which could be disease related, were more prevalent and thus should also be collected for these patients. PMID:26289592

  10. Liver X receptors inhibit proliferation of human colorectal cancer cells and growth of intestinal tumors in mice.

    PubMed

    Lo Sasso, Giuseppe; Bovenga, Fabiola; Murzilli, Stefania; Salvatore, Lorena; Di Tullio, Giuseppe; Martelli, Nicola; D'Orazio, Andria; Rainaldi, Stefania; Vacca, Michele; Mangia, Anita; Palasciano, Giuseppe; Moschetta, Antonio

    2013-06-01

    Liver X receptors (LXRs) are transcriptional regulators of cholesterol metabolism, controlling cholesterol flow into cells, catabolism, and efflux. Cholesterol controls cell proliferation; disruptions in cholesterol metabolism have been associated with the development of colon cancer. We investigated whether expression of activated LXR protects against intestinal tumorigenesis in mice. We analyzed the development of colon cancer in mice that express a constitutive active form of LXRα only in the intestinal epithelium, under the control of villin promoter (iVP16LXRα). These mice were crossed with adenomatous polyposis coli (Apc)(min/+) mice, or given azoxymethane followed by dextran sodium sulfate, to assess intestinal tumor formation. We also assessed proliferation and apoptosis of a human colorectal cancer cell line (HT29) transfected with an adenoviral vector that expressed Ad VP16hLXRα, compared with cells expressing AdVP16 (control), and their ability to form xenograft tumors in mice. HT29 cells also were incubated with the LXR ligand GW3965. In human colorectal cancer cells, ligand-induced activation of LXR or transfection with Ad VP16hLXRα blocked the G1 phase, increased caspase-dependent apoptosis, and slowed growth of xenograft tumors in mice. iVP16LXRα mice formed fewer, smaller tumors than VP16 (control) mice after administration of azoxymethane and dextran sodium sulfate. APC(min/+)/iVP16LXRα mice also developed fewer, smaller intestinal tumors than APC(min/+)/iVP16 mice. Gene expression analysis indicated that activation of LXRα affected lipid metabolic networks and increased cholesterol efflux in the intestine. Expression of activated LXRα blocks proliferation of human colorectal cancer cells and slows the growth of xenograft tumors in mice. It also reduces intestinal tumor formation after administration of chemical carcinogens, and in Apc(min/+) mice. LXR agonists therefore might be developed as therapeutic treatments for colorectal cancer

  11. Sodium Selenite Radiosensitizes Hormone-Refractory Prostate Cancer Xenograft Tumors but Not Intestinal Crypt Cells In Vivo

    SciTech Connect

    Tian Junqiang; Ning Shouchen; Knox, Susan J.

    2010-09-01

    Purpose: We have previously shown that sodium selenite (SSE) increases radiation-induced cell killing of human prostate carcinoma cells in vitro. In this study we further evaluated the in vivo radiosensitizing effect of SSE in prostate cancer xenograft tumors and normal radiosensitive intestinal crypt cells. Methods and Materials: Immunodeficient (SCID) mice with hormone-independent LAPC-4 (HI-LAPC-4) and PC-3 xenograft tumors (approximately 200 mm{sup 3}) were divided into four groups: control (untreated), radiation therapy (XRT, local irradiation), SSE (2 mg/kg, intraperitoneally, 3 times/week), and XRT plus SSE. The XRT was given at the beginning of the regimen as a single dose of 5 Gy for HI-LAPC-4 tumors and a single dose of 7 Gy followed by a fractional dose of 3 Gy/d for 5 days for PC-3 tumors. The tumor volume was measured 3 times per week. The radiosensitizing effect of SSE on normal intestinal epithelial cells was assessed by use of a crypt cell microcolony assay. Results: In the efficacy study, SSE alone significantly inhibited the tumor growth in HI-LAPC-4 tumors but not PC-3 tumors. Sodium selenite significantly enhanced the XRT-induced tumor growth inhibition in both HI-LAPC-4 and PC-3 tumors. In the toxicity study, SSE did not affect the intestinal crypt cell survival either alone or in combination with XRT. Conclusions: Sodium selenite significantly enhances the effect of radiation on well-established hormone-independent prostate tumors and does not sensitize the intestinal epithelial cells to radiation. These results suggest that SSE may increase the therapeutic index of XRT for the treatment of prostate cancer.

  12. Aloe vera Non-Decolorized Whole Leaf Extract-Induced Large Intestinal Tumors in F344 Rats Share Similar Molecular Pathways with Human Sporadic Colorectal Tumors

    PubMed Central

    Pandiri, Arun R.; Sills, Robert C.; Hoenerhoff, Mark J.; Peddada, Shyamal D.; Ton, Thai-Vu T.; Hong, Hue-Hua L.; Flake, Gordon P.; Malarkey, David E.; Olson, Greg R.; Pogribny, Igor P.; Walker, Nigel J.; Boudreau, Mary D.

    2016-01-01

    Aloe vera is one of the most commonly used botanicals for various prophylactic and therapeutic purposes. Recently, NTP/NCTR has demonstrated a dose-dependent increase in large intestinal tumors in F344 rats chronically exposed to Aloe barbadensis Miller (Aloe vera) non-decolorized whole leaf extract (AVNWLE) in drinking water. The morphological and molecular pathways of AVNWLE-induced large intestinal tumors in the F344 rats were compared to human colorectal cancer (hCRC) literature. Defined histological criteria were used to compare AVNWLE-induced large intestinal tumors with hCRC. The commonly mutated genes (Kras, Ctnnb1, and Tp53) and altered signaling pathways (MAPK, WNT, and TGF-β) important in hCRC were evaluated within AVNWLE-induced large intestinal tumors. Histological evaluation of the large intestinal tumors indicated eight of twelve adenomas (Ads) and four of twelve carcinomas (Cas). Mutation analysis of eight Ads and four Cas identified point mutations in exons 1 and 2 of the Kras gene (two of eight Ads, two of four Cas), and in exon 2 of the Ctnnb1 gene (three of eight Ads, one of four Cas). No Tp53 (exons 5–8) mutations were found in Ads or Cas. Molecular pathways important in hCRC such as MAPK, WNT, and TGF-β signaling were also altered in AVNWLE-induced Ads and Cas. In conclusion, the AVNWLE-induced large intestinal tumors in F344 rats share several similarities with hCRC at the morphological and molecular levels. PMID:21937742

  13. Aloe vera non-decolorized whole leaf extract-induced large intestinal tumors in F344 rats share similar molecular pathways with human sporadic colorectal tumors.

    PubMed

    Pandiri, Arun R; Sills, Robert C; Hoenerhoff, Mark J; Peddada, Shyamal D; Ton, Thai-Vu T; Hong, Hue-Hua L; Flake, Gordon P; Malarkey, David E; Olson, Greg R; Pogribny, Igor P; Walker, Nigel J; Boudreau, Mary D

    2011-12-01

    Aloe vera is one of the most commonly used botanicals for various prophylactic and therapeutic purposes. Recently, NTP/NCTR has demonstrated a dose-dependent increase in large intestinal tumors in F344 rats chronically exposed to Aloe barbadensis Miller (Aloe vera) non-decolorized whole leaf extract (AVNWLE) in drinking water. The morphological and molecular pathways of AVNWLE-induced large intestinal tumors in the F344 rats were compared to human colorectal cancer (hCRC) literature. Defined histological criteria were used to compare AVNWLE-induced large intestinal tumors with hCRC. The commonly mutated genes (Kras, Ctnnb1, and Tp53) and altered signaling pathways (MAPK, WNT, and TGF-β) important in hCRC were evaluated within AVNWLE-induced large intestinal tumors. Histological evaluation of the large intestinal tumors indicated eight of twelve adenomas (Ads) and four of twelve carcinomas (Cas). Mutation analysis of eight Ads and four Cas identified point mutations in exons 1 and 2 of the Kras gene (two of eight Ads, two of four Cas), and in exon 2 of the Ctnnb1 gene (three of eight Ads, one of four Cas). No Tp53 (exons 5-8) mutations were found in Ads or Cas. Molecular pathways important in hCRC such as MAPK, WNT, and TGF-β signaling were also altered in AVNWLE-induced Ads and Cas. In conclusion, the AVNWLE-induced large intestinal tumors in F344 rats share several similarities with hCRC at the morphological and molecular levels.

  14. Tumor Necrosis Factor α-Dependent Neutrophil Priming Prevents Intestinal Ischemia/Reperfusion-Induced Bacterial Translocation.

    PubMed

    Lu, Yen-Zhen; Huang, Ching-Ying; Huang, Yi-Cheng; Lee, Tsung-Chun; Kuo, Wei-Ting; Pai, Yu-Chen; Yu, Linda Chia-Hui

    2017-06-01

    Intestinal ischemia/reperfusion (I/R) causes barrier impairment and bacterial influx. Protection against I/R injury in sterile organs by hypoxic preconditioning (HPC) had been attributed to erythropoietic and angiogenic responses. Our previous study showed attenuation of intestinal I/R injury by HPC for 21 days in a neutrophil-dependent manner. To investigate the underlying mechanisms of neutrophil priming by HPC, and explore whether adoptive transfer of primed neutrophils is sufficient to ameliorate intestinal I/R injury. Rats raised in normoxia (NM) and HPC for 3 or 7 days were subjected to sham operation or superior mesenteric artery occlusion for I/R challenge. Neutrophils isolated from rats raised in NM or HPC for 21 days were intravenously injected into naïve controls prior to I/R. Similar to the protective effect of HPC-21d, I/R-induced mucosal damage was attenuated by HPC-7d but not by HPC-3d. Naïve rats reconstituted with neutrophils of HPC-21d rats showed increase in intestinal phagocytic infiltration and myeloperoxidase activity, and barrier protection against I/R insult. Elevated free radical production, and higher bactericidal and phagocytic activity were observed in HPC neutrophils compared to NM controls. Moreover, increased serum levels of tumor necrosis factor α (TNFα) and cytokine-induced neutrophil chemoattractant-1 (CINC-1) were seen in HPC rats. Naïve neutrophils incubated with HPC serum or recombinant TNFα, but not CINC-1, exhibited heightened respiratory burst and bactericidal activity. Lastly, neutrophil priming effect was abolished by neutralization of TNFα in HPC serum. TNFα-primed neutrophils by HPC act as effectors cells for enhancing barrier integrity under gut ischemia.

  15. Tumor burden as the most important prognostic factor in early stage Hodgkin's disease. Relations to other prognostic factors and implications for choice of treatment

    SciTech Connect

    Specht, L.; Nordentoft, A.M.; Cold, S.; Clausen, N.T.; Nissen, N.I.

    1988-04-15

    Two hundred ninety patients with Hodgkin's disease pathologic stage (PS) I or II were treated in the prospective randomized trial of the Danish National Hodgkin Study with radiotherapy +/- adjuvant combination chemotherapy. The initial tumor burden of each patient was assessed, combining tumor size of each involved region and number of regions involved. Multivariate analyses of prognostic factors including treatment, tumor burden, histologic subtype, pathologic stage, number of involved regions, mediastinal size, systemic symptoms, erythrocyte sedimentation rate (ESR), sex, and age were carried out. With regard to disease-free survival tumor burden was by far the most important prognostic factor for patients treated with adjuvant chemotherapy as well as for patients treated with radiotherapy alone. With regard to survival from Hodgkin's disease only tumor burden and age were independently significant. A combination of tumor burden, histologic subtype, and sex singled out patients with a high relapse rate both after radiotherapy only, and after radiotherapy plus chemotherapy. This combination also singled out patients destined to die from Hodgkin's disease more accurately than other prognostic factors.

  16. Relationship between pretreatment level of plasma Epstein-Barr virus DNA, tumor burden, and metabolic activity in advanced nasopharyngeal carcinoma

    SciTech Connect

    Ma, Brigette; King, Ann; Lo, Y.M. Dennis; Yau, Y.Y.; Zee, Benny; Hui, Edwin P.; Leung, Sing F.; Mo, Frankie; Kam, Michael K.; Ahuja, Anil; Kwan, Wing H.; Chan, Anthony . E-mail: anthony@clo.cuhk.edu.hk

    2006-11-01

    Purpose: Plasma Epstein-Barr virus DNA (pEBV DNA) is an important prognostic marker in nasopharyngeal carcinoma (NPC). This study tested the hypotheses that pEBV DNA reflects tumor burden and metabolic activity by evaluating its relationship with tumor volume and {sup 18}F-fluorodeoxyglucose ({sup 18}F-FDG) uptake in NPC. Methods and Materials: Pre-treatment pEBV DNA analysis, {sup 18}F-FDG positron emission tomography-computed tomography scan (PET-CT) and magnetic resonance imaging (MRI) of the head and neck were performed in 57 patients. Net volume (cm{sup 3}) of the primary tumor (T{sub vol}) and regional nodes (N{sub vol}) were quantified on MRI. {sup 18}F-FDG uptake was expressed as the maximum standardized uptake value (SUV{sub max}) at the primary tumor (T{sub suv}) and regional nodes (N{sub suv}). Lesions with SUV{sub max} {>=} 2.5 were considered malignant. Relationship between SUV{sub max}, natural logarithm (log) of pEBV DNA, and square root (sq) of MRI volumes was analyzed using the Wilcoxon test. A linear regression model was constructed to test for any interaction between variables and disease stage. Results: Log-pEBV DNA showed significant correlation with sq-T{sub vol} (r = 0.393), sq-N{sub vol} (r = 0.452), total tumor volume (sq-Total{sub vol} = T{sub vol} + N{sub vol}, r = 0.554), T{sub suv} (r = 0.276), N{sub suv} (r = 0.434), and total SUV{sub max} (Total{sub suv} = T{sub suv} + N{sub suv}, r = 0.457). Likewise, sq-T{sub vol} was correlated to T{sub suv} (r 0.426), and sq-N{sub vol} with N{sub suv} (r = 0.651). Regression analysis showed that only log-pEBV DNA was significantly associated with sq-Total{sub vol} (p < 0.001; parameter estimate = 8.844; 95% confidence interval = 3.986-13.703), whereas Sq-T{sub vol} was significantly associated with T{sub suv} (p = 0.002; parameter estimate = 3.923; 95% confidence interval = 1.498-6.348). Conclusion: This study supports the hypothesis that cell-free plasma EBV DNA is a marker of tumor burden in EBV

  17. Clinical significance of post-surgical residual tumor burden and radiation therapy in treating patients with lacrimal adenoid cystic carcinoma

    PubMed Central

    Ahn, Yong Chan; Oh, Dongryul; Kim, Yoon-Duck; Woo, Kyung In; Ko, Young-Hyeh; Kim, Seokhwi

    2016-01-01

    Retrospective analyses were done on 19 lacrimal adenoid cystic carcinoma (ACC) patients who underwent curative treatment between 1997 and 2013. Nine patients (47.4%) had T1-2 disease and ten (52.6%) had T4 disease. Surgical procedures were globe-preserving tumor resection in 11 patients (57.9%), incisional biopsy in five (26.3%), and orbital exenteration was undertaken in three (15.8%). Residual tumor burdens were R0/1 in 12 patients (63.2%) and R2 in seven (36.8%). Radiation therapy (RT) was recommended to all patients, and 16 (84.2%) completed RT (median 60 Gy). After median follow-up of 57.5 months, seven (36.8%) developed progression and three (15.8%) died. Local recurrence occurred in four patients (21.1%), distant metastasis in one (5.3%), and combined local recurrence and distant metastasis in two (10.5%). Progression-free survival and overall survival rates at 5-years were 64.5% and 82.6%, respectively. Among 12 patients following R0/1 resection, two (16.7%) developed local recurrence and none died, while among seven following R2 resection, five (71.4%) developed progression and three (42.9%) died. RT following R0/R1 resection could reduce progression. Globe-preserving surgery and RT seemed optimal strategy for T1-2 disease. Careful attention should to be paid to minimize residual tumor burden at surgery and effort for safe radiation dose escalation would be desired. PMID:27372060

  18. UV exposure inhibits intestinal tumor growth and progression to malignancy in intestine-specific Apc mutant mice kept on low vitamin D diet.

    PubMed

    Rebel, Heggert; der Spek, Celia Dingemanse-van; Salvatori, Daniela; van Leeuwen, Johannes P T M; Robanus-Maandag, Els C; de Gruijl, Frank R

    2015-01-15

    Mortality from colorectal cancer increases with latitude and decreases with ambient UV radiation. We investigated whether moderate UV dosages could inhibit intestinal tumor development and whether this corresponded with UV-induced vitamin D. FabplCre;Apc(15lox/+) mice, which develop intestinal tumors, and their parents were put on a vitamin D-deficient diet. Next to a control group, one group was vitamin D supplemented and another one group was daily UV irradiated from 6 weeks of age. Vitamin D statuses after 6 weeks of treatment were markedly increased: mean ± SD from 7.7 ± 1.9 in controls to 75 ± 15 nmol/l with vitamin D supplementation (no gender difference), and to 31 ± 13 nmol/l in males and 85 ± 17 nmol/l in females upon UV irradiation. The tumor load (area covered by tumors) at 7.5 months of age was significantly reduced in both the vitamin D-supplemented group (130 ± 25 mm(2), p = 0.018) and the UV-exposed group (88 ± 9 mm(2), p < 0.0005; no gender differences) compared to the control group (202 ± 23 mm(2)). No reductions in tumor numbers were found. Only UV exposure appeared to reduce progression to malignancy (p = 0.014). Our experiments clearly demonstrate for the first time an inhibitory effect of moderate UV exposure on outgrowth and malignant progression of primary intestinal tumors, which at least in part can be attributed to vitamin D. © 2014 UICC.

  19. Skeletal Tumor Burden on Baseline 18F-Fluoride PET/CT Predicts Bone Marrow Failure After 223Ra Therapy.

    PubMed

    Etchebehere, Elba C; Araujo, John C; Milton, Denái R; Erwin, William D; Wendt, Richard E; Swanston, Nancy M; Fox, Patricia; Macapinlac, Homer A; Rohren, Eric M

    2016-04-01

    Determine if skeletal tumor burden on 18F-fluoride PET/CT (fluoride PET/CT) predicts the risk of bone marrow failure (BMF) after 223Ra dichloride therapy (223Ra). Forty-one metastatic prostate cancer patients (43-89 years old; mean, 71 ± 9 years.) underwent fluoride PET/CT prior to 223Ra. Bone marrow failure was the primary end point and was defined as (1) development of hematologic toxicity (World Health Organization grade 3 or 4) associated with no recovery after 6 weeks or (2) death due to BMF after the last 223Ra dose. Bone marrow failure was correlated to fluoride PET/CT skeletal tumor burden (TLF10 [total lesion on fluoride PET/CT with SUVmax of 10 or greater]), use of chemotherapy, serum hemoglobin concentration, serum ALP, and serum prostate-specific antigen. The number of 223Ra cycles ranged from 2 to 6 (mean, 5). Of the 41 patients, 16 developed BMF (G3 = 12; G4 = 4). A significantly increased risk of developing BMF was observed in patients with TLF10 of 12,000 or greater (hazard ratio [HR], 11.09; P < 0.0001), hemoglobin of less than 10 g/dL (HR, 7.35; P = 0.0002), and AP > 146 UI/L (HR, 4.52; P = 0.0100). Neither concomitant (HR, 0.91; P = 0.88) nor subsequent use of chemotherapy (HR, 0.14; P = 0.84) increased the risk of BMF, nor was prostate-specific antigen greater than 10 μg/L (HR, 0.90; P = 0.86). Moreover, in a multivariable analysis, TLF10 was the only independent predictor of BMF (HR, 6.66; P = 0.0237). 223Ra was beneficial and reduced the risk of death even in patients with a high skeletal tumor burden. Fluoride PET/CT is able to determine which patients will benefit from 223Ra and which will develop BMF.

  20. Is reduction of tumor burden sufficient for the 21st century?

    PubMed

    Nahas, George; Bliss, Sarah A; Sinha, Garima; Ganta, Teja; Greco, Steven J; Rameshwar, Pranela

    2015-01-28

    Currently, animal models are used to test the efficacy of tumor treatment. A significant reduction of tumor mass is lauded as great improvement. As we begin the 21st century, one wonders if this is sufficient and acceptable for cancer treatment. Although the presence of cancer stem cell (CSCs) is not a new phenomenon, their role in the initiation of the tumor for clinical resurgence is mostly ignored when testing drugs. The current treatment then poses a major limitation to aggressively target the cells most responsible for tumor initiation and resurgence. The review does not trivialize the problem since it is acknowledged that the tumors and cells within the tissue microenvironment would interact through complex mechanisms. It is quite possible that the interaction by CSCs and the microenvironment will vary, depending on the tissue, e.g., bone marrow versus brain. Research studies are needed to investigate if CSCs from the same organ differ after migrating to other tissues. If so, this will pose an economic dilemma for targeted drug development. It will not be feasible to develop drugs for each organ. Besides, the cost, there could be problems to effectively deliver the drugs to all organs, problems to assess drug distribution to particular tissues and toxicity for specific drugs. If multiple drugs are required to eradicate CSCs in different tissues, there is a problem of possible untoward effect for the simultaneous delivery of multiple drugs to a single cancer patient. As new drugs are developed, the investigators will need to pay attention for dedifferentiation of non-CSCs to CSCs. The metabolic pathways will have to be given equal attention as the stem cells genes since their pathways might show major differences rather than the stem cells genes, which are shared by the normal stem cells.

  1. Radioprotection and Cell Cycle Arrest of Intestinal Epithelial Cells by Darinaparsin, a Tumor Radiosensitizer

    SciTech Connect

    Tian, Junqiang; Doi, Hiroshi; Saar, Matthias; Santos, Jennifer; Li, Xuejun; Peehl, Donna M.; Knox, Susan J.

    2013-12-01

    Purpose: It was recently reported that the organic arsenic compound darinaparsin (DPS) is a cytotoxin and radiosensitizer of tumor cells in vitro and in subcutaneous xenograft tumors. Surprisingly, it was also found that DPS protects normal intestinal crypt epithelial cells (CECs) from clonogenic death after ionizing radiation (IR). Here we tested the DPS radiosensitizing effect in a clinically relevant model of prostate cancer and explored the radioprotective effect and mechanism of DPS on CECs. Methods and Materials: The radiation modification effect of DPS was tested in a mouse model of orthotopic xenograft prostate cancer and of IR-induced acute gastrointestinal syndrome. The effect of DPS on CEC DNA damage and DNA damage responses was determined by immunohistochemistry. Results: In the mouse model of IR-induced gastrointestinal syndrome, DPS treatment before IR accelerated recovery from body weight loss and increased animal survival. DPS decreased post-IR DNA damage and cell death, suggesting that the radioprotective effect was mediated by enhanced DNA damage repair. Shortly after DPS injection, significant cell cycle arrest was observed in CECs at both G1/S and G2/M checkpoints, which was accompanied by the activation of cell cycle inhibitors p21 and growth arrest and DNA-damage-inducible protein 45 alpha (GADD45A). Further investigation revealed that DPS activated ataxia telangiectasia mutated (ATM), an important inducer of DNA damage repair and cell cycle arrest. Conclusions: DPS selectively radioprotected normal intestinal CECs and sensitized prostate cancer cells in a clinically relevant model. This effect may be, at least in part, mediated by DNA damage response activation and has the potential to significantly increase the therapeutic index of radiation therapy.

  2. Accuracy and variability of tumor burden measurement on multi-parametric MRI

    NASA Astrophysics Data System (ADS)

    Salarian, Mehrnoush; Gibson, Eli; Shahedi, Maysam; Gaed, Mena; Gómez, José A.; Moussa, Madeleine; Romagnoli, Cesare; Cool, Derek W.; Bastian-Jordan, Matthew; Chin, Joseph L.; Pautler, Stephen; Bauman, Glenn S.; Ward, Aaron D.

    2014-03-01

    Measurement of prostate tumour volume can inform prognosis and treatment selection, including an assessment of the suitability and feasibility of focal therapy, which can potentially spare patients the deleterious side effects of radical treatment. Prostate biopsy is the clinical standard for diagnosis but provides limited information regarding tumour volume due to sparse tissue sampling. A non-invasive means for accurate determination of tumour burden could be of clinical value and an important step toward reduction of overtreatment. Multi-parametric magnetic resonance imaging (MPMRI) is showing promise for prostate cancer diagnosis. However, the accuracy and inter-observer variability of prostate tumour volume estimation based on separate expert contouring of T2-weighted (T2W), dynamic contrastenhanced (DCE), and diffusion-weighted (DW) MRI sequences acquired using an endorectal coil at 3T is currently unknown. We investigated this question using a histologic reference standard based on a highly accurate MPMRIhistology image registration and a smooth interpolation of planimetric tumour measurements on histology. Our results showed that prostate tumour volumes estimated based on MPMRI consistently overestimated histological reference tumour volumes. The variability of tumour volume estimates across the different pulse sequences exceeded interobserver variability within any sequence. Tumour volume estimates on DCE MRI provided the lowest inter-observer variability and the highest correlation with histology tumour volumes, whereas the apparent diffusion coefficient (ADC) maps provided the lowest volume estimation error. If validated on a larger data set, the observed correlations could support the development of automated prostate tumour volume segmentation algorithms as well as correction schemes for tumour burden estimation on MPMRI.

  3. [Studies on the biotransformation of escin Ia by human intestinal bacteria and the anti-tumor activities of desacylescin I].

    PubMed

    Yang, Xiu-Wei; Zhao, Jing; Cui, Jing-Rong; Guo, Wei

    2004-02-01

    To study Biotransformation of escin Ia by the crude enzymes of human intestinal bacteria and Lactobacillus brevis, determine the structures of biotransformation products and assay the inhibitory effect of desacylescin I on the tumor cell growth. The escin Ia was incubated with crude enzymes of human intestinal bacteria and Lactobacillus brevis in vitro, respectively. The biotransformation products were isolated and purified by the chromatographic methods and the structures were determined by the spectroscopic techniques. Escin Ia was converted into isoescin Ia, desacylescin I, 21beta-O-tigloylprotoaescigenin and protoaescigenin by crude enzymes of human intestinal bacteria and Lactobacillus brevis. Desacylescin I showed potentially inhibitory effects on tumor cell growth of mouse sarcoma-180, hepatic carcinoma H(22) and lung carcinoma in vivo. The results suggest that Escin Ia was a prodrug and its structure can be converted by human intestinal bacteria and Lactobacillus brevis. Desacylescin I as a biotransformation product showed potentially inhibitory effects on mouse tumor, and a potential candidate for anti tumor agents.

  4. Expression profiling of small intestinal neuroendocrine tumors identifies subgroups with clinical relevance, prognostic markers and therapeutic targets.

    PubMed

    Andersson, Ellinor; Arvidsson, Yvonne; Swärd, Christina; Hofving, Tobias; Wängberg, Bo; Kristiansson, Erik; Nilsson, Ola

    2016-06-01

    We wanted to define the transcriptome of small intestinal neuroendocrine tumors in order to identify clinically relevant subgroups of tumors, prognostic markers and novel targets for treatment. Genome-wide expression profiling was conducted on tumor biopsies from 33 patients with well-differentiated neuroendocrine tumors of the distal ileum and metastatic disease at the time of diagnosis. Unsupervised hierarchical clustering analysis identified three groups of tumors. The largest group, comprising half of the tumors, was characterized by longer patient survival and higher expression of neuroendocrine markers, including SSTR2. Tumors with higher grade (G2/3) or gain of chromosome 14 were associated with shorter patient survival and increased expression of cell cycle-promoting genes. Pathway analysis predicted the prostaglandin E receptor 2 (PTGER2) as the most significantly activated regulator in tumors of higher grade, whereas Forkhead box M1 (FOXM1) was the most significantly activated regulator in tumors with gain of chromosome 14. Druggable genes identified from expression profiles included clinically proven SSTR2 and also novel targets, for example, receptor tyrosine kinases (RET, FGFR1/3, PDGFRB and FLT1), epigenetic regulators, molecular chaperones and signal transduction molecules. Evaluation of candidate drug targets on neuroendocrine tumors cells (GOT1) showed significant inhibition of tumor cell growth after treatment with tyrosine kinase inhibitors or inhibitors of HDAC, HSP90 and AKT. In conclusion, we have defined the transcriptome of small intestinal neuroendocrine tumors and identified novel subgroups with clinical relevance. We found specific gene expression patterns associated with tumor grade and chromosomal alterations. Our data also suggest novel prognostic biomarkers and therapies for these patients.

  5. Involvement of trefoil factor family 2 in the enlargement of intestinal tumors in Apc(Min/+) mice.

    PubMed

    Fujimoto, Kyoko; Fujii, Gen; Taguchi, Kenichi; Yasuda, Kaori; Matsuo, Yuta; Hashiyama, Airi; Mutoh, Michihiro; Tanaka, Hiromitsu; Wada, Morimasa

    2015-08-07

    It is assumed that tumor size may be associated with malignant tumor conversion. However, the molecules responsible for determination of tumor size are not well understood. We counted the number of intestinal tumors in 8, 12 and 30-week-old Apc(Min/+) mice and measured tumor sizes, respectively. Genes involved in determining tumor size were examined using microarray analysis. Cultured cells were then, transfected with a mammalian expression vector containing a candidate gene to examine the functional role of the gene. The effect of forced expression of candidate gene on cell growth was evaluated by measuring the doubling time of the cultured cells and the growth of grafted cells in nude mice. Unexpectedly, microarray analysis identified trefoil factor family 2 (Tff2) rather than growth related genes and/or oncogenes as a most variable gene. Overexpressing Tff2 in cultured cells reduced doubling time in vitro and rapidly increased xenograft tumor size in vivo. We found Tff2 as a novel important factor that to be able to enlarge an intestinal tumor size. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  6. The cluster microRNAs miR-194 and miR-215 suppress the tumorigenicity of intestinal tumor organoids.

    PubMed

    Nakaoka, Toshiaki; Saito, Yoshimasa; Shimamoto, Yuriko; Muramatsu, Toshihide; Kimura, Masaki; Kanai, Yae; Saito, Hidetsugu

    2017-01-16

    Tumor stem cells with self-renewal and multipotent capacity play critical roles in the initiation and progression of cancer. Recently, a new 3D culture system known as organoid culture has been developed, allowing Lgr5-positive stem cells to form organoids that resemble the properties of original tissues. Here we established organoids derived from intestinal tumors of Apc(min/+) mice and normal intestinal epithelia of C57BL/6J mice and investigated the roles of microRNAs (miRNAs) in intestinal tumor organoids. The results of microarray analyses revealed that expression of the cluster miRNAs, miR-194 and miR-215, was markedly suppressed in intestinal tumor organoids in comparison with organoids derived from normal intestinal epithelia. Enforced expression of miR-194 resulted in inhibition of E2f3, a positive regulator of the cell cycle and growth suppression of intestinal tumor organoids. In addition, enforced expression of miR-215 suppressed the cancer stem cell signature through down-regulation of intestinal stem cell markers including Lgr5. These findings indicate that the miRNA cluster including miR-194 and miR-215 plays important roles in suppressing the growth and attenuating the stemness of intestinal tumor organoids. This article is protected by copyright. All rights reserved.

  7. An Orally Available Small-Molecule Inhibitor of c-Met, PF-2341066, Reduces Tumor Burden and Metastasis in a Preclinical Model of Ovarian Cancer Metastasis1

    PubMed Central

    Zillhardt, Marion; Christensen, James G; Lengyel, Ernst

    2010-01-01

    Deregulated expression of the hepatocyte growth factor (HGF) receptor, c-Met, in cancer contributes to tumor progression and metastasis. The objective of this study was to determine whether blocking c-Met with an orally available c-Met inhibitor, PF-2341066, reduces tumor burden and increases survival in a xenograft model of ovarian cancer metastasis. Treatment of mice injected interperitoneally with SKOV3ip1 cells showed reduced overall tumor burden. Tumor weight and the number of metastases were reduced by 55% (P < .0005) and 62% (P < .0001), respectively. Treatment also increased median survival from 45 to 62 days (P = .0003). In vitro, PF-2341066 reduced HGF-stimulated phosphorylation of c-Met in the tyrosine kinase domain as well as phosphorylation of the downstream signaling effectors, Akt and Erk. It was apparent that inhibition of the pathways was functionally important because HGF-induced branching morphogenesis was also inhibited. In addition, proliferation and adhesion to various extracellular matrices were inhibited by treatment with PF-2341066, and the activity of matrix metalloproteinases was decreased in tumor tissue from treated mice compared with those receiving vehicle. Overall, these data indicate that PF-2341066 effectively reduces tumor burden in an in vivo model of ovarian cancer metastasis and may be a good therapeutic candidate in the treatment of patients with ovarian cancer. PMID:20072648

  8. Antibodies to merkel cell polyomavirus T antigen oncoproteins reflect tumor burden in merkel cell carcinoma patients.

    PubMed

    Paulson, Kelly G; Carter, Joseph J; Johnson, Lisa G; Cahill, Kevin W; Iyer, Jayasri G; Schrama, David; Becker, Juergen C; Madeleine, Margaret M; Nghiem, Paul; Galloway, Denise A

    2010-11-01

    Merkel cell polyomavirus (MCPyV) is a common infectious agent that is likely involved in the etiology of most Merkel cell carcinomas (MCC). Serum antibodies recognizing the MCPyV capsid protein VP1 are detectable at high titer in nearly all MCC patients and remain stable over time. Although antibodies to the viral capsid indicate prior MCPyV infection, they provide limited clinical insight into MCC because they are also detected in more than half of the general population. We investigated whether antibodies recognizing MCPyV large and small tumor-associated antigens (T-Ag) would be more specifically associated with MCC. Among 530 population control subjects, these antibodies were present in only 0.9% and were of low titer. In contrast, among 205 MCC cases, 40.5% had serum IgG antibodies that recognize a portion of T-Ag shared between small and large T-Ags. Among cases, titers of T-Ag antibodies fell rapidly (∼8-fold per year) in patients whose cancer did not recur, whereas they rose rapidly in those with progressive disease. Importantly, in several patients who developed metastases, the rise in T-Ag titer preceded clinical detection of disease spread. These results suggest that antibodies recognizing T-Ag are relatively specifically associated with MCC, do not effectively protect against disease progression, and may serve as a clinically useful indicator of disease status.

  9. Chemoimmunotherapy by combining oxaliplatin with immune checkpoint blockades reduced tumor burden in colorectal cancer animal model.

    PubMed

    Wang, Weiwei; Wu, Ling; Zhang, Jiansheng; Wu, Huiguo; Han, Enkun; Guo, Qiang

    2017-05-20

    Colorectal cancer (CRC) is among one of the top common cancers worldwide. Developing novel comprehensive treatment strategies is critical for improving survival of late stage CRC patients. Recent advances in immune checkpoint blockades provided a novel strategy for treating cancers via stimulating the antitumor immune response. However, the effects of immune checkpoint blockades were limited in CRC due to intrinsic resistance. Oxaliplatin (OXA) based chemotherapy was the foundation of CRC adjuvant chemotherapy. Here, we investigated the potential roles of OXA in inducing immunogenicity and synergizing with immune checkpoints in CRC. Immunogenicity of OXA was tested in CRC cell lines. Immune checkpoint blockades sensitive and resistant CRC models were used to study the potential synergistic roles of OXA with immune checkpoint blockades. We found CT26 mouse model was sensitive to immune checkpoint blockades, while MC38 mouse model was resistant. OXA could induce immunogenic cell death in several human and mouse CRC cell lines. Short term OXA treatment increased immune cell infiltration in MC38 mouse model and therefore enhanced the efficacy of immune checkpoint in MC38 mouse model. As a response to the OXA and immune checkpoint blockades combination, inhibitory immune checkpoints were down-regulated in MC38 tumors, while immune enhancing cytokines were up-regulated. Short term OXA treatment induced antitumor immune response in an immune checkpoint blockades resistant mouse model, therefore synergized with immune checkpoint blockades. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Bile Acid Administration Elicits an Intestinal Antimicrobial Program and Reduces the Bacterial Burden in Two Mouse Models of Enteric Infection.

    PubMed

    Tremblay, Sarah; Romain, Guillaume; Roux, Mélisange; Chen, Xi-Lin; Brown, Kirsty; Gibson, Deanna L; Ramanathan, Sheela; Menendez, Alfredo

    2017-06-01

    In addition to their chemical antimicrobial nature, bile acids are thought to have other functions in the homeostatic control of gastrointestinal immunity. However, those functions have remained largely undefined. In this work, we used ileal explants and mouse models of bile acid administration to investigate the role of bile acids in the regulation of the intestinal antimicrobial response. Mice fed on a diet supplemented with 0.1% chenodeoxycholic acid (CDCA) showed an upregulated expression of Paneth cell α-defensins as well as an increased synthesis of the type-C lectins Reg3b and Reg3g by the ileal epithelium. CDCA acted on several epithelial cell types, by a mechanism independent from farnesoid X receptor (FXR) and not involving STAT3 or β-catenin activation. CDCA feeding did not change the relative abundance of major commensal bacterial groups of the ileum, as shown by 16S analyses. However, administration of CDCA increased the expression of ileal Muc2 and induced a change in the composition of the mucosal immune cell repertoire, decreasing the proportion of Ly6G(+) and CD68(+) cells, while increasing the relative amount of IgGκ(+) B cells. Oral administration of CDCA to mice attenuated infections with the bile-resistant pathogens Salmonella enterica serovar Typhimurium and Citrobacter rodentium, promoting lower systemic colonization and faster bacteria clearance, respectively. Our results demonstrate that bile acid signaling in the ileum triggers an antimicrobial program that can be potentially used as a therapeutic option against intestinal bacterial infections. Copyright © 2017 American Society for Microbiology.

  11. Assessment of the mode of action underlying development of rodent small intestinal tumors following oral exposure to hexavalent chromium and relevance to humans

    PubMed Central

    Proctor, Deborah M.; Suh, Mina; Haws, Laurie C.; Kirman, Christopher R.; Harris, Mark A.

    2013-01-01

    Chronic exposure to high concentrations of hexavalent chromium (Cr(VI)) in drinking water causes intestinal adenomas and carcinomas in mice, but not in rats. Cr(VI) causes damage to intestinal villi and crypt hyperplasia in mice after only one week of exposure. After two years of exposure, intestinal damage and crypt hyperplasia are evident in mice (but not rats), as are intestinal tumors. Although Cr(VI) has genotoxic properties, these findings suggest that intestinal tumors in mice arise as a result of chronic mucosal injury. To better understand the mode of action (MOA) of Cr(VI) in the intestine, a 90-day drinking water study was conducted to collect histological, biochemical, toxicogenomic and pharmacokinetic data in intestinal tissues. Using MOA analyses and human relevance frameworks proposed by national and international regulatory agencies, the weight of evidence supports a cytotoxic MOA with the following key events: (a) absorption of Cr(VI) from the intestinal lumen, (b) toxicity to intestinal villi, (c) crypt regenerative hyperplasia and (d) clonal expansion of mutations within the crypt stem cells, resulting in late onset tumorigenesis. This article summarizes the data supporting each key event in the MOA, as well as data that argue against a mutagenic MOA for Cr(VI)-induced intestinal tumors. PMID:23445218

  12. Automated Tracking of Quantitative Assessments of Tumor Burden in Clinical Trials1

    PubMed Central

    Rubin, Daniel L; Willrett, Debra; O'Connor, Martin J; Hage, Cleber; Kurtz, Camille; Moreira, Dilvan A

    2014-01-01

    There are two key challenges hindering effective use of quantitative assessment of imaging in cancer response assessment: 1) Radiologists usually describe the cancer lesions in imaging studies subjectively and sometimes ambiguously, and 2) it is difficult to repurpose imaging data, because lesion measurements are not recorded in a format that permits machine interpretation and interoperability. We have developed a freely available software platform on the basis of open standards, the electronic Physician Annotation Device (ePAD), to tackle these challenges in two ways. First, ePAD facilitates the radiologist in carrying out cancer lesion measurements as part of routine clinical trial image interpretation workflow. Second, ePAD records all image measurements and annotations in a data format that permits repurposing image data for analyses of alternative imaging biomarkers of treatment response. To determine the impact of ePAD on radiologist efficiency in quantitative assessment of imaging studies, a radiologist evaluated computed tomography (CT) imaging studies from 20 subjects having one baseline and three consecutive follow-up imaging studies with and without ePAD. The radiologist made measurements of target lesions in each imaging study using Response Evaluation Criteria in Solid Tumors 1.1 criteria, initially with the aid of ePAD, and then after a 30-day washout period, the exams were reread without ePAD. The mean total time required to review the images and summarize measurements of target lesions was 15% (P < .039) shorter using ePAD than without using this tool. In addition, it was possible to rapidly reanalyze the images to explore lesion cross-sectional area as an alternative imaging biomarker to linear measure. We conclude that ePAD appears promising to potentially improve reader efficiency for quantitative assessment of CT examinations, and it may enable discovery of future novel image-based biomarkers of cancer treatment response. PMID:24772204

  13. Characterization, pharmacokinetics, tissue distribution and antitumor activity of honokiol submicron lipid emulsions in tumor-burdened mice.

    PubMed

    Zheng, Jiaxin; Tang, Yujie; Sun, Moran; Zhao, Yuanyuan; Li, Qiang; Zhou, Jie; Wang, Yanzhi

    2013-01-01

    Honokiol, isolated from the Chinese traditional herb magnolia, is a poorly water-soluble component and has been found to have anti-tumor properties. In the current study, honokiol submicron lipid emulsions (HK-SLEs) were prepared by high pressure homogenization technology. After HK-SLEs were physically characterized, their pharmacokinetics, tissue distribution and antitumor activity after intravenous (i.v.) administration to tumor-burdened mice were examined, using honokiol solution (HK-SOL) as the control. The results showed that the mean particle size, zeta potential, pH value, osmolality, drug loading (DL)% and entrapment efficiency (EE)% of HK-SLEs were 186.6 +/- 1.7 nm, -35.65 +/- 0.67 mV, 7.22 +/- 0.26, 298 +/- 2.3 mOsm/L, 7.1 +/- 0.2% and 95.5 +/- 0.2%, respectively. HK-SLEs were stable for at least 12 months when stored at 4 +/- 2 degrees C. The pharmacokinetic results showed that the drug concentration-time curves of HK-SLEs and HK-SOL could both be described by an open two-compartment model. The half-life of HK-SLEs (t1/2(alpha) = 8.014 min, t1/2(beta) = 35.784 min) was remarkably prolonged compared to that of HK-SOL (t1/2(alpha) = 4.318 min, t1/2(beta) = 15.522 min). HK-SLEs exhibited a greater AUC and reduced plasma clearance. The tissue distribution results indicated that HK-SLEs have better targeting properties to lung and tumor tissues compared with those of HK-SOL. Both HK-SLEs and HK-SOL tended to accumulate in brain tissue. In vivo study showed that HK-SLEs treatment caused significant inhibition of mouse sarcoma S180 tumor growth compared to HK-SOL. These results suggest that HK-SLEs might be an effective parenteral carrier for honokiol delivery in cancer treatment.

  14. Constitutive TLR4 signalling in intestinal epithelium reduces tumor load by increasing apoptosis in APC(Min/+) mice.

    PubMed

    Li, Y; Teo, W L; Low, M J; Meijer, L; Sanderson, I; Pettersson, S; Greicius, G

    2014-01-16

    The microbial pattern-recognizing Toll-like receptors (TLRs) are major signal transducers known to shape and influence the postnatal maturation of host intestinal epithelium. Perturbations in this intricate host-microbe cross-talk have been reported to be associated with uncontrolled epithelial cell growth and thus potential cancer development by mechanisms which are largely unknown. We therefore generated transgenic mice carrying a constitutively active TLR4 (CD4-TLR4) linked to an intestinal epithelial cell-specific promoter. Ex vivo analysis of transgenic crypt-villus organoid cultures revealed an increased proliferative capacity and a lowered cyclooxygenase 2 (Cox-2) expression in these organoids compared with wild-type control cultures. Introducing the CD4-TLR4 transgene into APC(Min/+) mice (CD4-TLR4-APC(Min/+)), a model of colorectal carcinoma, resulted in a dramatic drop in tumor load as compared with control APC(Min/+) mice. Intestinal tumors from CD4-TLR4-APC(Min/+) mice displayed reduced Cox-2 protein, elevated interferon β expression and increased caspase-3 activity, which correlated with increased apoptosis in vivo. Thus, our data reveal that host microbiota-mediated signal transduction via TLR4 in intestinal epithelial cells is far more complex than what is previously reported.

  15. Other paradigms: growth rate constants and tumor burden determined using computed tomography data correlate strongly with the overall survival of patients with renal cell carcinoma.

    PubMed

    Stein, Wilfred D; Huang, Hui; Menefee, Michael; Edgerly, Maureen; Kotz, Herb; Dwyer, Andrew; Yang, James; Bates, Susan E

    2009-01-01

    In solid tumors, where curative therapies still elude oncologists, novel paradigms are needed to assess the efficacy of new therapies and those already approved. We used radiologic measurements obtained in patients with metastatic renal cell carcinoma enrolled in a phase II study of the epothilone B analog, ixabepilone (Ixempra), to address this issue. Using a novel 2-phase mathematical equation, we used the radiologic measurements to estimate the concomitant rates of tumor regression and growth (regression and growth rate constants). Eighty-one patients were enrolled on the ixabepilone trial at the time of this analysis. Growth rate constants were determined using computed tomography measurements obtained exclusively while a patient was enrolled on study. The growth rate constants of renal cell carcinomas treated with ixabepilone were significantly reduced compared with those of tumors in patients who received placebo in a previous trial. Furthermore, a correlation with overall survival was found for both the growth rate constant and the initial tumor burden; and this correlation was even stronger when both the growth rate constant and the initial tumor burden were combined. The readily amenable mathematical model described herein has potential applications to many tumor types that can be assessed with imaging modalities. Because the growth rate constant seems to be a surrogate for survival, assessment could aid in the evaluation of relative efficacies of different therapies and perhaps in assessing the potential individual benefit of an experimental therapy.

  16. 18F-fludrodeoxyglucose maximal standardized uptake value and metabolic tumor burden are associated with major chemotherapy-related tumor markers in NSCLC patients

    PubMed Central

    Bai, Lu; Guo, Chihua; Wang, Jiansheng; Liu, Xiang; Li, Yang; Li, Miao; Guo, Youmin; Duan, Xiaoyi

    2016-01-01

    Objective Metabolic activity and tumor burden are significant for prognosis and metastasis of non-small cell lung cancer (NSCLC), including maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG). Chemotherapy resistance is a great challenge for treating NSCLC patients and is also closely related with several biomarkers such as epidermal growth factor receptor (EGFR), p53, and excision repair cross-complementing group 1 protein (ERCC1). Our purpose was to determine the correlation between positron emission tomography/computed tomography (PET/CT) parameters and tumor markers-related chemotherapy resistance in NSCLC. Methods Forty-six NSCLC chemotherapy-naïve patients were enrolled. The SUVmax, MTV, and TLG were calculated by PET/CT imaging, and expression of EGFR, p53, and ERCC1 were analyzed by immunohistochemistry on tissues. SUVmax, MTV, and TLG compared for their performance in predicting the expression of EGFR, p53, and ERCC1 were illustrated with statistical analysis. Results SUVmax was significantly correlated with p53 expression (P=0.001), and MTV and TLG were significantly associated with ERCC1 (P=0.000; P=0.000). Furthermore, multiple stepwise regression analysis revealed that SUVmax was the primary predictor for p53, MTV and TLG was the primary predictor for ERCC1. SUVmax had a sensitivity of 91% and specificity of 50% for the detection of p53 positive. The sensitivities of MTV and TLG were 83% and 80%, and specificities were 69% and 75% for the detection of ERCC1 positive, respectively. When we suggested p53 or ERCC1 positive, the cutoff value of SUVmax, MTV, and TLG were 7.68, 23.62, and 129.65 cm3, respectively. Conclusion SUVmax, MTV, and TLG were closely associated with p53 and ERCC1’ expressions. Therefore, 18F-fludrodeoxyglucose PET/CT could be a new way of predicting p53 or ERCC1-related chemotherapy effect in NSCLC patients with more convenience. PMID:27789962

  17. A three-decade analysis of 3,911 small intestinal neuroendocrine tumors: the rapid pace of no progress.

    PubMed

    Modlin, Irvin M; Champaneria, Manish C; Chan, Anthony K C; Kidd, Mark

    2007-07-01

    Small intestinal neuroendocrine tumors (SI-NETs) are the most common gastrointestinal neuroendocrine tumor, but their natural history and outcome remain poorly defined, which hinders both the prediction of disease progression and appropriate therapeutic options. We examined patterns, incidence, prognosis, and outcomes of these tumors over a 30-yr period. Data were extracted from the NCI's SEER registry (1973-2002). Incidence rates, distribution, and 5-yr survival rates were analyzed and adjusted (U.S. decennial census data). Of the 18,641 NETs, 3,911 (21.0%) were SI-NETs, of which 1,953 (49.6%) were ileal. Since 1973, both SI-NET and its ileal variant have increased annually by 3.8% and 2.1%, respectively. Ileal tumors, as a percentage of SI tumors, have increased from 52% to 63.6%. The age-adjusted incidence of ileal, small intestinal, and digestive system NETs has increased 225%, 460%, and 720% over 30 yr. Ileal tumors have specifically increased in prevalence in white (274%) and black (500%) men and women (213% and 286%, respectively); an overall increase of fourfold in blacks and 2.4-fold in whites. Although 83.3% of SI-NETs were staged, 83.7% were histologically ungraded. Five-year survival rates for SI-NETs were 62.6 +/- 1% (all stages), 73.8% (localized), 72% (regional), and 43.2% (distant). These have not significantly altered since 1973 (P= 0.11). SI-NETs have increased, particularly in men and in the black population, which may be due to in vivo changes, increased clinical and pathological awareness, or increased detection of tumors. SI-NETs are malignant, diagnosed late, and survival rates have remained unchanged over 30 yr.

  18. Somatostatin Analogs Treated Small Intestinal Neuroendocrine Tumor Patients Circulating MicroRNAs

    PubMed Central

    Li, Su-Chen; Khan, Mohid; Caplin, Martyn; Meyer, Tim; Öberg, Kjell; Giandomenico, Valeria

    2015-01-01

    We previously detected and investigated nine altered microRNAs in small intestinal neuroendocrine tumor (SI-NET) tissues at different stages of disease. The aims of this study are to: 1) analyze whether SI-NET tissue microRNAs can be also detected in patient serum samples, 2) investigate a potential somatostatin analogs (SSAs) role on microRNA levels regulation in SSA-treated patient samples and 3) elucidate whether the serum microRNA levels in samples collected in different hospitals are predictable and steady. Our results show that tissue microRNAs are detectable in patient serum samples, and miR-96, -182, -183, -196a and -200a levels are lower in SI-NET untreated patients than in SSA-treated patients at all different stages. Conversely, miR-31, -129-5p, -133a and -215 levels do not show any difference in untreated SI-NET patients and SSA-treated patients at all different stages. Our findings also show that miR-200a exhibits an atypical behavior with high levels in both untreated and SSA-treated patients at liver metastasis stage, and unequivocally never at the earlier stages. Serum samples collected in two hospitals keep alike microRNA level pattern, elucidating that the results are not dependent on samples handling. In conclusion, SI-NET tissue microRNAs are always detectable in untreated and SSA-treated patient serum samples, SSAs play an unknown role in eliciting SSA-treated patients’ microRNA levels higher than in untreated patients, and this study enlightens that miR-200a might be involved in the liver metastasis during SI-NET progression. PMID:25942502

  19. Patient-Reported Burden of a Neuroendocrine Tumor (NET) Diagnosis: Results From the First Global Survey of Patients With NETs

    PubMed Central

    Granberg, Dan; Wolin, Edward; Warner, Richard; Sissons, Maia; Kolarova, Teodora; Goldstein, Grace; Pavel, Marianne; Öberg, Kjell; Leyden, John

    2017-01-01

    Purpose Despite the considerable impact of neuroendocrine tumors (NETs) on patients’ daily lives, the journey of the patient with a NET has rarely been documented, with published data to date being limited to small qualitative studies. NETs are heterogeneous malignancies with nonspecific symptomology, leading to extensive health care use and diagnostic delays that affect survival. A large, international patient survey was conducted to increase understanding of the experience of the patient with a NET and identify unmet needs, with the aim of improving disease awareness and care worldwide. Methods An anonymous, self-reported survey was conducted (online or on paper) from February to May 2014, recruiting patients with NETs from > 12 countries as a collaboration between the International Neuroendocrine Cancer Alliance and Novartis Pharmaceuticals. Survey questions captured information on sociodemographics, clinical characteristics, NET diagnostic experience, disease impact/management, interaction with medical teams, NET knowledge/awareness, and sources of information. This article reports the most relevant findings on patient experience with NETs and the impact of NETs on health care system resources. Results A total of 1,928 patients with NETs participated. A NET diagnosis had a substantially negative impact on patients’ personal and work lives. Patients reported delayed diagnosis and extensive NET-related health care resource use. Patients desired improvement in many aspects of NET care, including availability of a wider range of NET-specific treatment options, better access to NET experts or specialist centers, and a more knowledgeable, better-coordinated/-aligned NET medical team. Conclusion This global patient-reported survey demonstrates the considerable burden of NETs with regard to symptoms, work and daily life, and health care resource use, and highlights considerable unmet needs. Further intervention is required to improve the patient experience among

  20. Prognostic Factors in Patients Treated with 223Ra: The Role of Skeletal Tumor Burden on Baseline 18F-Fluoride PET/CT in Predicting Overall Survival.

    PubMed

    Etchebehere, Elba C; Araujo, John C; Fox, Patricia S; Swanston, Nancy M; Macapinlac, Homer A; Rohren, Eric M

    2015-08-01

    The purpose of this study was to evaluate outcome after (223)Ra dichloride therapy ((223)Ra) and to determine whether skeletal tumor burden on whole-body (18)F-fluoride PET/CT can be used as a predictive biomarker of survival in patients treated with (223)Ra. Forty-two patients with hormone-refractory prostate cancer underwent (223)Ra and a baseline fluoride PET/CT scan. Fluoride PET/CT parameters were generated, including maximum standardized uptake value (SUVmax) of the hottest lesion (hSUVmax), average SUV of disease (Mean10), and skeletal tumor burden indices of total fluoride skeletal metastatic lesion uptake (TLF10) and total volume of fluoride avid bone metastases (FTV10). Overall survival (OS) was the primary endpoint. Secondary endpoints were progression-free survival and skeletal-related event (SRE). Skeletal tumor burden indices (TLF10 and FTV10) derived from fluoride PET/CT at baseline were highly correlated and significant independent predictors of OS (P = 0.0212; hazard ratio = 5.990; 95% confidence interval = 1.306-27.475). A TLF10 cutoff value of 8,000 discriminated survivors from nonsurvivors after (223)Ra (with TLF10 values < 8,000, the median OS was not estimated, whereas with TLF10 > 8,000, the median OS was 6.67 mo). Visual analysis, Mean10, and hSUVmax were not predictors of OS or progression-free survival. Mean10 was found to be a significant univariate predictor of the odds of having an SRE (P = 0.0445; odds ratio = 1.30; 95% confidence interval = 1.006-1.681), with a Mean10 greater than 19 increasing the risk of SRE. Skeletal tumor burden on baseline fluoride PET/CT is a predictive biomarker of OS and the risk of an SRE in patients treated with (223)Ra. © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

  1. Resources Required for Semi-Automatic Volumetric Measurements in Metastatic Chordoma: Is Potentially Improved Tumor Burden Assessment Worth the Time Burden?

    PubMed

    Fenerty, Kathleen E; Patronas, Nicholas J; Heery, Christopher R; Gulley, James L; Folio, Les R

    2016-06-01

    The Response Evaluation Criteria in Solid Tumors (RECIST) is the current standard for assessing therapy response in patients with malignant solid tumors; however, volumetric assessments are thought to be more representative of actual tumor size and hence superior in predicting patient outcomes. We segmented all primary and metastatic lesions in 21 chordoma patients for comparison to RECIST. Primary tumors were segmented on MR and validated by a neuroradiologist. Metastatic lesions were segmented on CT and validated by a general radiologist. We estimated times for a research assistant to segment all primary and metastatic chordoma lesions using semi-automated volumetric segmentation tools available within our PACS (v12.0, Carestream, Rochester, NY), as well as time required for radiologists to validate the segmentations. We also report success rates of semi-automatic segmentation in metastatic lesions on CT and time required to export data. Furthermore, we discuss the feasibility of volumetric segmentation workflow in research and clinical settings. The research assistant spent approximately 65 h segmenting 435 lesions in 21 patients. This resulted in 1349 total segmentations (average 2.89 min per lesion) and over 13,000 data points. Combined time for the neuroradiologist and general radiologist to validate segmentations was 45.7 min per patient. Exportation time for all patients totaled only 6 h, providing time-saving opportunities for data managers and oncologists. Perhaps cost-neutral resource reallocation can help acquire volumes paralleling our example workflow. Our results will provide researchers with benchmark resources required for volumetric assessments within PACS and help prepare institutions for future volumetric assessment criteria.

  2. Imaging Biomarkers of Tumor Response in Neuroendocrine Liver Metastases Treated with Transarterial Chemoembolization: Can Enhancing Tumor Burden of the Whole Liver Help Predict Patient Survival?

    PubMed

    Sahu, Sonia; Schernthaner, Ruediger; Ardon, Roberto; Chapiro, Julius; Zhao, Yan; Sohn, Jae Ho; Fleckenstein, Florian; Lin, MingDe; Geschwind, Jean-François; Duran, Rafael

    2017-06-01

    Purpose To investigate whether whole-liver enhancing tumor burden [ETB] can serve as an imaging biomarker and help predict survival better than World Health Organization (WHO), Response Evaluation Criteria in Solid Tumors (RECIST), modified RECIST (mRECIST), and European Association for the Study of the Liver (EASL) methods in patients with multifocal, bilobar neuroendocrine liver metastases (NELM) after the first transarterial chemoembolization (TACE) procedure. Materials and Methods This HIPAA-compliant, institutional review board-approved retrospective study included 51 patients (mean age, 57.8 years ± 13.2; range, 13.5-85.8 years) with multifocal, bilobar NELM treated with TACE. The largest area (WHO), longest diameter (RECIST), longest enhancing diameter (mRECIST), largest enhancing area (EASL), and largest enhancing volume (ETB) were measured at baseline and after the first TACE on contrast material-enhanced magnetic resonance images. With three-dimensional software, ETB was measured as more than 2 standard deviations the signal intensity of a region of interest in normal liver. Response was assessed with WHO, RECIST, mRECIST, and EASL methods according to their respective criteria. For ETB response, a decrease in enhancement of at least 30%, 50%, and 65% was analyzed by using the Akaike information criterion. Survival analysis included Kaplan-Meier curves and Cox regressions. Results Treatment response occurred in 5.9% (WHO criteria), 2.0% (RECIST), 25.5% (mRECIST), and 23.5% (EASL criteria) of patients. With 30%, 50%, and 65% cutoffs, ETB response was seen in 60.8%, 39.2%, and 21.6% of patients, respectively, and was the only biomarker associated with a survival difference between responders and nonresponders (45.0 months vs 10.0 months, 84.3 months vs 16.7 months, and 85.2 months vs 21.2 months, respectively; P < .01 for all). The 50% cutoff provided the best survival model (hazard ratio [HR]: 0.2; 95% confidence interval [CI]: 0.1, 0.4). At multivariate

  3. Induction of duodenal mucosal tumors of intestinal epithelial cell origin showing frequent nuclear β-catenin accumulation similar to the concurrently induced colorectal tumors in rats after treatment with azoxymethane.

    PubMed

    Kikuchihara, Yoh; Onda, Nobuhiko; Kimura, Masayuki; Kangawa, Yumi; Mizukami, Sayaka; Yoshida, Toshinori; Shibutani, Makoto

    2015-01-01

    Azoxymethane (AOM) is a potent carcinogen used for induction of colon tumors in rats and mice. It is also known that AOM treatment induces small bowel tumors in addition to colorectal tumors in rats. The present study examined the histogenesis of AOM-induced rat duodenal tumors in comparison with concurrently induced colorectal tumors by histochemical and immunohistochemical approaches. Duodenal and colorectal tumors were positive for both periodic acid-Schiff reaction and Alcian blue staining. Immunohistochemically, duodenal tumors were positive for intestinal epithelial markers such as cytokeratin (CK) 20 (100%) and mucin (MUC) 2 (91.7%) but negative for pancreaticobiliary markers such as CK7 (100%) and MUC1 (100%). All colorectal tumors were also negative for CK7 and MUC1 but positive for CK20. Eighty percent of colorectal tumors were positive for MUC2. In addition, nuclear accumulation of β-catenin was found in duodenal tumors (70.8%), which was similar to colorectal tumors (90.0%). These results indicate that duodenal tumors induced by AOM treatment of rats were derived from intestinal epithelium. Similar to colorectal tumors, nuclear accumulation of β-catenin indicates activation of Wnt signaling as a driving force for tumor progression in AOM-induced duodenal tumors.

  4. Effects of exercise training together with tamoxifen in reducing mammary tumor burden in mice: Possible underlying pathway of miR-21.

    PubMed

    Khori, Vahid; Amani Shalamzari, Sadegh; Isanejad, Amin; Alizadeh, Ali Mohammad; Alizadeh, Shaban; Khodayari, Saeed; Khodayari, Hamid; Shahbazi, Shirin; Zahedi, Ali; Sohanaki, Hamid; Khaniki, Mahmood; Mahdian, Reza; Saffari, Mojtaba; Fayad, Raja

    2015-10-15

    Exercise training has an anti-tumor effect and can reduce tumor growth; however, the exact underlying mechanisms of its protective effects are still obscure. MicroRNA (miR)-21 is a predictor in cancer survival, and has a potential use as an indicator of therapeutic outcome in breast malignancies. Forty-eight female BALB/c mice were equally divided into six groups to investigate the effects of interval exercise training with tamoxifen on miR-21 expression and its possible assumed mechanisms in an estrogen receptor-positive breast cancer model. ELISA, immunohistochemistry, western blot, qRT-PCR assays were performed at the end of the study. Tumor size was significantly declined in exercise training and tamoxifen groups compared to tumor group (P<0.05). Expression of miR-21 was significantly down-regulated in trained and tamoxifen treated mice in comparison with tumor group (P<0.05). Exercise training was as effective as tamoxifen treatment in decreasing serum estradiol and ER-α expression (P<0.05). Exercise training and tamoxifen reduced tumor IL-6 levels, NF-kB and STAT3 expressions, and up-regulated TPM1 and PDCD4 expressions (P<0.05). Both exercise and tamoxifen had synergistic effects in reducing miR-21 and Bcl-2, and up-regulating PDCD4 expression. Results showed that interval exercise training may reduce mammary tumor burden in mice through possible underlying pathway of miR-21.

  5. Preventative topical diclofenac treatment differentially decreases tumor burden in male and female Skh-1 mice in a model of UVB-induced cutaneous squamous cell carcinoma.

    PubMed

    Burns, Erin M; Tober, Kathleen L; Riggenbach, Judith A; Schick, Jonathan S; Lamping, Keith N; Kusewitt, Donna F; Young, Gregory S; Oberyszyn, Tatiana M

    2013-02-01

    Ultraviolet B (UVB) light is the major environmental carcinogen contributing to non-melanoma skin cancer (NMSC) development. There are over 3.5 million NMSC diagnoses in two million patients annually, with men having a 3-fold greater incidence of squamous cell carcinoma (SCC) compared with women. Chronic inflammation has been linked to tumorigenesis, with a key role for the cyclooxygenase-2 (COX-2) enzyme. Diclofenac, a COX-2 inhibitor and non-steroidal anti-inflammatory drug, currently is prescribed to patients as a short-term therapeutic agent to induce SCC precursor lesion regression. However, its efficacy as a preventative agent in patients without evidence of precursor lesions but with significant UVB-induced cutaneous damage has not been explored. We previously demonstrated in a murine model of UVB-induced skin carcinogenesis that when exposed to equivalent UVB doses, male mice had lower levels of inflammation but developed increased tumor multiplicity, burden and grade compared with female mice. Because of the discrepancy in the degree of inflammation between male and female skin, we sought to determine if topical treatment of previously damaged skin with an anti-inflammatory COX-2 inhibitor would decrease tumor burden and if it would be equally effective in the sexes. Our results demonstrated that despite observed sex differences in the inflammatory response, prolonged topical diclofenac treatment of chronically UVB-damaged skin effectively reduced tumor multiplicity in both sexes. Unexpectedly, tumor burden was significantly decreased only in male mice. Our data suggest a new therapeutic use for currently available topical diclofenac as a preventative intervention for patients predisposed to cutaneous SCC development before lesions appear.

  6. Preventative topical diclofenac treatment differentially decreases tumor burden in male and female Skh-1 mice in a model of UVB-induced cutaneous squamous cell carcinoma

    PubMed Central

    Oberyszyn, Tatiana M.

    2013-01-01

    Ultraviolet B (UVB) light is the major environmental carcinogen contributing to non-melanoma skin cancer (NMSC) development. There are over 3.5 million NMSC diagnoses in two million patients annually, with men having a 3-fold greater incidence of squamous cell carcinoma (SCC) compared with women. Chronic inflammation has been linked to tumorigenesis, with a key role for the cyclooxygenase-2 (COX-2) enzyme. Diclofenac, a COX-2 inhibitor and non-steroidal anti-inflammatory drug, currently is prescribed to patients as a short-term therapeutic agent to induce SCC precursor lesion regression. However, its efficacy as a preventative agent in patients without evidence of precursor lesions but with significant UVB-induced cutaneous damage has not been explored. We previously demonstrated in a murine model of UVB-induced skin carcinogenesis that when exposed to equivalent UVB doses, male mice had lower levels of inflammation but developed increased tumor multiplicity, burden and grade compared with female mice. Because of the discrepancy in the degree of inflammation between male and female skin, we sought to determine if topical treatment of previously damaged skin with an anti-inflammatory COX-2 inhibitor would decrease tumor burden and if it would be equally effective in the sexes. Our results demonstrated that despite observed sex differences in the inflammatory response, prolonged topical diclofenac treatment of chronically UVB-damaged skin effectively reduced tumor multiplicity in both sexes. Unexpectedly, tumor burden was significantly decreased only in male mice. Our data suggest a new therapeutic use for currently available topical diclofenac as a preventative intervention for patients predisposed to cutaneous SCC development before lesions appear. PMID:23125227

  7. Occurrence of FSH, inhibin and other hypothalamic-pituitary-intestinal hormones in normal fertility, subfertility, and tumors of human testes.

    PubMed

    Mehta, M K; Garde, S V; Sheth, A R

    1995-01-01

    To compare the distribution of peptide hormones in presumably normal human testicular tissues and specimens exhibiting any of five pathologies. Biopsies from patients having testicular malfunctions were prepared as sections and specifically immunohistochemically stained for inhibin, FSH, serotonin, AUP, and oxytocin. Immunocytochemical studies revealed the presence of various hypophysial-pituitary-intestinal hormones, viz., FSH, inhibin, arginine vasopressin (AVP), calcitonin, serotonin, oxytocin, adrenocorticotropin (ACTH), gastrin, secretin, and somatostatin in human testicular biopsies exhibiting normal spermatogenesis, Sertoli-cell-only syndrome, spermatogenic arrest, Leydig cell hyperplasia, Leydig cell tumor, and seminoma. Intensity of immunostaining for all peptides except FSH was stronger in cases of subfertile as compared to normal testis. Intensity of immunostaining with inhibin was maximum in Leydig cell tumor. These regulatory peptides may be involved in the pathophysiology of the testes.

  8. PKCα TUMOR SUPPRESSION IN THE INTESTINE IS ASSOCIATED WITH TRANSCRIPTIONAL AND TRANSLATIONAL INHIBITION OF CYCLIN D1

    PubMed Central

    Pysz, Marybeth A.; Leontieva, Olga V.; Bateman, Nicholas W.; Uronis, Joshua M.; Curry, Kathryn J.; Threadgill, David W.; Janssen, Klaus-Peter; Robine, Sylvie; Velcich, Anna; Augenlicht, Leonard; Black, Adrian R.; Black, Jennifer D.

    2009-01-01

    Alterations in PKC isozyme expression and aberrant induction of cyclin D1 are early events in intestinal tumorigenesis. Previous studies have identified cyclin D1 as a major target in the antiproliferative effects of PKCα in non-transformed intestinal cells; however, a link between PKC signaling and cyclin D1 in colon cancer remained to be established. The current study further characterized PKC isozyme expression in intestinal neoplasms and explored the consequences of restoring PKCα or PKCδ in a panel of colon carcinoma cell lines. Consistent with patterns of PKC expression in primary tumors, PKCα and δ levels were generally reduced in colon carcinoma cell lines, PKCβII was elevated and PKCε showed variable expression, thus establishing the suitability of these models for analysis of PKC signaling. While colon cancer cells were insensitive to the effects of PKC agonists on cyclin D1 levels, restoration of PKCα downregulated cyclin D1 by two independent mechanisms. PKCα expression consistently (a) reduced steady-state levels of cyclin D1 by a novel transcriptional mechanism not previously seen in non-transformed cells, and (b) re-established the ability of PKC agonists to activate the translational repressor 4E-BP1 and inhibit cyclin D1 translation. In contrast, PKCδ had modest and variable effects on cyclin D1 steady state levels and failed to restore responsiveness to PKC agonists. Notably, PKCα expression blocked anchorage-independent growth in colon cancer cells via a mechanism partially dependent on cyclin D1 deficiency, while PKCδ had only minor effects. Loss of PKCα and effects of its re-expression were independent of the status of the APC/β-catenin signaling pathway or known genetic alterations, indicating that they are a general characteristic of colon tumors. Thus, PKCα is a potent negative regulator of cyclin D1 expression and anchorage-independent cell growth in colon tumor cells, findings that offer important perspectives on the

  9. Beneficial effects of combining computed tomography enteroclysis/enterography with capsule endoscopy for screening tumor lesions in the small intestine.

    PubMed

    Shibata, Hiroaki; Hashimoto, Shinichi; Shimizu, Kensaku; Kawasato, Ryo; Shirasawa, Tomohiro; Yokota, Takayuki; Onoda, Hideko; Okamoto, Takeshi; Nishikawa, Jun; Matsunaga, Naofumi; Sakaida, Isao

    2015-01-01

    Aim. To compare the efficacy of using computed tomography enteroclysis/enterography (CTE), capsule endoscopy (CE), and CTE with CE for diagnosing tumor lesions in the small intestine. Materials and Methods. We included 98 patients who underwent CE during the observation period and were subjected to CTE at our hospital from April 2008 to May 2014. Results. CTE had a significantly higher sensitivity than CE (84.6% versus 46.2%, P = 0.039), but there were no significant differences in specificity, positive or negative predictive values, or diagnostic accuracy rates. The sensitivity of CTE/CE was 100%, again significantly higher than that of CE (P = 0.002). The difference in specificity between CTE/CE and CE was not significant, but there were significant differences in positive predictive values (100% for CTE/CE versus 66.7% for CE, P = 0.012), negative predictive values (100% versus 92.1%, P = 0.008), and diagnostic accuracy rate (100% versus 89.8%, P = 0.001). The diagnostic accuracy rate was also significantly higher in CTE/CE versus CTE (100% versus 95.9%, P = 0.043). Conclusion. Our findings suggested that a combination of CTE and CE was useful for screening tumor lesions in the small intestine. This trial is registered with number UMIN000016154.

  10. Beneficial Effects of Combining Computed Tomography Enteroclysis/Enterography with Capsule Endoscopy for Screening Tumor Lesions in the Small Intestine

    PubMed Central

    Shibata, Hiroaki; Hashimoto, Shinichi; Shimizu, Kensaku; Kawasato, Ryo; Shirasawa, Tomohiro; Yokota, Takayuki; Onoda, Hideko; Okamoto, Takeshi; Matsunaga, Naofumi; Sakaida, Isao

    2015-01-01

    Aim. To compare the efficacy of using computed tomography enteroclysis/enterography (CTE), capsule endoscopy (CE), and CTE with CE for diagnosing tumor lesions in the small intestine. Materials and Methods. We included 98 patients who underwent CE during the observation period and were subjected to CTE at our hospital from April 2008 to May 2014. Results. CTE had a significantly higher sensitivity than CE (84.6% versus 46.2%, P = 0.039), but there were no significant differences in specificity, positive or negative predictive values, or diagnostic accuracy rates. The sensitivity of CTE/CE was 100%, again significantly higher than that of CE (P = 0.002). The difference in specificity between CTE/CE and CE was not significant, but there were significant differences in positive predictive values (100% for CTE/CE versus 66.7% for CE, P = 0.012), negative predictive values (100% versus 92.1%, P = 0.008), and diagnostic accuracy rate (100% versus 89.8%, P = 0.001). The diagnostic accuracy rate was also significantly higher in CTE/CE versus CTE (100% versus 95.9%, P = 0.043). Conclusion. Our findings suggested that a combination of CTE and CE was useful for screening tumor lesions in the small intestine. This trial is registered with number UMIN000016154. PMID:25792979

  11. Enhanced Intestinal Tumor Multiplicity and Grade in vivo after HZE Exposure: Mouse Models for Space Radiation Risk Estimates

    PubMed Central

    Trani, Daniela; Datta, Kamal; Doiron, Kathryn; Kallakury, Bhaskar; Fornace, Albert J.

    2013-01-01

    Carcinogenesis induced by space radiation is considered a major risk factor in manned interplanetary and other extended missions. The models presently used to estimate the risk for cancer induction following deep space radiation exposure are based on data from A-bomb survivor cohorts and do not account for important biological differences existing between high-linear energy transfer (LET) and low-LET-induced DNA damage. High-energy and charge (HZE) radiation, the main component of galactic cosmic rays (CGR), causes highly complex DNA damage compared to low-LET radiation, which may lead to increased frequency of chromosomal rearrangements, and contribute to carcinogenic risk in astronauts. Gastrointestinal (GI) tumors are frequent in the United States, and colorectal cancer (CRC) is the third most common cancer accounting for 10% of all cancer deaths. On the basis of the aforementioned epidemiological observations and the frequency of spontaneous precancerous GI lesions in the general population, even a modest increase in incidence by space radiation exposure could have a significant effect on health risk estimates for future manned space flights. Ground-based research is necessary to reduce the uncertainties associated with projected cancer risk estimates and to gain insights into molecular mechanisms involved in space radiation-induced carcinogenesis. We investigated in vivo differential effects of γ-rays and HZE ions on intestinal tumorigenesis using two different murine models, ApcMin/+ and Apc1638 N/+. We showed that γ- and/or HZE exposure significantly enhances development and progression of intestinal tumors in a mutant-line-specific manner, and identified suitable models for in vivo studies of space radiation–induced intestinal tumorigenesis. PMID:20490531

  12. Enhanced intestinal tumor multiplicity and grade in vivo after HZE exposure: mouse models for space radiation risk estimates.

    PubMed

    Trani, Daniela; Datta, Kamal; Doiron, Kathryn; Kallakury, Bhaskar; Fornace, Albert J

    2010-08-01

    Carcinogenesis induced by space radiation is considered a major risk factor in manned interplanetary and other extended missions. The models presently used to estimate the risk for cancer induction following deep space radiation exposure are based on data from A-bomb survivor cohorts and do not account for important biological differences existing between high-linear energy transfer (LET) and low-LET-induced DNA damage. High-energy and charge (HZE) radiation, the main component of galactic cosmic rays (GCR), causes highly complex DNA damage compared to low-LET radiation, which may lead to increased frequency of chromosomal rearrangements, and contribute to carcinogenic risk in astronauts. Gastrointestinal (GI) tumors are frequent in the United States, and colorectal cancer (CRC) is the third most common cancer accounting for 10% of all cancer deaths. On the basis of the aforementioned epidemiological observations and the frequency of spontaneous precancerous GI lesions in the general population, even a modest increase in incidence by space radiation exposure could have a significant effect on health risk estimates for future manned space flights. Ground-based research is necessary to reduce the uncertainties associated with projected cancer risk estimates and to gain insights into molecular mechanisms involved in space-induced carcinogenesis. We investigated in vivo differential effects of gamma-rays and HZE ions on intestinal tumorigenesis using two different murine models, ApcMin/+ and Apc1638N/+. We showed that gamma- and/or HZE exposure significantly enhances development and progression of intestinal tumors in a mutant-line-specific manner, and identified suitable models for in vivo studies of space radiation-induced intestinal tumorigenesis.

  13. A phase I toxicity, pharmacology, and dosimetry trial of monoclonal antibody OKB7 in patients with non-Hodgkin's lymphoma: Effects of tumor burden and antigen expression

    SciTech Connect

    Scheinberg, D.A.; Straus, D.J.; Yeh, S.D.; Divgi, C.; Garin-Chesa, P.; Graham, M.; Pentlow, K.; Coit, D.; Oettgen, H.F.; Old, L.J. )

    1990-05-01

    Eighteen patients with relapsed non-Hodgkin's lymphoma (NHL) were infused with escalating doses of monoclonal antibody (mAb) OKB7, trace-labeled with iodine-131 (131I), in order to study toxicity, pharmacology, antibody localization, and dosimetry of radioiodine. OKB7 is a noncytotoxic mouse immunoglobulin G2b (IgG2b) mAb reactive with B cells and most B-cell NHL. Three patients each were treated at six dose levels ranging from 0.1 mg to 40 mg. All patients had radionuclide imaging and counting daily, had serial blood sampling to study pharmacokinetics, human antimouse antibody (HAMA), and circulating antigen, and had a biopsy of accessible lymphoma to determine delivery of isotope to tumors and assess the effect of tumor antigen expression on mAb delivery. Bone marrow biopsies were also done in the majority of patients. There was no toxicity. Serum clearance showed a median early phase half-life of 1.9 hours and a later phase half-life of 21.7 hours. Median total body clearance half-life was 22 hours. Pharmacokinetics were not dose-related. Circulating blocking antigen was detected in the serum of four patients, but at levels that were of pharmacologic consequence only in one. Biopsied tumor tissue from five patients did not express OKB7 antigen. No significant uptake of antibody was seen in these tumor sites. Mean total uptake of isotope into lymphoma measured in biopsies correlated linearly over the 400-fold increase in injected mAb dose. However, the percent of injected dose found per gram of tumor was unrelated to dose, but correlated inversely with tumor burden. In two patients with minimal tumor burden, 1.0 mg and 5.0 mg doses of OKB7 resulted in tumor to body radioisotope dose ratios of 22 and 7, which would theoretically permit tolerable delivery of 4,400 and 1,400 rads to these tumors, respectively, if OKB7 were conjugated with higher doses of 131I.

  14. Prediction of PSA Progression in Castration-Resistant Prostate Cancer Based on Treatment-Associated Change in Tumor Burden Quantified by 18F-Fluorocholine PET/CT.

    PubMed

    Lee, Joohee; Sato, Miles M; Coel, Marc N; Lee, Kyung-Han; Kwee, Sandi A

    2016-07-01

    Measurements of metabolically active tumor volume (MATV) can be applied to (18)F-fluorocholine PET/CT to quantify whole-body tumor burden. This study evaluated the serial application of these measurements as systemic treatment response markers and predictors of disease progression in patients with castration-resistant prostate cancer (CRPC). Forty-two patients completed sequential (18)F-fluorocholine PET/CT scans before and 1-3 mo after starting treatment for CRPC. Whole-body tumor segmentation was applied to determine net MATV from each scan. Changes in net MATV were evaluated as predictors of time to prostate-specific antigen (PSA) progression by Kaplan-Meier and proportional hazards regression analysis. Treatments consisted of chemotherapy in 16 patients, antiandrogens in 19 patients, (223)Ra-dichloride in 5 patients, and sipuleucel-T in 2 patients. A significant MATV response (defined as a ≥30% decrease in net MATV) was observed in 20 patients on the basis of in-treatment PET/CT performed an average of 51 d (median, 49 d) into treatment. Significantly longer times to PSA progression were observed in patients who exhibited an MATV response (418 d vs. 116 d, P = 0.0067). MATV response was associated with a hazard ratio of 0.246 (P = 0.0113) for PSA progression, which remained significant when adjusted for treatment type. Significant changes in whole-body tumor burden can be measured on (18)F-fluorocholine PET/CT over the course of contemporary treatments for CRPC. In this study, these changes were found to be predictive of PSA progression as a potential surrogate marker of treatment outcome. Because (18)F-fluorocholine PET/CT can also be used for localizing resistant tumors, this modality can potentially complement other measures of response in the precision management of advanced prostate cancer. © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

  15. High expressions of BCL6 and Lewis y antigen are correlated with high tumor burden and poor prognosis in epithelial ovarian cancer.

    PubMed

    Zhu, Liancheng; Feng, Huilin; Jin, Shan; Tan, Mingzi; Gao, Song; Zhuang, Huiyu; Hu, Zhenhua; Wang, Huimin; Song, Zuofei; Lin, Bei

    2017-07-01

    Aberrant regulation of BCL6 plays crucial oncogenic roles in various malignant tumors; howbeit, the function of BCL6 in tumorigenesis of ovarian cancer remains unclear. The aim of this study is to investigate the role of BCL6 in ovarian cancer. The methods of immunohistochemical staining, quantitative real-time polymerase chain reaction, immunocytochemical staining, and gene expression profile enrichment analysis were performed to identify the possible role of BCL6 in ovarian cancer. We observed that the expression of BCL6 was significantly higher in ovarian cancer tissues and correlated with higher tumor burden including advanced International Federation of Gynecology and Obstetrics stages, poor differentiation, Type II ovarian cancer, the presence of >1 cm residual tumor size, and appearance of recurrence or death (all p < 0.05). The expression patterns of Lewis y were similar to these of BCL6. Multivariate Cox analysis demonstrated that advanced International Federation of Gynecology and Obstetrics stage, lymph node metastasis, residual tumor size >1 cm, as well as high expressions of BCL6 and Lewis y antigen were independent factors of worse progression-free survival and overall survival (all p < 0.05). There was a positive correlation of the expressions of BCL6 and Lewis y antigen. The associated genes with BCL6 in response to Lewis y antigen were identified, including four upregulated genes ( SOCS3, STAT1, PPARG, and GADD45A) and three downregulated genes ( ACAN, E2F3, and ZBTB7B). In conclusion, the high expressions of BCL6 and Lewis y antigen are associated with development, high tumor burden, and worse prognosis of ovarian cancer and targeting BCL6 could be a novel therapeutic strategy for ovarian cancer treatment.

  16. Quantification of metabolic tumor activity and burden in patients with non-small-cell lung cancer: Is manual adjustment of semiautomatic gradient-based measurements necessary?

    PubMed

    Obara, Piotr; Liu, Haiping; Wroblewski, Kristen; Zhang, Chen-Peng; Hou, Peng; Jiang, Yulei; Chen, Ping; Pu, Yonglin

    2015-08-01

    Metabolic tumor burden (MTB) measurements including metabolic tumor volume and total lesion glycolysis have been shown to have prognostic value in non-small-cell lung cancer (NSCLC). The calculation of MTB typically utilizes software to semiautomatically draw volumes of interest around the tumor, which are subsequently manually adjusted by the radiologist to include the entire tumor. The manual adjustment step can be time-consuming and observer-dependent. We compared the agreement of MTB values obtained using the semiautomatic method with and without manual adjustment in NSCLC patients. This IRB-approved prospective study included 134 patients with histologically proven NSCLC who underwent fluorine-18 fluorodeoxyglucose PET/computed tomography. The MTB of the primary tumor was measured with a semiautomatic gradient-based method without manual adjustment (the semiautomatic gradient method) and with manual adjustment (the manually adjusted semiautomatic gradient method) by two radiologists using the MIM PETedge tool. The paired t-test, Wilcoxon signed-rank test, and concordance correlation coefficient (CCC) were calculated to evaluate the agreement between MTB measures obtained with these two methods, as well as agreement between the two radiologists for each method. Maximum standardized uptake value was identical between the two methods. No statistically significant difference was present for peak standardized uptake value, metabolic tumor volume, and total lesion glycolysis values between the two methods (P=0.23, 0.45, and 0.37, respectively). Excellent agreement between the two methods was found in terms of CCC (CCC>0.98 for all measures). Interobserver reliability was excellent for all measures (CCC>0.90). The semiautomatic gradient-based tumor-segmentation method can be used without the additional manual adjustment step for MTB quantification of primary NSCLC tumors.

  17. Supplementation with L-glutamine prevents tumor growth and cancer-induced cachexia as well as restores cell proliferation of intestinal mucosa of Walker-256 tumor-bearing rats.

    PubMed

    Martins, Heber Amilcar; Sehaber, Camila Caviquioli; Hermes-Uliana, Catchia; Mariani, Fernando Augusto; Guarnier, Flavia Alessandra; Vicentini, Geraldo Emílio; Bossolani, Gleison Daion Piovezana; Jussani, Laraine Almeida; Lima, Mariana Machado; Bazotte, Roberto Barbosa; Zanoni, Jacqueline Nelisis

    2016-12-01

    This study aimed to evaluate the intestinal mucosa of the duodenum and jejunum of Walker-256 tumor-bearing rats supplemented with L-glutamine. Thirty-two male 50-day-old Wistar rats (Rattus norvegicus) were randomly divided into four groups: control (C), control supplemented with 2 % L-glutamine (GC), Walker-256 tumor (WT), and Walker-256 tumor supplemented with 2 % L-glutamine (TWG). Walker-256 tumor was induced by inoculation viable tumor cells in the right rear flank. After 10 days, celiotomy was performed and duodenal and jejunal tissues were removed and processed. We evaluated the cachexia index, proliferation index, villus height, crypt depth, total height of the intestinal wall, and number of goblet cells by the technique of periodic acid-Schiff (PAS). Induction of Walker-256 tumor promoted a reduction of metaphase index in the TW group animals, which was accompanied by a reduction in the villous height and crypt depths, resulting in atrophy of the intestinal wall as well as increased PAS-positive goblet cells. Supplementation with L-glutamine reduced the tumor growth and inhibited the development of the cachectic syndrome in animals of the TWG group. Furthermore, amino acid supplementation promoted beneficial effects on the intestinal mucosa in the TWG animals through restoration of the number of PAS-positive goblet cells. Therefore, supplementation with 2 % L-glutamine exhibited a promising role in the prevention of tumor growth and cancer-associated cachexia as well as restoring the intestinal mucosa in the duodenum and jejunum of Walker-256 tumor-bearing rats.

  18. IL-33 targeting attenuates intestinal mucositis and enhances effective tumor chemotherapy in mice.

    PubMed

    Guabiraba, R; Besnard, A G; Menezes, G B; Secher, T; Jabir, M S; Amaral, S S; Braun, H; Lima-Junior, R C P; Ribeiro, R A; Cunha, F Q; Teixeira, M M; Beyaert, R; Graham, G J; Liew, F Y

    2014-09-01

    Intestinal damage and severe diarrhea are serious side effects of cancer chemotherapy and constrain the usage of most such therapies. Here we show that interleukin-33 (IL-33) mediates the severe intestinal mucositis in mice treated with irinotecan (CPT-11), a commonly used cancer chemotherapeutic agent. Systemic CPT-11 administration led to severe mucosal damage, diarrhea, and body weight loss concomitant with the induction of IL-33 in the small intestine (SI). This mucositis was markedly reduced in mice deficient in the IL-33R (ST2(-/-)). Moreover, recombinant IL-33 exacerbated the CPT-11-induced mucositis, whereas IL-33 blockade with anti-IL-33 antibody or soluble ST2 markedly attenuated the disease. CPT-11 treatment increased neutrophil accumulation in the SI and adhesion to mesenteric veins. Supernatants from SI explants treated with CPT-11 enhanced transmigration of neutrophils in vitro in an IL-33-, CXCL1/2-, and CXCR2-dependent manner. Importantly, IL-33 blockade reduced mucositis and enabled prolonged CPT-11 treatment of ectopic CT26 colon carcinoma, leading to a beneficial outcome of the chemotherapy. These results suggest that inhibition of the IL-33/ST2 pathway may represent a novel approach to limit mucositis and thus improve the effectiveness of chemotherapy.

  19. [Intestinal intussusception secondary to myofibroblastic tumor in an elderly patient. Case report].

    PubMed

    Gallegos-Sierra, Cuauhtly; Belmonte-Chico Goerne, Manuel Alfonso; Ramírez-Jaimez, Juan; de la Cruz-Temores, Salvador; Leonher-Ruezga, Karla Lisseth

    2016-08-24

    Intussusception is defined as a segment of the gastrointestinal tract and mesentery within the lumen of an adjacent segment. It is a rare condition in adults that can occur anywhere in the gastrointestinal tract from the stomach to the rectum. Only 5% of all intussusceptions are presented in adults, and in 1-5% of all cases of intestinal obstruction. Inflammatory myofibroblastic tumour is rare, and is usually found in the lung, and rarely detected in some intestinal portions. It causes a variety of non-specific symptoms, with those that present as an intussusception being uncommon. A female of 69 years with partial bowel obstruction secondary to intestinal intussusception due to an inflammatory myofibroblastic tumour, a rarely diagnosed condition and never published before. Inflammatory myofibroblastic tumours are rare, and in this case with an atypical presentation that was surgically resolved satisfactorily. These entities are difficult to diagnose, with histopathology giving the definitive diagnosis. A literature review was performed to gather recent information about their diagnosis and treatment. Inflammatory myofibroblastic tumours require a high level of suspicion, as diagnosis prior to surgery is difficult. Surgery is considered the treatment of choice, requiring leaving free surgical edges to prevent recurrences. Copyright © 2016 Academia Mexicana de Cirugía A.C. Publicado por Masson Doyma México S.A. All rights reserved.

  20. Heavy ion radiation exposure triggered higher intestinal tumor frequency and greater β-catenin activation than γ radiation in APC(Min/+) mice.

    PubMed

    Datta, Kamal; Suman, Shubhankar; Kallakury, Bhaskar V S; Fornace, Albert J

    2013-01-01

    Risk of colorectal cancer (CRC) after exposure to low linear energy transfer (low-LET) radiation such as γ-ray is highlighted by the studies in atom bomb survivors. On the contrary, CRC risk prediction after exposure to high-LET cosmic heavy ion radiation exposure is hindered due to scarcity of in vivo data. Therefore, intestinal tumor frequency, size, cluster, and grade were studied in APC(Min/+) mice (n = 20 per group; 6 to 8 wks old; female) 100 to 110 days after exposure to 1.6 or 4 Gy of heavy ion (56)Fe radiation (energy: 1000 MeV/nucleon) and results were compared to γ radiation doses of 2 or 5 Gy, which are equitoxic to 1.6 and 4 Gy (56)Fe respectively. Due to relevance of lower doses to radiotherapy treatment fractions and space exploration, we followed 2 Gy γ and equitoxic 1.6 Gy (56)Fe for comparative analysis of intestinal epithelial cell (IEC) proliferation, differentiation, and β-catenin signaling pathway alterations between the two radiation types using immunoblot, and immunohistochemistry. Relative to controls and γ-ray, intestinal tumor frequency and grade was significantly higher after (56)Fe radiation. Additionally, tumor incidence per unit of radiation (per cGy) was also higher after (56)Fe radiation relative to γ radiation. Staining for phospho-histone H3, indicative of IEC proliferation, was more and alcian blue staining, indicative of IEC differentiation, was less in (56)Fe than γ irradiated samples. Activation of β-catenin was more in (56)Fe-irradiated tumor-free and tumor-bearing areas of the intestinal tissues. When considered along with higher levels of cyclin D1, we infer that relative to γ radiation exposure to (56)Fe radiation induced markedly reduced differentiation, and increased proliferative index in IEC resulting in increased intestinal tumors of larger size and grade due to preferentially greater activation of β-catenin and its downstream effectors.

  1. Soy isoflavone exposure through all life stages accelerates 17β-estradiol-induced mammary tumor onset and growth, yet reduces tumor burden, in ACI rats.

    PubMed

    Möller, Frank Josef; Pemp, Daniela; Soukup, Sebastian T; Wende, Kathleen; Zhang, Xiajie; Zierau, Oliver; Muders, Michael H; Bosland, Maarten C; Kulling, Sabine E; Lehmann, Leane; Vollmer, Günter

    2016-08-01

    There is an ongoing debate whether the intake of soy-derived isoflavones (sISO) mediates beneficial or adverse effects with regard to breast cancer risk. Therefore, we investigated whether nutritional exposure to a sISO-enriched diet from conception until adulthood impacts on 17β-estradiol (E2)-induced carcinogenesis in the rat mammary gland (MG). August-Copenhagen-Irish (ACI) rats were exposed to dietary sISO from conception until postnatal day 285. Silastic tubes containing E2 were used to induce MG tumorigenesis. Body weight, food intake, and tumor growth were recorded weekly. At necropsy, the number, position, size, and weight of each tumor were determined. Plasma samples underwent sISO analysis, and the morphology of MG was analyzed. Tumor incidence and multiplicity were reduced by 20 and 56 %, respectively, in the sISO-exposed rats compared to the control rats. Time-to-tumor onset was shortened from 25 to 20 weeks, and larger tumors developed in the sISO-exposed rats. The histological phenotype of the MG tumors was independent of the sISO diet received, and it included both comedo and cribriform phenotypes. Morphological analyses of the whole-mounted MGs also showed no diet-dependent differences. Lifelong exposure to sISO reduced the overall incidence of MG carcinomas in ACI rats, although the time-to-tumor was significantly shortened.

  2. Intestinal helminths regulate lethal acute graft-versus-host disease and preserve the graft-versus-tumor effect in mice.

    PubMed

    Li, Yue; Chen, Hung-Lin; Bannick, Nadine; Henry, Michael; Holm, Adrian N; Metwali, Ahmed; Urban, Joseph F; Rothman, Paul B; Weiner, George J; Blazar, Bruce R; Elliott, David E; Ince, M Nedim

    2015-02-01

    Donor T lymphocyte transfer with hematopoietic stem cells suppresses residual tumor growth (graft-versus-tumor [GVT]) in cancer patients undergoing bone marrow transplantation (BMT). However, donor T cell reactivity to host organs causes severe and potentially lethal inflammation called graft-versus-host disease (GVHD). High-dose steroids or other immunosuppressive drugs are used to treat GVHD that have limited ability to control the inflammation while incurring long-term toxicity. Novel strategies are needed to modulate GVHD, preserve GVT, and improve the outcome of BMT. Regulatory T cells (Tregs) control alloantigen-sensitized inflammation of GVHD, sustain GVT, and prevent mortality in BMT. Helminths colonizing the alimentary tract dramatically increase the Treg activity, thereby modulating intestinal or systemic inflammatory responses. These observations led us to hypothesize that helminths can regulate GVHD and maintain GVT in mice. Acute GVHD was induced in helminth (Heligmosomoides polygyrus)-infected or uninfected BALB/c recipients of C57BL/6 donor grafts. Helminth infection suppressed donor T cell inflammatory cytokine generation and reduced GVHD-related mortality, but maintained GVT. H. polygyrus colonization promoted the survival of TGF-β-generating recipient Tregs after a conditioning regimen with total body irradiation and led to a TGF-β-dependent in vivo expansion/maturation of donor Tregs after BMT. Helminths did not control GVHD when T cells unresponsive to TGF-β-mediated immune regulation were used as donor T lymphocytes. These results suggest that helminths suppress acute GVHD using Tregs and TGF-β-dependent pathways in mice. Helminthic regulation of GVHD and GVT through intestinal immune conditioning may improve the outcome of BMT. Copyright © 2015 by The American Association of Immunologists, Inc.

  3. Intestinal Helminths Regulate Lethal Acute Graft Versus Host Disease and Preserve Graft Versus Tumor Effect in Mice

    PubMed Central

    Li, Yue; Chen, Hung-lin; Bannick, Nadine; Henry, Michael; Holm, Adrian N.; Metwali, Ahmed; Urban, Joseph F.; Rothman, Paul B.; Weiner, George J.; Blazar, Bruce R.; Elliott, David E.; Ince, M. Nedim

    2014-01-01

    Donor T lymphocyte transfer with hematopoietic stem cells suppresses residual tumor growth (graft-versus-tumor; GVT) in cancer patients undergoing bone marrow transplantation (BMT). However, donor T cell reactivity to host organs causes severe and potentially lethal inflammation, called graft-versus-host disease (GVHD). High dose steroids or other immune suppressives are used to treat GVHD that have limited ability to control the inflammation while incurring long-term toxicity. Novel strategies are needed to modulate GVHD, preserve GVT and improve the outcome of BMT. Regulatory T cells (Tregs) control alloantigen-sensitized inflammation of GVHD, sustain GVT and prevent mortality in bone marrow transplantation. Helminths colonizing the alimentary tract dramatically increase the Treg activity, thereby modulating intestinal or systemic inflammatory responses. These observations led us to hypothesize that helminths can regulate GVHD and maintain GVT in mice. Acute GVHD was induced in helminth (Heligmosomoides polygyrus)-infected or uninfected Balb/C recipients of C57BL/6 donor grafts. Helminth infection suppressed donor T cell inflammatory cytokine generation along with reduction in GVHD lethality and maintenance of GVT. H. polygyrus colonization promoted the survival of TGFβ generating recipient Tregs after a conditioning regimen with total body irradiation and led to a TGFβ-dependent in vivo expansion/maturation of donor Tregs after BMT. Helminths did not control GVHD, when T cells unresponsive to TGFβ-mediated immune regulation were used as donor T lymphocytes. These results suggest that helminths suppress acute GVHD, employing regulatory T cells and TGFβ-dependent pathways in mice. Helminthic regulation of GVHD and GVT through intestinal immune conditioning may improve the outcome of BMT. PMID:25527786

  4. GK-1 peptide reduces tumor growth, decreases metastatic burden, and increases survival in a murine breast cancer model.

    PubMed

    Torres-García, D; Pérez-Torres, A; Manoutcharian, K; Orbe, U; Servín-Blanco, R; Fragoso, G; Sciutto, E

    2017-10-09

    GK-1 is a parasite-derived peptide adjuvant of 18 amino acid-length that enhances T-cell function and increases survival in B16-F10 melanoma tumor-bearing mice. This study was designed to evaluate in vivo the antitumor efficacy of GK-1 on 4T1 mouse mammary carcinoma. BALB/c mice with palpable primary tumors were weekly intravenously injected three times with saline solution or three different concentrations (10, 50, or 100μg per mouse) of GK-1. GK-1 significantly increased lifespan (p<0.0001) and reduced the primary tumor weight (p=0.014) and volume (p<0.0001) with respect to control mice, with no statistically significant differences among GK-1 doses. At the primary tumor, we found increased necrotic areas associated with a reduction in tumor mass, as well as an increase in the antitumor cytokine IL-12. Especially encouraging is the ability of GK-1 to reduce the number of lung metastasis (p=0.006) disregarding the dose used. The participation of IL-6 in metastasis development and the decreased levels of CCL-2, CCL-3, TNF-α, CXCL-9, GM-CSF, and b-FGF found in lungs of GK-1-treated mice is discussed. Our study supports the effectiveness of GK-1 as an antineoplastic agent that merits further exploration in combination with other therapeutic approaches in future translational studies. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. Gastrin promotes intestinal polyposis through cholecystokinin-B receptor-mediated proliferative signaling and fostering tumor microenvironment.

    PubMed

    Han, Y-M; Park, J-M; Park, S-H; Hahm, K B; Hong, S P; Kim, E-H

    2013-08-01

    Increased serum gastrin concentrations in patients with colorectal cancer suggested the tumorigenic trophic effect of gastrin. Detailed and global molecular mechanisms explaining trophic effect of gastrin had not been revealed. In the current study, intestinal polyposis of APC(Min/⁺) mice was compared between phosphate buffered saline (PBS) injected and gastrin (10 μg/kg, thrice per week) injected group. Total number of intestinal polyposis was counted and immunohistochemical staining with F4/80 and CD3 was done. MTT assay, cell cycle analysis, and Western blot for cyclin D1, CDK4, and β-catenin were performed in Raw 264.7 and HCT116 cells before and after gastrin administration. Experiments were repeated with YM022 or transfection with si-cholecystokinin-B receptor (CCK-B-R). Intraperitoneal gastrin significantly increased intestinal polyposis in APC(Min/⁺) mice (P<0.005), in which significant increases in macrophage were noted on F4/80 immunohistochemical staining (Plt;0.05) as well as Ki-67 staining (Plt;0.05) after gastrin. On comparative cytokine array, gastrin increased interleukin-1β (IL-1β), interleukin 3Rβ (IL-3Rβ), stromal cell-derived factor-1α (SDF-1α), thymus and activation-regulated chemokine (TARC), and thymus-derived chemotactic agent 3 (TCA-3) in macrophage cells, which was further confirmed with real time polymerase chain reaction (RT-PCR) analysis (P<0.05). In addition to increased inflammatory cytokines, gastrin increased macrophage proliferation accompanied with increased cyclin D1 and CDK4. Targeted for HCT116 cells, gastrin significantly increased proliferation as well as increases in synthetic phase of cell cycle. YM022 as gastrin antagonist significantly abolished the trophic actions of gastrin (P<0.05). HCT116 cells transfected with siCCK-B-R, gastrin did not increase either cell cycle or β-catenin in spite of gastrin administration. Conclusively, gastrin promoted intestinal polyposis through either direct gastrin receptor

  6. Successful Mitigation of Delayed Intestinal Radiation Injury Using Pravastatin is not Associated with Acute Injury Improvement or Tumor Protection

    SciTech Connect

    Haydont, Valerie; Bourhis, Jean; Vozenin-Brotons, Marie-Catherine |. E-mail: vozenin@igr.fr

    2007-08-01

    Purpose: To investigate whether pravastatin mitigates delayed radiation-induced enteropathy in rats, by focusing on the effects of pravastatin on acute cell death and fibrosis according to connective tissue growth factor (CTGF) expression and collagen inhibition. Methods and Materials: Mitigation of delayed radiation-induced enteropathy was investigated in rats using pravastatin administered in drinking water (30 mg/kg/day) 3 days before and 14 days after irradiation. The ileum was irradiated locally after surgical exteriorization (X-rays, 19 Gy). Acute apoptosis, acute and late histologic alterations, and late CTGF and collagen deposition were monitored by semiquantitative immunohistochemistry and colorimetric staining (6 h, 3 days, 14 days, 15 weeks, and 26 weeks after irradiation). Pravastatin antitumor action was studied in HT-29, HeLa, and PC-3 cells by clonogenic cell survival assays and tumor growth delay experiments. Results: Pravastatin improved delayed radiation enteropathy in rats, whereas its benefit in acute and subacute injury remained limited (6 h, 3 days, and 14 days after irradiation). Delayed structural improvement was associated with decreased CTGF and collagen deposition but seemed unrelated to acute damage. Indeed, the early apoptotic index increased, and severe subacute structural damage occurred. Pravastatin elicited a differential effect, protecting normal intestine but not tumors from radiation injury. Conclusion: Pravastatin provides effective protection against delayed radiation enteropathy without interfering with the primary antitumor action of radiotherapy, suggesting that clinical transfer is feasible.

  7. Exploration of the relationship between the tumor burden and the concentration of vascular endothelial growth factor in liver-cancer-bearing animals using immunomagnetic reduction assay.

    PubMed

    Huang, K W; Yang, S Y; Yu, C Y; Chieh, J J; Yang, Che-Chuan; Horng, Herng-Er; Hong, Chin-Yih; Yang, Hong-Chang; Wu, Chau-Chung

    2011-08-01

    To achieve early-stage diagnosis, a high-sensitivity assay method is needed. As a biomarker, vascular endothelial growth factor (VEGF) has played a growing role in diagnosing and treating hepatocellular carcinoma (HCC). In this work, an immunomagnetic reduction (IMR) through bio-functionalized magnetic nanoparticles and a high-temperature superconducting-quantum-interference-device magnetometer were utilized for quantitative detection of low-concentration VEGF in serum from rats with HCC. The precision and accuracy of IMR on VEGF were characterized. Further, the results of assaying VEGF in the serum of rats were compared with those of using enzyme-linked immunosorbant assay (ELISA). It was found the correlations between the detected VEGF concentration in the rat serum and tumor burdens were 0.99 and 0.90 for IMR and ELISA, respectively, within the range from 2 pg/ml to 8000 pg/ml of VEGF concentration.

  8. Volumetric tumor burden and its effect on brachial plexus dosimetry in head and neck intensity-modulated radiotherapy

    SciTech Connect

    Romesser, Paul B.; Qureshi, Muhammad M.; Kovalchuk, Nataliya; Truong, Minh Tam

    2014-07-01

    To determine the effect of gross tumor volume of the primary (GTV-P) and nodal (GTV-N) disease on planned radiation dose to the brachial plexus (BP) in head and neck intensity-modulated radiotherapy (IMRT). Overall, 75 patients underwent definitive IMRT to a median total dose of 69.96 Gy in 33 fractions. The right BP and left BP were prospectively contoured as separate organs at risk. The GTV was related to BP dose using the unpaired t-test. Receiver operating characteristics curves were constructed to determine optimized volumetric thresholds of GTV-P and GTV-N corresponding to a maximum BP dose cutoff of > 66 Gy. Multivariate analyses were performed to account for factors associated with a higher maximal BP dose. A higher maximum BP dose (> 66 vs ≤ 66 Gy) correlated with a greater mean GTV-P (79.5 vs 30.8 cc; p = 0.001) and ipsilateral GTV-N (60.6 vs 19.8 cc; p = 0.014). When dichotomized by the optimized nodal volume, patients with an ipsilateral GTV-N ≥ 4.9 vs < 4.9 cc had a significant difference in maximum BP dose (64.2 vs 59.4 Gy; p = 0.001). Multivariate analysis confirmed that an ipsilateral GTV-N ≥ 4.9 cc was an independent predictor for the BP to receive a maximal dose of > 66 Gy when adjusted individually for BP volume, GTV-P, the use of a low anterior neck field technique, total planned radiation dose, and tumor category. Although both the primary and the nodal tumor volumes affected the BP maximal dose, the ipsilateral nodal tumor volume (GTV-N ≥ 4.9 cc) was an independent predictor for high maximal BP dose constraints in head and neck IMRT.

  9. Protective role of tumor necrosis factor (TNF) receptors in chronic intestinal inflammation: TNFR1 ablation boosts systemic inflammatory response.

    PubMed

    Wang, Yi; Han, Gencheng; Chen, Yu; Wang, Ke; Liu, Guijun; Wang, Renxi; Xiao, He; Li, Xinying; Hou, Chunmei; Shen, Beifen; Guo, Renfeng; Li, Yan; Chen, Guojiang

    2013-09-01

    Tumor necrosis factor-α (TNF-α) acts as a key factor for the development of inflammatory bowel diseases (IBDs), whose function is known to be mediated by TNF receptor 1 (TNFR1) or TNFR2. However, the precise role of the two receptors in IBD remains poorly understood. Herein, chronic colitis was established by oral administration of dextran sulfate sodium (DSS) in TNFR1 or TNFR2-/- mice. Unexpectedly, TNFR1 or TNFR2 deficiency led to exacerbation of signs of colitis compared with wild-type (WT) counterparts. Of note, TNFR1 ablation rendered significantly increased mortality compared with TNFR2 and WT mice after DSS. Aggravated pathology of colitis in TNFR1-/- or TNFR2-/- mice correlated with elevated colonic expression of proinflammatory cytokines and chemokines. Importantly, ablation of TNFR1 or TNFR2 increased apoptosis of colonic epithelial cells, which might be due to the heightened ratio of Bax/Bcl-2 and increased expression of caspase-8. Intriguingly, despite comparable intensity of intestinal inflammation in TNFR-deficient mice after DSS, systemic inflammatory response (including splenomegaly and myeloid expansion) was augmented dramatically in TNFR1-/- mice, instead of TNFR2-/- mice. Granulocyte-macrophage colony-stimulating factor (GMCSF) was identified as a key mediator in this process, as neutralization of GMCSF dampened peripheral inflammatory reaction and reduced mortality in TNFR1-/- mice. These data suggest that signaling via TNFR1 or TNFR2 has a protective role in chronic intestinal inflammation, and that lacking TNFR1 augments systemic inflammatory response in GMCSF-dependent manner.

  10. Targeted Inhibition of Heat Shock Protein 90 Suppresses Tumor Necrosis Factor–α and Ameliorates Murine Intestinal Inflammation

    PubMed Central

    Collins, Colm B.; Strassheim, Derek; Aherne, Carol M.; Yeckes, Alyson R.; Jedlicka, Paul; de Zoeten, Edwin F.

    2015-01-01

    Inflammatory bowel diseases are chronic intestinal inflammatory diseases thought to reflect a dysregulated immune response. Although antibody-based inhibition of tumor necrosis factor-α (TNF-α) has provided relief to many inflammatory bowel diseases patients, these therapies are either ineffective in a patient subset or lose their efficacy over time, leaving an unmet need for alternatives. Given the critical role of the heat shock response in regulating inflammation, this study proposed to define the impact of selective inhibition of heat shock protein 90 (HSP90) on intestinal inflammation. Using multiple preclinical mouse models of inflammatory bowel diseases, we demonstrate a potent anti-inflammatory effect of selective inhibition of the HSP90 C-terminal ATPase using the compound novobiocin. Novobiocin-attenuated dextran sulfate sodium-induced colitis and CD45RBhigh adoptive-transfer colitis through the suppression of inflammatory cytokine secretion, including TNF-α. In vitro assays demonstrate that CD4+ T cells treated with novobiocin produced significantly less TNF-α measured by intracellular cytokine staining and by enzyme-linked immunosorbent assay. This corresponded to significantly decreased nuclear p65 translocation by Western blot and a decrease in nuclear factor-κB luciferase activity in Jurkat T cells. Finally, to verify the anti-TNF action of novobiocin, 20-week-old TNFΔARE mice were treated for 2 weeks with subcutaneous administration of novobiocin. This model has high levels of circulating TNF-α and exhibits spontaneous transmural segmental ileitis. Novobiocin treatment significantly reduced inflammatory cell infiltrate in the ileal lamina propria. HSP90 inhibition with novobiocin offers a novel method of inflammatory cytokine suppression without potential for the development of tolerance that limits current antibody-based methods. PMID:24552830

  11. Chronic intermittent abdominal pain in young woman with intestinal malrotation, Fitz-Hugh-Curtis Syndrome and appendiceal neuroendocrine tumor: a rare case report and literature review.

    PubMed

    Cusimano, Alessia; Abdelghany, Ahmed Mohammed Alaaeldien Beniamin; Donadini, Andrea

    2016-01-16

    There are a lot of different causes of abdominal pain; in this case, a young woman suffers from three diseases with similar symptoms. Adult intestinal mal-rotation is a rare condition of deviation from the normal 270° counter clockwise rotation of the midgut resulting in, not only mal-position of the small intestine, but also mal-fixation of the mesentery. Fitz-Hugh-Curtis syndrome is a rare complication of pelvic inflammatory disease; it involves liver capsule inflammation associated with genital tract infection, which is usually caused by Neisseria gonorrhoea and Chlamydia trachomatis. Neuroendocrine tumors are enterochromaffin cell neoplasms that arise from cells of the endocrine (hormonal) and nervous systems; the appendicular one is the most common primary malignant lesion of these tumors, it's incidence is about 0.3 - 0.9% of appendectomies done. Just for knowledge, this is the first described case of concomitant presence of all these diseases with clinical symptoms attributable to each one. 40-years-old woman suffers from acute abdominal pain, predominantly on the right quadrants, without abdominal distension, no guarding nor rigidity and normal intestinal peristalsis. She has a long history of abdominal intermittent pain, with cramps every 30-40 min, resolving spontaneously. She was diagnosed as intestinal mal-rotation through computed tomography scan which has evidenced a mobilized intra--peritoneal duodenum with cecum/ascending colon predominately lying on the left side and the small intestine almost entirely lying on the right side of abdomen, without evidence of effusion, edema or signs of intestinal ischemia or infarction. Exploratory laparoscopy demonstrated an inflammatory process in the hepatic-renal space, with bloody adhesions above the liver capsule; this is additional to the typical pelvic inflammatory disease signs (Fitz-Hugh-Curtis syndrome). Appendectomy was performed with histological analysis resulting in appendicular neuroendocrine tumor

  12. Lack of anti-tumor activity with the β-catenin expression inhibitor EZN-3892 in the C57BL/6J Min/+ model of intestinal carcinogenesis

    SciTech Connect

    Hasson, Rian M.; Briggs, Alexandra; Rizvi, Hira; Carothers, Adelaide M.; Davids, Jennifer S.; Bertagnolli, Monica M.; Cho, Nancy L.

    2014-02-14

    Highlights: • Wnt/β-catenin signaling is aberrantly activated in most colorectal cancers. • Locked nucleic acid (LNA)-based antisense is a novel tool for cancer therapy. • β-Catenin inhibition was observed in mature intestinal tissue of LNA-treated mice. • Further investigation of Wnt/β-catenin targeted therapies is warranted. - Abstract: Background: Previously, we showed that short-term inhibition of β-catenin expression and reversal of aberrant β-catenin subcellular localization by the selective COX-2 inhibitor celecoxib is associated with adenoma regression in the C57BL/6J Min/+ mouse. Conversly, long-term administration resulted in tumor resistance, leading us to investigate alternative methods for selective β-catenin chemoprevention. In this study, we hypothesized that disruption of β-catenin expression by EZN-3892, a selective locked nucleic acid (LNA)-based β-catenin inhibitor, would counteract the tumorigenic effect of Apc loss in Min/+ adenomas while preserving normal intestinal function. Materials and methods: C57BL/6J Apc{sup +/+} wild-type (WT) and Min/+ mice were treated with the maximum tolerated dose (MTD) of EZN-3892 (30 mg/kg). Drug effect on tumor numbers, β-catenin protein expression, and nuclear β-catenin localization were determined. Results: Although the tumor phenotype and β-catenin nuclear localization in Min/+ mice did not change following drug administration, we observed a decrease in β-catenin expression levels in the mature intestinal tissue of treated Min/+ and WT mice, providing proof of principle regarding successful delivery of the LNA-based antisense vehicle. Higher doses of EZN-3892 resulted in fatal outcomes in Min/+ mice, likely due to β-catenin ablation in the intestinal tissue and loss of function. Conclusions: Our data support the critical role of Wnt/β-catenin signaling in maintaining intestinal homeostasis and highlight the challenges of effective drug delivery to target disease without permanent

  13. Partial inhibition of gp130-Jak-Stat3 signaling prevents Wnt-β-catenin-mediated intestinal tumor growth and regeneration.

    PubMed

    Phesse, Toby J; Buchert, Michael; Stuart, Emma; Flanagan, Dustin J; Faux, Maree; Afshar-Sterle, Shoukat; Walker, Francesca; Zhang, Hui-Hua; Nowell, Cameron J; Jorissen, Robert; Tan, Chin Wee; Hirokawa, Yumiko; Eissmann, Moritz F; Poh, Ashleigh R; Malaterre, Jordane; Pearson, Helen B; Kirsch, David G; Provero, Paolo; Poli, Valeria; Ramsay, Robert G; Sieber, Oliver; Burgess, Antony W; Huszar, Dennis; Vincan, Elizabeth; Ernst, Matthias

    2014-09-30

    Most colon cancers arise from somatic mutations in the tumor suppressor gene APC (adenomatous polyposis coli), and these mutations cause constitutive activation of the Wnt-to-β-catenin pathway in the intestinal epithelium. Because Wnt-β-catenin signaling is required for homeostasis and regeneration of the adult intestinal epithelium, therapeutic targeting of this pathway is challenging. We found that genetic activation of the cytokine-stimulated pathway mediated by the receptor gp130, the associated Jak (Janus kinase) kinases, and the transcription factor Stat3 (signal transducer and activator of transcription 3) was required for intestinal regeneration in response to irradiation-induced damage in wild-type mice and for tumorigenesis in Apc-mutant mice. Systemic pharmacological or partial genetic inhibition of gp130-Jak-Stat3 signaling suppressed intestinal regeneration, the growth of tumors in Apc-mutant mice, and the growth of colon cancer xenografts. The growth of Apc-mutant tumors depended on gp130-Jak-Stat3 signaling for induction of the polycomb repressor Bmi-1, and the associated repression of genes encoding the cell cycle inhibitors p16 and p21. However, suppression of gp130-Jak-Stat3 signaling did not affect Wnt-β-catenin signaling or homeostasis in the intestine. Thus, these data not only suggest a molecular mechanism for how the gp130-Jak-Stat3 pathway can promote cancer but also provide a rationale for therapeutic inhibition of Jak in colon cancer. Copyright © 2014, American Association for the Advancement of Science.

  14. Methotrexate-conjugated PEGylated dendrimers show differential patterns of deposition and activity in tumor-burdened lymph nodes after intravenous and subcutaneous administration in rats.

    PubMed

    Kaminskas, Lisa M; McLeod, Victoria M; Ascher, David B; Ryan, Gemma M; Jones, Seth; Haynes, John M; Trevaskis, Natalie L; Chan, Linda J; Sloan, Erica K; Finnin, Benjamin A; Williamson, Mark; Velkov, Tony; Williams, Elizabeth D; Kelly, Brian D; Owen, David J; Porter, Christopher J H

    2015-02-02

    The current study sought to explore whether the subcutaneous administration of lymph targeted dendrimers, conjugated with a model chemotherapeutic (methotrexate, MTX), was able to enhance anticancer activity against lymph node metastases. The lymphatic pharmacokinetics and antitumor activity of PEGylated polylysine dendrimers conjugated to MTX [D-MTX(OH)] via a tumor-labile hexapeptide linker was examined in rats and compared to a similar system where MTX was α-carboxyl O-tert-butylated [D-MTX(OtBu)]. The latter has previously been shown to exhibit longer plasma circulation times. D-MTX(OtBu) was well absorbed from the subcutaneous injection site via the lymph, and 3 to 4%/g of the dose was retained by sentinel lymph nodes. In contrast, D-MTX(OH) showed limited absorption from the subcutaneous injection site, but absorption was almost exclusively via the lymph. The retention of D-MTX(OH) by sentinel lymph nodes was also significantly elevated (approximately 30% dose/g). MTX alone was not absorbed into the lymph. All dendrimers displayed lower lymph node targeting after intravenous administration. Despite significant differences in the lymph node retention of D-MTX(OH) and D-MTX(OtBu) after subcutaneous and intravenous administration, the growth of lymph node metastases was similarly inhibited. In contrast, the administration of MTX alone did not significantly reduce lymph node tumor growth. Subcutaneous administration of drug-conjugated dendrimers therefore provides an opportunity to improve drug deposition in downstream tumor-burdened lymph nodes. In this case, however, increased lymph node biodistribution did not correlate well with antitumor activity, possibly suggesting constrained drug release at the site of action.

  15. Moxibustion inhibits interleukin-12 and tumor necrosis factor alpha and modulates intestinal flora in rat with ulcerative colitis

    PubMed Central

    Wang, Xiao-Mei; Lu, Yuan; Wu, Lu-Yi; Yu, Shu-Guang; Zhao, Bai-Xiao; Hu, Hong-Yi; Wu, Huan-Gan; Bao, Chun-Hui; Liu, Hui-Rong; Wang, Jin-Hai; Yao, Yi; Hua, Xue-Gui; Guo, Hui-Ying; Shen, Li-Rong

    2012-01-01

    AIM: To investigate the effect of moxibustion on intestinal flora and release of interleukin-12 (IL-12) and tumor necrosis factor-α (TNF-α) from the colon in rat with ulcerative colitis (UC). METHODS: A rat model of UC was established by local stimulation of the intestine with supernatant from colonic contents harvested from human UC patients. A total of 40 male Sprague-Dawley rats were randomly divided into the following groups: normal (sham), model (UC), herb-partition moxibustion (HPM-treated), and positive control sulfasalazine (SA-treated). Rats treated with HPM received HPM at acupuncture points ST25 and RN6, once a day for 15 min, for a total of 8 d. Rats in the SA group were perfused with SA twice a day for 8 d. The colonic histopathology was observed by hematoxylin-eosin. The levels of intestinal flora, including Bifidobacterium, Lactobacillus, Escherichia coli (E. coli), and Bacteroides fragilis (B. fragilis), were tested by real-time quantitative polymerase chain reaction to detect bacterial 16S rRNA/DNA in order to determine DNA copy numbers of each specific species. Immunohistochemical assays were used to observe the expression of TNF-α and IL-12 in the rat colons. RESULTS: HPM treatment inhibited immunopathology in colonic tissues of UC rats; the general morphological score and the immunopathological score were significantly decreased in the HPM and SA groups compared with the model group [3.5 (2.0-4.0), 3.0 (1.5-3.5) vs 6.0 (5.5-7.0), P < 0.05 for the general morphological score, and 3.00 (2.00-3.50), 3.00 (2.50-3.50) vs 5.00 (4.50-5.50), P < 0.01 for the immunopathological score]. As measured by DNA copy number, we found that Bifidobacterium and Lactobacillus, which are associated with a healthy colon, were significantly higher in the HPM and SA groups than in the model group (1.395 ± 1.339, 1.461 ± 1.152 vs 0.045 ± 0.036, P < 0.01 for Bifidobacterium, and 0.395 ± 0.325, 0.851 ± 0.651 vs 0.0015 ± 0.0014, P < 0.01 for Lactobacillus). On the

  16. Cosecretion of peptide histidine methionine (PHM) and vasoactive intestinal peptide (VIP) in patients with VIP-producing tumors.

    PubMed

    Fahrenkrug, J; Pedersen, J H

    1986-01-01

    Regional specific antibodies and chromatography were used to analyze the concentration and molecular forms of vasoactive intestinal peptide (VIP) and peptide histidine methionine (PHM) in plasma from 39 patients with VIP-producing tumors. Plasma VIP concentrations ranged from 29 to 2550 pmol/l and the corresponding PHM immunoreactive values measured with C-terminally directed antibody were 42 to 2100 pmol/l which correlated closely with the VIP concentrations. N-terminal PHM concentrations were significantly higher than the C-terminal values ranging from 92 to 5850 pmol/l and correlated poorly with the corresponding VIP concentrations. Infusion experiments with PHM disclosed that the higher levels of N-terminal immunoreactivity could not be explained by slower metabolic clearance or by degradation to smaller N-terminal immunoreactive forms. N-terminally directed PHM antibody revealed, in addition to intact PHM, a larger immunoreactive form in patient plasma which constituted the major proportion of the total immunoreactivity. In conclusion, VIP and PHM are cosecreted from VIPomas and measurement of PHM, especially N-terminal immunoreactivity, may be useful in this condition.

  17. Metabolic Tumor Burden Assessed by Dual Time Point [(18)F]FDG PET/CT in Locally Advanced Breast Cancer: Relation with Tumor Biology.

    PubMed

    Garcia-Vicente, Ana María; Pérez-Beteta, Julián; Pérez-García, Víctor Manuel; Molina, David; Jiménez-Londoño, German Andrés; Soriano-Castrejón, Angel; Martínez-González, Alicia

    2017-08-01

    The aim of the study was to investigate the influence of dual time point 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) positron emission tomography/x-ray computed tomography (PET/CT) on the standard uptake value (SUV) and volume-based metabolic variables of breast lesions and their relation with biological characteristics and molecular phenotypes. Retrospective analysis including 67 patients with locally advanced breast cancer (LABC). All patients underwent a dual time point [(18)F]FDG PET/CT, 1 h (PET-1) and 3 h (PET-2) after [(18)F]FDG administration. Tumors were segmented following a three-dimensional methodology. Semiquantitative metabolic variables (SUVmax, SUVmean, and SUVpeak) and volume-based variables (metabolic tumor volume, MTV, and total lesion glycolysis, TLG) were obtained. Biologic prognostic parameters, such as the hormone receptors status, p53, HER2 expression, proliferation rate (Ki-67), and grading were obtained. Molecular phenotypes and risk-classification [low: luminal A, intermediate: luminal B HER2 (-) or luminal B HER2 (+), and high: HER2 pure or triple negative] were established. Relations between clinical and biological variables with the metabolic parameters were studied. The relevance of each metabolic variable in the prediction of phenotype risk was assessed using a multivariate analysis. SUV-based variables and TLG obtained in the PET-1 and PET-2 showed high and significant correlations between them. MTV and SUV variables (SUVmax, SUVmean, and SUVpeak) where only marginally correlated. Significant differences were found between mean SUV variables and TLG obtained in PET-1 and PET-2. High and significant associations were found between metabolic variables obtained in PET-1 and their homonymous in PET-2. Based on that, only relations of PET-1 variables with biological tumor characteristics were explored. SUV variables showed associations with hormone receptors status (p < 0.001 and p = 0.001 for estrogen and progesterone receptor

  18. Heavy Ion Radiation Exposure Triggered Higher Intestinal Tumor Frequency and Greater β-Catenin Activation than γ Radiation in APCMin/+ Mice

    PubMed Central

    Datta, Kamal; Suman, Shubhankar; Kallakury, Bhaskar V. S.; Fornace, Albert J.

    2013-01-01

    Risk of colorectal cancer (CRC) after exposure to low linear energy transfer (low-LET) radiation such as γ-ray is highlighted by the studies in atom bomb survivors. On the contrary, CRC risk prediction after exposure to high-LET cosmic heavy ion radiation exposure is hindered due to scarcity of in vivo data. Therefore, intestinal tumor frequency, size, cluster, and grade were studied in APCMin/+ mice (n = 20 per group; 6 to 8 wks old; female) 100 to 110 days after exposure to 1.6 or 4 Gy of heavy ion 56Fe radiation (energy: 1000 MeV/nucleon) and results were compared to γ radiation doses of 2 or 5 Gy, which are equitoxic to 1.6 and 4 Gy 56Fe respectively. Due to relevance of lower doses to radiotherapy treatment fractions and space exploration, we followed 2 Gy γ and equitoxic 1.6 Gy 56Fe for comparative analysis of intestinal epithelial cell (IEC) proliferation, differentiation, and β-catenin signaling pathway alterations between the two radiation types using immunoblot, and immunohistochemistry. Relative to controls and γ-ray, intestinal tumor frequency and grade was significantly higher after 56Fe radiation. Additionally, tumor incidence per unit of radiation (per cGy) was also higher after 56Fe radiation relative to γ radiation. Staining for phospho-histone H3, indicative of IEC proliferation, was more and alcian blue staining, indicative of IEC differentiation, was less in 56Fe than γ irradiated samples. Activation of β-catenin was more in 56Fe-irradiated tumor-free and tumor-bearing areas of the intestinal tissues. When considered along with higher levels of cyclin D1, we infer that relative to γ radiation exposure to 56Fe radiation induced markedly reduced differentiation, and increased proliferative index in IEC resulting in increased intestinal tumors of larger size and grade due to preferentially greater activation of β-catenin and its downstream effectors. PMID:23555653

  19. Paraneoplastic Antigen Ma2 Autoantibodies as Specific Blood Biomarkers for Detection of Early Recurrence of Small Intestine Neuroendocrine Tumors

    PubMed Central

    Cui, Tao; Hurtig, Monica; Elgue, Graciela; Li, Su-Chen; Veronesi, Giulia; Essaghir, Ahmed; Demoulin, Jean-Baptiste; Pelosi, Giuseppe; Alimohammadi, Mohammad; Öberg, Kjell; Giandomenico, Valeria

    2010-01-01

    Background Small intestine neuroendocrine tumors (SI-NETs) belong to a rare group of cancers. Most patients have developed metastatic disease at the time of diagnosis, for which there is currently no cure. The delay in diagnosis is a major issue in the clinical management of the patients and new markers are urgently needed. We have previously identified paraneoplastic antigen Ma2 (PNMA2) as a novel SI-NET tissue biomarker. Therefore, we evaluated whether Ma2 autoantibodies detection in the blood stream is useful for the clinical diagnosis and recurrence of SI-NETs. Methodology/Principal Findings A novel indirect ELISA was set up to detect Ma2 autoantibodies in blood samples of patients with SI-NET at different stages of disease. The analysis was extended to include typical and atypical lung carcinoids (TLC and ALC), to evaluate whether Ma2 autoantibodies in the blood stream become a general biomarker for NETs. In total, 124 blood samples of SI-NET patients at different stages of disease were included in the study. The novel Ma2 autoantibody ELISA showed high sensitivity, specificity and accuracy with ROC curve analysis underlying an area between 0.734 and 0.816. Ma2 autoantibodies in the blood from SI-NET patients were verified by western blot and sequential immunoprecipitation. Serum antibodies of patients stain Ma2 in the tumor tissue and neurons. We observed that SI-NET patients expressing Ma2 autoantibody levels below the cutoff had a longer progression and recurrence-free survival compared to those with higher titer. We also detected higher levels of Ma2 autoantibodies in blood samples from TLC and ALC patients than from healthy controls, as previously shown in small cell lung carcinoma samples. Conclusion Here we show that high Ma2 autoantibody titer in the blood of SI-NET patients is a sensitive and specific biomarker, superior to chromogranin A (CgA) for the risk of recurrence after radical operation of these tumors. PMID:21209860

  20. Comprehensive Genomic Profiling of 282 Pediatric Low- and High-Grade Gliomas Reveals Genomic Drivers, Tumor Mutational Burden, and Hypermutation Signatures.

    PubMed

    Johnson, Adrienne; Severson, Eric; Gay, Laurie; Vergilio, Jo-Anne; Elvin, Julia; Suh, James; Daniel, Sugganth; Covert, Mandy; Frampton, Garrett M; Hsu, Sigmund; Lesser, Glenn J; Stogner-Underwood, Kimberly; Mott, Ryan T; Rush, Sarah Z; Stanke, Jennifer J; Dahiya, Sonika; Sun, James; Reddy, Prasanth; Chalmers, Zachary R; Erlich, Rachel; Chudnovsky, Yakov; Fabrizio, David; Schrock, Alexa B; Ali, Siraj; Miller, Vincent; Stephens, Philip J; Ross, Jeffrey; Crawford, John R; Ramkissoon, Shakti H

    2017-09-14

    Pediatric brain tumors are the leading cause of death for children with cancer in the U.S. Incorporating next-generation sequencing data for both pediatric low-grade (pLGGs) and high-grade gliomas (pHGGs) can inform diagnostic, prognostic, and therapeutic decision-making. We performed comprehensive genomic profiling on 282 pediatric gliomas (157 pHGGs, 125 pLGGs), sequencing 315 cancer-related genes and calculating the tumor mutational burden (TMB; mutations per megabase [Mb]). In pLGGs, we detected genomic alterations (GA) in 95.2% (119/125) of tumors. BRAF was most frequently altered (48%; 60/125), and FGFR1 missense (17.6%; 22/125), NF1 loss of function (8.8%; 11/125), and TP53 (5.6%; 7/125) mutations were also detected. Rearrangements were identified in 35% of pLGGs, including KIAA1549-BRAF, QKI-RAF1, FGFR3-TACC3, CEP85L-ROS1, and GOPC-ROS1 fusions. Among pHGGs, GA were identified in 96.8% (152/157). The genes most frequently mutated were TP53 (49%; 77/157), H3F3A (37.6%; 59/157), ATRX (24.2%; 38/157), NF1 (22.2%; 35/157), and PDGFRA (21.7%; 34/157). Interestingly, most H3F3A mutations (81.4%; 35/43) were the variant K28M. Midline tumor analysis revealed H3F3A mutations (40%; 40/100) consisted solely of the K28M variant. Pediatric high-grade gliomas harbored oncogenic EML4-ALK, DGKB-ETV1, ATG7-RAF1, and EWSR1-PATZ1 fusions. Six percent (9/157) of pHGGs were hypermutated (TMB >20 mutations per Mb; range 43-581 mutations per Mb), harboring mutations deleterious for DNA repair in MSH6, MSH2, MLH1, PMS2, POLE, and POLD1 genes (78% of cases). Comprehensive genomic profiling of pediatric gliomas provides objective data that promote diagnostic accuracy and enhance clinical decision-making. Additionally, TMB could be a biomarker to identify pediatric glioblastoma (GBM) patients who may benefit from immunotherapy. By providing objective data to support diagnostic, prognostic, and therapeutic decision-making, comprehensive genomic profiling is necessary for advancing

  1. The Effect of Inflammatory Status on Butyrate and Folate Uptake by Tumoral (Caco-2) and Non-Tumoral (IEC-6) Intestinal Epithelial Cells.

    PubMed

    Couto, Mafalda R; Gonçalves, Pedro; Catarino, Telmo A; Martel, Fátima

    2017-01-01

    Colorectal cancer (CRC) is the second leading cause of cancer death in occidental countries. Chronic inflammatory bowel disease (crohn's disease and ulcerative colitis) is associated with an increased risk for CRC development. The aim of this work was to investigate the relationship between inflammatory status and absorption of nutrients with a role in CRC pathogenesis. In this experimental study, we evaluated the in vitro effect of tumour necrosis factor-alpha (TNF-α), interferon-γ (IF-γ), and acetylsalicylic acid on 14C-butyrate (14C- BT), 3H-folic acid (3H-FA) uptake, and on proliferation, viability and differentiation of Caco-2 and IEC-6 cells in culture. The proinflammatory cytokines TNF-α and INF-γ were found to decrease uptake of a low concentration of 14C-BT (10 µM) by Caco-2 (tumoral) and IEC-6 (normal) intestinal epithelial cell lines. However, the effect of TNF-α and INF-γ in IEC-6 cells is most probably related to a cytotoxic and antiproliferative impact. In contrast, INF-γ increases uptake of a high concentration (10 mM) of 14C-BT in Caco-2 cells. The anticarcinogenic effect of BT (10 mM) in these cells is not affected by the presence of this cytokine. On the other hand, acetylsalicylic acid stimulates 14C-BT uptake by Caco-2 cells and potentiates its antiproliferative effect. Finally, both TNF-α and INF-γ cause a significant decrease in 3H-FA uptake by Caco-2 cells. The inflammatory status has an impact upon cellular uptake of BT and FA, two nutrients with a role in CRC pathogenesis. Moreover, the anti-inflammatory acetylsalicylic acid potentiates the anticarcinogenic effect of BT in Caco-2 cells by increasing its cellular uptake.

  2. Exploring New Multimodal Quantitative Imaging Indices for the Assessment of Osseous Tumor Burden in Prostate Cancer Using (68)Ga-PSMA PET/CT.

    PubMed

    Bieth, Marie; Krönke, Markus; Tauber, Robert; Dahlbender, Marielena; Retz, Margitta; Nekolla, Stephan G; Menze, Bjoern; Maurer, Tobias; Eiber, Matthias; Schwaiger, Markus

    2017-10-01

    PET combined with CT and prostate-specific membrane antigen (PSMA) ligands has gained significant interest for staging prostate cancer (PC). In this study, we propose 2 multimodal quantitative indices as imaging biomarkers for the assessment of osseous tumor burden using (68)Ga-PSMA PET/CT and present preliminary clinical data. Methods: We defined 2 bone PET indices (BPIs) that incorporate anatomic information from CT and functional information from (68)Ga-PSMA PET: BPIVOL is the percentage of bone volume affected by tumor and BPISUV additionally considers the level of PSMA expression. We describe a semiautomatic computation method based on segmentation of bones in CT and of lesions in PET. Data from 45 patients with castration-resistant PC and bone metastases during (223)Ra-dichloride were retrospectively analyzed. We evaluated the computational stability and reproducibility of the proposed indices and explored their relation to the prostate-specific antigen blood value, the bone scan index (BSI), and disease classification using PERCIST. Results: On the technical side, BPIVOL and BPISUV showed an interobserver maximum difference of 3.5%, and their computation took only a few minutes. On the clinical side, BPIVOL and BPISUV showed significant correlations with BSI (r = 0.76 and 0.74, respectively, P < 0.001) and prostate-specific antigen values (r = 0.57 and 0.54, respectively, P < 0.01). When the proposed indices were compared against expert rating using PERCIST, BPIVOL and BPISUV showed better agreement than BSI, indicating their potential for objective response evaluation. Conclusion: We propose the evaluation of BPIVOL and BPISUV as imaging biomarkers for (68)Ga-PSMA PET/CT in a prospective study exploring their potential for outcome prediction in patients with bone metastases from PC. © 2017 by the Society of Nuclear Medicine and Molecular Imaging.

  3. Prognostic significance of metabolic tumor burden by positron emission tomography/computed tomography in patients with relapsed/refractory diffuse large B-cell lymphoma

    PubMed Central

    Tateishi, Ukihide; Tatsumi, Mitsuaki; Terauchi, Takashi; Ando, Kiyoshi; Niitsu, Nozomi; Kim, Won Seog; Suh, Cheolwon; Ogura, Michinori; Tobinai, Kensei

    2015-01-01

    The aim of the present study was to investigate the feasibility of measuring metabolic tumor burden using [F-18] fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) treated with bendamustine–rituximab. Because the standardized uptake value is a critical parameter of tumor characterization, we carried out a phantom study of 18F-FDG PET/CT to ensure quality control for 28 machines in the 24 institutions (Japan, 17 institutions; Korea, 7 institutions) participating in our clinical study. Fifty-five patients with relapsed or refractory DLBCL were enrolled. The 18F-FDG PET/CT was acquired before treatment, after two cycles, and after the last treatment cycle. Treatment response was assessed after two cycles and after the last cycle using the Lugano classification. Using this classification, remission was complete in 15 patients (27%) and incomplete in 40 patients (73%) after two cycles of therapy, and remission was complete in 32 patients (58%) and incomplete in 23 patients (42%) after the last treatment cycle. The percentage change in all PET/CT parameters except for the area under the curve of the cumulative standardized uptake value–volume histogram was significantly greater in complete response patients than in non-complete response patients after two cycles and the last cycle. The Cox proportional hazard model and best subset selection method revealed that the percentage change of the sum of total lesion glycolysis after the last cycle (relative risk, 5.24; P = 0.003) was an independent predictor of progression-free survival. The percent change of sum of total lesion glycolysis, calculated from PET/CT, can be used to quantify the response to treatment and can predict progression-free survival after the last treatment cycle in patients with relapsed or refractory DLBCL treated with bendamustine–rituximab. PMID:25495273

  4. Cellular localization of tumor necrosis factor (TNF)-alpha transcripts in normal bowel and in necrotizing enterocolitis. TNF gene expression by Paneth cells, intestinal eosinophils, and macrophages.

    PubMed Central

    Tan, X.; Hsueh, W.; Gonzalez-Crussi, F.

    1993-01-01

    Tumor necrosis factor-alpha (TNF) has been shown to induce intestinal necrosis in animals. Moreover, plasma TNF levels are elevated in patients with necrotizing enterocolitis. Thus, it is possible that TNF plays a role in the pathogenesis of NEC. In the present study we used in situ hybridization (with human TNF riboprobes) to localize TNF transcripts in the intestinal tissues from normal biopsies and NEC patients. We found that in normal intestine a small amount of TNF mRNA was present only in Paneth cells. In contrast, in the acute stage of NEC, a high amount of TNF transcripts was detected in Paneth cells as well as in infiltrating eosinophils. In one case that showed infiltrating macrophages, TNF mRNA was also detected in these cells. Resident macrophages in the lamina propria and other inflammatory cells were negative for TNF transcripts. Our results suggest that: 1) Paneth cells are the major source of TNF transcripts in normal intestine, and 2) there is a marked increase in TNF mRNA formation in Paneth cells, as well as in infiltrating eosinophils and macrophages in patients with NEC. TNF-containing cells may play an important role in the pathophysiology of NEC. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:8506954

  5. Epithelial-derived IL-33 promotes intestinal tumorigenesis in Apc (Min/+) mice.

    PubMed

    He, Zhengxiang; Chen, Lili; Souto, Fabricio O; Canasto-Chibuque, Claudia; Bongers, Gerold; Deshpande, Madhura; Harpaz, Noam; Ko, Huaibin M; Kelley, Kevin; Furtado, Glaucia C; Lira, Sergio A

    2017-07-14

    Increased expression of Interleukin (IL)-33 has been detected in intestinal samples of patients with ulcerative colitis, a condition associated with increased risk for colon cancer, but its role in the development of colorectal cancer has yet to be fully examined. Here, we investigated the role of epithelial expressed IL-33 during development of intestinal tumors. IL-33 expression was detected in epithelial cells in colorectal cancer specimens and in the Apc (Min/+) mice. To better understand the role of epithelial-derived IL-33 in the intestinal tumorigenesis, we generated transgenic mice expressing IL-33 in intestinal epithelial cells (V33 mice). V33 Apc (Min/+) mice, resulting from the cross of V33 with Apc (Min/+) mice, had increased intestinal tumor burden compared with littermate Apc (Min/+) mice. Consistently, Apc (Min/+) mice deficient for IL-33 receptor (ST2), had reduced polyp burden. Mechanistically, overexpression of IL-33 promoted expansion of ST2(+) regulatory T cells, increased Th2 cytokine milieu, and induced alternatively activated macrophages in the gut. IL-33 promoted marked changes in the expression of antimicrobial peptides, and antibiotic treatment of V33 Apc (Min/+) mice abrogated the tumor promoting-effects of IL-33 in the colon. In conclusion, elevated IL-33 signaling increases tumor development in the Apc (Min/+) mice.

  6. Pulmonary Sarcomatoid Carcinomas Commonly Harbor Either Potentially Targetable Genomic Alterations or High Tumor Mutational Burden as Observed by Comprehensive Genomic Profiling.

    PubMed

    Schrock, Alexa B; Li, Shuyu D; Frampton, Garrett M; Suh, James; Braun, Eduardo; Mehra, Ranee; Buck, Steven C; Bufill, Jose A; Peled, Nir; Karim, Nagla Abdel; Hsieh, K Cynthia; Doria, Manuel; Knost, James; Chen, Rong; Ou, Sai-Hong Ignatius; Ross, Jeffrey S; Stephens, Philip J; Fishkin, Paul; Miller, Vincent A; Ali, Siraj M; Halmos, Balazs; Liu, Jane J

    2017-06-01

    Pulmonary sarcomatoid carcinoma (PSC) is a high-grade NSCLC characterized by poor prognosis and resistance to chemotherapy. Development of targeted therapeutic strategies for PSC has been hampered because of limited and inconsistent molecular characterization. Hybrid capture-based comprehensive genomic profiling was performed on DNA from formalin-fixed paraffin-embedded sections of 15,867 NSCLCs, including 125 PSCs (0.8%). Tumor mutational burden (TMB) was calculated from 1.11 megabases (Mb) of sequenced DNA. The median age of the patients with PSC was 67 years (range 32-87), 58% were male, and 78% had stage IV disease. Tumor protein p53 gene (TP53) genomic alterations (GAs) were identified in 74% of cases, which had genomics distinct from TP53 wild-type cases, and 62% featured a GA in KRAS (34%) or one of seven genes currently recommended for testing in the National Comprehensive Cancer Network NSCLC guidelines, including the following: hepatocyte growth factor receptor gene (MET) (13.6%), EGFR (8.8%), BRAF (7.2%), erb-b2 receptor tyrosine kinase 2 gene (HER2) (1.6%), and ret proto-oncogene (RET) (0.8%). MET exon 14 alterations were enriched in PSC (12%) compared with non-PSC NSCLCs (∼3%) (p < 0.0001) and were more prevalent in PSC cases with an adenocarcinoma component. The fraction of PSC with a high TMB (>20 mutations per Mb) was notably higher than in non-PSC NSCLC (20% versus 14%, p = 0.056). Of nine patients with PSC treated with targeted or immunotherapies, three had partial responses and three had stable disease. Potentially targetable GAs in National Comprehensive Cancer Network NSCLC genes (30%) or intermediate or high TMB (43%, >10 mutations per Mb) were identified in most of the PSC cases. Thus, the use of comprehensive genomic profiling in clinical care may provide important treatment options for a historically poorly characterized and difficult to treat disease. Copyright © 2017 International Association for the Study of Lung Cancer. Published

  7. Quantitative polymerase chain reaction analysis with allele-specific oligonucleotide primers for individual IgH VDJ regions to evaluate tumor burden in myeloma patients.

    PubMed

    Sata, Hiroshi; Shibayama, Hirohiko; Maeda, Ikuhiro; Habuchi, Yoko; Nakatani, Eiji; Fukushima, Kentaro; Fujita, Jiro; Ezoe, Sachiko; Tadokoro, Seiji; Maeda, Tetsuo; Mizuki, Masao; Kosugi, Satoru; Nakagawa, Masashi; Ueda, Shuji; Iida, Masato; Tokumine, Yukihiro; Azenishi, Yasuhiko; Mitsui, Hideki; Oritani, Kenji; Kanakura, Yuzuru

    2015-05-01

    Quantitative polymerase chain reaction (PCR) with patient-specific, allele-specific oligonucleotide (ASO) primers for individual immunoglobulin H VDJ region (ASO-PCR) amplification was performed using several sources of clinical material, including mRNA from peripheral blood cells (PBMNCs), whole bone marrow cells (BMMNCs), and the CD20+ CD38- B-cell population in bone marrow, as well as cell-free DNA from the sera of patients with multiple myeloma (MM). We designed the ASO primers and produced sufficient PCR fragments to evaluate tumor burden in 20 of 30 bone marrow samples at diagnosis. Polymerase chain reaction amplification efficiency depended on primer sequences because the production of ASO-PCR fragments did not correlate with serum M-protein levels. However, the ASO-PCR levels in BMMNCs showed statistically significant correlations with those in PBMNCs and CD20+ CD38- B-cells. The good association between the BMMNC and PBMNC data indicated that PBMNCs could be a suitable source for monitoring minimal residual disease (MRD). In the case of cell-free DNA, ASO-PCR levels showed a unique pattern and remained high even after treatment. Because the sequence information for each ASO-PCR product was identical to the original, the cell-free DNA might also be useful for evaluating MRD. Moreover, the ASO-PCR products were clearly detected in 17 of 22 mRNA samples from CD20+ CD38- populations, suggesting that MM clones might exist in relatively earlier stages of B cells than in plasma cells. Thus, ASO-PCR analysis using various clinical materials is useful for detecting MRD in MM patients as well as for clarifying MM pathogenesis. Copyright © 2015 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.

  8. Exceptional Response to Nivolumab and Stereotactic Body Radiation Therapy (SBRT) in Neuroendocrine Cervical Carcinoma with High Tumor Mutational Burden: Management Considerations from the Center For Personalized Cancer Therapy at UC San Diego Moores Cancer Center.

    PubMed

    Sharabi, Andrew; Kim, Sangwoo Shawn; Kato, Shumei; Sanders, Philip D; Patel, Sandip Pravin; Sanghvi, Parag; Weihe, Elizabeth; Kurzrock, Razelle

    2017-06-01

    Neuroendocrine carcinoma of the cervix is an ultra-rare malignancy with a poor prognosis and limited treatment options. Checkpoint blockade immunotherapy has rapidly developed into an emerging standard of care for several common disease types. Interestingly, in preclinical and retrospective clinical data, radiation therapy has been demonstrated to synergize with checkpoint inhibitors. Here we report a patient with metastatic, chemotherapy-refractory neuroendocrine carcinoma who presented with partial bowel obstruction due to a large tumor burden. Genomic analysis demonstrated a high number of alterations on liquid biopsy (circulating tumor DNA [ctDNA]), which prompted treatment with stereotactic body radiation therapy (SBRT) combined with anti-programmed cell death protein 1 antibody. Tissue rebiopsy and comprehensive genomic profiling confirmed high tumor mutational burden and a mismatch repair gene defect. The patient manifested near-complete systemic resolution of disease, ongoing at 10+ months. We discuss the novel treatment modality of SBRT combined with a checkpoint inhibitor and the implications of molecular profiling and tumor mutational burden as potential predictors of response. High-grade, large-cell neuroendocrine carcinoma of the cervix is an ultra-rare malignancy that carries a grim prognosis.Next-generation sequencing may reveal key mutations in MSH2 genes amongst others. MSH2 mutations target the DNA mismatch repair process and can predispose patients to malignancies with high mutational burdens.Immunotherapy combined with radiation therapy can elicit a significant response, both within and outside the field of radiation. The latter is termed the "abscopal" effect, perhaps mediated by radiation-induced cross presentation of tumor antigens resulting in immune activation.Sequencing of blood-derived ctDNA showed a high number of alterations, and tissue sequencing confirmed a high tumor mutational burden as a consequence of a mismatch repair gene defect

  9. Mimicking Metastases Including Tumor Stroma: A New Technique to Generate a Three-Dimensional Colorectal Cancer Model Based on a Biological Decellularized Intestinal Scaffold

    PubMed Central

    Nietzer, Sarah; Baur, Florentin; Sieber, Stefan; Hansmann, Jan; Schwarz, Thomas; Stoffer, Carolin; Häfner, Heide; Gasser, Martin; Waaga-Gasser, Ana Maria; Walles, Heike

    2016-01-01

    Tumor models based on cancer cell lines cultured two-dimensionally (2D) on plastic lack histological complexity and functionality compared to the native microenvironment. Xenogenic mouse tumor models display higher complexity but often do not predict human drug responses accurately due to species-specific differences. We present here a three-dimensional (3D) in vitro colon cancer model based on a biological scaffold derived from decellularized porcine jejunum (small intestine submucosa+mucosa, SISmuc). Two different cell lines were used in monoculture or in coculture with primary fibroblasts. After 14 days of culture, we demonstrated a close contact of human Caco2 colon cancer cells with the preserved basement membrane on an ultrastructural level as well as morphological characteristics of a well-differentiated epithelium. To generate a tissue-engineered tumor model, we chose human SW480 colon cancer cells, a reportedly malignant cell line. Malignant characteristics were confirmed in 2D cell culture: SW480 cells showed higher vimentin and lower E-cadherin expression than Caco2 cells. In contrast to Caco2, SW480 cells displayed cancerous characteristics such as delocalized E-cadherin and nuclear location of β-catenin in a subset of cells. One central drawback of 2D cultures—especially in consideration of drug testing—is their artificially high proliferation. In our 3D tissue-engineered tumor model, both cell lines showed decreased numbers of proliferating cells, thus correlating more precisely with observations of primary colon cancer in all stages (UICC I-IV). Moreover, vimentin decreased in SW480 colon cancer cells, indicating a mesenchymal to epithelial transition process, attributed to metastasis formation. Only SW480 cells cocultured with fibroblasts induced the formation of tumor-like aggregates surrounded by fibroblasts, whereas in Caco2 cocultures, a separate Caco2 cell layer was formed separated from the fibroblast compartment beneath. To foster tissue

  10. [Association of intestinal epithelial tight junctions, E.coli, intestinal mucosa Toll-like receptor-4 and tumor necrosis factor-alpha in rabbit with non-alcoholic fatty liver disease].

    PubMed

    Wang, Haikun; Gao, Hongliang; Yao, Ping

    2014-12-01

    To explore the variation and association of intestinal epithelial tight junctions, E.coli, and expression of Toll-like receptor-4 (TLR-4) and tumor necrosis factor-alpha (TNFα) in a rabbit model of non-alcoholic fatty liver disease (NAFLD). Fourteen male New Zealand rabbits were randomly divided into two groups. The control group was given a normal diet, while the NAFLD group was given a high-fat diet. After 12 weeks, the two groups were sacrificed. Both length and width of the tight junctions of ileum epithelial cells were measured by electron microscopy. Enzyme-linked immunosorbent assay was used to detect the concentration of TNFα in venous blood serum. Location and expression of TLR-4 were observed by immunohistochemical staining. Copies of E.coli genes were measured by RT-PCR. The relationship between TNFα and tight junctions, TLR-4, and E.coli were respectively analyzed by stepwise multiple linear regression. Compared with the control group, the NAFLD group has significantly shortened ileum epithelial fight junctions (t=5.031, P<0.01), increased copies of E. coli genes (t=-3.492, P<0.01), and increased ileal expression of TLR-4 (t=-44.089, P<0.01). A significant increase of TNFα was also observed in the NAFLD group (t=-17.768, P<0.01). Regression analysis showed that E.coli and intestinal epithelial tight junctions were correlated (standardized beta=-0.385), and showed a positive correlation between E. coli and TLR-4 (standardized beta=0.332 and 0.427). Damage to the intestine as a physical barrier, biological barrier and immune barrier is closely related to TNFα expression, and the relation between the immune barrier and TNFα is more significant.

  11. The presence of JC virus in gastric carcinomas correlates with patient's age, intestinal histological type and aberrant methylation of tumor suppressor genes.

    PubMed

    Ksiaa, Feryel; Ziadi, Sonia; Mokni, Moncef; Korbi, Sadok; Trimeche, Mounir

    2010-04-01

    JC virus (JCV) is a neurotropic polyomavirus and the causative agent of progressive multifocal leukoencephalopathy. A role for JCV in gastrointestinal malignancies has been recently suggested. This study was carried out to determine the prevalence of polyomaviruses including JCV, BKV and SV40 in gastric cancers in Tunisia and to determine the clinicopathological characteristics of virus-associated gastric carcinomas. The presence of polyomaviruses DNA sequences was surveyed in 61 cases of primary gastric carcinomas and in 53 paired non-tumor gastric mucosa by PCR. Findings were correlated to clinicopathological parameters, p53 expression and methylation status of 11 tumor-related genes. Using PCR assays, JCV T-antigen sequence was more frequently detected in gastric carcinomas than in non-tumor gastric mucosa (26 vs 6%, P=0.03), while those of SV40 and BKV were not detected in any cases. Correlation analysis showed that JCV had higher frequency in patients older than 55 years (P=0.034) and in the intestinal histological type (P=0.04). With regard to methylation status, P16 and P14 showed significantly higher methylation frequencies in JCV-positive gastric carcinomas than in JCV-negative cases (P=0.007 and P=0.003, respectively). Moreover, the mean of the methylation index was significantly higher in JCV-positive than in JCV-negative cases (P=0.024). In multivariate logistic regression analysis, age of patients and the methylation index are only the two independent factors associated with JCV infection. Kaplan-Meier survival analysis showed a trend toward better survival for JCV-associated gastric carcinomas patients (log-rank, P=0.11). Our study suggests a role of JCV as cofactor in the pathogenesis of the intestinal type of gastric carcinomas in older persons.

  12. Intestinal stromal tumors in a simian immunodeficiency virus-infected, simian retrovirus-2 negative rhesus macaque (Macaca mulatta).

    PubMed

    Bielefeldt-Ohmann, H; Barouch, D H; Bakke, A M; Bruce, A G; Durning, M; Grant, R; Letvin, N L; Ryan, J T; Schmidt, A; Thouless, M E; Rose, T M

    2005-05-01

    Multifocal submucosal stromal tumors were diagnosed in a 5.5-year-old rhesus macaque (Macaca mulatta) experimentally infected with simian immunodeficiency virus, strain SIVsmE660, and CD4+ T cell depleted. The animal was negative for simian retroviruses, SRV-1, -2, and -5. Polymerase chain reaction analysis of DNA from tumor and spleen tissue revealed abundant, preferential presence of retroperitoneal fibromatosis herpesvirus, the macaque homologue of the Kaposi sarcoma-associated herpesvirus (human herpesvirus-8), in the tumors. This was corroborated by demonstration of viral latent nuclear antigen-1 in the nuclei of a majority of the spindeloid tumor cells. Low levels of an additional macaque herpesvirus, rhesus rhadinovirus, were also detected in the spleen and tumor tissues. The spindeloid cells labeled positively for vimentin and CD117 but were negative for CD31, CD68, desmin, and smooth muscle cell actin. Collectively, these findings suggest a relation to but not absolute identity with simian mesenchymoproliferative disorders (MPD) or typical gastrointestinal stromal tumors (GISTs).

  13. Somatostatin receptor imaging with (111)In-pentetreotide in gastro-intestinal tract and lung neuroendocrine tumors-Impact on targeted treatment.

    PubMed

    Gerasimou, George; Moralidis, Efstratios; Gotzamani-Psarrakou, Anna

    2010-01-01

    Somatostatin is a neuropeptide that confers a wide range of pharmacological properties. Indium-111-tagged pentetreotide ((111)In-P) is a radiolabeled analogue of somatostatin indicated for the in vivo scintigraphic localization of neuroendocrine tumors (NET). In cases of NET of the gastro-intestinal tract we describe the sensitivity compared to conventional anatomical imaging modalities and especially the possibility that (111)In-P may change therapeutic management into up one fourth of the patients. In cases of small cell lung carcinoma it has been used for the evaluation of somatostatin receptor status and a substantial tool for differentiation between limited and extensive disease, especially when combined with anatomical imaging methods. We also describe the radiolabeled with yttrium-90 or lutetium-177 somatostatin analogue peptides in the treatment of NET and also the use of (111)In-P for the selection of patients for targeted treatment.

  14. Intestine Transplant

    MedlinePlus

    ... Heart/Lung Kidney Pancreas Kidney/Pancreas Liver Intestine Intestine Transplant Although it is possible for a living donor to donate an intestine segment, most intestine transplants involve a whole organ ...

  15. Tumor

    MedlinePlus

    ... excessively in the body. Normally, the body controls cell growth and division. New cells are created to replace ... room for healthy replacements. If the balance of cell growth and death is disturbed, a tumor may form. ...

  16. One stage curative resection of double intestinal neuroendocrine tumors with thirty-two bilobar liver metastases. A case report.

    PubMed

    Mirarchi, Mariateresa; De Raffele, Emilio; Cuicchi, Dajana; Lecce, Ferdinando; Cruciani, Giorgio; Cola, Bruno

    2015-01-01

    Neuroendocrine tumours (NETs) of the midgut are often multifocal and have a noticeable attitude to metastasize to locoregional lymph nodes and liver. Surgery is the only curative treatment for metastatic NETs of the midgut, even though only a minority of patients are candidates to radical surgical resection. The optimal timing for surgical resection in case of synchronous presentation of primary intestinal neoplasms and resectable LM is still controversial, especially when LM are multiple and/or involve multiple liver segments. Even though a staged approach with initial intestinal resection followed by liver resection is still preferred, recent studies have shown favourable results for simultaneous procedures, which have the striking advantage of avoiding a second laparotomy, with morbidity and mortality rates comparable to staged resections. We report here the case of a patient with double midgut well-differentiated NET and thirty-two synchronous bilobar LM who received successful simultaneous curative right hemicolectomy and radical but conservative liver resection and radiofrequency thermal ablation with the guidance of intraoperative ultrasonography. He is alive without evidence of recurrence 48 months after surgery.

  17. Tumor Necrosis Factor-alpha Stimulates the Overproduction of Intestinal Apolipoprotein B48-containing Very Low Density Lipoproproteins

    USDA-ARS?s Scientific Manuscript database

    Tumor necrosis factor-alpha(a)(TNFa), a proinflammatory cytokine, is involved in obesity-associated pathologies including type 2 diabetes and atherosclerosis. TNFa enhanced postprandial apoB48-VLDL1 overproduction by about 89% compared with the control after 90 min olive oil loading; TNFa did not si...

  18. Intestinal microsporidiosis: a hidden risk in rheumatic disease patients undergoing anti-tumor necrosis factor therapy combined with disease-modifying anti-rheumatic drugs?

    PubMed Central

    Aikawa, Nadia Emi; de Oliveira Twardowsky, Aline; de Carvalho, Jozélio Freire; Silva, Clovis A; Silva, Ivan Leonardo Avelino França e; de Medeiros Ribeiro, Ana Cristina; Saad, Carla Gonçalves Schain; Moraes, Julio César Bertacini; de Toledo, Roberto Acayaba; Bonfá, Eloísa

    2011-01-01

    OBJECTIVE: Immunosuppressed patients are at risk of microsporidiosis, and this parasitosis has an increased rate of dissemination in this population. Our objective was to evaluate the presence of microsporidiosis and other intestinal parasites in rheumatic disease patients undergoing anti-tumor necrosis factor/disease-modifying anti-rheumatic drug treatment. METHODS: Ninety-eight patients (47 with rheumatoid arthritis, 31 with ankylosing spondylitis and 11 with psoriatic arthritis) and 92 healthy control patients were enrolled in the study. Three stool samples and cultures were collected from each subject. RESULTS: The frequency of microsporidia was significantly higher in rheumatic disease patients than in control subjects (36 vs. 4%, respectively; p<0.0001), as well as in those with rheumatic diseases (32 vs. 4%, respectively; p<0.0001), ankylosing spondylitis (45 vs. 4%, respectively; p<0.0001) and psoriatic arthritis (40 vs. 4%, respectively; p<0.0001), despite a similar social-economic class distribution in both the patient and control groups (p = 0.1153). Of note, concomitant fecal leukocytes were observed in the majority of the microsporidia-positive patients (79.5%). Approximately 80% of the patients had gastrointestinal symptoms, such as diarrhea (26%), abdominal pain (31%) and weight loss (5%), although the frequencies of these symptoms were comparable in patients with and without this infection (p>0.05). Rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis disease activity parameters were comparable in both groups (p>0.05). The duration of anti-tumor necrosis factor/disease-modifying anti-rheumatic drugs and glucocorticoid use were also similar in both groups. CONCLUSION: We have documented that microsporidiosis with intestinal mucosa disruption is frequent in patients undergoing concomitant anti-tumor necrosis factor/disease-modifying anti-rheumatic drug therapy. Impaired host defenses due to the combination of the underlying disease

  19. Sex-dependent Differences in Intestinal Tumorigenesis Induced in Apc1638N/+ Mice by Exposure to {gamma} Rays

    SciTech Connect

    Trani, Daniela; Moon, Bo-Hyun; Kallakury, Bhaskar; Hartmann, Dan P.; Datta, Kamal; Fornace, Albert J.

    2013-01-01

    Purpose: The purpose of the present study was to assess the effect of 1 and 5 Gy radiation doses and to investigate the interplay of gender and radiation with regard to intestinal tumorigenesis in an adenomatous polyposis coli (APC) mutant mouse model. Methods and Materials: Apc1638N/+ female and male mice were exposed whole body to either 1 Gy or 5 Gy of {gamma} rays and euthanized when most of the treated mice became moribund. Small and large intestines were processed to determine tumor burden, distribution, and grade. Expression of proliferation marker Ki-67 and estrogen receptor (ER)-{alpha} were also assessed by immunohistochemistry. Results: We observed that, with both 1 Gy and 5 Gy of {gamma} rays, females displayed reduced susceptibility to radiation-induced intestinal tumorigenesis compared with males. As for radiation effect on small intestinal tumor progression, although no substantial differences were found in the relative frequency and degree of dysplasia of adenomas in irradiated animals compared with controls, invasive carcinomas were found in 1-Gy- and 5-Gy-irradiated animals. Radiation exposure was also shown to induce an increase in protein levels of proliferation marker Ki-67 and sex-hormone receptor ER-{alpha} in both non tumor mucosa and intestinal tumors from irradiated male mice. Conclusions: We observed important sex-dependent differences in susceptibility to radiation-induced intestinal tumorigenesis in Apc1638N/+ mutants. Furthermore, our data provide evidence that exposure to radiation doses as low as 1 Gy can induce a significant increase in intestinal tumor multiplicity as well as enhance tumor progression in vivo.

  20. Sex-dependent differences in intestinal tumorigenesis induced in Apc1638N/+ mice by exposure to γ rays.

    PubMed

    Trani, Daniela; Moon, Bo-Hyun; Kallakury, Bhaskar; Hartmann, Dan P; Datta, Kamal; Fornace, Albert J

    2013-01-01

    The purpose of the present study was to assess the effect of 1 and 5 Gy radiation doses and to investigate the interplay of gender and radiation with regard to intestinal tumorigenesis in an adenomatous polyposis coli (APC) mutant mouse model. Apc1638N/+ female and male mice were exposed whole body to either 1 Gy or 5 Gy of γ rays and euthanized when most of the treated mice became moribund. Small and large intestines were processed to determine tumor burden, distribution, and grade. Expression of proliferation marker Ki-67 and estrogen receptor (ER)-α were also assessed by immunohistochemistry. We observed that, with both 1 Gy and 5 Gy of γ rays, females displayed reduced susceptibility to radiation-induced intestinal tumorigenesis compared with males. As for radiation effect on small intestinal tumor progression, although no substantial differences were found in the relative frequency and degree of dysplasia of adenomas in irradiated animals compared with controls, invasive carcinomas were found in 1-Gy- and 5-Gy-irradiated animals. Radiation exposure was also shown to induce an increase in protein levels of proliferation marker Ki-67 and sex-hormone receptor ER-α in both non tumor mucosa and intestinal tumors from irradiated male mice. We observed important sex-dependent differences in susceptibility to radiation-induced intestinal tumorigenesis in Apc1638N/+ mutants. Furthermore, our data provide evidence that exposure to radiation doses as low as 1 Gy can induce a significant increase in intestinal tumor multiplicity as well as enhance tumor progression in vivo. Copyright © 2013 Elsevier Inc. All rights reserved.

  1. Intestinal Obstruction

    MedlinePlus

    An intestinal obstruction occurs when food or stool cannot move through the intestines. The obstruction can be complete or partial. ... abdomen Inability to pass gas Constipation A complete intestinal obstruction is a medical emergency. It often requires surgery. ...

  2. Intestinal obstruction

    MedlinePlus

    Paralytic ileus; Intestinal volvulus; Bowel obstruction; Ileus; Pseudo-obstruction - intestinal; Colonic ileus ... objects that are swallowed and block the intestines) Gallstones (rare) Hernias Impacted stool Intussusception (telescoping of 1 ...

  3. Intestinal leiomyoma

    MedlinePlus

    Leiomyoma - intestine ... McLaughlin P, Maher MM. The duodenum and small intestine. In: Adam A, Dixon AK, Gillard JH, Schaefer- ... Roline CE, Reardon RF. Disorders of the small intestine. In: Marx JA, Hockberger RS, Walls RM, et ...

  4. Intestinal Cancer

    MedlinePlus

    ... connects your stomach to your large intestine. Intestinal cancer is rare, but eating a high-fat diet ... increase your risk. Possible signs of small intestine cancer include Abdominal pain Weight loss for no reason ...

  5. Silibinin modulates caudal-type homeobox transcription factor (CDX2), an intestine specific tumor suppressor to abrogate colon cancer in experimental rats.

    PubMed

    Sangeetha, N; Nalini, N

    2015-01-01

    To authenticate the colon cancer preventive potential of silibinin, the efficacy of silibinin needs to be tested by evaluating an organ-specific biomarker. The aim of this study was to evaluate the impact of silibinin on the colonic expression of the caudal-type homeobox transcription factor (CDX2) an intestine specific tumor suppressor gene and its downstream targets in the colon of rats challenged with 1,2 dimethyl hydrazine (DMH). Rats of groups 1 and 2 were treated as control and silibinin control. Rats under groups 3 and 4 were given DMH (20 mg/kg body weight (b.w.) subcutaneously) once a week for 15 consecutive weeks from the 4th week of the experimental period. In addition, group 4 rats alone were treated with silibinin (50 mg/kg b.w. per os) everyday throughout the study period of 32 weeks. Histological investigation and messenger RNA and protein expression studies were performed in the colonic tissues of experimental rats. Findings of the study revealed that DMH administration significantly decreased the expression of CDX2 and Guanylyl cyclase C (GCC) in the colon of experimental rats. Further the decreased levels of CDX2 protein, colonic mucin content, and increased number of mast cells in the colon of DMH alone-administered rats reflects the onset of carcinogenesis. The pathological changes caused due to CDX2 suppression were attenuated by silibinin supplementation.

  6. Loss of ADAM17-Mediated Tumor Necrosis Factor Alpha Signaling in Intestinal Cells Attenuates Mucosal Atrophy in a Mouse Model of Parenteral Nutrition

    PubMed Central

    Feng, Yongjia; Tsai, Yu-Hwai; Xiao, Weidong; Ralls, Matthew W.; Stoeck, Alex; Wilson, Carole L.; Raines, Elaine W.

    2015-01-01

    Total parenteral nutrition (TPN) is commonly used clinically to sustain patients; however, TPN is associated with profound mucosal atrophy, which may adversely affect clinical outcomes. Using a mouse TPN model, removing enteral nutrition leads to decreased crypt proliferation, increased intestinal epithelial cell (IEC) apoptosis and increased mucosal tumor necrosis factor alpha (TNF-α) expression that ultimately produces mucosal atrophy. Upregulation of TNF-α signaling plays a central role in mediating TPN-induced mucosal atrophy without intact epidermal growth factor receptor (EGFR) signaling. Currently, the mechanism and the tissue-specific contributions of TNF-α signaling to TPN-induced mucosal atrophy remain unclear. ADAM17 is an ectodomain sheddase that can modulate the signaling activity of several cytokine/growth factor receptor families, including the TNF-α/TNF receptor and ErbB ligand/EGFR pathways. Using TPN-treated IEC-specific ADAM17-deficient mice, the present study demonstrates that a loss of soluble TNF-α signaling from IECs attenuates TPN-induced mucosal atrophy. Importantly, this response remains dependent on the maintenance of functional EGFR signaling in IECs. TNF-α blockade in wild-type mice receiving TPN confirmed that soluble TNF-α signaling is responsible for downregulation of EGFR signaling in IECs. These results demonstrate that ADAM17-mediated TNF-α signaling from IECs has a significant role in the development of the proinflammatory state and mucosal atrophy observed in TPN-treated mice. PMID:26283731

  7. Sex-dependent Differences in Intestinal Tumorigenesis Induced in Apc1638N/+ Mice by Exposure to γ Rays

    PubMed Central

    Trani, Daniela; Moon, Bo-Hyun; Kallakury, Bhaskar; Hartmann, Dan P.; Datta, Kamal; Fornace, Albert J.

    2013-01-01

    Summary A study was carried out in an adenomatous polyposis coli (APC) mutant mouse model to assess the effect of 1 and 5 Gy of radiation on intestinal tumorigenesis, and to compare susceptibility of females vs males. We report sex-dependent differences in susceptibility to radiation induced intestinal tumorigenesis and provide evidence that exposure to radiation doses as low as 1 Gy can induce a significant increase in intestinal tumor multiplicity and enhance tumor progression in vivo. Purpose The purpose of the present study was to assess the effect of 1 and 5 Gy radiation doses and to investigate the interplay of gender and radiation with regard to intestinal tumorigenesis in an adenomatous polyposis coli (APC) mutant mouse model. Methods and Materials Apc1638N/+ female and male mice were exposed whole body to either 1 Gy or 5 Gy of γ rays and euthanized when most of the treated mice became moribund. Small and large intestines were processed to determine tumor burden, distribution, and grade. Expression of proliferation marker Ki-67 and estrogen receptor (ER)-α were also assessed by immunohistochemistry. Results We observed that, with both 1 Gy and 5 Gy of γ rays, females displayed reduced susceptibility to radiation-induced intestinal tumorigenesis compared with males. As for radiation effect on small intestinal tumor progression, although no substantial differences were found in the relative frequency and degree of dysplasia of adenomas in irradiated animals compared with controls, invasive carcinomas were found in 1-Gy- and 5-Gy-irradiated animals. Radiation exposure was also shown to induce an increase in protein levels of proliferation marker Ki-67 and sex-hormone receptor ER-α in both non tumor mucosa and intestinal tumors from irradiated male mice. Conclusions We observed important sex-dependent differences in susceptibility to radiation-induced intestinal tumorigenesis in Apc1638N/+ mutants. Furthermore, our data provide evidence that exposure to

  8. Melena as presentation of primary small intestine inflammatory myofibroblastic tumor in an adult woman. A case report.

    PubMed

    Alloni, Rossana; Ancona, Gianluca; Gallo, Ida; Crescenzi, Anna; Coppola, Roberto

    2015-07-29

    È il caso di una paziente di 32 anni affetta da Miofibroblastoma non noto, trasferita da altra struttura sanitaria presso il nostro reparto perché affetta da melena da fonte non determinata. All’anamnesi risultava un precedente ricovero in altro Pronto Soccorso per un quadro clinico caratterizzato da dispnea, cefalea, tachicardia e astenia profonda., oltre a profonda anemia (Hg 5.8 g/dl). La gastroscopia non aveva evidenziato alcun motivo di sanguinamento e l’ecografia addomino-pelvica era risultata negativa. Dopo ripetute emotrasfusioni la tentata rettosigmoidoscopia era stata interrotto per intolleranza della paziente. Una volta stabilizzata si era proceduto al trasferimento presso la nostra struttura, e qui alla Risonanza Magnetica dell’addome veniva evidenziato, un ispessimento parietale esteso per 8 cm a del digiuno medio distale, in corrispondenza del fianco destro, antero – lateralmente al duodeno, ed adiacente ad esso una formazione ipervascolare solida di 20 mm. In prima ipotesi poteva trattarsi di un tratto invaginato del piccolo intestino con all’apice una lesione parietale solida, verosimile causa del sanguinamento. Persistendo il quadro anemico e avendo localizzato una lesione sospetta, la paziente è stata sottoposta ad intervento chirurgico, che portava alla conferma dell’esistenza di una lesione nodulare parietale del piccolo intestino, per cui si procedeva ad una sua resezione segmentaria comprendente la suddetta massa, sottoponendo il pezzo operatorio ad esame istologico definitivo. L’anatomo-patologo formulava la diagnosi isto-immunologica di pseudotumore infiammatorio (c.d. Tumore miofibroblastico infiammatorio) responsabile di invaginazione digiuno-digiunale. I margini di resezione risultavano indenni. Dimessa dopo un decorso postoperatorio senza complicanze, al follow-up di 6 mesi non si è ripresentato alcun sintomo di nuovo sanguinamento. Il sanguinamento della neoformazione responsabile della melena da fonte ignota era

  9. Treatment of Gastrointestinal Carcinoid Tumors by Stage

    MedlinePlus

    ... partial gastrectomy) along with nearby lymph nodes. Small intestine Some small tumors in the duodenum (the first ... vessels and lymph nodes) for larger tumors. Large intestine (other than appendix and rectum) The usual treatment ...

  10. Inhibition of heat-shock protein 90 sensitizes liver cancer stem-like cells to magnetic hyperthermia and enhances anti-tumor effect on hepatocellular carcinoma-burdened nude mice

    PubMed Central

    Yang, Rui; Tang, Qiusha; Miao, Fengqin; An, Yanli; Li, Mengfei; Han, Yong; Wang, Xihui; Wang, Juan; Liu, Peidang; Chen, Rong

    2015-01-01

    Purpose To explore the thermoresistance and expression of heat-shock protein 90 (HSP90) in magnetic hyperthermia-treated human liver cancer stem-like cells (LCSCs) and the effects of a heat-shock protein HSP90 inhibitor 17-allylamino-17-demethoxgeldanamycin (17-AAG) on hepatocellular carcinoma-burdened nude mice. Methods CD90+ LCSCs were isolated by magnetic-activated cell sorting from BEL-7404. Spheroid formation, proliferation, differentiation, drug resistance, and tumor formation assays were performed to identify stem cell characteristics. CD90-targeted thermosensitive magnetoliposomes (TMs)-encapsulated 17-AAG (CD90@17-AAG/TMs) was prepared by reverse-phase evaporation and its characteristics were studied. Heat tolerance in CD90+ LCSCs and the effect of CD90@17-AAG/TMs-mediated heat sensitivity were examined in vitro and in vivo. Results CD90+ LCSCs showed significant stem cell-like properties. The 17-AAG/TMs were successfully prepared and were spherical in shape with an average size of 128.9±7.7 nm. When exposed to magnetic hyperthermia, HSP90 was up-regulated in CD90+ LCSCs. CD90@17-AAG/TMs inhibited the activity of HSP90 and increased the sensitivity of CD90+ LCSCs to magnetic hyperthermia. Conclusion The inhibition of HSP90 could sensitize CD90+ LCSCs to magnetic hyperthermia and enhance its anti-tumor effects in vitro and in vivo. PMID:26677324

  11. Contribution of the TP53 R337H mutation to the cancer burden in southern Brazil: Insights from the study of 55 families of children with adrenocortical tumors.

    PubMed

    Mastellaro, Maria J; Seidinger, Ana L; Kang, Guolian; Abrahão, Renata; Miranda, Eliana C M; Pounds, Stanley B; Cardinalli, Izilda A; Aguiar, Simone S; Figueiredo, Bonald C; Rodriguez-Galindo, Carlos; Brandalise, Silvia R; Yunes, José A; Barros-Filho, Antônio de A; Ribeiro, Raul C

    2017-08-15

    The tumor protein p53 (TP53) arginine-to-histidine mutation at codon 337 (R337H) predisposes children to adrenocortical tumors (ACTs) and, rarely, to other childhood tumors, but its impact on adult cancer remains undetermined. The objective of this study was to investigate the frequency and types of cancer in relatives of children with ACT who carry the TP53 R337H mutation. TP53 R337H testing was offered to relatives of probands with ACT. The parental lineage segregating the R337H mutation was identified in all families. The frequency and distribution of cancer types were compared according to R337H status. The authors' data also were compared with those publicly available for children with TP53 mutations other than R337H. The mean and median follow-up times for the probands with ACT were 11.2 years and 9.7 years (range, 3-32 years), respectively. During this time, cancer was diagnosed in 12 of 81 first-degree relatives (14.8%) carrying the R337H mutation but in only 1 of 94 noncarriers (1.1%; P = .0022). At age 45 years, the cumulative risk of cancer was 21% (95% confidence interval, 5%-33%) in carriers and 2% (95% confidence interval, 0%-4%) in noncarriers (P = .008). The frequency of cancer was higher in the R337H segregating lineages than in the nonsegregating lineages (249 of 1410 vs 66 of 984 individuals; P < .001). Breast and gastric cancer were the most common types. TP53 R337H carriers have a lifelong predisposition to cancer with a bimodal age distribution: 1 peak, represented by ACT, occurs in the first decade of life, and another peak of diverse cancer types occurs in the fifth decade. The current findings have implications for genetic counseling and surveillance of R337H carriers. Cancer 2017;123:3150-58. © 2017 American Cancer Society. © 2017 American Cancer Society.

  12. Serum calcitonin may falsely estimate tumor burden in chronic hypercalcemia: a case of prostatic and multiple bone metastases from medullary thyroid cancer.

    PubMed

    Kim, Hee Kyung; Bae, Woo Kyun; Choi, Yoo Duk; Shim, Hyun Jeong; Yoon, Jee Hee; Kang, Ho-Cheol

    2014-03-01

    Medullary thyroid cancer (MTC) is a calcitonin (Ct)-secreting tumor of the parafollicular or C cells of the thyroid gland. Higher serum Ct levels are associated with larger tumor size, distant metastases, and prognosis. We report herein a case of prostate and multiple bone metastases of nonfamilial MTC with mildly elevated Ct levels. A 73-year-old man who was found to have a 2.5 cm MTC in the left thyroid lobe with cervical lymph node metastases presented with confused mental status because of severe hypercalcemia (albumin-modified serum calcium concentration 15.2 mg/dL) associated with multiple bone metastases. Prostate biopsy was performed because the patient had frequent urination with mildly elevated serum prostate-specific antigen (5.297 ng/mL). Histologically, the prostate was diagnosed as MTC metastasis, forming a tissue architecture closely resembling the previously diagnosed MTC, and the cells were positive for Ct, carcinoembryonic antigen, and thyroid transcription factor 1. Although the patient had multiple MTC metastases, basal and calcium-stimulated serum Ct levels were not significantly elevated, measuring 22.7 pg/mL (normal <10 pg/mL) and 22.1 pg/mL, respectively. A chronic hypercalcemic state may exhaust Ct reserves and diminish the Ct response to an acute intravenous calcium injection. Therefore, the Ct level of a patient in a hypercalcemic state should be carefully interpreted. To our knowledge, this is the first reported case in the literature in which serum Ct levels were not significantly increased when associated with hypercalcemia, and an MTC metastasis to the prostate.

  13. Stages of Gastrointestinal Carcinoid Tumors

    MedlinePlus

    ... cancer cells have spread within the stomach and intestines or to other parts of the body. Staging ... the NCI website . Carcinoid Tumors in the Small Intestine It is not clear what the best treatment ...

  14. Evaluation of epidemiological studies of intestinal bacteria that affected occurrence of colorectal cancer: studies of prevention of colorectal tumors by dairy products and lactic acid bacteria.

    PubMed

    Kawano, Atsuko; Ishikawa, Hideki; Nakamura, Tomiyo; Kono, Koichi

    2010-05-01

    Enviromental factors have been consistently associated with colon cancer risk. In particular, consumption of Western-style diet including red meat is the most widely accepted etiologic risk factor. It has been reported that dietary factors change the proportion of intestinal flora, and it also affects the composition of fecal bile acids and the intestinal activity of some mutagens. In addition, it was suggested that modulating the composition of intestinal flora may reduce the occurrence of colorectal cancer. In this review, we present the clinical studies on the association between intestinal flora and the risk of colorectal cancer that have been carried out to date. The clinical studies of intestinal bacteria related to colorectal cancer risk have not shown consistent results so far, compared with the accomplishments of some basic studies. On the other hand, it was suggested in some clinical studies that lactic acid bacteria reduce the occurrence of colorectal cancer.

  15. Small intestinal ischemia and infarction

    MedlinePlus

    Intestinal necrosis; Ischemic bowel - small intestine; Dead bowel - small intestine; Dead gut - small intestine; Infarcted bowel - small intestine; Atherosclerosis - small intestine; Hardening of the arteries - small intestine

  16. The role of glucagon-like peptide-2 on apoptosis, cell proliferation, and oxidant-antioxidant system at a mouse model of intestinal injury induced by tumor necrosis factor-alpha/actinomycin D.

    PubMed

    Arda-Pirincci, Pelin; Bolkent, Sehnaz

    2011-04-01

    Tumor necrosis factor-alpha (TNF-α) is a multifunctional cytokine, which has the ability to produce cytotoxicity via induction of cell death and cell cycle arrest. Blocking the synthesis of protective proteins through a transcriptional inhibitor such as actinomycin D (Act D) sensitizes many cell types to TNF-α toxicity. Teduglutide, h[Gly(2)]GLP-2, is a protease-resistant synthetic analog of glucagon-like peptide-2 (GLP-2) which is an intestinotrophic peptide. In this study, we evaluated this potential of GLP-2 on apoptosis, cell proliferation, and oxidant-antioxidant system on a mouse model of intestinal injury induced by TNF-α/Act D. The intestinal injury was induced by intraperitoneal administration of 15 μg/kg TNF-α and 800 μg/kg Act D per mouse. Animals were injected subcutaneously 200 μg/kg h[Gly(2)]GLP-2 every 12 h for 10 consecutive days prior to the administration of TNF-α and Act D. The model of intestinal injury induced by TNF-α/Act D, which is the new animal model for the intestinal disorders, was characterized by the degeneration of intestinal mucosa, an increase in apoptotic index, expression of active caspase-3, lipid peroxidation and glutathione (GSH) levels, glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities; a decrease in cell proliferation and catalase (CAT) activity. h[Gly(2)]GLP-2 pretreatment prevented the TNF-α/Act D-induced oxidative injury by a significant reduction in the intestinal injury, apoptotic index, expression of active caspase-3, lipid peroxidation and GSH levels, GPx and SOD activities; a markedly increase in cell proliferation, and CAT activity. These results demonstrate that GLP-2 has a protective, antiapoptotic, proliferative, and antioxidant effects against to TNF-α/Act D-induced intestinal injury. It is suggested that GLP-2 may potentially be useful as a therapeutic agent in TNF-α-mediated intestinal disorders.

  17. Common flora and intestine

    PubMed Central

    Wang, Kepeng; Karin, Michael

    2013-01-01

    Commensal microflora engages in a symbiotic relationship with their host, and plays an important role in the development of colorectal cancer (CRC). Pathogenic bacteria promote chronic intestinal inflammation and accelerate tumorigenesis. In sporadic CRC, loss of an effective epithelial barrier occurs at early stage of CRC development. As a result, non-pathogenic bacteria and/or their products infiltrate tumor stroma, drive “tumor-elicited inflammation” and promote CRC progression by activating tumor-associated myeloid and immune cells that produce IL-23 and IL-17. In this article we will summarize the recent advances in understanding the relationship between gut flora and CRC. PMID:24516778

  18. Intestinal Obstruction

    MedlinePlus

    ... Wall Hernias Inguinal Hernia Acute Mesenteric Ischemia Appendicitis Ileus Intestinal Obstruction Ischemic Colitis Perforation of the Digestive ... Wall Hernias Inguinal Hernia Acute Mesenteric Ischemia Appendicitis Ileus Intestinal Obstruction Ischemic Colitis Perforation of the Digestive ...

  19. Burden of illness.

    PubMed

    McGuire, Tom; Wells, Kenneth B; Bruce, Martha L; Miranda, Jeanne; Scheffler, Richard; Durham, Mary; Ford, Daniel E; Lewis, Lydia

    2002-12-01

    The burden of affective disorders includes costs and the pain and suffering of affected individuls. Burden can be perceived from social and private perspectives. Although no ideal measure of burden exists, ample evidence documents the extensive cost and other negative impacts of affective disorders. Affective disorders are associated with disruptive family relations, higher health care costs for comorbid conditions, elevated rates of suicide, and lower productivity. Reserch should focus on improving measures of burden in general and on quantifying burden from the standpoint of diverse population groups.

  20. Burden of Sexual Dysfunction.

    PubMed

    Balon, Richard

    2017-01-02

    Similar to the burden of other diseases, the burden of sexual dysfunction has not been systematically studied. However, there is growing evidence of various burdens (e.g., economic, symptomatic, humanistic) among patients suffering from sexual dysfunctions. The burden of sexual dysfunction has been studied a bit more often in men, namely the burden of erectile dysfunction (ED), premature ejaculation (PE) and testosterone deficiency syndrome (TDS). Erectile dysfunction is frequently associated with chronic conditions such as cardiovascular disease, diabetes, and depression. These conditions could go undiagnosed, and ED could be a marker of those diseases. The only available report from the United Kingdom estimated the total economic burden of ED at £53 million annually in terms of direct costs and lost productivity. The burden of PE includes significant psychological distress: anxiety, depression, lack of sexual confidence, poor self-esteem, impaired quality of life, and interpersonal difficulties. Some suggest that increase in female sexual dysfunction is associated with partner's PE, in addition to significant interpersonal difficulties. The burden of TDS includes depression, sexual dysfunction, mild cognitive impairment, and osteoporosis. One UK estimate of the economic burden of female sexual dysfunctions demonstrated that the average cost per patient was higher than the per annum cost of ED. There are no data on burden of paraphilic disorders. The burden of sexual dysfunctions is underappreciated and not well studied, yet it is significant for both the patients and the society.

  1. Intestinal Surgery.

    PubMed

    Desrochers, André; Anderson, David E

    2016-11-01

    A wide variety of disorders affecting the intestinal tract in cattle may require surgery. Among those disorders the more common are: intestinal volvulus, jejunal hemorrhage syndrome and more recently the duodenal sigmoid flexure volvulus. Although general principles of intestinal surgery can be applied, cattle has anatomical and behavior particularities that must be known before invading the abdomen. This article focuses on surgical techniques used to optimize outcomes and discusses specific disorders of small intestine. Diagnoses and surgical techniques presented can be applied in field conditions. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Intestinal Parasitoses.

    ERIC Educational Resources Information Center

    Lagardere, Bernard; Dumburgier, Elisabeth

    1994-01-01

    Intestinal parasites have become a serious public health problem in tropical countries because of the climate and the difficulty of achieving efficient hygiene. The objectives of this journal issue are to increase awareness of the individual and collective repercussions of intestinal parasites, describe the current conditions of contamination and…

  3. Global Burden of Stroke.

    PubMed

    Feigin, Valery L; Norrving, Bo; Mensah, George A

    2017-02-03

    On the basis of the GBD (Global Burden of Disease) 2013 Study, this article provides an overview of the global, regional, and country-specific burden of stroke by sex and age groups, including trends in stroke burden from 1990 to 2013, and outlines recommended measures to reduce stroke burden. It shows that although stroke incidence, prevalence, mortality, and disability-adjusted life-years rates tend to decline from 1990 to 2013, the overall stroke burden in terms of absolute number of people affected by, or who remained disabled from, stroke has increased across the globe in both men and women of all ages. This provides a strong argument that "business as usual" for primary stroke prevention is not sufficiently effective. Although prevention of stroke is a complex medical and political issue, there is strong evidence that substantial prevention of stroke is feasible in practice. The need to scale-up the primary prevention actions is urgent.

  4. Treatment Option Overview (Gastrointestinal Carcinoid Tumors)

    MedlinePlus

    ... cancer cells have spread within the stomach and intestines or to other parts of the body. Staging ... the NCI website . Carcinoid Tumors in the Small Intestine It is not clear what the best treatment ...

  5. General Information about Gastrointestinal Carcinoid Tumors

    MedlinePlus

    ... cancer cells have spread within the stomach and intestines or to other parts of the body. Staging ... the NCI website . Carcinoid Tumors in the Small Intestine It is not clear what the best treatment ...

  6. Treatment Options for Gastrointestinal Carcinoid Tumors

    MedlinePlus

    ... cancer cells have spread within the stomach and intestines or to other parts of the body. Staging ... the NCI website . Carcinoid Tumors in the Small Intestine It is not clear what the best treatment ...

  7. Phosphatidylcholine passes through lateral tight junctions for paracellular transport to the apical side of the polarized intestinal tumor cell-line CaCo2.

    PubMed

    Stremmel, Wolfgang; Staffer, Simone; Gan-Schreier, Hongying; Wannhoff, Andreas; Bach, Margund; Gauss, Annika

    2016-09-01

    Phosphatidylcholine (PC) is the most abundant phospholipid in intestinal mucus, indicative of a specific transport system across the mucosal epithelium to the intestinal lumen. To elucidate this transport mechanism, we employed a transwell tissue culture system with polarized CaCo2 cells. It was shown that PC could not substantially be internalized by the cells. However, after basal application of increasing PC concentrations, an apical transport of 47.1±6.3nmolh(-1)mMPC(-1) was observed. Equilibrium distribution studies with PC applied in equal concentrations to the basal and apical compartments showed a 1.5-fold accumulation on the expense of basal PC. Disruption of tight junctions (TJ) by acetaldehyde or PPARγ inhibitors or by treatment with siRNA to TJ proteins suppressed paracellular transport by at least 50%. Transport was specific for the choline containing the phospholipids PC, lysoPC and sphingomyelin. We showed that translocation is driven by an electrochemical gradient generated by apical accumulation of Cl(-) and HCO3(-) through CFTR. Pretreatment with siRNA to mucin 3 which anchors in the apical plasma membrane of mucosal cells inhibited the final step of luminal PC secretion. PC accumulates in intestinal mucus using a paracellular, apically directed transport route across TJs. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  8. Alcohol and the Intestine

    PubMed Central

    Patel, Sheena; Behara, Rama; Swanson, Garth R.; Forsyth, Christopher B.; Voigt, Robin M.; Keshavarzian, Ali

    2015-01-01

    Alcohol abuse is a significant contributor to the global burden of disease and can lead to tissue damage and organ dysfunction in a subset of alcoholics. However, a subset of alcoholics without any of these predisposing factors can develop alcohol-mediated organ injury. The gastrointestinal tract (GI) could be an important source of inflammation in alcohol-mediated organ damage. The purpose of review was to evaluate mechanisms of alcohol-induced endotoxemia (including dysbiosis and gut leakiness), and highlight the predisposing factors for alcohol-induced dysbiosis and gut leakiness to endotoxins. Barriers, including immunologic, physical, and biochemical can regulate the passage of toxins into the portal and systemic circulation. In addition, a host of environmental interactions including those influenced by circadian rhythms can impact alcohol-induced organ pathology. There appears to be a role for therapeutic measures to mitigate alcohol-induced organ damage by normalizing intestinal dysbiosis and/or improving intestinal barrier integrity. Ultimately, the inflammatory process that drives progression into organ damage from alcohol appears to be multifactorial. Understanding the role of the intestine in the pathogenesis of alcoholic liver disease can pose further avenues for pathogenic and treatment approaches. PMID:26501334

  9. Intestinal Ischemia

    MedlinePlus

    ... and hormone medications, such as estrogen Cocaine or methamphetamine use Vigorous exercise, such as long-distance running ... anti-phospholipid syndrome. Illegal drug use. Cocaine and methamphetamine use have been linked to intestinal ischemia. Complications ...

  10. Intestinal Capillariasis

    DTIC Science & Technology

    1987-12-01

    bhIll inenais, the tiny nematode causing Intestinal capillariasis In humans, Is a Iunique parasite. It is one of the newest parasites that has been...Capillariaphilippinensis, the tiny nematode causing intestinal capillariasis in humans, is a unique parasite. It is one of the newest parasites that has been shown to...stichocytes surrounding the oesophagus. The posterior half of the nematode is wider than the anterior half and contains the digestive tract and the

  11. Burden of Mental Illness

    MedlinePlus

    ... this? Submit What's this? Submit Button Burden of Mental Illness Recommend on Facebook Tweet Share Compartir Depression: According ... anxiety disorder, are the most common class of mental disorders present in the general population. 5 The estimated ...

  12. [Study on burden of disease in Chongqing, 2010-2013].

    PubMed

    Wen, Xiaoyan; Sun, Anlong; Peng, Bin; Xu, Xiaolan; Tan, Tao; Xu, Yuchen; Hu, Shan; Chen, Jiangpeng; Que, Ping

    2015-10-01

    To analysis the burden of diseases (BOD) and economic burden of disease (EBOD) in Chongqing and provide scientific evidence for effective prevention and control of diseases. The burden of diseases of Chongqing were estimated by use of disability-adjusted life year (DALY) from 2010 to 2013, two-step method was used in the calculation of direct economic burden of diseases. DALY combined with the human capital method were used to measure the indirect economic burden. From 2010 to 2013, DALY loss by all causes for the residents in Chongqing were 123.90, 127.01, 123.30 and 125.99 person year per thousand persons, respectively. The diseases mainly included non-communicable diseases, accounting for 83%-87%, followed by injure and infectious diseases. The five leading diseases of BOD in Chongqing were respiratory system disease, circulatory system disease, malignant tumor, accidental death, neuropsychiatric disease, respectively. The total economic burden of diseases was 1 621.34 million yuan RMB in 2013. The direct and indirect economic burden of diseases were 794.42 million yuan RMB and 826.92 million yuan RMB, which could be attributed to circulatory system disease, respiratory system diseases, injury, malignant tumor and muscle bones and connective tissue diseases. Respiratory system disease, circulatory system diseases, malignant tumor, and injury have caused heavy burden both in people's health and economic status in Chongqing. It is necessary to take effective measures to prevent and control these diseases.

  13. Dietary anthocyanin-rich tart cherry extract inhibits intestinal tumorigenesis in APC(Min) mice fed suboptimal levels of sulindac.

    PubMed

    Bobe, Gerd; Wang, Bing; Seeram, Navindra P; Nair, Muraleedharan G; Bourquin, Leslie D

    2006-12-13

    A promising approach for cancer chemoprevention might be a combination therapy utilizing dietary phytochemicals and anticarcinogenic pharmaceuticals at a suboptimal dosage to minimize any potential adverse side effects. To test this hypothesis, various dosages of anthocyanin-rich tart cherry extract were fed in combination with suboptimal levels of the nonsteroidal anti-inflammatory drug sulindac to APCMin mice for 19 weeks. By the end of the feeding period, fewer mice that were fed the anthocyanin-rich extract in combination with sulindac lost more than 10% of body weight than mice fed sulindac alone. Mice that were fed anthocyanin-rich extract (at any dose) in combination with sulindac had fewer tumors and a smaller total tumor burden (total tumor area per mouse) in the small intestine when compared to mice fed sulindac alone. These results suggest that a dietary combination of tart cherry anthocyanins and sulindac is more protective against colon cancer than sulindac alone.

  14. Diffuse intestinal ganglioneuromatosis in a child

    PubMed Central

    Matthews, Mika A.B.; Adler, Brent H.; Arnold, Michael A.; Kumar, Soma; Carvalho, Ryan; Besner, Gail E.

    2014-01-01

    A 7 year old male with a history of congenital neutropenia and growth hormone deficiency presented with abdominal pain, fevers, and diarrhea. Imaging and endoscopy revealed significant inflammation of the ascending colon with stenosis at the level of the hepatic flexure. A right hemicolectomy was performed, and pathologic findings were consistent with diffuse intestinal ganglioneuromatosis. Due to recurrent mass effect at the intestinal anastomotic site detected radiologically, a second intestinal resection was performed 7 months later. Genetic testing was negative for mutations in the RET protooncogene, NF1 and PTEN tumor suppressor genes. We report a case of diffuse intestinal ganglioneuromatosis in a child with congenital neutropenia. PMID:23701793

  15. LIN28 cooperates with WNT signaling to drive invasive intestinal and colorectal adenocarcinoma in mice and humans.

    PubMed

    Tu, Ho-Chou; Schwitalla, Sarah; Qian, Zhirong; LaPier, Grace S; Yermalovich, Alena; Ku, Yuan-Chieh; Chen, Shann-Ching; Viswanathan, Srinivas R; Zhu, Hao; Nishihara, Reiko; Inamura, Kentaro; Kim, Sun A; Morikawa, Teppei; Mima, Kosuke; Sukawa, Yasutaka; Yang, Juhong; Meredith, Gavin; Fuchs, Charles S; Ogino, Shuji; Daley, George Q

    2015-05-15

    Colorectal cancer (CRC) remains a major contributor to cancer-related mortality. LIN28A and LIN28B are highly related RNA-binding protein paralogs that regulate biogenesis of let-7 microRNAs and influence development, metabolism, tissue regeneration, and oncogenesis. Here we demonstrate that overexpression of either LIN28 paralog cooperates with the Wnt pathway to promote invasive intestinal adenocarcinoma in murine models. When LIN28 alone is induced genetically, half of the resulting tumors harbor Ctnnb1 (β-catenin) mutation. When overexpressed in Apc(Min/+) mice, LIN28 accelerates tumor formation and enhances proliferation and invasiveness. In conditional genetic models, enforced expression of a LIN28-resistant form of the let-7 microRNA reduces LIN28-induced tumor burden, while silencing of LIN28 expression reduces tumor volume and increases tumor differentiation, indicating that LIN28 contributes to tumor maintenance. We detected aberrant expression of LIN28A and/or LIN28B in 38% of a large series of human CRC samples (n = 595), where LIN28 expression levels were associated with invasive tumor growth. Our late-stage CRC murine models and analysis of primary human tumors demonstrate prominent roles for both LIN28 paralogs in promoting CRC growth and progression and implicate the LIN28/let-7 pathway as a therapeutic target. © 2015 Tu et al.; Published by Cold Spring Harbor Laboratory Press.

  16. LIN28 cooperates with WNT signaling to drive invasive intestinal and colorectal adenocarcinoma in mice and humans

    PubMed Central

    Tu, Ho-Chou; Schwitalla, Sarah; Qian, Zhirong; LaPier, Grace S.; Yermalovich, Alena; Ku, Yuan-Chieh; Chen, Shann-Ching; Viswanathan, Srinivas R.; Zhu, Hao; Nishihara, Reiko; Inamura, Kentaro; Kim, Sun A.; Morikawa, Teppei; Mima, Kosuke; Sukawa, Yasutaka; Yang, Juhong; Meredith, Gavin; Fuchs, Charles S.; Ogino, Shuji

    2015-01-01

    Colorectal cancer (CRC) remains a major contributor to cancer-related mortality. LIN28A and LIN28B are highly related RNA-binding protein paralogs that regulate biogenesis of let-7 microRNAs and influence development, metabolism, tissue regeneration, and oncogenesis. Here we demonstrate that overexpression of either LIN28 paralog cooperates with the Wnt pathway to promote invasive intestinal adenocarcinoma in murine models. When LIN28 alone is induced genetically, half of the resulting tumors harbor Ctnnb1 (β-catenin) mutation. When overexpressed in ApcMin/+ mice, LIN28 accelerates tumor formation and enhances proliferation and invasiveness. In conditional genetic models, enforced expression of a LIN28-resistant form of the let-7 microRNA reduces LIN28-induced tumor burden, while silencing of LIN28 expression reduces tumor volume and increases tumor differentiation, indicating that LIN28 contributes to tumor maintenance. We detected aberrant expression of LIN28A and/or LIN28B in 38% of a large series of human CRC samples (n = 595), where LIN28 expression levels were associated with invasive tumor growth. Our late-stage CRC murine models and analysis of primary human tumors demonstrate prominent roles for both LIN28 paralogs in promoting CRC growth and progression and implicate the LIN28/let-7 pathway as a therapeutic target. PMID:25956904

  17. Analysis of Cell Death Induction in Intestinal Organoids In Vitro.

    PubMed

    Grabinger, Thomas; Delgado, Eugenia; Brunner, Thomas

    2016-01-01

    The intestinal epithelium has an important function in the absorption of nutrients contained in the food. Furthermore, it also has an important barrier function, preventing luminal pathogens from entering the bloodstream. This single cell layer epithelium is quite sensitive to various cell death-promoting triggers, including drugs, irradiation, and TNF family members, leading to loss of barrier integrity, epithelial erosion, inflammation, malabsorption, and diarrhea. In order to assess the intestinal epithelium-damaging potential of treatments and substances specific test systems are required. As intestinal tumor cell lines are a poor substitute for primary intestinal epithelial cells, and in vivo experiments in mice are costly and often unethical, the use of intestinal organoids cultured from intestinal crypts provide an ideal tool to study cell death induction and mechanisms in primary intestinal epithelial cells. This protocol describes the isolation and culture of intestinal organoids from murine small intestinal crypts, and the quantitative assessment of cell death induction in these organoids.

  18. [A Case of Familial Adenomatous Polyposis with a Desmoid Tumor Probably Communicating to the Intestinal Lumen That Was Successfully Treated with Non-Surgical Therapy].

    PubMed

    Ito, Tetsuya; Chika, Noriyasu; Yamamoto, Azusa; Ogura, Toshiro; Amano, Kunihiko; Ishiguro, Toru; Fukuchi, Minoru; Kumagai, Youichi; Ishibashi, Keiichiro; Eguchi, Hidetaka; Okazaki, Yasushi; Mochiki, Erito; Ishida, Hideyuki

    2016-11-01

    A 44-year-old man with familial adenomatous polyposis underwent laparoscopic-assistedtotal proctocolectomy with ilealpouch anal anastomosis(IPAA). Computed tomography conducted 21 months after IPAA demonstrated bilateral hydronephrosis andan intra-abdominal mass with a maximal diameter of 22 cm, leading to a diagnosis of stage IV desmoid disease, according to the classification by Church and associates. Six courses of combination chemotherapy with doxorubicin plus dacarbazine were administered. Computed tomography after chemotherapy demonstrated marked shrinkage of the desmoidtumor with intraabdominal air andfluidcollection extending just below the skin of the ileostomy closure site. Stoollike fluidoverflowedspontaneously through the site of the ileostomy closure andthe abscess cavity was successfully drained. The patient was discharged 30 days after the start of drainage. The patient is doing well 10 months after the drainage without regrowth of the desmoid tumor, even though a cavity-like lesion encapsulatedby a thick wall remains.

  19. Levofloxacin to Prevent Infection Following Chemotherapy in Treating Patients With Solid Tumors or Lymphoma

    ClinicalTrials.gov

    2013-08-01

    Brain and Central Nervous System Tumors; Breast Cancer; Extragonadal Germ Cell Tumor; Infection; Lung Cancer; Lymphoma; Ovarian Cancer; Small Intestine Cancer; Testicular Germ Cell Tumor; Unspecified Adult Solid Tumor, Protocol Specific

  20. Lactobacillus casei Zhang and vitamin K2 prevent intestinal tumorigenesis in mice via adiponectin-elevated different signaling pathways.

    PubMed

    Zhang, Yong; Ma, Chen; Zhao, Jie; Xu, Haiyan; Hou, Qiangchuan; Zhang, Heping

    2017-04-11

    The incidence of colon cancer has increased considerably and the intestinal microbiota participate in the development of colon cancer. We showed that the L. casei Zhang or vitamin K2 (Menaquinone-7) intervention significantly alleviated intestinal tumor burden in mice. This was associated with increased serum adiponectin levels in both treatments. But osteocalcin level was only increased by L. casei Zhang. Furthermore, the anti-carcinogenic actions of L. casei Zhang were mediated by hepatic Chloride channel-3(CLCN3)/Nuclear Factor Kappa B(NF-κB) and intestinal Claudin15/Chloride intracellular channel 4(CLIC4)/Transforming Growth Factor Beta(TGF-β) signaling, while the vitamin K2 effect involved a hepatic Vitamin D Receptor(VDR)-phosphorylated AMPK signaling pathway. Fecal DNA sequencing by the Pacbio RSII method revealed there was significantly lower Helicobacter apodemus, Helicobacter mesocricetorum, Allobaculum stercoricanis and Adlercreutzia equolifaciens following both interventions compared to the model group. Moreover, different caecum acetic acid and butyric acid levels and enrichment of other specific microbes also determined the activity of the different regulatory pathways. Together these data show that L. casei Zhang and Vitamin K2 can suppress gut risk microbes and promote beneficial microbial metabolites to reduce colonic tumor development in mice.

  1. INTESTINAL CAPILLARIES

    PubMed Central

    Clementi, Francesco; Palade, George E.

    1969-01-01

    Perfusion of the fenestrated capillaries of the intestinal mucosa of the rat with 0.05–0.1 M EDTA removes the diaphragms of the endothelial cells and detaches these cells from one another and from the basement membrane. The latter, even when completely denuded, retains effectively particles of 340 A (average) diameter. Perfusion with histamine (1 µg/ml) results in partial removal of fenestral diaphragms, occasional detachment of the endothelium from the basement membrane, and focal separation of endothelial intercellular junctions. PMID:4979362

  2. [Intestinal carcinoid tumour: Case report].

    PubMed

    Mussan-Chelminsky, Gil; Vidal-González, Pablo; Núñez-García, Edgar; Valencia-García, Luis César; Márquez-Ugalde, Miguel Ángel

    2015-01-01

    Carcinoid of the small intestine, is a well-differentiated neuroendocrine tumor that rarely presents with clinical signs. This tumour can be associated with other conditions, such as inflammatory bowel disease, presenting a wide range of symptoms. In some cases they have an aggressive and highly symptomatic behaviour; thus, clinical suspicion must be high to make an early diagnosis. A 60 year-old male patient with Crohn's disease and gastrointestinal symptoms attributed to this disease within the last year. He presented with intestinal obstruction initially treated with conservative management with no improvement. Exploratory laparotomy was performed finding a mesenteric tumour that caused the bowel obstruction. Bowel resection with primary anastomosis was performed. The pathology report showed an intestinal carcinoid tumour with lymph node metastases. The patient recovered well, and was discharged without complications to continue medical treatment and follow-up by the Oncology department. In almost 42% of the cases, the most common site of carcinoid tumours is the small intestine, and of these, 41% are presented as locoregional disease. Patients with Crohn's disease present a higher incidence. In these cases, the most common presentation is an acute intestinal obstruction (90%). Surgery is usually curative, and follow up is important as the symptoms of Crohn's disease can hide any recurrence. Copyright © 2015 Academia Mexicana de Cirugía A.C. Published by Masson Doyma México S.A. All rights reserved.

  3. Small Intestine Cancer Treatment

    MedlinePlus

    ... Health Professional Small Intestine Cancer Treatment Research Small Intestine Cancer Treatment (PDQ®)–Patient Version General Information About Small Intestine Cancer Go to Health Professional Version Key Points ...

  4. Intestinal capillariasis.

    PubMed Central

    Cross, J H

    1992-01-01

    Intestinal capillariasis caused by Capillaria philippinensis appeared first in the Philippines and subsequently in Thailand, Japan, Iran, Egypt, and Taiwan, but most infections occur in the Philippines and Thailand. As established experimentally, the life cycle involves freshwater fish as intermediate hosts and fish-eating birds as definitive hosts. Embryonated eggs from feces fed to fish hatch and grow as larvae in the fish intestines. Infective larvae fed to monkeys, Mongolian gerbils, and fish-eating birds develop into adults. Larvae become adults in 10 to 11 days, and the first-generation females produce larvae. These larvae develop into males and egg-producing female worms. Eggs pass with the feces, reach water, embryonate, and infect fish. Autoinfection is part of the life cycle and leads to hyperinfection. Humans acquire the infection by eating small freshwater fish raw. The parasite multiplies, and symptoms of diarrhea, borborygmus, abdominal pain, and edema develop. Chronic infections lead to malabsorption and hence to protein and electrolyte loss, and death results from irreversible effects of the infection. Treatment consists of electrolyte replacement and administration of an antidiarrheal agent and mebendazole or albendazole. Capillariasis philippinensis is considered a zoonotic disease of migratory fish-eating birds. The eggs are disseminated along flyways and infect the fish, and when fish are eaten raw, the disease develops. Images PMID:1576584

  5. Intestinal capillariasis.

    PubMed

    Cross, J H

    1992-04-01

    Intestinal capillariasis caused by Capillaria philippinensis appeared first in the Philippines and subsequently in Thailand, Japan, Iran, Egypt, and Taiwan, but most infections occur in the Philippines and Thailand. As established experimentally, the life cycle involves freshwater fish as intermediate hosts and fish-eating birds as definitive hosts. Embryonated eggs from feces fed to fish hatch and grow as larvae in the fish intestines. Infective larvae fed to monkeys, Mongolian gerbils, and fish-eating birds develop into adults. Larvae become adults in 10 to 11 days, and the first-generation females produce larvae. These larvae develop into males and egg-producing female worms. Eggs pass with the feces, reach water, embryonate, and infect fish. Autoinfection is part of the life cycle and leads to hyperinfection. Humans acquire the infection by eating small freshwater fish raw. The parasite multiplies, and symptoms of diarrhea, borborygmus, abdominal pain, and edema develop. Chronic infections lead to malabsorption and hence to protein and electrolyte loss, and death results from irreversible effects of the infection. Treatment consists of electrolyte replacement and administration of an antidiarrheal agent and mebendazole or albendazole. Capillariasis philippinensis is considered a zoonotic disease of migratory fish-eating birds. The eggs are disseminated along flyways and infect the fish, and when fish are eaten raw, the disease develops.

  6. Global burden of COPD.

    PubMed

    López-Campos, José Luis; Tan, Wan; Soriano, Joan B

    2016-01-01

    It is estimated that the world population will reach a record 7.3 billion in 2015, and the high burden of chronic conditions associated with ageing and smoking will increase further. Respiratory diseases in general receive little attention and funding in comparison with other major causes of global morbidity and mortality. In particular, chronic obstructive pulmonary disease (COPD) has been a major public health problem and will remain a challenge for clinicians within the 21st century. Worldwide, COPD is in the spotlight, since its high prevalence, morbidity and mortality create formidable challenges for health-care systems. This review emphasizes the magnitude of the COPD problem from a clinician's standpoint by drawing extensively from the new findings of the Global Burden of Disease study. Updated, distilled information on the population distribution of COPD is useful for the clinician to help provide an appreciation of the relative impact of COPD in daily practice compared with other chronic conditions, and to allocate minimum resources in anticipation of future needs in care. Despite recent trends in reduction of COPD standardized mortality rates and some recent successes in anti-smoking efforts in a number of Western countries, the overarching demographic impact of ageing in an ever-expanding world population, joined with other factors such as high rates of smoking and air pollution in Asia, will ensure that COPD will continue to pose an ever-increasing problem well into the 21st century.

  7. Salmonella burden in Lebanon.

    PubMed

    Malaeb, M; Bizri, A R; Ghosn, N; Berry, A; Musharrafieh, U

    2016-06-01

    Salmonellosis is a disease that represents a major public health concern in both developing and developed countries. The aim of this article is to evaluate the public health burden of Salmonella illness in Lebanon. The current scope of the Salmonella infection problem was assessed in relation to disease incidence and distribution with respect to age, gender and district. Factors that provide a better understanding of the magnitude of the problem were explored and highlighted. Data reported to the Epidemiologic Surveillance Department at the Lebanese Ministry of Public Health between 2001 and 2013 was reviewed. Information obtained was compared to information reported regionally and globally. The estimated true incidence was derived using multipliers from the CDC and Jordan. A literature review of all published data from Lebanon about Salmonella susceptibility/resistance patterns and its serious clinical complications was conducted. The estimated incidence was 13·34 cases/100 000 individuals, most cases occurred in the 20-39 years age group with no significant gender variation. Poor and less developed districts of Lebanon had the highest number of cases and the peak incidence was in summer. Reflecting on the projected incidence derived from the use of multipliers indicates a major discrepancy between what is reported and what is estimated. We conclude that data about Salmonella infection in Lebanon and many Middle Eastern and developing countries lack crucial information and are not necessarily representative of the true incidence, prevalence and burden of illness.

  8. Joint model for left-censored longitudinal data, recurrent events and terminal event: Predictive abilities of tumor burden for cancer evolution with application to the FFCD 2000-05 trial.

    PubMed

    Król, Agnieszka; Ferrer, Loïc; Pignon, Jean-Pierre; Proust-Lima, Cécile; Ducreux, Michel; Bouché, Olivier; Michiels, Stefan; Rondeau, Virginie

    2016-09-01

    In oncology, the international WHO and RECIST criteria have allowed the standardization of tumor response evaluation in order to identify the time of disease progression. These semi-quantitative measurements are often used as endpoints in phase II and phase III trials to study the efficacy of new therapies. However, through categorization of the continuous tumor size, information can be lost and they can be challenged by recently developed methods of modeling biomarkers in a longitudinal way. Thus, it is of interest to compare the predictive ability of cancer progressions based on categorical criteria and quantitative measures of tumor size (left-censored due to detection limit problems) and/or appearance of new lesions on overall survival. We propose a joint model for a simultaneous analysis of three types of data: a longitudinal marker, recurrent events, and a terminal event. The model allows to determine in a randomized clinical trial on which particular component treatment acts mostly. A simulation study is performed and shows that the proposed trivariate model is appropriate for practical use. We propose statistical tools that evaluate predictive accuracy for joint models to compare our model to models based on categorical criteria and their components. We apply the model to a randomized phase III clinical trial of metastatic colorectal cancer, conducted by the Fédération Francophone de Cancérologie Digestive (FFCD 2000-05 trial), which assigned 410 patients to two therapeutic strategies with multiple successive chemotherapy regimens.

  9. Intestinal protozoa.

    PubMed

    Juckett, G

    1996-06-01

    Giardia is the best known cause of protozoal gastrointestinal disease in North America, producing significant but not life-threatening gastrointestinal distress and diarrhea. Although diagnosis of giardiasis may be challenging, treatment is usually successful. Entamoeba histolytica poses a rarer but far more difficult clinical challenge. Dysentery caused by E. histolytica may be the most feared intestinal protozoal infection, although Cryptosporidium parvum, Balantidium coli, Isospora belli, Sarcocystis species and other newly described protozoa also may cause diarrhea in healthy individuals and may result in intractable, life-threatening illness in patients with acquired immunodeficiency syndrome or other immunosuppressive diseases. Certain protozoa once considered relatively unimportant, such as Cryptosporidium, are now recognized as significant causes of morbidity even in the United States, since transmission readily occurs through contaminated water.

  10. The Burden of Mental Disorders

    PubMed Central

    Eaton, William W.; Martins, Silvia S.; Nestadt, Gerald; Bienvenu, O. Joseph; Clarke, Diana; Alexandre, Pierre

    2009-01-01

    In the last decade, there has been an increase in interest in the burden of chronic and disabling health conditions that are not necessarily fatal, such as the mental disorders. This review systematically summarizes data on the burden associated with 11 major mental disorders of adults. The measures of burden include estimates of prevalence, mortality associated with the disorders, disabilities and impairments related to the disorders, and costs. This review expands the range of mental disorders considered in a report on the global burden of disease, updates the literature, presents information on the range and depth of sources of information on burden, and adds estimates of costs. The purpose is to provide an accessible guide to the burden of mental disorders, especially for researchers and policy makers who may not be familiar with this subfield of epidemiology. PMID:18806255

  11. The prostaglandin E{sub 1} analog, misoprostol, a normal tissue protector, does not protect four murine tumors in vivo from radiation injury

    SciTech Connect

    Hanson, W.R.; Zhen, W.; Geng, L.

    1995-06-01

    The clinical development of radioprotectors, such as misoprostol, to protect normal tissue during cancer treatment must proceed with the assurance that tumors are not protected similarly or significantly. To provide data on this critical question, radiation-induced growth delay with or without the presence of misoprostol was measured in four murine tumors grown in the flanks of mice: the Lewis lung carcinoma, M-5076 ovarian sarcoma, FSA and NFSA. The effect of misoprostol on the tumor control dose (TCD{sub 50}) of radiation was measured in FSA-bearing mice with or without prior treatment with the nonsteroidal anti-inflammatory agent, indomethacin. Misoprostol did not influence the in vivo growth of any of the four tumors, nor did it protect any of the tumors from radiation-induced growth delay. Likewise, there was no increase in the radiation TCD{sub 50} to treat the FSA in vivo in control or indomethacin-treated tumor-bearing mice. To measure any possible influence of tumor burden on the protective effect of miso-prostol on normal tissue in mice, the protective effect of misoprostol on the survival of intestinal clonogenic cells was measured in M-5076-bearing mice and found to be the same as in non-tumor-bearing mice. These data suggest that misoprostol protects normal tissue in mice without protecting at least four experimental murine tumors. The data support the contention that misoprostol can achieve therapeutic gain by protecting normal tissues without protecting tumors. 44 refs., 5 figs., 1 tab.

  12. [Intestinal microbiota].

    PubMed

    Perez, Horacio Joaquín; Menezes, Maria Elisabeth; d'Acâmpora, Armando José

    2014-01-01

    There is accumulative evidence on the multiple functions of the intestinal microflora in relation to the homeostasis of the host. At first considered as a simple mutualism, today this relationship proves to be essential to the health and to pathologic processes, particularly metabolic (eg, obesity) and gastrointestinal (eg, inflammatory bowel disease and functional disorders). The first studies were conducted on the microbiota from fecal material cultured anaerobically. With the advent of molecular biology, it has become possible to determine qualitative and quantitatively the dominant, subdominant and transients species. In recent years, there were advances in the understanding of the relationship betwen the microbiota and the host, as well as among the microorganisms in their respective niches. These advances result from translational integration of microbiology with specialities such as molecular biology, cell phisiology, immunology and ecology. There are few studies on the spatial distribution of the microflora in the gut. Unravelling the topography of the microflora in mammals is a way to validate new animal models for the study of microflora.

  13. Giant primary angiosarcoma of the small intestine showing severe sepsis.

    PubMed

    Takahashi, Mizuna; Ohara, Masanori; Kimura, Noriko; Domen, Hiromitsu; Yamabuki, Takumi; Komuro, Kazuteru; Tsuchikawa, Takahiro; Hirano, Satoshi; Iwashiro, Nozomu

    2014-11-21

    Primary malignant tumors of the small intestine are rare, comprising less than 2% of all gastrointestinal tumors. An 85-year-old woman was admitted with fever of 40 °C and marked abdominal distension. Her medical history was unremarkable, but blood examination showed elevated inflammatory markers. Abdominal computed tomography showed a giant tumor with central necrosis, extending from the epigastrium to the pelvic cavity. Giant gastrointestinal stromal tumor of the small intestine communicating with the gastrointestinal tract or with superimposed infection was suspected. Because no improvement occurred in response to antibiotics, surgery was performed. Laparotomy revealed giant hemorrhagic tumor adherent to the small intestine and occupying the peritoneal cavity. The giant tumor was a solid tumor weighing 3490 g, measuring 24 cm × 17.5 cm × 18 cm and showing marked necrosis. Histologically, the tumor comprised spindle-shaped cells with anaplastic large nuclei. Immunohistochemical studies showed tumor cells positive for vimentin, CD31, and factor VIII-related antigen, but negative for c-kit and CD34. Angiosarcoma was diagnosed. Although no postoperative complications occurred, the patient experienced enlargement of multiple metastatic tumors in the abdominal cavity and died 42 d postoperatively. The prognosis of small intestinal angiosarcoma is very poor, even after volume-reducing palliative surgery.

  14. Measuring the Burden of Neglected Tropical Diseases: The Global Burden of Disease Framework

    PubMed Central

    Mathers, Colin D.; Ezzati, Majid; Lopez, Alan D.

    2007-01-01

    Reliable, comparable information about the main causes of disease and injury in populations, and how these are changing, is a critical input for debates about priorities in the health sector. Traditional sources of information about the descriptive epidemiology of diseases, injuries, and risk factors are generally incomplete, fragmented, and of uncertain reliability and comparability. The Global Burden of Disease (GBD) study has provided a conceptual and methodological framework to quantify and compare the health of populations using a summary measure of both mortality and disability, the disability-adjusted life year (DALY). This paper describes key features of the Global Burden of Disease analytic approach, which provides a standardized measurement framework to permit comparisons across diseases and injuries, as well as risk factors, and a systematic approach to the evaluation of data. The paper describes the evolution of the GBD, starting from the first study for the year 1990, summarizes the methodological improvements incorporated into GBD revisions for the years 2000–2004 carried out by the World Health Organization, and examines priorities and issues for the next major GBD study, funded by the Bill & Melinda Gates Foundation, and commencing in 2007. The paper presents an overview of summary results from the Global Burden of Disease study 2002, with a particular focus on the neglected tropical diseases, and also an overview of the comparative risk assessment for 26 global risk factors. Taken together, trypanosomiasis, Chagas disease, schistosomiasis, leishmaniasis, lymphatic filariasis, onchocerciasis, intestinal nematode infections, Japanese encephalitis, dengue, and leprosy accounted for an estimated 177,000 deaths worldwide in 2002, mostly in sub-Saharan Africa, and about 20 million DALYs, or 1.3% of the global burden of disease and injuries. Further research is currently underway to revise and update these estimates. PMID:18060077

  15. Burden sharing or burden shifting Armaments cooperation within NATO

    SciTech Connect

    Smith, R.W.

    1993-01-01

    This study has explored the nature of decision-making under conditions of conflicting political and economic imperatives. The participants want the cooperative program to succeed. They also want to bear the least burden necessary for success by shifting it to others. The concepts of burden sharing and burden shifting have been explored in the context of armaments cooperation through analysis of six armaments cooperation cases. The cases ranged from the NATO Sea Sparrow Missile System to the 155MM Autonomous Precision Guided Missile. Ideal models of burden sharing and burden shifting were developed to aid the analysis. The resultant theoretical framework of armaments cooperation within the NATO alliance has been used to explain success or lack of success in cooperative programs. Each case study addressed the categories of: Political Environment, Program Inception, Management Structure, and Results. Comparative analysis between programs was facilitated by using similar criteria for success or failure throughout. Each of the hypotheses making up the ideal models for burden sharing and burden shifting were examined considering the individual cases. An assessment of validity was made. Comparative analysis of selected case pairs facilitated isolation of factors that may have contributed to different results. These assessments were combined and formed the basis for the final conclusions on each hypothesis and their respective importance. This study adds to the theoretical understanding of alliance politics by examining in depth these concepts. It also supports future efforts to understand alliance politics by providing a framework for examining and testing deductively derived propositions against experience.

  16. Diffuse intestinal ganglioneuromatosis in a child.

    PubMed

    Matthews, Mika A B; Adler, Brent H; Arnold, Michael A; Kumar, Soma; Carvalho, Ryan; Besner, Gail E

    2013-05-01

    A 7 year old male with a history of congenital neutropenia and growth hormone deficiency presented with abdominal pain, fevers, and diarrhea. Imaging and endoscopy revealed significant inflammation of the ascending colon with stenosis at the level of the hepatic flexure. A right hemicolectomy was performed, and pathologic findings were consistent with diffuse intestinal ganglioneuromatosis. Due to recurrent mass effect at the intestinal anastomotic site detected radiologically, a second intestinal resection was performed 7 months later. Genetic testing was negative for mutations in the RET protooncogene, NF1 and PTEN tumor suppressor genes. We report a case of diffuse intestinal ganglioneuromatosis in a child with congenital neutropenia. Copyright © 2013 Elsevier Inc. All rights reserved.

  17. [Adult intestinal malrotation associated with intestinal volvulus].

    PubMed

    Hernando-Almudí, Ernesto; Cerdán-Pascual, Rafael; Vallejo-Bernad, Cristina; Martín-Cuartero, Joaquín; Sánchez-Rubio, María; Casamayor-Franco, Carmen

    2016-06-23

    Intestinal malrotation is a congenital anomaly of the intestinal rotation and fixation, and usually occurs in the neonatal age. Description of a clinical case associated with acute occlusive symptoms. A case of intestinal malrotation is presented in a previously asymptomatic woman of 46 years old with an intestinal obstruction, with radiology and surgical findings showing an absence of intestinal rotation. Intestinal malrotation in adults is often asymptomatic, and is diagnosed as a casual finding during a radiological examination performed for other reasons. Infrequently, it can be diagnosed in adults, associated with an acute abdomen. Copyright © 2016 Academia Mexicana de Cirugía A.C. Published by Masson Doyma México S.A. All rights reserved.

  18. Hypertension burden in Luxembourg

    PubMed Central

    Ruiz-Castell, Maria; Kandala, Ngianga-Bakwin; Kuemmerle, Andrea; Schritz, Anna; Barré, Jessica; Delagardelle, Charles; Krippler, Serge; Schmit, Jean-Claude; Stranges, Saverio

    2016-01-01

    Abstract Hypertension is a modifiable risk factor for cardiovascular disease, but it remains the main cause of death in Luxembourg. We aimed to estimate the current prevalence of hypertension, associated risk factors, and its geographic variation in Luxembourg. Cross-sectional, population-based data on 1497 randomly selected Luxembourg residents aged 25 to 64 years were collected as part of the European Health Examination Survey from 2013 to 2015. Hypertension was defined as systolic/diastolic blood pressure ≥140/90 mm Hg, self-report of a physician diagnosis or on antihypertensive medication. Standard and Bayesian regressions were used to examine associations between hypertension and covariates, and also geographic distribution of hypertension across the country. Nearly 31% of Luxembourg residents were hypertensive, and over 70% of those were either unaware of their condition or not adequately controlled. The likelihood of hypertension was lower in men more physically active (odds ratio [95% credible region] 0.6 [0.4, 0.9]) and consuming alcohol daily (0.3 [0.1, 0.8]), and higher in men with a poor health perception (1.6 [1.0, 2.7]) and in women experiencing depressive symptoms (1.8 [1.3, 2.7]). There were geographic variations in hypertension prevalence across cantons and municipalities. The highest odds ratio was observed in the most industrialized region (South-West) (1.2 [0.9, 1.6]) with a positive effect at 90% credible region. In Luxembourg, the vast majority of people with hypertension are either unaware of their condition or not adequately controlled, which constitutes a major, neglected public health challenge. There are geographic variations in hypertension prevalence in Luxembourg, hence the role of individual and regional risk factors along with public health initiatives to reduce disease burden should be considered. PMID:27603374

  19. Gastrin attenuates ischemia-reperfusion-induced intestinal injury in rats

    PubMed Central

    Liu, Zhihao; Luo, Yongli; Cheng, Yunjiu; Zou, Dezhi; Zeng, Aihong; Yang, Chunhua

    2016-01-01

    Intestinal ischemia-reperfusion (I/R) injury is a devastating complication when the blood supply is reflowed in ischemic organs. Gastrin has critical function in regulating acid secretion, proliferation, and differentiation in the gastric mucosa. We aimed to determine whether gastrin has an effect on intestinal I/R damage. Intestinal I/R injury was induced by 60-min occlusion of the superior mesenteric artery followed by 60-min reperfusion, and the rats were induced to be hypergastrinemic by pretreated with omeprazole or directly injected with gastrin. Some hypergastrinemic rats were injected with cholecystokinin-2 (CCK-2) receptor antagonist prior to I/R operation. After the animal surgery, the intestine was collected for histological analysis. Isolated intestinal epithelial cells or crypts were harvested for RNA and protein analysis. CCK-2 receptor expression, intestinal mucosal damage, cell apoptosis, and apoptotic protein caspase-3 activity were measured. We found that high gastrin in serum significantly reduced intestinal hemorrhage, alleviated extensive epithelial disruption, decreased disintegration of lamina propria, downregulated myeloperoxidase activity, tumor necrosis factor-α, and caspase-3 activity, and lead to low mortality in response to I/R injury. On the contrary, CCK-2 receptor antagonist L365260 could markedly impair intestinal protection by gastrin on intestinal I/R. Severe edema of mucosal villi with severe intestinal crypt injury and numerous intestinal villi disintegrated were observed again in the hypergastrinemic rats with L365260. The survival in the hypergastrinemic rats after intestinal I/R injury was shortened by L365260. Finally, gastrin could remarkably upregulated intestinal CCK-2 receptor expression. Our data suggest that gastrin by omeprazole remarkably attenuated I/R induced intestinal injury by enhancing CCK-2 receptor expression and gastrin could be a potential mitigator for intestinal I/R damage in the clinical setting. PMID

  20. The Global Burden of Anemia.

    PubMed

    Kassebaum, Nicholas J

    2016-04-01

    Anemia is an important cause of health loss. We estimated levels and trends of nonfatal anemia burden for 23 distinct etiologies in 188 countries, 20 age groups, and both sexes from 1990 to 2013. All available population-level anemia data were collected and standardized. We estimated mean hemoglobin, prevalence of anemia by severity, quantitative disability owing to anemia, and underlying etiology for each population using the approach of the Global Burden of Disease, Injuries and Risk Factors 2013 Study. Anemia burden is high. Developing countries account for 89% of all anemia-related disability. Iron-deficiency anemia remains the dominant cause of anemia. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. Reproducibility of residual cancer burden for prognostic assessment of breast cancer after neoadjuvant chemotherapy.

    PubMed

    Peintinger, Florentia; Sinn, Bruno; Hatzis, Christos; Albarracin, Constance; Downs-Kelly, Erinn; Morkowski, Jerzy; Gould, Rebekah; Symmans, W Fraser

    2015-07-01

    The residual cancer burden index was developed as a method to quantify residual disease ranging from pathological complete response to extensive residual disease. The aim of this study was to evaluate the inter-Pathologist reproducibility in the residual cancer burden index score and category, and in their long-term prognostic utility. Pathology slides and pathology reports of 100 cases from patients treated in a randomized neoadjuvant trial were reviewed independently by five pathologists. The size of tumor bed, average percent overall tumor cellularity, average percent of the in situ cancer within the tumor bed, size of largest axillary metastasis, and number of involved nodes were assessed separately by each pathologist and residual cancer burden categories were assigned to each case following calculation of the numerical residual cancer burden index score. Inter-Pathologist agreement in the assessment of the continuous residual cancer burden score and its components and agreement in the residual cancer burden category assignments were analyzed. The overall concordance correlation coefficient for the agreement in residual cancer burden score among pathologists was 0.931 (95% confidence interval (CI) 0.908-0.949). Overall accuracy of the residual cancer burden score determination was 0.989. The kappa coefficient for overall agreement in the residual cancer burden category assignments was 0.583 (95% CI 0.539-0.626). The metastatic component of the residual cancer burden index showed stronger concordance between pathologists (overall concordance correlation coefficient=0.980; 95% CI 0.954-0.992), than the primary component (overall concordance correlation coefficient=0.795; 95% CI 0.716-0.853). At a median follow-up of 12 years residual cancer burden determined by each of the pathologists had the same prognostic accuracy for distant recurrence-free and survival (overall concordance correlation coefficient=0.995; 95% CI 0.989-0.998). Residual cancer burden

  2. Disorders of the Small Intestine

    MedlinePlus

    ... Disorders of the Stomach Disorders of the Small Intestine Disorders of the Large Intestine Disorders of the Pelvic Floor Motility Testing Personal ... Disorders of the Stomach Disorders of the Small Intestine Disorders of the Large Intestine Disorders of the ...

  3. Disorders of the Large Intestine

    MedlinePlus

    ... Disorders of the Stomach Disorders of the Small Intestine Disorders of the Large Intestine Disorders of the Pelvic Floor Motility Testing Personal ... Disorders of the Stomach Disorders of the Small Intestine Disorders of the Large Intestine Disorders of the ...

  4. Small Intestine Disorders

    MedlinePlus

    Your small intestine is the longest part of your digestive system - about twenty feet long! It connects your stomach to ... many times to fit inside your abdomen. Your small intestine does most of the digesting of the foods ...

  5. Small intestine (image)

    MedlinePlus

    The small intestine is the portion of the digestive system most responsible for absorption of nutrients from food into the ... the duodenum. This short first portion of the small intestine is followed by the jejunum and the ileum. ...

  6. HIV / AIDS: An Unequal Burden

    MedlinePlus

    ... Navigation Bar Home Current Issue Past Issues HIV / AIDS HIV / AIDS: An Unequal Burden Past Issues / Summer 2009 Table ... Victoria Cargill talks to students about HIV and AIDS at the opening of a National Library of ...

  7. The FDP Faculty Burden Survey

    PubMed Central

    Rockwell, Sara

    2010-01-01

    To better understand the administrative burdens placed on faculty who perform research, the Faculty Standing Committee of the Federal Demonstration Partnership (FDP) invited 23,325 full-time faculty members who were Principal Investigators (PI) or Co-Principal Investigators (Co-PI) on active federally funded research grants to participate in a web-based survey that contained questions on the nature, size, and impact of the administrative tasks associated with their research projects. The responses of the 6,081 faculty respondents show that the administrative burden on faculty is very significant: 42% of the time spent by an average PI on a federally funded research project was reported to be expended on administrative tasks related to that project rather than on research. This administrative burden does not stem from one or a few exceptionally onerous tasks, but instead reflects the cumulative effect of the many administrative burdens imposed by different funding agencies, different offices within agencies, auditing and accrediting agencies, and academic institutions. The lack of institutional assistance contributes to the administrative workload of the faculty. Many burdens are remarkably constant across funding agencies, universities, disciplines, and faculty subgroups. The report documents the negative effect reported for these administrative burdens on the productivity of researchers, the careers of young faculty members, and the training of students. PMID:20563268

  8. Acetate Dependence of Tumors

    PubMed Central

    Comerford, Sarah A.; Huang, Zhiguang; Du, Xinlin; Wang, Yun; Cai, Ling; Witkiewicz, Agnes; Walters, Holly; Tantawy, Mohammed N.; Fu, Allie; Manning, H. Charles; Horton, Jay D.; Hammer, Robert E.; McKnight, Steven L.; Tu, Benjamin P.

    2014-01-01

    SUMMARY Acetyl-CoA represents a central node of carbon metabolism that plays a key role in bioenergetics, cell proliferation and the regulation of gene expression. How highly glycolytic or hypoxic tumors are able to produce sufficient quantities of this metabolite to support cell growth and survival under nutrient-limiting conditions remains poorly understood. Here we show that the nucleocytosolic acetyl-CoA synthetase enzyme, ACSS2, supplies a key source of acetyl-CoA for tumors by capturing acetate as a carbon source. Despite exhibiting no gross deficits in growth or development, adult mice lacking ACSS2 exhibit a significant reduction in tumor burden in two different models of hepatocellular carcinoma. ACSS2 is expressed in a large proportion of human tumors and its activity is responsible for the majority of cellular acetate uptake into both lipids and histones. These observations may qualify ACSS2 as a targetable metabolic vulnerability of a wide spectrum of tumors. PMID:25525877

  9. ER stress transcription factor Xbp1 suppresses intestinal tumorigenesis and directs intestinal stem cells

    PubMed Central

    Niederreiter, Lukas; Fritz, Teresa M.J.; Adolph, Timon E.; Krismer, Anna-Maria; Offner, Felix A.; Tschurtschenthaler, Markus; Flak, Magdalena B.; Hosomi, Shuhei; Tomczak, Michal F.; Kaneider, Nicole C.; Sarcevic, Edina; Kempster, Sarah L.; Raine, Tim; Esser, Daniela; Rosenstiel, Philip; Kohno, Kenji; Iwawaki, Takao; Tilg, Herbert

    2013-01-01

    Unresolved endoplasmic reticulum (ER) stress in the epithelium can provoke intestinal inflammation. Hypomorphic variants of ER stress response mediators, such as X-box–binding protein 1 (XBP1), confer genetic risk for inflammatory bowel disease. We report here that hypomorphic Xbp1 function instructs a multilayered regenerative response in the intestinal epithelium. This is characterized by intestinal stem cell (ISC) expansion as shown by an inositol-requiring enzyme 1α (Ire1α)–mediated increase in Lgr5+ and Olfm4+ ISCs and a Stat3-dependent increase in the proliferative output of transit-amplifying cells. These consequences of hypomorphic Xbp1 function are associated with an increased propensity to develop colitis-associated and spontaneous adenomatous polyposis coli (APC)–related tumors of the intestinal epithelium, which in the latter case is shown to be dependent on Ire1α. This study reveals an unexpected role for Xbp1 in suppressing tumor formation through restraint of a pathway that involves an Ire1α- and Stat3-mediated regenerative response of the epithelium as a consequence of ER stress. As such, Xbp1 in the intestinal epithelium not only regulates local inflammation but at the same time also determines the propensity of the epithelium to develop tumors. PMID:24043762

  10. Epigenetic Regulation of the Intestinal Epithelium

    PubMed Central

    Elliott, Ellen N.; Kaestner, Klaus H.

    2015-01-01

    The intestinal epithelium is an ideal model system for the study of normal and pathological differentiation processes. The mammalian intestinal epithelium is a single cell layer comprised of proliferative crypts and differentiated villi. The crypts contain both proliferating and quiescent stem cell populations that self-renew and produce all the differentiated cell types, which are replaced every 3 to 5 days. The genetics of intestinal development, homeostasis, and disease are well defined, but less is known about the contribution of epigenetics in modulating these processes. Epigenetics refers to heritable phenotypic traits, including gene expression, which are independent of mutations in the DNA sequence. We have known for several decades that human colorectal cancers contain hypomethylated DNA, but the causes and consequences of this phenomenon are not fully understood. In contrast, tumor suppressor gene promoters are often hypermethylated in colorectal cancer, resulting in decreased expression of the associated gene. In this review, we describe the role that epigenetics plays in intestinal homeostasis and disease, with an emphasis on results from mouse models. We highlight the importance of producing and analyzing next-generation sequencing data detailing the epigenome from intestinal stem cell to differentiated intestinal villus cell. PMID:26220502

  11. Establishment of Intestinal Bacteriology

    PubMed Central

    MITSUOKA, Tomotari

    2014-01-01

    Research on intestinal bacteria began around the end of the 19th century. During the last 5 decades of the 20th century, research on the intestinal microbiota made rapid progress. At first, in my work, I first developed a method of comprehensive analysis of the intestinal microbiota, and then I established classification and identification methods for intestinal anaerobes. Using these methods I discovered a number of ecological rules governing the intestinal microbiota and the role of the intestinl microbiota in health and disease. Moreover, using germfree animals, it was proven that the intestinal microbiota has a role in carcinogenesis and aging in the host. Thus, a new interdisciplinary field, “intestinal bacteriology” was established. PMID:25032084

  12. Burden of Proof in Bioethics.

    PubMed

    Koplin, Julian J; Selgelid, Michael J

    2015-11-01

    A common strategy in bioethics is to posit a prima facie case in favour of one policy, and to then claim that the burden of proof (that this policy should be rejected) falls on those with opposing views. If the burden of proof is not met, it is claimed, then the policy in question should be accepted. This article illustrates, and critically evaluates, examples of this strategy in debates about the sale of organs by living donors, human enhancement, and the precautionary principle. We highlight general problems with this style of argument, and particular problems with its use in specific cases. We conclude that the burden ultimately falls on decision-makers (i.e. policy-makers) to choose the policy supported by the best reasons.

  13. BURDEN FALLS ROADLESS AREA, ILLINOIS.

    USGS Publications Warehouse

    Klasner, John S.; Thompson, Robert M.

    1984-01-01

    The Burden Falls Roadless Area lies in the Shawnee National Forest of southern Illinois, about 5 mi west of the western edge of the Illinois-Kentucky fluorspar district. Geologic mapping and geochemical surveys indicate that the area has little promise for the occurrence of fluorspar and associated minerals; other special studies also indicate little promise for oil and gas and construction materials. Traces of gold and silver were detected in some geochemical samples but follow-up studies indicate little promise for the occurrence of resources of these metals within the Burden Falls Roadless Area.

  14. PUMA Suppresses Intestinal Tumorigenesis in Mice

    PubMed Central

    Qiu, Wei; Carson-Walter, Eleanor B.; Kuan, Shih Fan; Zhang, Lin; Yu, Jian

    2010-01-01

    Defective apoptosis contributes to tumorigenesis, although the critical molecular targets remain to be fully characterized. PUMA, a BH3-only protein essential for p53-dependent apoptosis, has been shown to suppress lymphomagenesis. In this study, we investigated the role of PUMA in intestinal tumorigenesis using two animal models. In the azoxymethane (AOM)/dextran sulfate sodium salt model, PUMA deficiency increased the multiplicity and size of colon tumors but reduced the frequency of β-catenin hotspot mutations. The absence of PUMA led to a significantly elevated incidence of precursor lesions induced by AOM. AOM was found to induce p53-dependent PUMA expression and PUMA-dependent apoptosis in the colonic crypts and stem cell compartment. Furthermore, PUMA deficiency significantly enhanced the formation of spontaneous macroadenomas and microadenomas in the distal small intestine and colon of APCMin/+ mice. These results show an essential role of PUMA-mediated apoptosis in suppressing intestinal tumorigenesis in mice. PMID:19491259

  15. Intestinal parasitism in Malayan aborigines (Orang Asli)*

    PubMed Central

    Dunn, F. L.

    1972-01-01

    Surveys were conducted in the southern Malay peninsula to assess intestinal parasitism in the aboriginal ethnic minority groups. Faecal specimens from 1 273 persons were examined by the thiomersal—iodine—formol direct-smear technique. Prevalences are reported and, for helminth infections, data on worm burdens. The state of sanitation in each of 9 cultural-ecological groups was assessed by means of a simplified system of scoring for variables. Particular attention was paid to relationships between cultural and ecological factors, sanitation, and observed patterns of intestinal parasitism. The author also discusses the fact that the number of parasitic species diminishes in habitats simplified by man, whereas an increase occurs in the prevalence and intensity of the more adaptable species that persist in ecosystems of low complexity. PMID:4537337

  16. Intestinal M cells

    PubMed Central

    Ohno, Hiroshi

    2016-01-01

    We have an enormous number of commensal bacteria in our intestine, moreover, the foods that we ingest and the water we drink is sometimes contaminated with pathogenic microorganisms. The intestinal epithelium is always exposed to such microbes, friend or foe, so to contain them our gut is equipped with specialized gut-associated lymphoid tissue (GALT), literally the largest peripheral lymphoid tissue in the body. GALT is the intestinal immune inductive site composed of lymphoid follicles such as Peyer’s patches. M cells are a subset of intestinal epithelial cells (IECs) residing in the region of the epithelium covering GALT lymphoid follicles. Although the vast majority of IEC function to absorb nutrients from the intestine, M cells are highly specialized to take up intestinal microbial antigens and deliver them to GALT for efficient mucosal as well as systemic immune responses. I will discuss recent advances in our understanding of the molecular mechanisms of M-cell differentiation and functions. PMID:26634447

  17. The Burden of Parasitic Zoonoses in Nepal: A Systematic Review

    PubMed Central

    Devleesschauwer, Brecht; Ale, Anita; Torgerson, Paul; Praet, Nicolas; Maertens de Noordhout, Charline; Pandey, Basu Dev; Pun, Sher Bahadur; Lake, Rob; Vercruysse, Jozef; Joshi, Durga Datt; Havelaar, Arie H.; Duchateau, Luc; Dorny, Pierre; Speybroeck, Niko

    2014-01-01

    Background Parasitic zoonoses (PZs) pose a significant but often neglected threat to public health, especially in developing countries. In order to obtain a better understanding of their health impact, summary measures of population health may be calculated, such as the Disability-Adjusted Life Year (DALY). However, the data required to calculate such measures are often not readily available for these diseases, which may lead to a vicious circle of under-recognition and under-funding. Methodology We examined the burden of PZs in Nepal through a systematic review of online and offline data sources. PZs were classified qualitatively according to endemicity, and where possible a quantitative burden assessment was conducted in terms of the annual number of incident cases, deaths and DALYs. Principal Findings Between 2000 and 2012, the highest annual burden was imposed by neurocysticercosis and congenital toxoplasmosis (14,268 DALYs [95% Credibility Interval (CrI): 5450–27,694] and 9255 DALYs [95% CrI: 6135–13,292], respectively), followed by cystic echinococcosis (251 DALYs [95% CrI: 105–458]). Nepal is probably endemic for trichinellosis, toxocarosis, diphyllobothriosis, foodborne trematodosis, taeniosis, and zoonotic intestinal helminthic and protozoal infections, but insufficient data were available to quantify their health impact. Sporadic cases of alveolar echinococcosis, angiostrongylosis, capillariosis, dirofilariosis, gnathostomosis, sparganosis and cutaneous leishmaniosis may occur. Conclusions/Significance In settings with limited surveillance capacity, it is possible to quantify the health impact of PZs and other neglected diseases, thereby interrupting the vicious circle of neglect. In Nepal, we found that several PZs are endemic and are imposing a significant burden to public health, higher than that of malaria, and comparable to that of HIV/AIDS. However, several critical data gaps remain. Enhanced surveillance for the endemic PZs identified in this

  18. The Physical Burdens of Secrecy

    ERIC Educational Resources Information Center

    Slepian, Michael L.; Masicampo, E. J.; Toosi, Negin R.; Ambady, Nalini

    2012-01-01

    The present work examined whether secrets are experienced as physical burdens, thereby influencing perception and action. Four studies examined the behavior of people who harbored important secrets, such as secrets concerning infidelity and sexual orientation. People who recalled, were preoccupied with, or suppressed an important secret estimated…

  19. The Physical Burdens of Secrecy

    ERIC Educational Resources Information Center

    Slepian, Michael L.; Masicampo, E. J.; Toosi, Negin R.; Ambady, Nalini

    2012-01-01

    The present work examined whether secrets are experienced as physical burdens, thereby influencing perception and action. Four studies examined the behavior of people who harbored important secrets, such as secrets concerning infidelity and sexual orientation. People who recalled, were preoccupied with, or suppressed an important secret estimated…

  20. Biomarkers of Renal Tumor Burden and Progression in TSC

    DTIC Science & Technology

    2012-09-01

    solid lesions (equivalent to 33% of all enrolled patients) underwent emergent or elective intervention in the form of biopsy, nephrectomy , embolization...database with event data (hemorrhage, embolization, biopsy, nephrectomy ) X X X X initiated ongoing planned planned Task 4: radiologic

  1. Intestinal lymphangiectasia in children

    PubMed Central

    Isa, Hasan M.; Al-Arayedh, Ghadeer G.; Mohamed, Afaf M.

    2016-01-01

    Intestinal lymphangiectasia (IL) is a rare disease characterized by dilatation of intestinal lymphatics. It can be classified as primary or secondary according to the underlying etiology. The clinical presentations of IL are pitting edema, chylous ascites, pleural effusion, acute appendicitis, diarrhea, lymphocytopenia, malabsorption, and intestinal obstruction. The diagnosis is made by intestinal endoscopy and biopsies. Dietary modification is the mainstay in the management of IL with a variable response. Here we report 2 patients with IL in Bahrain who showed positive response to dietary modification. PMID:26837404

  2. Intestinal transplantation: a review.

    PubMed

    Desai, Chirag Sureshchandra; Khan, Khalid Mahmood; Girlanda, Raffaele; Fishbein, Thomas M

    2012-09-01

    Parenteral nutrition is a life-saving therapy for patients with intestinal failure. Intestinal transplantation is now recognized as a treatment for patients who develop complications of parenteral nutrition and in whom attempts at intestinal rehabilitation have failed. Patients with parenteral nutrition related liver disease will require a liver graft typically part of a multivisceral transplant. Isolated intestinal transplants are more commonly performed in adults while multivisceral transplants are most commonly performed in infants. Isolated intestinal transplants have the best short-term outcome, with over 80 % survival at 1 year. Patients requiring multivisceral transplants have a high rate of attrition with a 1 year survival less than 70 %. Prognostic factors for a poor outcome include patient hospitalization at the time of transplant and donor age greater than 40 years while systemic sepsis and acute rejection are the major determinant of early postoperative outcome. For patients surviving the first year the outcome of transplantation of the liver in addition to intestine affords some survival advantage though long-term outcome does not yet match other abdominal organs. Outcomes for intestinal retransplantation are poor as a result of immunology and patient debility. Overall intestinal transplantation continues to develop and is a clear indication with cost and quality of life advantages in patients with intestinal failure that do not remain stable on parenteral nutrition.

  3. Concurrent Infection with an Intestinal Helminth Parasite Impairs Host Resistance to Enteric Citrobacter rodentium and Enhances Citrobacter-Induced Colitis in Mice

    PubMed Central

    Chen, Chien-Chang; Louie, Steve; McCormick, Beth; Walker, W. Allan; Shi, Hai Ning

    2005-01-01

    Infections with intestinal helminth and bacterial pathogens, such as enteropathogenic Escherichia coli, continue to be a major global health threat for children. To test the hypothesis that intestinal helminth infection may be a risk factor for enteric bacterial infection, a murine model was established by using the intestinal helminth Heligomosomoides polygyrus. To analyze the modulatory effect of a Th2-inducing helminth on the outcome of enteric bacterium Citrobacter rodentium infection, BALB/c and STAT 6 knockout (KO) mice were infected with H. polygyrus, C. rodentium, or both. We found that only BALB/c mice coinfected with H. polygyrus and C. rodentium displayed a marked morbidity and mortality. The enhanced susceptibility to C. rodentium and intestinal injury of coinfected BALB/c mice were shown to be associated with a significant increase in helminth-driven Th2 responses, mucosally and systemically, and correlated with a significant downregulation of protective gamma interferon and with a dramatic upregulation of the proinflammatory tumor necrosis factor alpha response. In addition, C. rodentium-associated colonic pathology in coinfected BALB/c mice was significantly enhanced, whereas bacterial burden was increased and clearance was delayed. In contrast, coinfection in STAT 6 KO mice failed to promote C. rodentium infection or to induce a more severe intestinal inflammation and tissue injury, demonstrating a mechanism by which helminth influences the development of host protective immunity and susceptibility to bacterial infections. We conclude that H. polygyrus coinfection can promote C. rodentium-associated disease and colitis through a STAT 6-mediated immune mechanism. PMID:16113263

  4. Three-Dimensional Coculture Of Human Small-Intestine Cells

    NASA Technical Reports Server (NTRS)

    Wolf, David; Spaulding, Glen; Goodwin, Thomas J.; Prewett, Tracy

    1994-01-01

    Complex three-dimensional masses of normal human epithelial and mesenchymal small-intestine cells cocultured in process involving specially designed bioreactors. Useful as tissued models for studies of growth, regulatory, and differentiation processes in normal intestinal tissues; diseases of small intestine; and interactions between cells of small intestine and viruses causing disease both in small intestine and elsewhere in body. Process used to produce other tissue models, leading to advances in understanding of growth and differentiation in developing organisms, of renewal of tissue, and of treatment of myriad of clinical conditions. Prior articles describing design and use of rotating-wall culture vessels include "Growing And Assembling Cells Into Tissues" (MSC-21559), "High-Aspect-Ratio Rotating Cell-Culture Vessel" (MSC-21662), and "In Vitro, Matrix-Free Formation Of Solid Tumor Spheroids" (MSC-21843).

  5. Hepatic Injury in Nonalcoholic Steatohepatitis Contributes to Altered Intestinal Permeability.

    PubMed

    Luther, Jay; Garber, John J; Khalili, Hamed; Dave, Maneesh; Bale, Shyam Sundhar; Jindal, Rohit; Motola, Daniel L; Luther, Sanjana; Bohr, Stefan; Jeoung, Soung Won; Deshpande, Vikram; Singh, Gurminder; Turner, Jerrold R; Yarmush, Martin L; Chung, Raymond T; Patel, Suraj J

    2015-03-01

    Emerging data suggest that changes in intestinal permeability and increased gut microbial translocation contribute to the inflammatory pathway involved in nonalcoholic steatohepatitis (NASH) development. Numerous studies have investigated the association between increased intestinal permeability and NASH. Our meta-analysis of this association investigates the underlying mechanism. A meta-analysis was performed to compare the rates of increased intestinal permeability in patients with NASH and healthy controls. To further address the underlying mechanism of action, we studied changes in intestinal permeability in a diet-induced (methionine-and-choline-deficient; MCD) murine model of NASH. In vitro studies were also performed to investigate the effect of MCD culture medium at the cellular level on hepatocytes, Kupffer cells, and intestinal epithelial cells. Nonalcoholic fatty liver disease (NAFLD) patients, and in particular those with NASH, are more likely to have increased intestinal permeability compared with healthy controls. We correlate this clinical observation with in vivo data showing mice fed an MCD diet develop intestinal permeability changes after an initial phase of liver injury and tumor necrosis factor-α (TNFα) induction. In vitro studies reveal that MCD medium induces hepatic injury and TNFα production yet has no direct effect on intestinal epithelial cells. Although these data suggest a role for hepatic TNFα in altering intestinal permeability, we found that mice genetically resistant to TNFα-myosin light chain kinase (MLCK)-induced intestinal permeability changes fed an MCD diet still develop increased permeability and liver injury. Our clinical and experimental results strengthen the association between intestinal permeability increases and NASH and also suggest that an early phase of hepatic injury and inflammation contributes to altered intestinal permeability in a fashion independent of TNFα and MLCK.

  6. High-fat Diet Accelerates Intestinal Tumorigenesis Through Disrupting Intestinal Cell Membrane Integrity

    PubMed Central

    Park, Mi-Young; Kim, Min Young; Seo, Young Rok; Kim, Jong-Sang; Sung, Mi-Kyung

    2016-01-01

    Background: Excess energy supply induces chronic low-grade inflammation in association with oxidative stress in various tissues including intestinal epithelium. The objective of this study was to investigate the effect of high-fat diet (HFD) on intestinal cell membrane integrity and intestinal tumorigenesis in ApcMin/+ mice. Methods: Mice were fed with either normal diet (ND) or HFD for 12 weeks. The number of intestinal tumors were counted and biomarkers of endotoxemia, oxidative stress, and inflammation were determined. Changes in intestinal integrity was measured by fluorescein isothiocyanate (FITC)-dextran penetration and membrane gap junction protein expression. Results: HFD group had significantly higher number of tumors compared to ND group (P < 0.05). Blood total antioxidant capacity was lower in HFD group, while colonic 8-hydroxy-2′-deoxyguanosine level, a marker of oxidative damage, was higher in HFD group compared to that of ND group (P < 0.05). The penetration of FITC-dextran was substantially increased in HFD group (P < 0.05) while the expressions of membrane gap junction proteins including zonula occludens-1, claudin-1, and occludin were lower in HFD group (P < 0.05) compared to those in ND group. Serum concentration of lipopolysaccharide (LPS) receptor (CD14) and colonic toll-like receptor 4 (a LPS receptor) mRNA expression were significantly higher in HFD group than in ND group (P < 0.05), suggesting that significant endotoxemia may occur in HFD group due to the increased membrane permeability. Serum interleukin-6 concentration and myeloperoxidase activity were also higher in HFD group compared to those of ND group (P < 0.05). Conclusions: HFD increases oxidative stress disrupting intestinal gap junction proteins, thereby accelerating membrane permeability endotoxemia, inflammation, and intestinal tumorigenesis. PMID:27390738

  7. Intestinal or bowel obstruction - discharge

    MedlinePlus

    ... medlineplus.gov/ency/patientinstructions/000150.htm Intestinal or bowel obstruction - discharge To use the sharing features on this ... your bowel (intestine). This condition is called an intestinal obstruction . The blockage may be partial or total (complete). ...

  8. Stages of Small Intestine Cancer

    MedlinePlus

    ... Health Professional Small Intestine Cancer Treatment Research Small Intestine Cancer Treatment (PDQ®)–Patient Version General Information About Small Intestine Cancer Go to Health Professional Version Key Points ...

  9. Recurrent intussusception as initial manifestation of primary intestinal melanoma: Case report and literature review.

    PubMed

    Kouladouros, Konstantinos; Gärtner, Daniel; Münch, Steffen; Paul, Mario; Schön, Michael R

    2015-03-14

    Enteric intussusception caused by primary intestinal malignant melanoma is a very rare cause of intestinal obstruction. We herein present a case of a 42-year-old female patient with no prior medical history of malignant melanoma, who was admitted with persistent abdominal pain, nausea, and vomiting. A computed tomography scan revealed an intestinal obstruction due to ileocolic intussusception. An emergency laparoscopy and subsequent laparotomy revealed multiple small solid tumors across the whole small bowel. An oncologic resection was not feasible due to the insufficient length of the remaining small bowel. Only a small segment of ileum, which included the largest tumors causing the intussusception, was resected. The pathologic examination revealed two intestinal malignant melanoma lesions. A systematic clinical examination, endoscopic procedures, and fluorodeoxyglucose positron emission tomography-computed tomography scan all failed to reveal any indication of cutaneous, anal, or retinal melanoma. Hence, the tumor was classified as a primary intestinal malignant melanoma with multiple intestinal metastases. Since a complete oncologic resection of tumors was not possible, in order to prevent future intestinal obstruction, a surgical resection of the largest lesions was performed with palliative intention. The epidemiology, clinical manifestations, diagnosis and management of primary intestinal malignant melanoma, and intestinal intussusception in adults are discussed along with a review of the current literature.

  10. Recurrent intussusception as initial manifestation of primary intestinal melanoma: Case report and literature review

    PubMed Central

    Kouladouros, Konstantinos; Gärtner, Daniel; Münch, Steffen; Paul, Mario; Schön, Michael R

    2015-01-01

    Enteric intussusception caused by primary intestinal malignant melanoma is a very rare cause of intestinal obstruction. We herein present a case of a 42-year-old female patient with no prior medical history of malignant melanoma, who was admitted with persistent abdominal pain, nausea, and vomiting. A computed tomography scan revealed an intestinal obstruction due to ileocolic intussusception. An emergency laparoscopy and subsequent laparotomy revealed multiple small solid tumors across the whole small bowel. An oncologic resection was not feasible due to the insufficient length of the remaining small bowel. Only a small segment of ileum, which included the largest tumors causing the intussusception, was resected. The pathologic examination revealed two intestinal malignant melanoma lesions. A systematic clinical examination, endoscopic procedures, and fluorodeoxyglucose positron emission tomography-computed tomography scan all failed to reveal any indication of cutaneous, anal, or retinal melanoma. Hence, the tumor was classified as a primary intestinal malignant melanoma with multiple intestinal metastases. Since a complete oncologic resection of tumors was not possible, in order to prevent future intestinal obstruction, a surgical resection of the largest lesions was performed with palliative intention. The epidemiology, clinical manifestations, diagnosis and management of primary intestinal malignant melanoma, and intestinal intussusception in adults are discussed along with a review of the current literature. PMID:25780313

  11. Combination Chemotherapy in Treating Patients With Recurrent, Refractory, or Metastatic Solid Tumors or Lymphomas

    ClinicalTrials.gov

    2012-03-21

    Colorectal Cancer; Esophageal Cancer; Extrahepatic Bile Duct Cancer; Gallbladder Cancer; Liver Cancer; Lung Cancer; Lymphoma; Pancreatic Cancer; Small Intestine Cancer; Unspecified Adult Solid Tumor, Protocol Specific

  12. Intestinal obstruction repair - slideshow

    MedlinePlus

    ... this page: //medlineplus.gov/ency/presentations/100116.htm Intestinal obstruction repair - series—Normal anatomy To use the sharing ... M. Editorial team. Related MedlinePlus Health Topics Adhesions Intestinal Obstruction A.D.A.M., Inc. is accredited by ...

  13. Intestinal obstruction (pediatric) - slideshow

    MedlinePlus

    ... this page: //medlineplus.gov/ency/presentations/100165.htm Intestinal obstruction (pediatric) - series—Normal anatomy To use the sharing ... A.M. Editorial team. Related MedlinePlus Health Topics Intestinal Obstruction A.D.A.M., Inc. is accredited by ...

  14. Grandmother caregivers and caregiver burden.

    PubMed

    Dowdell, Elizabeth Burgess

    2004-01-01

    To describe the experience of grandmothers who are parenting their grandchildren, and determine the amount of caregiver burden felt by the grandmothers. This descriptive correlational study had a sample of 104 grandmothers, reporting on 249 custodial grandchildren. Grandmothers completed the Caregiver Reactions Assessment to determine perceived physical health, family support, financial status, and caregiver burden. Overall, grandmothers perceived the health of their grandchildren as excellent. Of the grandchildren who had been born prematurely (30%), the primary health problems were hyperactivity and asthma. Parental drug use was reported as the reason for child placement with the grandmother in 80% of the cases. The range of time grandchildren had been living with the grandmother was 6 months to 15 years. Low ratings of grandchild physical health correlated with low ratings of grandmother physical health, which correlated strongly with low levels of self-esteem, a strong perception of poor family support, and poor financial status, all of which represent measures of caregiver burden. This study demonstrated that the well being of the grandmother and grandchild are both linked to good physical health. Thus, indicators of poor health for both grandchild and grandmother must be identified early. Grandmothers in this study were surprised at how much had changed in every aspect of child health since they had raised their own children. Nurses working with grandmothers who have custody of grandchildren should understand the dynamics of the relationship, the possibility of caregiver burden, provide anticipatory guidance about the changes in child care and child healthcare in the 21st century, and help link grandmothers who have little support to community programs.

  15. Intestinal Barrier and Behavior.

    PubMed

    Julio-Pieper, M; Bravo, J A

    2016-01-01

    The intestinal barrier function contributes to gut homeostasis by modulating absorption of water, electrolytes, and nutrients from the lumen into the circulation while restricting the passage of noxious luminal substances and microorganisms. Chronic conditions such as rheumatoid arthritis, inflammatory bowel disease, and celiac disease are associated to intestinal barrier dysfunction. Here, the hypothesis is that a leaky intestinal wall allowing for indiscriminate passage of intraluminal compounds to the vascular compartment could in turn lead to systemic inflammation. An increasing number of studies are now investigating the association between gut permeability and CNS disorders, under the premise that translocation of intestinal luminal contents could affect CNS function, either directly or indirectly. Still, it is unknown whether disruption of intestinal barrier is a causative agent or a consequence in these situations. Here, we discuss the latest evidence pointing to an association between increased gut permeability and disrupted behavioral responses.

  16. Paneth cell marker expression in intestinal villi and colon crypts characterizes dietary induced risk for mouse sporadic intestinal cancer.

    PubMed

    Wang, Donghai; Peregrina, Karina; Dhima, Elena; Lin, Elaine Y; Mariadason, John M; Augenlicht, Leonard H

    2011-06-21

    Nutritional and genetic risk factors for intestinal tumors are additive on mouse tumor phenotype, establishing that diet and genetic factors impact risk by distinct combinatorial mechanisms. In a mouse model of dietary-induced sporadic small and large intestinal cancer in WT mice in which tumor etiology, lag, incidence, and frequency reflect >90% of intestinal cancer in Western societies, dietary-induced risk altered gene expression profiles predominantly in villus cells of the histologically normal mucosa, in contrast to targeting of crypt cells by inheritance of an Apc(1638N) allele or homozygous inactivation of p21(Waf1/cip1), and profiles induced by each risk factor were distinct at the gene or functional group level. The dietary-induced changes in villus cells encompassed ectopic expression of Paneth cell markers (a lineage normally confined to the bottom of small intestinal crypts), elevated expression of the Wnt receptor Fzd5 and of EphB2 (genes necessary for Paneth cell differentiation and localization to the crypt bottom), and increased Wnt signaling in villus cells. Ectopic elevation of these markers was also present in the colon crypts, which are also sites of sporadic tumors in the nutritional model. Elevating dietary vitamin D(3) and calcium, which prevents tumor development, abrogated these changes in the villus and colon cells. Thus, common intestinal cancer driven by diet involves mechanisms of tumor development distinct from those mechanisms that cause tumors induced by the rare inheritance of a mutant adenomatous polyposis coli (Apc) allele. This is fundamental for understanding how common sporadic tumors arise and in evaluating relative risk in the population.

  17. Overlooking Informal Dementia Caregivers' Burden.

    PubMed

    Riedel, Oliver; Klotsche, Jens; Wittchen, Hans-Ulrich

    2016-07-01

    Patients with Alzheimer's disease (AD) need early caregiver support. Caregivers often have poor health, but usually do not have time to seek medical advice for their own conditions. Patients' physicians, who are frequently the sole medical practitioner caregivers contact regularly, have an important function in recognizing family caregivers' burdens. The current study investigated to what extent medical practitioners recognized family caregivers' problems. In a two-staged survey in neurology outpatient care, caregivers of patients with mild or moderate AD were enrolled and assessed by physicians regarding their physical and mental burden, as well as need for help and advice about AD. Subsequently, caregivers' mental health was evaluated in a comprehensive diagnostic interview by blinded psychologists. Overall, 73.7% of caregivers had at least one somatic condition and 43.7% had clinically relevant depressive symptoms (of these, 37.5% met criteria for major depression). The findings suggest that the burden of a substantial proportion of affected family caregivers is overlooked. [Res Gerontol Nurs. 2016; 9(4):167-174.]. Copyright 2016, SLACK Incorporated.

  18. Burden of epilepsy in Colombia.

    PubMed

    Méndez-Ayala, Alejandro; Nariño, Daniel; Rosselli, Diego

    2015-01-01

    Epilepsy lays an important burden on healthcare systems and society in general. Disability adjusted life years (DALYs) have been developed to compare the burden of this disease both between conditions and between geographical boundaries. With improving data on disease incidence and prevalence in Colombia, we can refine our DALYs-based estimates. Using different strategies, including the official healthcare provision database and death certificates, as well as extrapolation from published neuroepidemiologic studies, we estimated the incidence and prevalence by age groups, disease duration and attributable mortality. With this information we calculated DALYs for the year 2012. Overall, it was found that epilepsy was responsible for 0.88% of all deaths in Colombia. A total of 5.25 DALYs per 1,000 person-years are lost due to epilepsy in Colombia, 75% of which (3.91 DALYs) are due to premature mortality, with a higher burden in men (6.12 DALYs) than in women (4.41 DALYs). We reported new estimations on epilepsy incidence and prevalence by age groups in Colombia and conclude that DALYs lost due to epilepsy in Colombia are almost double the previous figure, mostly because of the underestimation of attributable mortality. With this figure, epilepsy ranks 12th instead of 19th in the list of the most important causes of DALYs lost. © 2015 S. Karger AG, Basel.

  19. Intestinal histoplasmosis in immunocompetent adults

    PubMed Central

    Zhu, Lin-Lin; Wang, Jin; Wang, Zi-Jing; Wang, Yi-Ping; Yang, Jin-Lin

    2016-01-01

    AIM: To present a retrospective analysis of clinical and endoscopic features of 4 cases of immunocompetent hosts with intestinal histoplasmosis (IH). METHODS: Four immunocompetent adults were diagnosed with IH between October 2005 and March 2015 at West China Hospital of Sichuan University. Clinical and endoscopic characteristics were summarized and analyzed retrospectively. GMS (Gomori methenamine silver), PAS (periodic acid-Schiff) and Giemsa staining technique were used to confirm Histoplasma capsulatum(H. capsulatum). The symptoms, signs, endoscopic presentations, radiographic imaging, pathological stain results and follow-up are presented as tables and illustrations. RESULTS: The cases were male patients, ranging from 33 to 61 years old, and primarily presented with non-specific symptoms such as irregular fever, weight loss, abdominal pain and distention. Hepatosplenomegaly and lymphadenopathy were the most common signs. Endoscopic manifestations were localized or diffuse congestion, edema, ulcers, and polypoid nodules with central erosion involving the terminal ileum, ascending colon, transverse colon, descending colon, sigmoid colon and rectum, similar to intestinal tuberculosis, tumor, and inflammatory bowel disease. Numerous yeast-like pathogens testing positive for PAS and GMS stains but negative for Giemsa were detected in the cytoplasm of the histiocytes, which were highly suggestive of H. capsulatum. CONCLUSION: Immunocompetent individuals suffering from histoplasmosis are rarely reported. It is necessary that gastroenterologists and endoscopists consider histoplasmosis as a differential diagnosis, even in immunocompetent patients. PMID:27099446

  20. Intestinal histoplasmosis in immunocompetent adults.

    PubMed

    Zhu, Lin-Lin; Wang, Jin; Wang, Zi-Jing; Wang, Yi-Ping; Yang, Jin-Lin

    2016-04-21

    To present a retrospective analysis of clinical and endoscopic features of 4 cases of immunocompetent hosts with intestinal histoplasmosis (IH). Four immunocompetent adults were diagnosed with IH between October 2005 and March 2015 at West China Hospital of Sichuan University. Clinical and endoscopic characteristics were summarized and analyzed retrospectively. GMS (Gomori methenamine silver), PAS (periodic acid-Schiff) and Giemsa staining technique were used to confirm Histoplasma capsulatum(H. capsulatum). The symptoms, signs, endoscopic presentations, radiographic imaging, pathological stain results and follow-up are presented as tables and illustrations. The cases were male patients, ranging from 33 to 61 years old, and primarily presented with non-specific symptoms such as irregular fever, weight loss, abdominal pain and distention. Hepatosplenomegaly and lymphadenopathy were the most common signs. Endoscopic manifestations were localized or diffuse congestion, edema, ulcers, and polypoid nodules with central erosion involving the terminal ileum, ascending colon, transverse colon, descending colon, sigmoid colon and rectum, similar to intestinal tuberculosis, tumor, and inflammatory bowel disease. Numerous yeast-like pathogens testing positive for PAS and GMS stains but negative for Giemsa were detected in the cytoplasm of the histiocytes, which were highly suggestive of H. capsulatum. Immunocompetent individuals suffering from histoplasmosis are rarely reported. It is necessary that gastroenterologists and endoscopists consider histoplasmosis as a differential diagnosis, even in immunocompetent patients.

  1. Intestinal permeability, leaky gut, and intestinal disorders.

    PubMed

    Hollander, D

    1999-10-01

    A major task of the intestine is to form a defensive barrier to prevent absorption of damaging substances from the external environment. This protective function of the intestinal mucosa is called permeability. Clinicians can use inert, nonmetabolized sugars such as mannitol, rhamnose, or lactulose to measure the permeability barrier or the degree of leakiness of the intestinal mucosa. Ample evidence indicates that permeability is increased in most patients with Crohn's disease and in 10% to 20% of their clinically healthy relatives. The abnormal leakiness of the mucosa in Crohn's patients and their relatives can be greatly amplified by aspirin preadministration. Permeability measurements in Crohn's patients reflect the activity, extent, and distribution of the disease and may allow us to predict the likelihood of recurrence after surgery or medically induced remission. Permeability is also increased in celiac disease and by trauma, burns, and nonsteroidal anti-inflammatory drugs. The major determinant of the rate of intestinal permeability is the opening or closure of the tight junctions between enterocytes in the paracellular space. As we broaden our understanding of the mechanisms and agents that control the degree of leakiness of the tight junctions, we will be increasingly able to use permeability measurements to study the etiology and pathogenesis of various disorders and to design or monitor therapies for their management.

  2. Reproducibility of Residual Cancer Burden For Prognostic Assessment of Breast Cancer After Neoadjuvant Chemotherapy

    PubMed Central

    Peintinger, Florentia; Sinn, Bruno; Hatzis, Christos; Albarracin, Constance; Downs-Kelly, Erinn; Morkowski, Jerzy; Gould, Rebekah; Symmans, W. Fraser

    2016-01-01

    The residual cancer burden index was developed as a method to quantify residual disease ranging from pathological complete response to extensive residual disease. The aim of this study was to evaluate the inter-pathologist reproducibility in the residual cancer burden index score and category, and in their long-term prognostic utility. Pathology slides and pathology reports from 100 cases selected at random from patients treated in a randomized neoadjuvant trial were reviewed independently by five pathologists at M.D Anderson Cancer Center without prior coaching. Size of tumor bed, average percent overall tumor cellularity, average percent of the in situ cancer within the tumor bed, size of largest axillary metastasis and number of involved nodes were assessed separately by each pathologist and residual cancer burden categories were assigned to each case following calculation of the numerical residual cancer burden index score. Inter-pathologist agreement in the assessment of the continuous residual cancer burden score and its components and agreement in the residual cancer burden category assignments were evaluated and analyzed. The overall concordance correlation coefficient for the agreement in residual cancer burden score among all five pathologists was 0.931 (95% Confidence Interval 0.908 – 0.949). Overall accuracy of the residual cancer burden score determination was 0.989. The kappa coefficient for overall agreement in the residual cancer burden category assignments was 0.583 (95% Confidence Interval 0.539 – 0.626), indicating good overall inter-pathologist agreement. The metastatic component of the residual cancer burden index showed stronger concordance between pathologists (overall concordance correlation coefficient = 0.980; 95% Confidence Interval 0.954 – 0.992), than the primary component (overall concordance correlation coefficient = 0.795; 95% Confidence Interval 0.716 – 0.853). At a median follow-up of 12 years residual cancer burden

  3. Biochemistry of intestinal development.

    PubMed Central

    Henning, S J

    1979-01-01

    In biochemical terms, the rat small intestine is relatively immature at birth and for the first two postnatal weeks. Then during the third week a dramatic array of enzymic changes begins, and by the end of the fourth week the intestine has the digestive and absorptive properties of the adult. Selective examples of these changes are discussed with emphasis on their implications for toxicological studies. The review also includes a detailed consideration of the roles of the dietary change of weaning and of glucocorticoid and thyroid hormones in the regulation of intestinal development. PMID:575507

  4. [Intestinal and hepatic parasitic diseases: diagnosis and treatment].

    PubMed

    Gétaz, L; Chappuis, F; Loutan, L

    2007-05-16

    Intestinal parasites represent an important burden of disease mainly in developing countries. Physicians practicing in Europe can be exposed to these diseases, mainly seen in immigrants or travellers returning from tropical countries. Several parasitic diseases remain ubiquitous and can be contracted in developed countries. Most often, parasitic infections cause no or only few symptoms, but some can lead to serious disease in immuno-compromised patients. Diagnostic procedures and treatments available are discussed.

  5. Burden of major musculoskeletal conditions.

    PubMed Central

    Woolf, Anthony D.; Pfleger, Bruce

    2003-01-01

    Musculoskeletal conditions are a major burden on individuals, health systems, and social care systems, with indirect costs being predominant. This burden has been recognized by the United Nations and WHO, by endorsing the Bone and Joint Decade 2000-2010. This paper describes the burden of four major musculoskeletal conditions: osteoarthritis, rheumatoid arthritis, osteoporosis, and low back pain. Osteoarthritis, which is characterized by loss of joint cartilage that leads to pain and loss of function primarily in the knees and hips, affects 9.6% of men and 18% of women aged > 60 years. Increases in life expectancy and ageing populations are expected to make osteoarthritis the fourth leading cause of disability by the year 2020. Joint replacement surgery, where available, provides effective relief. Rheumatoid arthritis is an inflammatory condition that usually affects multiple joints. It affects 0.3-1.0% of the general population and is more prevalent among women and in developed countries. Persistent inflammation leads to joint destruction, but the disease can be controlled with drugs. The incidence may be on the decline, but the increase in the number of older people in some regions makes it difficult to estimate future prevalence. Osteoporosis, which is characterized by low bone mass and microarchitectural deterioration, is a major risk factor for fractures of the hip, vertebrae, and distal forearm. Hip fracture is the most detrimental fracture, being associated with 20% mortality and 50% permanent loss in function. Low back pain is the most prevalent of musculoskeletal conditions; it affects nearly everyone at some point in time and about 4-33% of the population at any given point. Cultural factors greatly influence the prevalence and prognosis of low back pain. PMID:14710506

  6. Small area population disease burden.

    PubMed

    Taylor, R

    2001-08-01

    Small area health statistics has assumed increasing importance as the focus of population and public health moves to a more individualised approach of smaller area populations. Small populations and low event occurrence produce difficulties in interpretation and require appropriate statistical methods, including for age adjustment. There are also statistical questions related to multiple comparisons. Privacy and confidentiality issues include the possibility of revealing information on individuals or health care providers by fine cross-tabulations. Interpretation of small area population differences in health status requires consideration of migrant and Indigenous composition, socioeconomic status and rural-urban geography before assessment of the effects of physical environmental exposure and services and interventions. Burden of disease studies produce a single measure for morbidity and mortality--disability adjusted life year (DALY)--which is the sum of the years of life lost (YLL) from premature mortality and the years lived with disability (YLD) for particular diseases (or all conditions). Calculation of YLD requires estimates of disease incidence (and complications) and duration, and weighting by severity. These procedures often mean problematic assumptions, as does future discounting and age weighting of both YLL and YLD. Evaluation of the Victorian small area population disease burden study presents important cross-disciplinary challenges as it relies heavily on synthetic approaches of demography and economics rather than on the empirical methods of epidemiology. Both empirical and synthetic methods are used to compute small area mortality and morbidity, disease burden, and then attribution to risk factors. Readers need to examine the methodology and assumptions carefully before accepting the results.

  7. 45 CFR 672.17 - Burden of presentation; burden of persuasion.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 45 Public Welfare 3 2010-10-01 2010-10-01 false Burden of presentation; burden of persuasion. 672.17 Section 672.17 Public Welfare Regulations Relating to Public Welfare (Continued) NATIONAL SCIENCE FOUNDATION ENFORCEMENT AND HEARING PROCEDURES § 672.17 Burden of presentation; burden of persuasion. The...

  8. Burden of disease: psoriasis and psoriatic arthritis.

    PubMed

    Boehncke, Wolf-Henning; Menter, Alan

    2013-10-01

    Psoriatic arthritis (PsA) increases the disease burden associated with psoriasis by further diminishing quality of life, increasing health care costs and cardiovascular risk, and potentially causing progressive joint damage. The presence of PsA influences psoriasis treatment by increasing overall disease complexity and, within the framework of current guidelines and recommendations, requiring the use of conventional disease-modifying anti-rheumatic drugs or tumor necrosis factor-α inhibitors in order to prevent progressive joint damage. Despite its important impact, PsA is still under-diagnosed in dermatology practice. Dermatologists are well positioned to recognize and treat PsA, given that it characteristically presents, on average, 10 years subsequent to the appearance of skin symptoms. Regular screening of psoriasis patients for early evident joint symptoms should be incorporated into daily dermatologic practice. Although drugs effective in PsA are available, not all patients may respond to treatment, and others may lose their initial response over time. New investigational therapies, such as inhibitors of interleukin-17A, interleukin-12/23, Janus kinase 3, or phosphodiesterase-4, may address unmet needs in psoriatic disease, with further research needed to determine the role of these agents in reducing joint damage and other comorbidities.

  9. Predicted burden of venous disease.

    PubMed

    Onida, Sarah; Davies, Alun Huw

    2016-03-01

    Chronic venous disease is a common condition with clinical signs and symptoms ranging from spider veins, to varicose veins, to active venous ulceration. Both superficial and deep venous dysfunction may be implicated in the development of this disease. Socio-economic factors are shaping our population, with increasing age and body mass index resulting in significant pressure on healthcare systems worldwide. These risk factors also lead to an increased risk of developing superficial and/or deep venous insufficiency, increasing disease prevalence and morbidity. In this chapter, the authors review the current and future burden of chronic venous disease from an epidemiological, quality of life and economic perspective.

  10. Intestinal Complications of IBD

    MedlinePlus

    ... that only affects the colon). LOCAL COMPLICATIONS OF CROHN’S DISEASE INTESTINAL OBSTRUCTION The most common complication of Crohn’s disease, obstruction may arise from swelling and the formation ...

  11. Intestinal pseudo-obstruction

    MedlinePlus

    ... Taking drugs that slow intestinal movements. These include narcotic (pain) medicines and drugs used when you are ... that may have caused the problem (such as narcotic drugs) may help. In severe cases, surgery may ...

  12. Global Burden of Childhood Tuberculosis.

    PubMed

    Jenkins, Helen E

    2016-01-01

    In 2015, the World Health Organization (WHO) declared tuberculosis (TB) to be responsible for more deaths than any other single infectious disease. The burden of TB among children has frequently been dismissed as relatively low with resulting deaths contributing very little to global under-five all-cause mortality, although without rigorous estimates of these statistics, the burden of childhood TB was, in reality, unknown. Recent work in the area has resulted in a WHO estimate of 1 million new cases of childhood TB in 2014 resulting in 136,000 deaths. Around 3% of these cases likely have multidrug-resistant TB and at least 40,000 are in HIV-infected children. TB is now thought to be a major or contributory cause of many deaths in children under five years old, despite not being recorded as such, and is likely in the top ten causes of global mortality in this age group. In particular, recent work has shown that TB is an under-lying cause of a substantial proportion of pneumonia deaths in TB-endemic countries. Childhood TB should be given higher priority: we need to identify children at greatest risk of TB disease and death and make more use of tools such as active case-finding and preventive therapy. TB is a preventable and treatable disease from which no child should die.

  13. Global Burden of Childhood Tuberculosis

    PubMed Central

    Jenkins, Helen E.

    2016-01-01

    In 2015, the World Health Organization (WHO) declared tuberculosis (TB) to be responsible for more deaths than any other single infectious disease. The burden of TB among children has frequently been dismissed as relatively low with resulting deaths contributing very little to global under-five all-cause mortality, although without rigorous estimates of these statistics, the burden of childhood TB was, in reality, unknown. Recent work in the area has resulted in a WHO estimate of 1 million new cases of childhood TB in 2014 resulting in 136,000 deaths. Around 3% of these cases likely have multidrug-resistant TB and at least 40,000 are in HIV-infected children. TB is now thought to be a major or contributory cause of many deaths in children under five years old, despite not being recorded as such, and is likely in the top ten causes of global mortality in this age group. In particular, recent work has shown that TB is an under-lying cause of a substantial proportion of pneumonia deaths in TB-endemic countries. Childhood TB should be given higher priority: we need to identify children at greatest risk of TB disease and death and make more use of tools such as active case-finding and preventive therapy. TB is a preventable and treatable disease from which no child should die. PMID:28003956

  14. Intestinal parasitic infection.

    PubMed

    Park, Mi-Suk; Kim, Ki Whang; Ha, Hyun Kwon; Lee, Dong Ho

    2008-01-01

    In general, gastrointestinal tract is the primary involvement site of parasites during their life cycle. In this article, we will describe amebiasis, ascariasis, and anisakiasis among the many common intestinal parasitic diseases. We will review the epidemiology, life cycles, clinical manifestations and complications, and illustrate detailed imaging findings of intestinal parasites. Recognizing features of parasitic infection is important to establish an early diagnosis that leads to prompt treatment and helps avoid unnecessary surgery.

  15. Intestinal adaptation following resection.

    PubMed

    Tappenden, Kelly A

    2014-05-01

    Intestinal adaptation is a natural compensatory process that occurs following extensive intestinal resection, whereby structural and functional changes in the intestine improve nutrient and fluid absorption in the remnant bowel. In animal studies, postresection structural adaptations include bowel lengthening and thickening and increases in villus height and crypt depth. Functional changes include increased nutrient transporter expression, accelerated crypt cell differentiation, and slowed transit time. In adult humans, data regarding adaptive changes are sparse, and the mechanisms underlying intestinal adaptation remain to be fully elucidated. Several factors influence the degree of intestinal adaptation that occurs post resection, including site and extent of resection, luminal stimulation with enteral nutrients, and intestinotrophic factors. Two intestinotrophic growth factors, the glucagon-like peptide 2 analog teduglutide and recombinant growth hormone (somatropin), are now approved for clinical use in patients with short bowel syndrome (SBS). Both agents enhance fluid absorption and decrease requirements for parenteral nutrition (PN) and/or intravenous fluid. Intestinal adaptation has been thought to be limited to the first 1-2 years following resection in humans. However, recent data suggest that a significant proportion of adult patients with SBS can achieve enteral autonomy, even after many years of PN dependence, particularly with trophic stimulation.

  16. Claudins in intestines

    PubMed Central

    Lu, Zhe; Ding, Lei; Lu, Qun; Chen, Yan-Hua

    2013-01-01

    Intestines are organs that not only digest food and absorb nutrients, but also provide a defense barrier against pathogens and noxious agents ingested. Tight junctions (TJs) are the most apical component of the junctional complex, providing one form of cell-cell adhesion in enterocytes and playing a critical role in regulating paracellular barrier permeability. Alteration of TJs leads to a number of pathophysiological diseases causing malabsorption of nutrition and intestinal structure disruption, which may even contribute to systemic organ failure. Claudins are the major structural and functional components of TJs with at least 24 members in mammals. Claudins have distinct charge-selectivity, either by tightening the paracellular pathway or functioning as paracellular channels, regulating ions and small molecules passing through the paracellular pathway. In this review, we have discussed the functions of claudin family members, their distribution and localization in the intestinal tract of mammals, their alterations in intestine-related diseases and chemicals/agents that regulate the expression and localization of claudins as well as the intestinal permeability, which provide a therapeutic view for treating intestinal diseases. PMID:24478939

  17. High fat diet enhances stemness and tumorigenicity of intestinal progenitors

    PubMed Central

    Beyaz, Semir; Mana, Miyeko D.; Roper, Jatin; Kedrin, Dmitriy; Saadatpour, Assieh; Hong, Sue-Jean; Bauer-Rowe, Khristian E.; Xifaras, Michael E.; Akkad, Adam; Arias, Erika; Pinello, Luca; Katz, Yarden; Shinagare, Shweta; Abu-Remaileh, Monther; Mihaylova, Maria M.; Lamming, Dudley W.; Dogum, Rizkullah; Guo, Guoji; Bell, George W.; Selig, Martin; Nielsen, G. Petur; Gupta, Nitin; Ferrone, Cristina R.; Deshpande, Vikram; Yuan, Guo-Cheng; Orkin, Stuart H.; Sabatini, David M.; Yilmaz, Ömer H.

    2016-01-01

    Little is known about how pro-obesity diets regulate tissue stem and progenitor cell function. Here we find that high fat diet (HFD)-induced obesity augments the numbers and function of Lgr5+ intestinal stem-cells (ISCs) of the mammalian intestine. Mechanistically, HFD induces a robust peroxisome proliferator-activated receptor delta (PPAR-d) signature in intestinal stem and (non-ISC) progenitor cells, and pharmacologic activation of PPAR-d recapitulates the effects of a HFD on these cells. Like a HFD, ex vivo treatment of intestinal organoid cultures with fatty acid constituents of the HFD enhances the self-renewal potential of these organoid bodies in a PPAR-d dependent manner. Interestingly, HFD- and agonist-activated PPAR-d signaling endow organoid-initiating capacity to progenitors, and enforced PPAR-d signaling permits these progenitors to form in vivo tumors upon loss of the tumor suppressor Apc. These findings highlight how diet-modulated PPAR-d activation alters not only the function of intestinal stem and progenitor cells, but also their capacity to initiate tumors. PMID:26935695

  18. Clinicopathological characteristics of duodenal epithelial neoplasms: Focus on tumors with a gastric mucin phenotype (pyloric gland-type tumors)

    PubMed Central

    Mitsuishi, Takehiro; Hamatani, Shigeharu; Hirooka, Shinichi; Fukasawa, Nei; Aizawa, Daisuke; Hara, Yuko; Dobashi, Akira; Goda, Kenichi; Fukuda, Takahiro; Saruta, Masayuki; Urashima, Mitsuyoshi; Ikegami, Masahiro

    2017-01-01

    Objective Epithelial tumors less commonly occur in the duodenum than in the stomach or large intestine. The clinicopathological characteristics of duodenal epithelial tumors remain a matter of debate. We therefore studied resected specimens to investigate the clinicopathological characteristics of duodenal epithelial tumors. Materials and methods Among duodenal epithelial tumors resected endoscopically or surgically in our hospital, we studied the clinicopathological characteristics of 110 adenomas or intramucosal carcinomas. The grade of atypia of all tumors was classified into 3 groups according to the World Health Organization (WHO) 2010 classification. The tumors were immunohistochemically evaluated to determine the frequency of differentiation toward fundic glands. Results As for patient characteristics, there were 76 men (75.2%) and 25 women (24.8%), with a median age of 65 years (range, 34 to 84). The tumors most commonly arose in the first to second part of the duodenum. Many lesions were flat, and the median tumor diameter was 8.0 mm. The lesions were classified into 2 types according to mucin phenotype: intestinal-type tumors (98 lesions, 89.1%) and gastric-type tumors (12 lesions, 10.9%). Intestinal-type tumors were subdivided into 2 groups: tubular-type tumors (91 lesions, 82.7%) and tubulovillous-type tumors (7 lesions, 6.4%). Gastric-type tumors were classified into 2 types: foveolar type (3 lesions, 2.7%) and pyloric gland-type (PG) tumors (9 lesions, 8.2%). The grade of atypia was significantly higher in gastric-type tumors (p<0.01). PG tumors were gastric-type tumors characterized by pyloric glands and findings suggesting differentiation toward fundic glands. Conclusions About 10% of the duodenal tumors had a gastric-type mucin phenotype. Gastric-type tumors showed high-grade atypia. In particular, PG tumors showed similarities to PG tumors of the stomach, such as differentiation toward fundic glands. PMID:28376132

  19. Intestinal Stem Cell Markers in the Intestinal Metaplasia of Stomach and Barrett's Esophagus.

    PubMed

    Jang, Bo Gun; Lee, Byung Lan; Kim, Woo Ho

    2015-01-01

    Gastric intestinal metaplasia (IM) is a highly prevalent preneoplastic lesion; however, the molecular mechanisms regulating its development remain unclear. We have previously shown that a population of cells expressing the intestinal stem cell (ISC) marker LGR5 increases remarkably in IM. In this study, we further investigated the molecular characteristics of these LGR5+ cells in IM by examining the expression profile of several ISC markers. Notably, we found that ISC markers-including OLFM4 and EPHB2-are positively associated with the CDX2 expression in non-tumorous gastric tissues. This finding was confirmed in stomach lesions with or without metaplasia, which demonstrated that OLFM4 and EPHB2 expression gradually increased with metaplastic progression. Moreover, RNA in situ hybridization revealed that LGR5+ cells coexpress several ISC markers and remained confined to the base of metaplastic glands, reminiscent to that of normal intestinal crypts, whereas those in normal antral glands expressed none of these markers. Furthermore, a large number of ISC marker-expressing cells were diffusely distributed in gastric adenomas, suggesting that these markers may facilitate gastric tumorigenesis. In addition, Barrett's esophagus (BE)-which is histologically similar to intestinal metaplasia-exhibited a similar distribution of ISC markers, indicating the presence of a stem cell population with intestinal differentiation potential. In conclusion, we identified that LGR5+ cells in gastric IM and BE coexpress ISC markers, and exhibit the same expression profile as those found in normal intestinal crypts. Taken together, these results implicate an intestinal-like stem cell population in the pathogenesis of IM, and provide an important basis for understanding the development and maintenance of this disease.

  20. Fluorescence imaging to study cancer burden on lymph nodes

    NASA Astrophysics Data System (ADS)

    D'Souza, Alisha V.; Elliott, Jonathan T.; Gunn, Jason R.; Samkoe, Kimberley S.; Tichauer, Kenneth M.; Pogue, Brian W.

    2015-03-01

    Morbidity and complexity involved in lymph node staging via surgical resection and biopsy calls for staging techniques that are less invasive. While visible blue dyes are commonly used in locating sentinel lymph nodes, since they follow tumor-draining lymphatic vessels, they do not provide a metric to evaluate presence of cancer. An area of active research is to use fluorescent dyes to assess tumor burden of sentinel and secondary lymph nodes. The goal of this work was to successfully deploy and test an intra-nodal cancer-cell injection model to enable planar fluorescence imaging of a clinically relevant blue dye, specifically methylene blue along with a cancer targeting tracer, Affibody labeled with IRDYE800CW and subsequently segregate tumor-bearing from normal lymph nodes. This direct-injection based tumor model was employed in athymic rats (6 normal, 4 controls, 6 cancer-bearing), where luciferase-expressing breast cancer cells were injected into axillary lymph nodes. Tumor presence in nodes was confirmed by bioluminescence imaging before and after fluorescence imaging. Lymphatic uptake from the injection site (intradermal on forepaw) to lymph node was imaged at approximately 2 frames/minute. Large variability was observed within each cohort.

  1. The deubiquitinase USP28 controls intestinal homeostasis and promotes colorectal cancer

    PubMed Central

    Diefenbacher, Markus E.; Popov, Nikita; Blake, Sophia M.; Schülein-Völk, Christina; Nye, Emma; Spencer-Dene, Bradley; Jaenicke, Laura A.; Eilers, Martin; Behrens, Axel

    2014-01-01

    Colorectal cancer is the third most common cancer worldwide. Although the transcription factor c-MYC is misregulated in the majority of colorectal tumors, it is difficult to target directly. The deubiquitinase USP28 stabilizes oncogenic factors, including c-MYC; however, the contribution of USP28 in tumorigenesis, particularly in the intestine, is unknown. Here, using murine genetic models, we determined that USP28 antagonizes the ubiquitin-dependent degradation of c-MYC, a known USP28 substrate, as well as 2 additional oncogenic factors, c-JUN and NOTCH1, in the intestine. Mice lacking Usp28 had no apparent adverse phenotypes, but exhibited reduced intestinal proliferation and impaired differentiation of secretory lineage cells. In a murine model of colorectal cancer, Usp28 deletion resulted in fewer intestinal tumors, and importantly, in established tumors, Usp28 deletion reduced tumor size and dramatically increased lifespan. Moreover, we identified Usp28 as a c-MYC target gene highly expressed in murine and human intestinal cancers, which indicates that USP28 and c-MYC form a positive feedback loop that maintains high c-MYC protein levels in tumors. Usp28 deficiency promoted tumor cell differentiation accompanied by decreased proliferation, which suggests that USP28 acts similarly in intestinal homeostasis and colorectal cancer models. Hence, inhibition of the enzymatic activity of USP28 may be a potential target for cancer therapy. PMID:24960159

  2. Intestinal lymphangiectasia in adults.

    PubMed

    Freeman, Hugh James; Nimmo, Michael

    2011-02-15

    Intestinal lymphangiectasia in the adult may be characterized as a disorder with dilated intestinal lacteals causing loss of lymph into the lumen of the small intestine and resultant hypoproteinemia, hypogammaglobulinemia, hypoalbuminemia and reduced number of circulating lymphocytes or lymphopenia. Most often, intestinal lymphangiectasia has been recorded in children, often in neonates, usually with other congenital abnormalities but initial definition in adults including the elderly has become increasingly more common. Shared clinical features with the pediatric population such as bilateral lower limb edema, sometimes with lymphedema, pleural effusion and chylous ascites may occur but these reflect the severe end of the clinical spectrum. In some, diarrhea occurs with steatorrhea along with increased fecal loss of protein, reflected in increased fecal alpha-1-antitrypsin levels, while others may present with iron deficiency anemia, sometimes associated with occult small intestinal bleeding. Most lymphangiectasia in adults detected in recent years, however, appears to have few or no clinical features of malabsorption. Diagnosis remains dependent on endoscopic changes confirmed by small bowel biopsy showing histological evidence of intestinal lymphangiectasia. In some, video capsule endoscopy and enteroscopy have revealed more extensive changes along the length of the small intestine. A critical diagnostic element in adults with lymphangiectasia is the exclusion of entities (e.g. malignancies including lymphoma) that might lead to obstruction of the lymphatic system and "secondary" changes in the small bowel biopsy. In addition, occult infectious (e.g. Whipple's disease from Tropheryma whipplei) or inflammatory disorders (e.g. Crohn's disease) may also present with profound changes in intestinal permeability and protein-losing enteropathy that also require exclusion. Conversely, rare B-cell type lymphomas have also been described even decades following initial

  3. Mechanical intestinal obstruction secondary to appendiceal mucinous cystadenoma

    PubMed Central

    Xu, Zheng-shui; Xu, Wei; Ying, Jia-qi; Cheng, Hua

    2017-01-01

    Abstract Background: Appendiceal mucinous cystadenoma can present in various ways, and it is most commonly encountered incidentally during appendectomy, but mechanical intestinal obstruction secondary to an appendiceal mucocele has been rarely reported. Methods: We report a case of mechanical intestinal obstruction secondary to appendiceal mucinous cystadenoma. After nasogastric decompression and initial aggressive intravenous fluid resuscitation, an emergency operation was performed under the diagnosis of acute mechanical intestinal obstruction. Results: We performed an appendectomy and intraoperative enteral decompression without anastomoses. The pathologic examination (PE) revealed appendiceal mucinous cystadenoma. After the operation, the patient's recovery went smoothly, and the patient was discharged on the fifth postoperative day. No tumor recurrence was recorded over an 8 month follow-up period. Conclusion: Early operative intervention should be recommended to the patient with acute mechanical complete intestinal obstruction, especially the patient who had no previous abdominal surgery. And it is vital to discriminate benign and malignantappendiceal mucocel in determining the extent of surgery. PMID:28151903

  4. Obscure gastrointestinal bleeding due to multifocal intestinal angiosarcoma

    PubMed Central

    Navarro-Chagoya, Dolores; Figueroa-Ruiz, Marco; López-Gómez, Javier; Nava-Leyva, Héctor; Álvarez-Ponce, Carlos Eduardo; Guzmán-Sombrero, Gustavo; Velazquez-Garcia, José

    2015-01-01

    Introduction Intestinal angiosarcomas are an extremely rare and aggressive vascular tumors, with a few cases reported in the literature. Presentation of case A 45 years-old male arrived to our hospital with intermittent gastrointestinal bleeding presenting melena and weight loss, he has antecedent of pelvic radiotherapy ten years before admission for an unknown pelvic tumor. Emergency surgery was required because of uncontrolled bleeding and hemodynamic instability. Histopathological findings revealed a multifocal high-grade epithelioid angiosarcoma, with cells reactive for CD31, keratins CKAE 1/AE3 and factor VIII. Discussion Angiosarcomas are aggressive tumors with a high rate of lymph node metastasis and peripheral organs. The diagnosis is difficult because it present nonspecific clinical presentation, radiological and histopathological findings. There are few reports of angiosarcoma involving the small intestine and the most common presentation are abdominal pain and gastrointestinal bleeding. There is not enough information for intestinal angiosarcoma secondary to radiation therapy, but there have been proposed criteria for diagnosis: no microscopic or clinical evidence of antecedent malignant lesion, angiosarcoma presented in the field of irradiation, long latency period between radiation and angiosarcoma and histological confirmation. We suspect our patient course with a secondary form of angiosarcoma. Therapy for bleeding angiosarcoma consists in control of bleeding and medical management to stabilize the patient. Once accomplished surgical resection is required. Conclusion We should keep in mind this tumors as a cause of obscure intestinal bleeding in patients with medical history of radiation therapy. PMID:25853844

  5. Burden of stroke in Malaysia.

    PubMed

    Loo, Keat Wei; Gan, Siew Hua

    2012-02-01

    Stroke is one of the top five leading causes of death and one of the top 10 causes for hospitalization in Malaysia. Stroke is also in the top five diseases with the greatest burden of disease, based on disability-adjusted life years. However, prospective studies on stroke in Malaysia are limited. To date, neither the prevalence of stroke nor its incidence nationally has been recorded. Hypertension is the major risk factor for stroke. The mean age of stroke patients in Malaysia is between 54.5 and 62.6 years. Traditional medicine is commonly practiced. With the increasing number of stroke cases annually, more government and nongovernment organizations should be involved in primary and secondary prevention strategies.

  6. The intestine is a blender

    NASA Astrophysics Data System (ADS)

    Yang, Patricia; Lamarca, Morgan; Kravets, Victoria; Hu, David

    According to the U.S. Department of Health and Human Services, digestive disease affects 60 to 70 million people and costs over 140 billion annually. Despite the significance of the gastrointestinal tract to human health, the physics of digestion remains poorly understood. In this study, we ask a simple question: what sets the frequency of intestinal contractions? We measure the frequency of intestinal contractions in rats, as a function of distance down the intestine. We find that intestines Contract radially ten times faster than longitudinally. This motion promotes mixing and, in turn, absorption of food products by the intestinal wall. We calculate viscous dissipation in the intestinal fluid to rationalize the relationship between frequency of intestinal contraction and the viscosity of the intestinal contents. Our findings may help to understand the evolution of the intestine as an ideal mixer.

  7. The intestine is a blender

    NASA Astrophysics Data System (ADS)

    Yang, Patricia; Lamarca, Morgan; Hu, David

    2015-11-01

    According to the U.S. Department of Health and Human Services, digestive disease affects 60 to 70 million people and costs over 140 billion annually. Despite the significance of the gastrointestinal tract to human health, the physics of digestion remains poorly understood. In this study, we ask a simple question: what sets the frequency of intestinal contractions? We measure the frequency of intestinal contractions in rats, as a function of distance down the intestine. We find that intestines contract radially ten times faster than longitudinally. This motion promotes mixing and, in turn, absorption of food products by the intestinal wall. We calculate viscous dissipation in the intestinal fluid to rationalize the relationship between frequency of intestinal contraction and the viscosity of the intestinal contents. Our findings may help to understand the evolution of the intestine as an ideal mixer.

  8. The global burden of cholera

    PubMed Central

    Lopez, Anna Lena; You, Young Ae; Kim, Young Eun; Sah, Binod; Maskery, Brian; Clemens, John

    2012-01-01

    Abstract Objective To estimate the global burden of cholera using population-based incidence data and reports. Methods Countries with a recent history of cholera were classified as endemic or non-endemic, depending on whether they had reported cholera cases in at least three of the five most recent years. The percentages of the population in each country that lacked access to improved sanitation were used to compute the populations at risk for cholera, and incidence rates from published studies were applied to groups of countries to estimate the annual number of cholera cases in endemic countries. The estimates of cholera cases in non-endemic countries were based on the average numbers of cases reported from 2000 to 2008. Literature-based estimates of cholera case-fatality rates (CFRs) were used to compute the variance-weighted average cholera CFRs for estimating the number of cholera deaths. Findings About 1.4 billion people are at risk for cholera in endemic countries. An estimated 2.8 million cholera cases occur annually in such countries (uncertainty range: 1.4–4.3) and an estimated 87 000 cholera cases occur in non-endemic countries. The incidence is estimated to be greatest in children less than 5 years of age. Every year about 91 000 people (uncertainty range: 28 000 to 142 000) die of cholera in endemic countries and 2500 people die of the disease in non-endemic countries. Conclusion The global burden of cholera, as determined through a systematic review with clearly stated assumptions, is high. The findings of this study provide a contemporary basis for planning public health interventions to control cholera. PMID:22461716

  9. The global burden of cholera.

    PubMed

    Ali, Mohammad; Lopez, Anna Lena; You, Young Ae; Kim, Young Eun; Sah, Binod; Maskery, Brian; Clemens, John

    2012-03-01

    To estimate the global burden of cholera using population-based incidence data and reports. Countries with a recent history of cholera were classified as endemic or non-endemic, depending on whether they had reported cholera cases in at least three of the five most recent years. The percentages of the population in each country that lacked access to improved sanitation were used to compute the populations at risk for cholera, and incidence rates from published studies were applied to groups of countries to estimate the annual number of cholera cases in endemic countries. The estimates of cholera cases in non-endemic countries were based on the average numbers of cases reported from 2000 to 2008. Literature-based estimates of cholera case-fatality rates (CFRs) were used to compute the variance-weighted average cholera CFRs for estimating the number of cholera deaths. About 1.4 billion people are at risk for cholera in endemic countries. An estimated 2.8 million cholera cases occur annually in such countries (uncertainty range: 1.4-4.3) and an estimated 87,000 cholera cases occur in non-endemic countries. The incidence is estimated to be greatest in children less than 5 years of age. Every year about 91,000 people (uncertainty range: 28,000 to 142,000) die of cholera in endemic countries and 2500 people die of the disease in non-endemic countries. The global burden of cholera, as determined through a systematic review with clearly stated assumptions, is high. The findings of this study provide a contemporary basis for planning public health interventions to control cholera.

  10. Fecal microbiota transplantation broadening its application beyond intestinal disorders

    PubMed Central

    Xu, Meng-Que; Cao, Hai-Long; Wang, Wei-Qiang; Wang, Shan; Cao, Xiao-Cang; Yan, Fang; Wang, Bang-Mao

    2015-01-01

    Intestinal dysbiosis is now known to be a complication in a myriad of diseases. Fecal microbiota transplantation (FMT), as a microbiota-target therapy, is arguably very effective for curing Clostridium difficile infection and has good outcomes in other intestinal diseases. New insights have raised an interest in FMT for the management of extra-intestinal disorders associated with gut microbiota. This review shows that it is an exciting time in the burgeoning science of FMT application in previously unexpected areas, including metabolic diseases, neuropsychiatric disorders, autoimmune diseases, allergic disorders, and tumors. A randomized controlled trial was conducted on FMT in metabolic syndrome by infusing microbiota from lean donors or from self-collected feces, with the resultant findings showing that the lean donor feces group displayed increased insulin sensitivity, along with increased levels of butyrate-producing intestinal microbiota. Case reports of FMT have also shown favorable outcomes in Parkinson’s disease, multiple sclerosis, myoclonus dystonia, chronic fatigue syndrome, and idiopathic thrombocytopenic purpura. FMT is a promising approach in the manipulation of the intestinal microbiota and has potential applications in a variety of extra-intestinal conditions associated with intestinal dysbiosis. PMID:25574083

  11. Fecal microbiota transplantation broadening its application beyond intestinal disorders.

    PubMed

    Xu, Meng-Que; Cao, Hai-Long; Wang, Wei-Qiang; Wang, Shan; Cao, Xiao-Cang; Yan, Fang; Wang, Bang-Mao

    2015-01-07

    Intestinal dysbiosis is now known to be a complication in a myriad of diseases. Fecal microbiota transplantation (FMT), as a microbiota-target therapy, is arguably very effective for curing Clostridium difficile infection and has good outcomes in other intestinal diseases. New insights have raised an interest in FMT for the management of extra-intestinal disorders associated with gut microbiota. This review shows that it is an exciting time in the burgeoning science of FMT application in previously unexpected areas, including metabolic diseases, neuropsychiatric disorders, autoimmune diseases, allergic disorders, and tumors. A randomized controlled trial was conducted on FMT in metabolic syndrome by infusing microbiota from lean donors or from self-collected feces, with the resultant findings showing that the lean donor feces group displayed increased insulin sensitivity, along with increased levels of butyrate-producing intestinal microbiota. Case reports of FMT have also shown favorable outcomes in Parkinson's disease, multiple sclerosis, myoclonus dystonia, chronic fatigue syndrome, and idiopathic thrombocytopenic purpura. FMT is a promising approach in the manipulation of the intestinal microbiota and has potential applications in a variety of extra-intestinal conditions associated with intestinal dysbiosis.

  12. Humanistic burden in schizophrenia: a literature review.

    PubMed

    Millier, A; Schmidt, U; Angermeyer, M C; Chauhan, D; Murthy, V; Toumi, M; Cadi-Soussi, N

    2014-07-01

    Schizophrenia is a complex disease that affects 1% of the population. This disease has a considerable impact not only on patients' health and well-being but also on their surrounding environment. The costs of the disease's management remain large for individuals and society. While literature on the economic impact of schizophrenia is abundant, few studies have focused on its humanistic burden. This does not only concern patients, but also caregivers, relatives, neighbours and others in a patient's daily life. This burden appears through several dimensions, including treatment side effects and the impact on caregivers and features of the patient's environment. The aim of this review is to consider, compile and describe the humanistic burden of schizophrenia as documented in the literature. We conducted a literature review assessing the worldwide disease burden of schizophrenia, taking into account all humanistic burden topics. The search considered several databases, including Embase, Medline, Cochrane Library, The German Institute of Medical Documentation and Information (DIMDI) and the ISPOR conference websites. The search identified 200 literature reviews, covering several dimensions of humanistic burden and documenting many issues. Main findings included the high death rates that may be explained by long-lasting negative health habits, disease- and treatment-related metabolic disorders, and consequent increased frequencies of cardiovascular diseases. Co-existing depression was found to have adverse consequence on the course of schizophrenia progression, morbidity and mortality. Cognitive impairment also adds to the burden of schizophrenia. Social impairment is worsened by underestimated stigmatisation and lack of corresponding awareness within the professional and social spheres. Finally, caregiver burden was found to be considerable. Humanistic burden among patients with schizophrenia is substantial potentially impacted by co-morbid depressive symptoms

  13. Intestinal and multivisceral transplantation

    PubMed Central

    Meira, Sérgio Paiva; Guardia, Bianca Della; Evangelista, Andréia Silva; Matielo, Celso Eduardo Lourenço; Neves, Douglas Bastos; Pandullo, Fernando Luis; Felga, Guilherme Eduardo Gonçalves; Alves, Jefferson André da Silva; Curvelo, Lilian Amorim; Diaz, Luiz Gustavo Guedes; Rusi, Marcela Balbo; Viveiros, Marcelo de Melo; de Almeida, Marcio Dias; Epstein, Marina Gabrielle; Pedroso, Pamella Tung; Salvalaggio, Paolo; Meirelles, Roberto Ferreira; Rocco, Rodrigo Andrey; de Almeida, Samira Scalso; de Rezende, Marcelo Bruno

    2015-01-01

    Intestinal transplantation has shown exceptional growth over the past 10 years. At the end of the 1990’s, intestinal transplantation moved out of the experimental realm to become a routine practice in treating patients with severe complications related to total parenteral nutrition and intestinal failure. In the last years, several centers reported an increasing improvement in survival outcomes (about 80%), during the first 12 months after surgery, but long-term survival is still a challenge. Several advances led to clinical application of transplants. Immunosuppression involved in intestinal and multivisceral transplantation was the biggest gain for this procedure in the past decade due to tacrolimus, and new inducing drugs, mono- and polyclonal anti-lymphocyte antibodies. Despite the advancement of rigid immunosuppression protocols, rejection is still very frequent in the first 12 months, and can result in long-term graft loss. The future of intestinal transplantation and multivisceral transplantation appears promising. The major challenge is early recognition of acute rejection in order to prevent graft loss, opportunistic infections associated to complications, post-transplant lymphoproliferative disease and graft versus host disease; and consequently, improve results in the long run. PMID:25993080

  14. Tumor Quantification in Clinical Positron Emission Tomography

    PubMed Central

    Bai, Bing; Bading, James; Conti, Peter S

    2013-01-01

    Positron emission tomography (PET) is used extensively in clinical oncology for tumor detection, staging and therapy response assessment. Quantitative measurements of tumor uptake, usually in the form of standardized uptake values (SUVs), have enhanced or replaced qualitative interpretation. In this paper we review the current status of tumor quantification methods and their applications to clinical oncology. Factors that impede quantitative assessment and limit its accuracy and reproducibility are summarized, with special emphasis on SUV analysis. We describe current efforts to improve the accuracy of tumor uptake measurements, characterize overall metabolic tumor burden and heterogeneity of tumor uptake, and account for the effects of image noise. We also summarize recent developments in PET instrumentation and image reconstruction and their impact on tumor quantification. Finally, we offer our assessment of the current development needs in PET tumor quantification, including practical techniques for fully quantitative, pharmacokinetic measurements. PMID:24312151

  15. Carcinoid Tumor

    MedlinePlus

    ... are here Home > Types of Cancer > Carcinoid Tumor Carcinoid Tumor This is Cancer.Net’s Guide to Carcinoid Tumor. Use the menu below to choose the ... social workers, and patient advocates. Cancer.Net Guide Carcinoid Tumor Introduction Statistics Medical Illustrations Risk Factors Symptoms ...

  16. Ovine intestinal adenocarcinomas: histologic and phenotypic comparison with human colon cancer.

    PubMed

    Munday, John S; Brennan, Moira M; Jaber, Azhar M; Kiupel, Matti

    2006-04-01

    Approximately 7% of old, unthrifty sheep (Ovis aries) in New Zealand have intestinal adenocarcinomas. To investigate whether these sheep might be used as a model of human colonic neoplasia, the biologic behavior and histologic appearance of ovine intestinal adenocarcinomas were compared with those reported for human colonic adenocarcinomas. We collected 50 intestinal tracts with grossly visible intestinal neoplasia from slaughtered sheep. Neoplasms were assessed using World Health Organization guidelines for assessment of human colonic adenocarcinomas. All ovine adenocarcinomas developed in the small intestine. In contrast, only 4% of human intestinal tumors develop at this location, whereas the majority develop in the colon. A visible polyp is present within 89% of human colonic adenocarcinomas, whereas polyps were present in only 46% of the ovine neoplasms. Intestinal wall infiltration by the neoplastic cells and rates of lymph node (84% in sheep; 61% in humans) and distant (52% in sheep; 17% in humans) metastases were comparable between ovine and human adenocarcinomas. However, ovine adenocarcinomas developed more peritoneal and fewer hepatic metastases than human adenocarcinomas. Histologic grading of ovine tumors revealed cell differentiation similar to that reported within human colonic adenocarcinomas. In conclusion, ovine intestinal adenocarcinomas, like human colonic adenocarcinomas, typically arise spontaneously and consistently develop widespread metastases. In addition, tumors appear histologically similar between these species. Therefore, sheep may provide a model of advanced human colonic cancer, possibly allowing evaluation of novel therapeutics and surgical procedures.

  17. Intestinal anisakidosis (anisakiosis).

    PubMed

    Takei, Hidehiro; Powell, Suzanne Z

    2007-10-01

    A case of intestinal anisakidosis in a 42-year-old man in Japan is presented. His chief complaint was an acute onset of severe abdominal pain. Approximately 12 hours before the onset of this symptom, he had eaten sliced raw mackerel ("sashimi"). Upper endoscopy was unremarkable. At exploratory laparotomy, an edematous, diffusely thickened segment of jejunum was observed, which was resected. The postoperative course was uneventful. The segment of small intestine showed a granular indurated area on the mucosal surface, and microscopically, a helminthic larva penetrating the intestinal wall, which was surrounded by a cuff of numerous neutrophils and eosinophils, as well as diffuse acute serositis. A cross section of the larva revealed the internal structures, pathognomonic of Anisakis simplex. Although anisakidosis is rare in the United States, with the increasing popularity of Japanese cuisine, the incidence is expected to increase, and pathologists should be familiar with this disease.

  18. Small Intestinal Infections.

    PubMed

    Munot, Khushboo; Kotler, Donald P

    2016-06-01

    Small intestinal infections are extremely common worldwide. They may be bacterial, viral, or parasitic in etiology. Most are foodborne or waterborne, with specific etiologies differing by region and with diverse pathophysiologies. Very young, very old, and immune-deficient individuals are the most vulnerable to morbidity or mortality from small intestinal infections. There have been significant advances in diagnostic sophistication with the development and early application of molecular diagnostic assays, though these tests have not become mainstream. The lack of rapid diagnoses combined with the self-limited nature of small intestinal infections has hampered the development of specific and effective treatments other than oral rehydration. Antibiotics are not indicated in the absence of an etiologic diagnosis, and not at all in the case of some infections.

  19. General Treatment Information for Small Intestine Adenocarcinoma

    MedlinePlus

    ... Cancer A-Z Small Intestine Cancer Treating Small Intestine Cancer General treatment information Depending on the type ... questions about your treatment options. More In Small Intestine Cancer About Small Intestine Cancer Causes, Risk Factors, ...

  20. Assessment of intestinal malabsorption.

    PubMed

    Nikaki, K; Gupte, G L

    2016-04-01

    Significant efforts have been made in the last decade to either standardize the available tests for intestinal malabsorption or to develop new, more simple and reliable techniques. The quest is still on and, unfortunately, clinical practice has not dramatically changed. The investigation of intestinal malabsorption is directed by the patient's history and baseline tests. Endoscopy and small bowel biopsies play a major role although non-invasive tests are favored and often performed early on the diagnostic algorithm, especially in paediatric and fragile elderly patients. The current clinically available methods and research tools are summarized in this review article. Copyright © 2016 Elsevier Ltd. All rights reserved.

  1. [Intestinal microbiocenosis in children with intestinal enzymopathy].

    PubMed

    Kamilova, A T; Akhmedov, N N; Pulatova, D B; Nurmatov, B A

    2001-01-01

    141 children with different kinds of intestinal enzymopathy were examined; of these, 33 had celiac disease, 39--the syndrome of celiac disease, 12--congenital lactase deficiency and 57--the syndrome of disaccharidase insufficiency. In these patients a significant decrease in the average characteristics of the main protective flora and the growth of hemolytic and lactose-negative enterobacteria were established. In all groups of patients increased amounts of Proteus were detected, which was indicative of profound dysbiosis. The content of bifidobacteria was found to be decreased in 89.5-97% of the patients and the content of lactic acid bacteria, in 15.8-33.3%. The decreased content of Escherichia coli with normal enzymatic activity (less than 10(7) colony-forming units) was noted in one-third of the patients with the syndrome of celiac disease and congenital lactase deficiency, in about a half of the patients with the syndrome of disaccharidase insufficiency and least of all in patients with celiac disease (9.1%). The association of opportunistic microbes was detected in 15.6% of the patients, more often in those with celiac disease, the syndrome of celiac disease and congenital lactase deficiency. The severity of disturbances in intestinal eubiosis was found to depend on the gravity of the patients' state.

  2. Histologic classification of sinonasal intestinal-type adenocarcinoma

    SciTech Connect

    Franquemont, D.W.; Fechner, R.E.; Mills, S.E. )

    1991-04-01

    Kleinsasser and Schroeder recently described a histologic classification system for woodworker-associated, intestinal-type adenocarcinomas of the sinonasal region. To determine if their approach is easily applied and prognostically meaningful for both woodworker-associated and sporadic intestinal-type adenocarcinomas in the sinonasal region, we analyzed 15 such cases. The 12 men and three women ranged in age from 37 to 75 years. Only four were woodworkers. All tumors arose in the nasal cavity or paranasal sinuses. The three authors independently classified the tumors with unanimous agreement in 11 (73%) of 15 cases. Disagreements were resolved by group review and consensus. Ten tumors were papillary tubular cylinder cell type; these were subdivided into grades I (four cases) and II (six cases) on the basis of cytologic atypia. Three tumors were alveolar goblet cell type; one tumor was signet-ring type; and one had a mixed pattern. Median survivals were papillary tubular I, 9 years; papillary tubular II, 3 years; and alveolar goblet cell, 7 years. It is concluded that this classification system is easy to apply, reproducible, and appears to identify a group of sinonasal intestinal-type adenocarcinomas (papillary tubular I) with a prolonged survival.

  3. Melatonin protects rats from radiotherapy-induced small intestine toxicity.

    PubMed

    Fernández-Gil, Beatriz; Moneim, Ahmed E Abdel; Ortiz, Francisco; Shen, Ying-Qiang; Soto-Mercado, Viviana; Mendivil-Perez, Miguel; Guerra-Librero, Ana; Acuña-Castroviejo, Darío; Molina-Navarro, María M; García-Verdugo, José M; Sayed, Ramy K A; Florido, Javier; Luna, Juan D; López, Luis Carlos; Escames, Germaine

    2017-01-01

    Radiotherapy-induced gut toxicity is among the most prevalent dose-limiting toxicities following radiotherapy. Prevention of radiation enteropathy requires protection of the small intestine. However, despite the prevalence and burden of this pathology, there are currently no effective treatments for radiotherapy-induced gut toxicity, and this pathology remains unclear. The present study aimed to investigate the changes induced in the rat small intestine after external irradiation of the tongue, and to explore the potential radio-protective effects of melatonin gel. Male Wistar rats were subjected to irradiation of their tongues with an X-Ray YXLON Y.Tu 320-D03 irradiator, receiving a dose of 7.5 Gy/day for 5 days. For 21 days post-irradiation, rats were treated with 45 mg/day melatonin gel or vehicle, by local application into their mouths. Our results showed that mitochondrial oxidative stress, bioenergetic impairment, and subsequent NLRP3 inflammasome activation were involved in the development of radiotherapy-induced gut toxicity. Oral treatment with melatonin gel had a protective effect in the small intestine, which was associated with mitochondrial protection and, consequently, with a reduced inflammatory response, blunting the NF-κB/NLRP3 inflammasome signaling activation. Thus, rats treated with melatonin gel showed reduced intestinal apoptosis, relieving mucosal dysfunction and facilitating intestinal mucosa recovery. Our findings suggest that oral treatment with melatonin gel may be a potential preventive therapy for radiotherapy-induced gut toxicity in cancer patients.

  4. Melatonin protects rats from radiotherapy-induced small intestine toxicity

    PubMed Central

    Fernández-Gil, Beatriz; Moneim, Ahmed E. Abdel; Ortiz, Francisco; Shen, Ying-Qiang; Soto-Mercado, Viviana; Mendivil-Perez, Miguel; Guerra-Librero, Ana; Acuña-Castroviejo, Darío; Molina-Navarro, María M.; García-Verdugo, José M.; Sayed, Ramy K. A.; Florido, Javier; Luna, Juan D.; López, Luis Carlos; Escames, Germaine

    2017-01-01

    Radiotherapy-induced gut toxicity is among the most prevalent dose-limiting toxicities following radiotherapy. Prevention of radiation enteropathy requires protection of the small intestine. However, despite the prevalence and burden of this pathology, there are currently no effective treatments for radiotherapy-induced gut toxicity, and this pathology remains unclear. The present study aimed to investigate the changes induced in the rat small intestine after external irradiation of the tongue, and to explore the potential radio-protective effects of melatonin gel. Male Wistar rats were subjected to irradiation of their tongues with an X-Ray YXLON Y.Tu 320-D03 irradiator, receiving a dose of 7.5 Gy/day for 5 days. For 21 days post-irradiation, rats were treated with 45 mg/day melatonin gel or vehicle, by local application into their mouths. Our results showed that mitochondrial oxidative stress, bioenergetic impairment, and subsequent NLRP3 inflammasome activation were involved in the development of radiotherapy-induced gut toxicity. Oral treatment with melatonin gel had a protective effect in the small intestine, which was associated with mitochondrial protection and, consequently, with a reduced inflammatory response, blunting the NF-κB/NLRP3 inflammasome signaling activation. Thus, rats treated with melatonin gel showed reduced intestinal apoptosis, relieving mucosal dysfunction and facilitating intestinal mucosa recovery. Our findings suggest that oral treatment with melatonin gel may be a potential preventive therapy for radiotherapy-induced gut toxicity in cancer patients. PMID:28403142

  5. Intestinal Failure (Short Bowel Syndrome)

    MedlinePlus

    ... N Vitamin deficiencies as a result of poor absorption in the intestine N Electrolyte and mineral deficiencies ... N Kidney stones or gallstones due to poor absorption of calcium or bile How is intestinal failure ...

  6. Small intestine contrast injection (image)

    MedlinePlus

    ... and throat, through the stomach into the small intestine. When in place, contrast dye is introduced and ... means of demonstrating whether or not the small intestine is normal when abnormality is suspected.

  7. Intestinal Failure (Short Bowel Syndrome)

    MedlinePlus

    ... N Vitamin deficiencies as a result of poor absorption in the intestine N Electrolyte and mineral deficiencies ... N Kidney stones or gallstones due to poor absorption of calcium or bile How is intestinal failure ...

  8. Intestinal microbiota and ulcerative colitis.

    PubMed

    Ohkusa, Toshifumi; Koido, Shigeo

    2015-11-01

    There is a close relationship between the human host and the intestinal microbiota, which is an assortment of microorganisms, protecting the intestine against colonization by exogenous pathogens. Moreover, the intestinal microbiota play a critical role in providing nutrition and the modulation of host immune homeostasis. Recent reports indicate that some strains of intestinal bacteria are responsible for intestinal ulceration and chronic inflammation in inflammatory bowel diseases (IBD) such as ulcerative colitis (UC) and Crohn's disease (CD). Understanding the interaction of the intestinal microbiota with pathogens and the human host might provide new strategies treating patients with IBD. This review focuses on the important role that the intestinal microbiota plays in maintaining innate immunity in the pathogenesis and etiology of UC and discusses new antibiotic therapies targeting the intestinal microbiota. Copyright © 2015 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

  9. Small intestine aspirate and culture

    MedlinePlus

    ... page: //medlineplus.gov/ency/article/003731.htm Small intestine aspirate and culture To use the sharing features on this page, please enable JavaScript. Small intestine aspirate and culture is a lab test to ...

  10. Kaiso overexpression promotes intestinal inflammation and potentiates intestinal tumorigenesis in Apc(Min/+) mice.

    PubMed

    Pierre, Christina C; Longo, Joseph; Mavor, Meaghan; Milosavljevic, Snezana B; Chaudhary, Roopali; Gilbreath, Ebony; Yates, Clayton; Daniel, Juliet M

    2015-09-01

    Constitutive Wnt/β-catenin signaling is a key contributor to colorectal cancer (CRC). Although inactivation of the tumor suppressor adenomatous polyposis coli (APC) is recognized as an early event in CRC development, it is the accumulation of multiple subsequent oncogenic insults facilitates malignant transformation. One potential contributor to colorectal carcinogenesis is the POZ-ZF transcription factor Kaiso, whose depletion extends lifespan and delays polyp onset in the widely used Apc(Min/+) mouse model of intestinal cancer. These findings suggested that Kaiso potentiates intestinal tumorigenesis, but this was paradoxical as Kaiso was previously implicated as a negative regulator of Wnt/β-catenin signaling. To resolve Kaiso's role in intestinal tumorigenesis and canonical Wnt signaling, we generated a transgenic mouse model (Kaiso(Tg/+)) expressing an intestinal-specific myc-tagged Kaiso transgene. We then mated Kaiso(Tg/+) and Apc(Min/+) mice to generate Kaiso(Tg/+):Apc(Min/+) mice for further characterization. Kaiso(Tg/+):Apc(Min/+) mice exhibited reduced lifespan and increased polyp multiplicity compared to Apc(Min/+) mice. Consistent with this murine phenotype, we found increased Kaiso expression in human CRC tissue, supporting a role for Kaiso in human CRC. Interestingly, Wnt target gene expression was increased in Kaiso(Tg/+):Apc(Min/+) mice, suggesting that Kaiso's function as a negative regulator of canonical Wnt signaling, as seen in Xenopus, is not maintained in this context. Notably, Kaiso(Tg/+):Apc(Min/+) mice exhibited increased inflammation and activation of NFκB signaling compared to their Apc(Min/+) counterparts. This phenotype was consistent with our previous report that Kaiso(Tg/+) mice exhibit chronic intestinal inflammation. Together our findings highlight a role for Kaiso in promoting Wnt signaling, inflammation and tumorigenesis in the mammalian intestine. Copyright © 2015 Elsevier B.V. All rights reserved.

  11. Neuropsychiatric Burden in Huntington's Disease.

    PubMed

    Paoli, Ricardo Augusto; Botturi, Andrea; Ciammola, Andrea; Silani, Vincenzo; Prunas, Cecilia; Lucchiari, Claudio; Zugno, Elisa; Caletti, Elisabetta

    2017-06-16

    Huntington's disease is a disorder that results in motor, cognitive, and psychiatric problems. The symptoms often take different forms and the presence of disturbances of the psychic sphere reduces patients' autonomy and quality of life, also impacting patients' social life. It is estimated that a prevalence between 33% and 76% of the main psychiatric syndromes may arise in different phases of the disease, often in atypical form, even 20 years before the onset of chorea and dementia. We present a narrative review of the literature describing the main psychopathological patterns that may be found in Huntington's disease, searching for a related article in the main database sources (Medline, ISI Web of Knowledge, Scopus, and Medscape). Psychiatric conditions were classified into two main categories: affective and nonaffective disorders/symptoms; and anxiety and neuropsychiatric features such as apathy and irritability. Though the literature is extensive, it is not always convergent, probably due to the high heterogeneity of methods used. We summarize main papers for pathology and sample size, in order to present a synoptic vision of the argument. Since the association between Huntington's disease and psychiatric symptoms was demonstrated, we argue that the prevalent and more invalidating psychiatric components should be recognized as early as possible during the disease course in order to best address psychopharmacological therapy, improve quality of life, and also reduce burden on caregivers.

  12. Terminology and the Psychosocial Burden of Blindness

    ERIC Educational Resources Information Center

    Bolt, David

    2004-01-01

    Various denotations and connotations of the word "blindness" are examined and the inference is drawn that they constitute a psychosocial burden that perpetuates prejudice. The analysis leads on to a hypothesis in which a more progressive terminology could lead to reduction of this burden.

  13. 40 CFR 179.91 - Burden of going forward; burden of persuasion.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 24 2014-07-01 2014-07-01 false Burden of going forward; burden of...) PESTICIDE PROGRAMS FORMAL EVIDENTIARY PUBLIC HEARING Hearing Procedures § 179.91 Burden of going forward... of going forward in the hearing with evidence as to the issues relevant to that request for a hearing...

  14. 40 CFR 179.91 - Burden of going forward; burden of persuasion.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 24 2011-07-01 2011-07-01 false Burden of going forward; burden of...) PESTICIDE PROGRAMS FORMAL EVIDENTIARY PUBLIC HEARING Hearing Procedures § 179.91 Burden of going forward... of going forward in the hearing with evidence as to the issues relevant to that request for a hearing...

  15. 40 CFR 179.91 - Burden of going forward; burden of persuasion.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 25 2013-07-01 2013-07-01 false Burden of going forward; burden of...) PESTICIDE PROGRAMS FORMAL EVIDENTIARY PUBLIC HEARING Hearing Procedures § 179.91 Burden of going forward... of going forward in the hearing with evidence as to the issues relevant to that request for a hearing...

  16. 40 CFR 179.91 - Burden of going forward; burden of persuasion.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 25 2012-07-01 2012-07-01 false Burden of going forward; burden of...) PESTICIDE PROGRAMS FORMAL EVIDENTIARY PUBLIC HEARING Hearing Procedures § 179.91 Burden of going forward... of going forward in the hearing with evidence as to the issues relevant to that request for a hearing...

  17. 40 CFR 179.91 - Burden of going forward; burden of persuasion.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 23 2010-07-01 2010-07-01 false Burden of going forward; burden of...) PESTICIDE PROGRAMS FORMAL EVIDENTIARY PUBLIC HEARING Hearing Procedures § 179.91 Burden of going forward... of going forward in the hearing with evidence as to the issues relevant to that request for a hearing...

  18. 40 CFR 22.24 - Burden of presentation; burden of persuasion; preponderance of the evidence standard.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... persuasion; preponderance of the evidence standard. 22.24 Section 22.24 Protection of Environment... Burden of presentation; burden of persuasion; preponderance of the evidence standard. (a) The complainant has the burdens of presentation and persuasion that the violation occurred as set forth in the...

  19. OC29 - Caregiver burden in childhood asthma.

    PubMed

    Ekim, Ayfer

    2016-05-09

    Theme: Parenting/parenthood. As delivering care is an inherent part of becoming parents, providing high-level care to the child with health problems might be a burden for the caregiver. This systematic review investigated the effects of caregiver burden of parents who are primarily responsible for the caring of children with asthma. PubMed, CINAHL, Web of Science and Scopus databases were searched for the studies published between 2000-2015. Key search terms used were 'caregiver', 'burden, 'childhood asthma' and 'parent'. A total of 23 studies were examined for this review. Providing care to the child with asthma affects parents as caregivers negatively. Caregivers of the children with asthma often experience anxiety, fear, disappointment, grief, physical distress and low quality of life as the outcomes of caregiving burden. It is absolutely crucial to determine caregiver burden risks and protective factors since wellness level of caregivers affect the asthma management practices and decisions.

  20. p27kip1 in Intestinal Tumorigenesis and Chemoprevention in the Mouse

    PubMed Central

    Yang, WanCai; Bancroft, Laura; Liang, Jiao; Zhuang, Min; Augenlicht, Leonard H.

    2010-01-01

    Targeted inactivation of p27kip1 was sufficient for intestinal tumor formation in mice, but this was strictly a function of diet: tumors formed in p27+/− or p27−/− mice fed control AIN-76A diet and were increased by a western-style diet but did not develop in mice fed standard chow diet. When crossed with the Apc1638N+/− mouse, Apc+/−,p27+/− or Apc+/−,p27−/− mice not only formed twice as many tumors than the sum of the tumors from mutation at either locus alone, but on AIN76A diet also developed intestinal intussusception, a tumor-associated pathology in patients leading to intestinal blockage that has not been reported for intestinal cancer in mouse models. Moreover, the frequency of intussusception was increased when the compound mutant mice were maintained on the western diet, leading to early death. Despite this more aggressive tumor phenotype generated by inactivation of p27 than by inactivation of another cyclin-dependent kinase inhibitor, p21WAF1/cip1, the nonsteroidal anti-inflammatory drug sulindac was still effective in inhibiting intestinal tumor formation in Apc+/−,p27+/− or Apc+/−,p27−/− mice, which contrasts with the abrogation of the effects of sulindac in Apc+/−,p21+/− or Apc+/−,p21−/− mice, indicating that p27 is not necessary for tumor inhibition by sulindac. Furthermore, tumor inhibition by sulindac was linked to the induction of p21 expression by the drug, regardless of p27 status, leading to suppression of cell proliferation and promotion of cell differentiation and apoptosis in the intestinal mucosa. PMID:16230399

  1. Behavior of tumors under nonstationary therapy

    NASA Astrophysics Data System (ADS)

    Sotolongo-Costa, O.; Morales Molina, L.; Rodríguez Perez, D.; Antoranz, J. C.; Chacón Reyes, M.

    2003-04-01

    We present a model for the interaction dynamics of lymphocytes-tumor cells population. This model reproduces all known states for the tumor. Further, we develop it taking into account periodical immunotherapy treatment with cytokines alone. A detailed analysis for the evolution of tumor cells as a function of frequency and therapy burden applied for the periodical treatment is carried out. Certain threshold values for the frequency and applied doses are derived from this analysis. So it seems possible to control and reduce the growth of the tumor. Also, constant values for cytokines doses seems to be a successful treatment.

  2. Assessing the burden of injuries: competing measures.

    PubMed

    Hendrie, Delia; Miller, Ted R

    2004-09-01

    This paper compares the different types of injury burden measures in common use and examines criteria that may be useful to consider when selecting between alternative measures. A review was conducted of relevant literature relating to burden of injury measures, important characteristics of data information systems and ethical frameworks for normative analysis in the health sector. Four broad types of burden of injury measures can be distinguished: mortality-related indices; morbidity-related indices; composite measures combining mortality and morbidity; and monetary costs. Each type of measure uses its own construct of injury burden. For example, mortality data defines the injury burden as comprising only fatalities whereas comprehensive costs attempt to capture the total wellbeing lost through injury. Different measures of the burden of injury present differential rankings of the causes and intent of injury, thus the question arises as to what criteria should be used in selecting the best measure. Each measure of the burden of injury has merits and limitations. In selecting between injury measures, consideration should be given to the nature of the policy question, the construct of injury burden that each measure assesses, the availability of data for the measure and its quality and the ethical values inherent in each measure. Measures of the burden of injury play a useful role in positioning injury as a major public health problem and in policy work relating to injury prevention and control. No single measure of the burden of injury is ideal and several measures can be used together if necessary to provide different perspectives on an injury problem.

  3. Metastatic carcinoid tumor obstructing left ventricular outflow.

    PubMed

    Chrysant, George S; Horstmanshof, Douglas A; Guniganti, Uma M

    2011-01-01

    Cardiac tumors are rare and usually indicate metastatic disease. Characterizing a tumor and reaching an exact diagnosis can be difficult. Diagnosis has been aided greatly by advances in imaging, such as cardiovascular magnetic resonance with the use of gadolinium-pentetic acid. Carcinoid tumors are neuroendocrine neoplasms that are found most often in the intestinal tract, although they can also develop in the lung, stomach, or heart. Herein, we report the case of a 72-year-old woman with a history of intestinal carcinoid disease and presenting symptoms of dizziness, fatigue, and chest pain. We used cardiovascular magnetic resonance with gadolinium enhancement to identify a large mass obstructing left ventricular outflow. The histopathologic results of an endomyocardial biopsy confirmed that the mass was a left-sided metastatic carcinoid cardiac tumor. To our knowledge, we are reporting the 1st combined use of clinical evaluation, cardiovascular magnetic resonance, and histopathologic studies to reach such a diagnosis.

  4. Metastatic Carcinoid Tumor Obstructing Left Ventricular Outflow

    PubMed Central

    Chrysant, George S.; Horstmanshof, Douglas A.; Guniganti, Uma M.

    2011-01-01

    Cardiac tumors are rare and usually indicate metastatic disease. Characterizing a tumor and reaching an exact diagnosis can be difficult. Diagnosis has been aided greatly by advances in imaging, such as cardiovascular magnetic resonance with the use of gadolinium-pentetic acid. Carcinoid tumors are neuroendocrine neoplasms that are found most often in the intestinal tract, although they can also develop in the lung, stomach, or heart. Herein, we report the case of a 72-year-old woman with a history of intestinal carcinoid disease and presenting symptoms of dizziness, fatigue, and chest pain. We used cardiovascular magnetic resonance with gadolinium enhancement to identify a large mass obstructing left ventricular outflow. The histopathologic results of an endomyocardial biopsy confirmed that the mass was a left-sided metastatic carcinoid cardiac tumor. To our knowledge, we are reporting the 1st combined use of clinical evaluation, cardiovascular magnetic resonance, and histopathologic studies to reach such a diagnosis. PMID:21720473

  5. SRC activates TAZ for intestinal tumorigenesis and regeneration.

    PubMed

    Byun, Mi Ran; Hwang, Jun-Ha; Kim, A Rum; Kim, Kyung Min; Park, Jung Il; Oh, Ho Taek; Hwang, Eun Sook; Hong, Jeong-Ho

    2017-09-20

    Proto-oncogene tyrosine-protein kinase Src (cSRC) is involved in colorectal cancer (CRC) development and damage-induced intestinal regeneration, although the cellular mechanisms involved are poorly understood. Here, we report that transcriptional coactivator with PDZ binding domain (TAZ) is activated by cSRC, regulating CRC cell proliferation and tumor formation, where cSRC overexpression increases TAZ expression in CRC cells. In contrast, knockdown of cSRC decreases TAZ expression. Additionally, direct phosphorylation of TAZ at Tyr316 by cSRC stimulates nuclear localization and facilitates transcriptional enhancer factor TEF-3 (TEAD4)-mediated transcription. However, a TAZ phosphorylation mutant significantly decreased cell proliferation, wound healing, colony forming, and tumor formation. In a CRC mouse model, Apc(Min/+), activated SRC expression was associated with increased TAZ expression in polyps and TAZ depletion decreased polyp formation. Moreover, intestinal TAZ knockout mice had intestinal regeneration defects following γ-irradiation. Finally, significant correspondence between SRC activation and TAZ overexpression was observed in CRC patients. These results suggest that TAZ is a critical factor for SRC-mediated intestinal tumor formation and regeneration. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Mammary tumors

    SciTech Connect

    Weller, R.E.

    1988-10-01

    Mammary neoplasia is one of the more common malignancies affecting domestic species. Despite their importance, they are often over- diagnosed, undertreated and subject to several misconceptions propagated by veterinarians and pet owners alike. Mammary neoplasia is the most frequent tumor type encountered in the female accounting for almost half of all malignancies reported. The canine has the highest incidence of mammary tumors of all domestic species. In the dog, about 65 percent of mammary tumors are benign mixed tumors, and 25 percent are carcinomas. The rest are adenomas, myoepitheliomas, and malignant mixed tumors. The age distribution of mammary tumors closely follows the age distribution of most tumors in the dog. Mammary tumors are rare in dogs 2 years old, but incidence begins to increase sharply at approximately 6 years of age. Median age at diagnosis is about 10 years. No breed predilection has been consistently reported.

  7. [Carcinoid tumor of gastrointestinal tract: about two clinical cases].

    PubMed

    Blasco, María Del Carmen; Boselli O, F Giuliano; Blasco, Carmelo

    2016-01-01

    Carcinoid tumors belong to the families of neuroendocrine tumors. The major sites are the gastrointestinal tract 65% and lungs 25%. The small intestine, specifically the ileum, is the most common. These tumors although rare, are more common in tumors of neuroendocrine origin gastro-entero-pancreatic. In both cases we observe the different clinical presentations that may have carcinoid tumor; in case 1 ulceration of the tumor mass causing the elimination of melena, and severe diarrhea caused by neuroendocrine secretion. Case 2 typical course, totally asymptomatic incidental finding.

  8. [Disease burden on diabetes in China, 2010].

    PubMed

    Li, Yi-chong; Liu, Xiao-ting; Hu, Nan; Jiang, Yong; Zhao, Wen-hua

    2013-01-01

    To estimate the disease burden of diabetes in China, 2010. We calculated the disability adjusted life years (DALYs) of diabetes, using data from both the Mortality Surveillance in National Disease Surveillance Points System and the China Chronic Disease Surveillance (2010). We also examined the differences of DALYs by gender, age, urban/rural areas and geographical locations. The overall disease burden of diabetes was 19.12 DALYs per 1000 population. Men (18.30 DALYs per 1000) had a higher DALY rate than in women (19.97 DALYs per 1000). We observed an upside-down "U" relationship between DALY rate and age. Residents aged 15 - 79 years bore most part of disease burden and the burden peaked among population at age from 45 to 60 years (30.39 DALYs per 1000). There was a higher DALY rate seen in the population from the urban areas (17.83 DALYs per 1000) than those from the rural areas (17.03 DALYs per 1000). In order, the burden showed a decrease from the eastern region (22.28 DALYs per 1000), middle region (19.62 DALYs per 1000) to the western region (13.54 DALYs per 1000), in the country. China is currently carrying considerable burden caused by diabetes among the population of labor force while inequity of burden was seen among different geographical regions within China.

  9. Prevalence of intestinal parasitic infections among public school children in a rural village of Kathmandu Valley.

    PubMed

    Pradhan, P; Bhandary, S; Shakya, P R; Acharya, T; Shrestha, A

    2014-09-01

    Intestinal parasitic infections (IPI) are one of the most prevalent infections in humans residing in developing countries and its burden is high among school aged children. This cross-sectional study was conducted to determine the prevalence of intestinal parasitic infection and types of intestinal parasites in rural public school children of Nepal. It included students from Nursery to Class X of a rural public school located in the northeast part of the Kathmandu Valley, Nepal. Among the 194 participating children, prevalence of intestinal parasitic infection was found as 23.7%; (28.2% for boys; 20.2% for girls). Amongst the infected children, single and mixed parasitic infection was detected in 43 (93.5%) and 3 (6.5%) children respectively. Among protozoan parasites, Giardia lamblia was the most common (58.6%) whereas Hymenolepis nana was the most common (21.7%) among the helminths. Statistically different prevalence of intestinal parasitic infection was observed among children aged above 10 years and children aged below 6 years as well as 6 to 10 years. Gender-wise, there was no statistical difference in prevalence of intestinal parasitic infection. This study suggests the need of health education program in schools along with regular screening of intestinal parasites and treatment for effective management of the intestinal parasites among school children in Nepal.

  10. Urogenital tumors

    SciTech Connect

    Weller, R.E.

    1994-03-01

    An overview is provided for veterinary care of urogenital tumors in companion animals, especially the dog. Neoplasms discussed include tumors of the kidney, urinary bladder, prostate, testis, ovary, vagina, vulva and the canine transmissible venereal tumor. Topics addressed include description, diagnosis and treatment.

  11. Wilms Tumor

    MedlinePlus

    ... Old Feeding Your 1- to 2-Year-Old Wilms Tumor KidsHealth > For Parents > Wilms Tumor Print A A A What's in this article? ... their child has cancer. Fortunately, most kids with Wilms tumor, a rare kidney cancer, survive and go on ...

  12. Transgenic Expression of Human Lysophosphatidic Acid Receptor LPA2 in Mouse Intestinal Epithelial Cells Induces Intestinal Dysplasia.

    PubMed

    Yoshida, Michihiro; He, Peijian; Yun, C Chris

    2016-01-01

    Lysophosphatidic acid (LPA) acts on LPA2 receptor to mediate multiple pathological effects that are associated with tumorigenesis. The absence of LPA2 attenuates tumor progression in rodent models of colorectal cancer, but whether overexpression of LPA2 alone can lead to malignant transformation in the intestinal tract has not been studied. In this study, we expressed human LPA2 in intestinal epithelial cells (IECs) under control of the villin promoter. Less than 4% of F1-generation mice had germline transmission of transgenic (TG) human LPA2; as such only 3 F1 mice out of 72 genotyped had TG expression. These TG mice appeared anemic with hematochezia and died shortly after birth. TG mice were smaller in size compared with the wild type mouse of the same age and sex. Morphological analysis showed that TG LPA2 colon had hyper-proliferation of IECs resulting in increased colonic crypt depth. Surprisingly, TG small intestine had villus blunting and decreased IEC proliferation and dysplasia. In both intestine and colon, TG expression of LPA2 compromised the terminal epithelial differentiation, consistent with epithelial dysplasia. Furthermore, we showed that epithelial dysplasia was observed in founder mouse intestine, correlating LPA2 overexpression with epithelial dysplasia. The current study demonstrates that overexpression of LPA2 alone can lead to intestinal dysplasia.

  13. Intestinal ascariasis in children.

    PubMed

    Wani, Imtiaz; Rather, Muddasir; Naikoo, Ghulam; Amin, Abid; Mushtaq, Syed; Nazir, Mir

    2010-05-01

    Ascariasis is a staggering health problem commonly seen in children of endemic areas. In the abdomen, ascaris lumbricoides can cause a myriad of surgical complications. Intestinal obstruction by ascaris lumbricoides is commonly seen in children. Most cases are managed conservatively. The purpose was to study the clinical presentation and management of symptomatic intestinal ascariasis in children. A 3-year study was performed from April 2006 to April 2009 of pediatric-age patients who had symptomatic intestinal ascariasis. All patients had detailed clinical history, examination, plain X-ray of abdomen, and ultrasonography of abdomen. Peroperative findings were recorded in all patients who had surgical intervention. This prospective study had 360 patients. Male to female ratio was 1.37:1. 187 patients (52%) presented within 2-4 days of duration of illness. Mean +/- standard deviation (SD) age of patients was 6.35 +/- 2.25 years. Age group of 4-7 years (80%) was commonest group affected. Abdominal pain was a leading symptom in 357 patients (99%) with the pain in periumbilical area present in 215 patients (60%). In 227 patients (63%) abdominal distension was seen and was the commonest physical finding. Palpable worm masses were seen in 129 patients (36%); 81 patients (63%) had palpable worm masses in the umbilical quadrant. On X-ray of abdomen, visible worm masses were seen in 83 patients (23%). Abdominal sonography showed interloop fluid in 177 patients (49%) and free fluid in the pelvis of 97 patients (27%). The number of patients who were managed conservatively was 281 (78%), and 79 patients (22%) had surgical intervention. In patients who had surgical intervention, 39 patients (49%) had enterotomy and 7 patients (9%) had kneading of worms. Postoperative complications occurred in 33 patients, and an overall mortality of 1% (1 patient) was seen. Ascaridial intestinal obstruction is common in children in the Kashmir. Abdominal pain is the leading symptom in

  14. Gastrointestinal Stromal Tumors Treatment (PDQ®)—Patient Version

    Cancer.gov

    Gastrointestinal stromal tumors (GIST) are usually found on the stomach or small intestine, but they can be found anywhere in or near the GI tract. Find out about risk factors, symptoms, tests to diagnose, prognosis, staging, and treatment for gastrointestinal stromal tumors.

  15. The Cystic Fibrosis Intestine

    PubMed Central

    De Lisle, Robert C.; Borowitz, Drucy

    2013-01-01

    The clinical manifestations of cystic fibrosis (CF) result from dysfunction of the cystic fibrosis transmembrane regulator protein (CFTR). The majority of people with CF have a limited life span as a consequence of CFTR dysfunction in the respiratory tract. However, CFTR dysfunction in the gastrointestinal (GI) tract occurs earlier in ontogeny and is present in all patients, regardless of genotype. The same pathophysiologic triad of obstruction, infection, and inflammation that causes disease in the airways also causes disease in the intestines. This article describes the effects of CFTR dysfunction on the intestinal tissues and the intraluminal environment. Mouse models of CF have greatly advanced our understanding of the GI manifestations of CF, which can be directly applied to understanding CF disease in humans. PMID:23788646

  16. Unusual intestinal talcosis.

    PubMed

    Anani, P A; Ribaux, C; Gardiol, D

    1987-11-01

    A case of intestinal talcosis in a 46-year-old man is reported. At the age of 27, the patient was treated for pulmonary tuberculosis with tablets containing talc (183 g talc per 2,670 g total drug intake) over a period of 28 months. Eighteen years later, the patient was hospitalized for abdominal pain that remained refractory to antacids; he subsequently underwent a right hemicolectomy. Light-microscopic examination revealed a prominent fibrosis of the intestinal wall in which birefringent particles were demonstrated by polarized light. Using energy-dispersive spectroscopy, an analysis of these particles showed that they were predominantly composed of silicon and magnesium as well as small amounts of phosphorus, sulphur, calcium, and iron--the spectrum typically associated with talc. We believe that the source of this talc is the tablets ingested by the patient during prior antituberculosis therapy.

  17. Elenoside increases intestinal motility

    PubMed Central

    Navarro, E; Alonso, SJ; Navarro, R; Trujillo, J; Jorge, E

    2006-01-01

    AIM: To study the effects of elenoside, an arylnaph-thalene lignan from Justicia hyssopifolia, on gastro-intestinal motility in vivo and in vitro in rats. METHODS: Routine in vivo experimental assessments were catharsis index, water percentage of boluses, intestinal transit, and codeine antagonism. The groups included were vehicle control (propylene glycol-ethanol-plant oil-tween 80), elenoside (i.p. 25 and 50 mg/kg), cisapride (i.p. 10 mg/kg), and codeine phosphate (intragastric route, 50 mg/kg). In vitro approaches used isolated rat intestinal tissues (duodenum, jejunum, and ileum). The effects of elenoside at concentrations of 3.2 x 10-4, 6.4 x 10-4 and 1.2 x 10-3 mol/L, and cisapride at 10-6 mol/L were investigated. RESULTS: Elenoside in vivo produced an increase in the catharsis index and water percentage of boluses and in the percentage of distance traveled by a suspension of activated charcoal. Codeine phosphate antagonized the effect of 25 mg/kg of elenoside. In vitro, elenoside in duodenum, jejunum and ileum produced an initial decrease in the contraction force followed by an increase. Elenoside resulted in decreased intestinal frequency in duodenum, jejunum, and ileum. The in vitro and in vivo effects of elenoside were similar to those produced by cisapride. CONCLUSION: Elenoside is a lignan with an action similar to that of purgative and prokinetics drugs. Elenoside, could be an alternative to cisapride in treatment of gastrointestinal diseases as well as a preventive therapy for the undesirable gastrointestinal effects produced by opioids used for mild to moderate pain. PMID:17131476

  18. Advanced Intestinal Cancers often Maintain a Multi-Ancestral Architecture

    PubMed Central

    Zahm, Christopher D.; Szulczewski, Joseph M.; Leystra, Alyssa A.; Paul Olson, Terrah J.; Clipson, Linda; Albrecht, Dawn M.; Middlebrooks, Malisa; Thliveris, Andrew T.; Matkowskyj, Kristina A.; Washington, Mary Kay; Newton, Michael A.; Eliceiri, Kevin W.; Halberg, Richard B.

    2016-01-01

    A widely accepted paradigm in the field of cancer biology is that solid tumors are uni-ancestral being derived from a single founder and its descendants. However, data have been steadily accruing that indicate early tumors in mice and humans can have a multi-ancestral origin in which an initiated primogenitor facilitates the transformation of neighboring co-genitors. We developed a new mouse model that permits the determination of clonal architecture of intestinal tumors in vivo and ex vivo, have validated this model, and then used it to assess the clonal architecture of adenomas, intramucosal carcinomas, and invasive adenocarcinomas of the intestine. The percentage of multi-ancestral tumors did not significantly change as tumors progressed from adenomas with low-grade dysplasia [40/65 (62%)], to adenomas with high-grade dysplasia [21/37 (57%)], to intramucosal carcinomas [10/23 (43%]), to invasive adenocarcinomas [13/19 (68%)], indicating that the clone arising from the primogenitor continues to coexist with clones arising from co-genitors. Moreover, neoplastic cells from distinct clones within a multi-ancestral adenocarcinoma have even been observed to simultaneously invade into the underlying musculature [2/15 (13%)]. Thus, intratumoral heterogeneity arising early in tumor formation persists throughout tumorigenesis. PMID:26919712

  19. Tracheobronchial tumors

    PubMed Central

    Milenkovic, Branislava

    2016-01-01

    Tumors of trachea and bronchi are uncommon and can occur in the form of benign or low- and high-grade malignant tumors. Although tracheobronchial tumors (TBTs) represent only 0.6% of all pulmonary tumors, they are clinically significant. Delays in diagnosis of these tumors commonly occur because the signs and symptoms caused by these tumors are nonspecific and chest radiographs are often considered unremarkable. Therefore, novel radiological techniques and better access to flexible bronchoscopy enable detection of larger number of TBT. The purpose of this article is to provide a review of tracheal and bronchial tumors and discuss significant aspects of the different TBT with focus on clinical manifestations and diagnostic procedures. PMID:28066620

  20. Economic Study of Global Tobacco Burden

    Cancer.gov

    In an interview on Cancer Currents, Dr. Mark Parascandola discusses findings from an economics study showing that, globally, tobacco use burdens economies with more than US $1 trillion annually in health care costs and lost productivity.

  1. The Burden of Diabetes in Argentina

    PubMed Central

    González, Lorena; Caporale, Joaquín E.; Elgart, Jorge F.; Gagliardino, Juan J.

    2015-01-01

    Objective: To measure the economic burden of diabetes in Argentina by age, gender and region for the year 2005, in disability-adjusted life years (DALYs). Methods: DALYs were estimated by the sum of years of life lost due to premature death (YLL) and years of life lived with disability (YLD). Results: In the population studied (20 to 85 years), the burden of diabetes without complications was 1.3 million DALYs, 85% of which were caused by disabilities. Whereas mortality rates (YLL) increased as a function of age, YLD showed the opposite relationship. Women had higher burden of disease values, represented by 51 and 61% of YLL and YLD, respectively, independently of age. Conclusions: Our results demonstrate that disabilities are a key component of diabetes burden; its regular and systematic estimation would allow to design effective prevention strategies, to assess the impact of their implementation and to optimize resource allocation based on objective evidence. PMID:25948443

  2. Easing the Burden of External Reporting

    ERIC Educational Resources Information Center

    LoGrasso, Marc F.

    2015-01-01

    In this chapter, the author presents suggestions for improving the effectiveness of external reporting while minimizing burden. Recommendations include repurposing existing internal reports to address the needs of external reports.

  3. Easing the Burden of External Reporting

    ERIC Educational Resources Information Center

    LoGrasso, Marc F.

    2015-01-01

    In this chapter, the author presents suggestions for improving the effectiveness of external reporting while minimizing burden. Recommendations include repurposing existing internal reports to address the needs of external reports.

  4. The allometry of rodent intestines.

    PubMed

    Lovegrove, Barry G

    2010-06-01

    This study examined the allometry of the small intestine, caecum, colon and large intestine of rodents (n = 51) using a phylogenetically informed approach. Strong phylogenetic signal was detected in the data for the caecum, colon and large intestine, but not for the small intestine. Most of the phylogenetic signal could be attributed to clade effects associated with herbivorous versus omnivorous rodents. The herbivorous rodents have longer caecums, colons and large intestines, but their small intestines, with the exception of the desert otomyine rodents, are no different to those of omnivorous rodents. Desert otomyine rodents have significantly shorter small intestines than all other rodents, reflecting a possible habitat effect and providing a partial explanation for the low basal metabolic rates of small desert mammals. However, the desert otomyines do not have shorter colons or large intestines, challenging claims for adaptation to water retention in arid environments. Data for the Arvicolidae revealed significantly larger caecums and colons, and hence longer large intestines, with no compensatory reduction in the length of the small intestine, which may explain how the smallest mammalian herbivores manage to meet the demands of a very high mass-specific metabolic rate. This study provides phylogenetically corrected allometries suitable for future prediction testing.

  5. Solar geoengineering reduces atmospheric carbon burden

    NASA Astrophysics Data System (ADS)

    Keith, David W.; Wagner, Gernot; Zabel, Claire L.

    2017-09-01

    Solar geoengineering is no substitute for cutting emissions, but could nevertheless help reduce the atmospheric carbon burden. In the extreme, if solar geoengineering were used to hold radiative forcing constant under RCP8.5, the carbon burden may be reduced by ~100 GTC, equivalent to 12-26% of twenty-first-century emissions at a cost of under US$0.5 per tCO2.

  6. Metastatic carcinoid tumor--atypical presentation.

    PubMed

    Pleşa, Alina; Sarca, Emanuela; Maxim, Roxana

    2014-01-01

    Carcinoid tumor is a slow-growing type of neuroendocrine tumor, originating in the enterochromaffin cells and secreting mainly serotonin. Neuroendocrine tumors (NETs) are found throughout the intestinal tract, the appendix and terminal ileum being the most common locations, and are classified by site of origin and by degree of differentiation, with well-differentiated lesions representing those tumors formerly referred to as carcinoid tumors. The clinical symptoms are characterized by flushing, diarrhea, abdominal pain, and/or bronchial constriction and occur almost exclusively in patients with liver metastases due to the release of bioactive peptides and amines directly into the systemic circulation. We report the clinical, serological and histological diagnosis of a 67-years-old male patient with congestive heart failure secondary to carcinoid heart disease in the context of liver metastases of an ileum carcinoid tumor.

  7. Economic burden of colorectal cancer in Korea.

    PubMed

    Byun, Ju-Young; Yoon, Seok-Jun; Oh, In-Hwan; Kim, Young Ae; Seo, Hye-Young; Lee, Yo-Han

    2014-03-01

    The incidence and survival rate of colorectal cancer in Korea are increasing because of improved screening, treatment technologies, and lifestyle changes. In this aging population, increases in economic cost result. This study was conducted to estimate the economic burden of colorectal cancer utilizing claims data from the Health Insurance Review and Assessment Service. Economic burdens of colorectal cancer were estimated using prevalence data and patients were defined as those who received ambulatory treatment from medical institutions or who had been hospitalized due to colorectal cancer under the International Classification of Disease 10th revision codes from C18-C21. The economic burdens of colorectal cancer were calculated as direct costs and indirect costs. The prevalence rate (per 100 000 people) of those who were treated for colorectal cancer during 2010 was 165.48. The economic burdens of colorectal cancer in 2010 were 3 trillion and 100 billion Korean won (KRW), respectively. Direct costs included 1 trillion and 960 billion KRW (62.85%), respectively and indirect costs were 1 trillion and 160 billion (37.15%), respectively. Colorectal cancer has a large economic burden. Efforts should be made to reduce the economic burden of the disease through primary and secondary prevention.

  8. Correlation of urine TMPRSS2:ERG and PCA3 to ERG+ and total prostate cancer burden.

    PubMed

    Young, Allison; Palanisamy, Nallasivam; Siddiqui, Javed; Wood, David P; Wei, John T; Chinnaiyan, Arul M; Kunju, Lakshmi P; Tomlins, Scott A

    2012-11-01

    ERG rearrangements (most commonly transmembrane protease, serine 2 [TMPRSS2]:ERG [T2:ERG] gene fusions) have been identified in approximately 50% of prostate cancers . Quantification of T2:ERG in postdigital rectal examination urine, in combination with PCA3, improves the performance of serum prostate-specific antigen for prostate cancer prediction on biopsy. Here we compared urine T2:ERG and PCA3 scores with ERG+ (determined with immunohistochemical analysis) and total prostate cancer burden in 41 mapped prostatectomies. Prostatectomies had a median of 3 tumor foci (range, 1-15) and 2.6 cm of summed linear tumor dimension (range, 0.6-7.1 cm). Urine T2:ERG score correlated most with summed linear ERG+ tumor dimension and number of ERG+ foci (r(s) = 0.68 and 0.67, respectively, both P < .001). Urine PCA3 score showed weaker correlation with both number of tumor foci (r(s) = 0.34, P = .03) and summed linear tumor dimension (r(s) = 0.26, P = .10). In summary, we demonstrate a strong correlation between urine T2:ERG score and total ERG+ prostate cancer burden at prostatectomy, consistent with high tumor specificity.

  9. Correlation of Urine TMPRSS2:ERG and PCA3 to ERG+ and Total Prostate Cancer Burden

    PubMed Central

    Young, Allison; Palanisamy, Nallasivam; Siddiqui, Javed; Wood, David P.; Wei, John T.; Chinnaiyan, Arul M.; Kunju, Lakshmi P.; Tomlins, Scott A.

    2013-01-01

    ERG rearrangements, (most commonly TMPRSS2: ERG [T2:ERG] gene fusions), have been identified in approximately 50% of prostate cancers (PCa). Quantification of T2:ERG in post-DRE urine, in combination with PCA3, improves the performance of serum PSA for PCa prediction on biopsy Here we compared urine T2:ERG and PCA3 scores to ERG+ (determined by immunohistochemistry) and total prostate cancer burden in 41 mapped prostatectomies. Prostatectomies had a median of 3 tumor foci (range: 1–15) and 2.6 cm of summed linear tumor dimension (range: 0.6–7.1 cm). Urine T2:ERG score most correlated with summed linear ERG+ tumor dimension and number of ERG+ foci (rs=0.68 and 0.67, respectively, both p<0.001). Urine PCA3 score showed weaker correlation with both number of tumor foci (rs=0.34, p=0.03) and summed linear tumor dimension (rs=0.26, p=0.10). In summary, we demonstrate a strong correlation between urine T2:ERG score and total ERG+ PCa burden at prostatectomy, consistent with high tumor specificity. PMID:23086769

  10. Data Interoperability of Whole Exome Sequencing (WES) Based Mutational Burden Estimates from Different Laboratories

    PubMed Central

    Qiu, Ping; Pang, Ling; Arreaza, Gladys; Maguire, Maureen; Chang, Ken C. N.; Marton, Matthew J.; Levitan, Diane

    2016-01-01

    Immune checkpoint inhibitors, which unleash a patient’s own T cells to kill tumors, are revolutionizing cancer treatment. Several independent studies suggest that higher non-synonymous mutational burden assessed by whole exome sequencing (WES) in tumors is associated with improved objective response, durable clinical benefit, and progression-free survival in immune checkpoint inhibitors treatment. Next-generation sequencing (NGS) is a promising technology being used in the clinic to direct patient treatment. Cancer genome WES poses a unique challenge due to tumor heterogeneity and sequencing artifacts introduced by formalin-fixed, paraffin-embedded (FFPE) tissue. In order to evaluate the data interoperability of WES data from different sources to survey tumor mutational landscape, we compared WES data of several tumor/normal matched samples from five commercial vendors. A large data discrepancy was observed from vendors’ self-reported data. Independent data analysis from vendors’ raw NGS data shows that whole exome sequencing data from qualified vendors can be combined and analyzed uniformly to derive comparable quantitative estimates of tumor mutational burden. PMID:27136543

  11. Multiple intestinal lymphomatous polyposis in a Jindo dog

    PubMed Central

    Jeong, Da-Hee; Do, Sun-Hee; Hong, Il-Hwa; Yang, Hai-Jie; Yuan, Dong-Wei; Choi, Dong-Hag

    2006-01-01

    A male, 5-year-old Jindo dog underwent enterectomy and enteroanastomosis due to ileus of the intestine at a local veterinary hospital. Grossly, the excised intestine showed markedly thickened multinodular masses in the serosal layer of the upper part, and soft-to-firm, cream-colored neoplastic masses that displayed extensive nodular mucosal protuberances into the lumen. The neoplastic masses were filled with large round cells that were ovoid in shape and they had pale and/or hyperchromatic nuclei. The neoplastic cells had mainly infiltrated into the mucosal and submucosal layers, and they had diffusely invaded the muscular and serosal layers. Therefore, the diagnosis of canine multiple intestinal malignant lymphomatous polyposis was made based on the gross and histopathological findings. The origin of these tumor cells was determined to be B-cells since they were positive for anti-CD20. PMID:17106235

  12. T lymphocytes and macrophages in the intestinal tissues of dogs infected with Leishmania infantum.

    PubMed

    Silva, Diogo Tiago da; Alves, Maria Luana; Spada, Júlio Cesar Pereira; Silva, Aline Cristine da; Silveira, Rita de Cássia Viveiros da; Oliveira, Trícia Maria Ferreira de Sousa; Starke-Buzetti, Wilma Aparecida

    2017-01-01

    This study was about a semi-quantitative analysis of T lymphocytes (CD4+ and CD8+, FoxP3+ regulatory T cells), and macrophages in the gut wall of dogs naturally infected with Leishmania infantum. Thirteen dogs were divided into three groups: group 1 (G1, n=5), dogs with canine visceral leishmaniasis (CVL) and infected with L. infantum amastigotes in the intestine; group 2 (G2, n=5), dogs with CVL but without intestinal amastigotes; and group 3 (G3, n=3), uninfected dogs (control group). There was no significant difference (p ≥ 0.05) on CD4+ and Treg cell numbers among the groups, whereas the levels of CD8+ T cells and macrophages were significantly higher in dogs from G1 group than in G2 and G3 (p ≤ 0.05), especially in intestinal segments with high parasite burden. Parasite burden correlated positively with levels of CD8+ T cells and macrophages (p ≤ 0.05), but was inversely correlated to levels of CD4+ T lymphocytes and FoxP3+ Treg cells. In conclusion, in the intestine of dogs with CVL, the increase of CD8+ T cells and macrophages population associated with high parasite burdens, but no changes of CD4+ T cells and FoxP3+ Treg cells suggest a possible immunoregulation by the parasite not dependent on Treg cells.

  13. Alcohol-associated intestinal dysbiosis impairs pulmonary host defense against Klebsiella pneumoniae.

    PubMed

    Samuelson, Derrick R; Shellito, Judd E; Maffei, Vincent J; Tague, Eric D; Campagna, Shawn R; Blanchard, Eugene E; Luo, Meng; Taylor, Christopher M; Ronis, Martin J J; Molina, Patricia E; Welsh, David A

    2017-06-01

    Chronic alcohol consumption perturbs the normal intestinal microbial communities (dysbiosis). To investigate the relationship between alcohol-mediated dysbiosis and pulmonary host defense we developed a fecal adoptive transfer model, which allows us to investigate the impact of alcohol-induced gut dysbiosis on host immune response to an infectious challenge at a distal organ, independent of prevailing alcohol use. Male C57BL/6 mice were treated with a cocktail of antibiotics (ampicillin, gentamicin, neomycin, vancomycin, and metronidazole) via daily gavage for two weeks. A separate group of animals was fed a chronic alcohol (or isocaloric dextrose pair-fed controls) liquid diet for 10 days. Microbiota-depleted mice were recolonized with intestinal microbiota from alcohol-fed or pair-fed (control) animals. Following recolonization groups of mice were sacrificed prior to and 48 hrs. post respiratory infection with Klebsiella pneumoniae. Klebsiella lung burden, lung immunology and inflammation, as well as intestinal immunology, inflammation, and barrier damage were examined. Results showed that alcohol-associated susceptibility to K. pneumoniae is, in part, mediated by gut dysbiosis, as alcohol-naïve animals recolonized with a microbiota isolated from alcohol-fed mice had an increased respiratory burden of K. pneumoniae compared to mice recolonized with a control microbiota. The increased susceptibility in alcohol-dysbiosis recolonized animals was associated with an increase in pulmonary inflammatory cytokines, and a decrease in the number of CD4+ and CD8+ T-cells in the lung following Klebsiella infection but an increase in T-cell counts in the intestinal tract following Klebsiella infection, suggesting intestinal T-cell sequestration as a factor in impaired lung host defense. Mice recolonized with an alcohol-dysbiotic microbiota also had increased intestinal damage as measured by increased levels of serum intestinal fatty acid binding protein. Collectively, these

  14. Alcohol-associated intestinal dysbiosis impairs pulmonary host defense against Klebsiella pneumoniae

    PubMed Central

    Campagna, Shawn R.; Blanchard, Eugene E.; Ronis, Martin J. J.

    2017-01-01

    Chronic alcohol consumption perturbs the normal intestinal microbial communities (dysbiosis). To investigate the relationship between alcohol-mediated dysbiosis and pulmonary host defense we developed a fecal adoptive transfer model, which allows us to investigate the impact of alcohol-induced gut dysbiosis on host immune response to an infectious challenge at a distal organ, independent of prevailing alcohol use. Male C57BL/6 mice were treated with a cocktail of antibiotics (ampicillin, gentamicin, neomycin, vancomycin, and metronidazole) via daily gavage for two weeks. A separate group of animals was fed a chronic alcohol (or isocaloric dextrose pair-fed controls) liquid diet for 10 days. Microbiota-depleted mice were recolonized with intestinal microbiota from alcohol-fed or pair-fed (control) animals. Following recolonization groups of mice were sacrificed prior to and 48 hrs. post respiratory infection with Klebsiella pneumoniae. Klebsiella lung burden, lung immunology and inflammation, as well as intestinal immunology, inflammation, and barrier damage were examined. Results showed that alcohol-associated susceptibility to K. pneumoniae is, in part, mediated by gut dysbiosis, as alcohol-naïve animals recolonized with a microbiota isolated from alcohol-fed mice had an increased respiratory burden of K. pneumoniae compared to mice recolonized with a control microbiota. The increased susceptibility in alcohol-dysbiosis recolonized animals was associated with an increase in pulmonary inflammatory cytokines, and a decrease in the number of CD4+ and CD8+ T-cells in the lung following Klebsiella infection but an increase in T-cell counts in the intestinal tract following Klebsiella infection, suggesting intestinal T-cell sequestration as a factor in impaired lung host defense. Mice recolonized with an alcohol-dysbiotic microbiota also had increased intestinal damage as measured by increased levels of serum intestinal fatty acid binding protein. Collectively, these

  15. The protective role of montelukast against intestinal ischemia-reperfusion injury in rats

    PubMed Central

    Wu, Shenbao; Zhu, Xuxing; Jin, Zhonghai; Tong, Xiuping; Zhu, Liqin; Hong, Xiaofei; Zhu, Xianfei; Liu, Pengfei; Shen, Weidong

    2015-01-01

    Several drugs are effective in attenuating intestinal ischemia-reperfusion injury (IRI); however little is known about the effect of montelukast. Fifty rats were randomly assigned to 3 groups: model group (operation with clamping), sham group (operation without clamping), and study group (operation with clamping and 0.2, 2 and 20 mg/kg montelukast pretreatment). Intestinal ischemia-reperfusion was performed by occlusion (clamping) of the arteria mesenterica anterior for 45 min, followed by 24 h reperfusion. Intestinal IRI in the model group led to severe damage of the intestinal mucosa, liver and kidney. The Chiu scores of the intestines from the study group (2 and 20 mg/kg) were lower than that of the model group. Intestinal IRI induced a marked increase in CysLTR1, Caspase-8 and -9 expression in intestine, liver and kidney, which were markedly reduced by preconditioning with 2 mg/kg montelukast. Preconditioning with 2 g/kg montelukast significantly attenuated hepatic tissue injury and kidney damage, and decreased plasma interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels in plasma after intestinal IRI. In conclusion, preconditioning with montelukast could attenuate intestinal IRI and the subsequent systemic inflammatory response in rats. PMID:26497763

  16. The protective role of montelukast against intestinal ischemia-reperfusion injury in rats.

    PubMed

    Wu, Shenbao; Zhu, Xuxing; Jin, Zhonghai; Tong, Xiuping; Zhu, Liqin; Hong, Xiaofei; Zhu, Xianfei; Liu, Pengfei; Shen, Weidong

    2015-10-26

    Several drugs are effective in attenuating intestinal ischemia-reperfusion injury (IRI); however little is known about the effect of montelukast. Fifty rats were randomly assigned to 3 groups: model group (operation with clamping), sham group (operation without clamping), and study group (operation with clamping and 0.2, 2 and 20 mg/kg montelukast pretreatment). Intestinal ischemia-reperfusion was performed by occlusion (clamping) of the arteria mesenterica anterior for 45 min, followed by 24 h reperfusion. Intestinal IRI in the model group led to severe damage of the intestinal mucosa, liver and kidney. The Chiu scores of the intestines from the study group (2 and 20 mg/kg) were lower than that of the model group. Intestinal IRI induced a marked increase in CysLTR1, Caspase-8 and -9 expression in intestine, liver and kidney, which were markedly reduced by preconditioning with 2 mg/kg montelukast. Preconditioning with 2 g/kg montelukast significantly attenuated hepatic tissue injury and kidney damage, and decreased plasma interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels in plasma after intestinal IRI. In conclusion, preconditioning with montelukast could attenuate intestinal IRI and the subsequent systemic inflammatory response in rats.

  17. How to make an intestine

    PubMed Central

    Wells, James M.; Spence, Jason R.

    2014-01-01

    With the high prevalence of gastrointestinal disorders, there is great interest in establishing in vitro models of human intestinal disease and in developing drug-screening platforms that more accurately represent the complex physiology of the intestine. We will review how recent advances in developmental and stem cell biology have made it possible to generate complex, three-dimensional, human intestinal tissues in vitro through directed differentiation of human pluripotent stem cells. These are currently being used to study human development, genetic forms of disease, intestinal pathogens, metabolic disease and cancer. PMID:24496613

  18. Saireito (TJ-114), a Japanese traditional herbal medicine, reduces 5-fluorouracil-induced intestinal mucositis in mice by inhibiting cytokine-mediated apoptosis in intestinal crypt cells.

    PubMed

    Kato, Shinichi; Hayashi, Shusaku; Kitahara, Yumeno; Nagasawa, Koyo; Aono, Hitomi; Shibata, Junichiro; Utsumi, Daichi; Amagase, Kikuko; Kadowaki, Makoto

    2015-01-01

    Clinical chemotherapy frequently causes intestinal mucositis as a side effect, which is accompanied by severe diarrhea. We recently showed that the cytokine-mediated apoptotic pathway might be important for the development of intestinal mucositis induced by 5-fluorouracil (5-FU). Saireito, the traditional Japanese herbal (Kampo) medicine, is widely used to treat diarrhea and various inflammatory diseases in Japan. In the present study, we investigated the effect of saireito on 5-FU-induced intestinal mucositis in mice, especially in relation to apoptosis in the intestinal crypt. Male C57BL/6 mice were given 5-FU (50 mg/kg), i.p. once daily for 6 days. Intestinal mucositis was evaluated histochemically. Saireito (100-1000 mg/kg) was administered p.o. twice daily for 6 days. Repeated 5-FU treatment caused severe intestinal mucositis including morphological damage, which was accompanied by body weight loss and diarrhea. Daily administration of saireito reduced the severity of intestinal mucositis in a dose-dependent manner. Body weight loss and diarrhea during 5-FU treatment were also significantly attenuated by saireito administration. The number of apoptotic and caspase-3-activated cells in the intestinal crypt was increased, and was accompanied by up-regulated tumor necrosis factor (TNF)-α and interleukin (IL)-1β mRNA within 24 h of the first 5-FU injection. However, all of these measures were significantly lower after saireito administration. These results suggest that saireito attenuates 5-FU-induced intestinal mucositis. This action may come from the reduction of apoptosis in the intestinal crypt via suppression of the up-regulation of inflammatory cytokines. Therefore, saireito may be clinically useful for the prevention of intestinal mucositis during cancer chemotherapy.

  19. Attenuation of hydrogen peroxide and ferric reducing/antioxidant power serum levels in colorectal cancer patients with intestinal parasitic infection.

    PubMed

    Chandramathi, Samudi; Suresh, Kumar Govind; Anita, Zarina Bustam; Kuppusamy, Umah Rani

    2009-04-01

    This study assessed several common oxidative indices in subjects infected with intestinal parasites, as well as in colorectal cancer (CRC) patients both with and without intestinal parasites. Serum levels of malondialdehyde (MDA), ferric reducing/antioxidant power (FRAP), and hydrogen peroxide (H(2)O(2)) were measured, as were plasma levels of advanced oxidation protein products (AOPP), all according to established methods. The presence of intestinal parasites was confirmed by stool examination. All intestinal parasiteinfected subjects and CRC patients showed the presence of oxidative stress. Thirtysix percent of the CRC patients had intestinal parasitic infections. The levels of H(2)O(2) and FRAP in parasite-infected subjects were significantly higher than in CRC patients, but these levels were significantly lower in the CRC patients with parasitic infections. Parasitic infection and CRC may contribute to oxidative stress independently, but when present together, the oxidative stress burden imposed by parasites may be attenuated.

  20. The economic burden of schizophrenia in Malaysia.

    PubMed

    Teoh, Siew Li; Chong, Huey Yi; Abdul Aziz, Salina; Chemi, Norliza; Othman, Abdul Razak; Md Zaki, Nurzuriana; Vanichkulpitak, Possatorn; Chaiyakunapruk, Nathorn

    2017-01-01

    Schizophrenia (SCZ) is a highly debilitating disease despite its low prevalence. The economic burden associated with SCZ is substantial and mainly attributed to productivity loss. To improve the understanding of economic burden of SCZ in the low- and middle-income country regions, we aimed to determine the economic burden of SCZ in Malaysia. A retrospective study was conducted using a prevalence-based approach from a societal perspective in Malaysia with a 1 year period from 2013. We used micro-costing technique with bottom-up method and included direct medical cost, direct non-medical cost, and indirect cost. The main data source was medical chart review which was conducted in Hospital Kuala Lumpur (HKL). The medical charts were identified electronically by matching the unique patient's identification number registered under the National Mental Health Schizophrenia Registry and the list of patients in HKL in 2013. Other data sources were government documents, literatures, and local websites. To ensure robustness of result, probabilistic sensitivity analysis was conducted. The total estimated number of treated SCZ cases in Malaysia in 2015 was 15,104 with the total economic burden of USD 100 million (M) which was equivalent to 0.04% of the national gross domestic product. On average, the mean cost per patient was USD 6,594. Of the total economic burden of SCZ, 72% was attributed to indirect cost, costing at USD 72M, followed by direct medical cost (26%), costing at USD 26M, and direct non-medical cost (2%), costing at USD 1.7M. This study highlights the magnitude of economic burden of SCZ and informs the policy-makers that there is an inadequate support for SCZ patients. More resources should be allocated to improve the condition of SCZ patients and to reduce the economic burden.

  1. The economic burden of schizophrenia in Malaysia

    PubMed Central

    Teoh, Siew Li; Chong, Huey Yi; Abdul Aziz, Salina; Chemi, Norliza; Othman, Abdul Razak; Md Zaki, Nurzuriana; Vanichkulpitak, Possatorn; Chaiyakunapruk, Nathorn

    2017-01-01

    Introduction Schizophrenia (SCZ) is a highly debilitating disease despite its low prevalence. The economic burden associated with SCZ is substantial and mainly attributed to productivity loss. To improve the understanding of economic burden of SCZ in the low- and middle-income country regions, we aimed to determine the economic burden of SCZ in Malaysia. Methods A retrospective study was conducted using a prevalence-based approach from a societal perspective in Malaysia with a 1 year period from 2013. We used micro-costing technique with bottom-up method and included direct medical cost, direct non-medical cost, and indirect cost. The main data source was medical chart review which was conducted in Hospital Kuala Lumpur (HKL). The medical charts were identified electronically by matching the unique patient’s identification number registered under the National Mental Health Schizophrenia Registry and the list of patients in HKL in 2013. Other data sources were government documents, literatures, and local websites. To ensure robustness of result, probabilistic sensitivity analysis was conducted. Results The total estimated number of treated SCZ cases in Malaysia in 2015 was 15,104 with the total economic burden of USD 100 million (M) which was equivalent to 0.04% of the national gross domestic product. On average, the mean cost per patient was USD 6,594. Of the total economic burden of SCZ, 72% was attributed to indirect cost, costing at USD 72M, followed by direct medical cost (26%), costing at USD 26M, and direct non-medical cost (2%), costing at USD 1.7M. Conclusion This study highlights the magnitude of economic burden of SCZ and informs the policy-makers that there is an inadequate support for SCZ patients. More resources should be allocated to improve the condition of SCZ patients and to reduce the economic burden. PMID:28814869

  2. High rates of chromosome missegregation suppress tumor progression but do not inhibit tumor initiation

    PubMed Central

    Zasadil, Lauren M.; Britigan, Eric M. C.; Ryan, Sean D.; Kaur, Charanjeet; Guckenberger, David J.; Beebe, David J.; Moser, Amy R.; Weaver, Beth A.

    2016-01-01

    Aneuploidy, an abnormal chromosome number that deviates from a multiple of the haploid, has been recognized as a common feature of cancers for >100 yr. Previously, we showed that the rate of chromosome missegregation/chromosomal instability (CIN) determines the effect of aneuploidy on tumors; whereas low rates of CIN are weakly tumor promoting, higher rates of CIN cause cell death and tumor suppression. However, whether high CIN inhibits tumor initiation or suppresses the growth and progression of already initiated tumors remained unclear. We tested this using the ApcMin/+ mouse intestinal tumor model, in which effects on tumor initiation versus progression can be discriminated. ApcMin/+ cells exhibit low CIN, and we generated high CIN by reducing expression of the kinesin-like mitotic motor protein CENP-E. CENP-E+/−;ApcMin/+ doubly heterozygous cells had higher rates of chromosome missegregation than singly heterozygous cells, resulting in increased cell death and a substantial reduction in tumor progression compared with ApcMin/+ animals. Intestinal organoid studies confirmed that high CIN does not inhibit tumor cell initiation but does inhibit subsequent cell growth. These findings support the conclusion that increasing the rate of chromosome missegregation could serve as a successful chemotherapeutic strategy. PMID:27146113

  3. Preoperative diagnosis of cavernous hemangioma presenting with melena using wireless capsule endoscopy of the small intestine

    PubMed Central

    Akazawa, Yu; Hiramatsu, Katsushi; Nosaka, Takuto; Saito, Yasushi; Ozaki, Yoshihiko; Takahashi, Kazuto; Naito, Tatsushi; Ofuji, Kazuya; Matsuda, Hidetaka; Ohtani, Masahiro; Nemoto, Tomoyuki; Suto, Hiroyuki; Yamaguchi, Akio; Imamura, Yoshiaki; Nakamoto, Yasunari

    2016-01-01

    Background and study aims: Primary neoplasms of the small intestine are relatively rare in all age groups, accounting for about 5 % of all gastrointestinal tumors 1. Cavernous hemangiomas of the small intestine are also rare, can cause gastrointestinal bleeding, and are extremely difficult to diagnose preoperatively 2. We present a patient who presented with melena and iron deficiency anemia, for whom wireless capsule endoscopy and single-balloon enteroscopy facilitated the diagnosis of cavernous hemangioma. PMID:27004239

  4. Immunoglobulin in intestinal secretions.

    PubMed

    Cutropia de Guirao, C

    1977-12-01

    The objective of the present investigation is the study and interpretation of the role played by the immunoglobulins, especially IgA, during acute diarrhea in children. IgA, IGG and IgM values in serum and IgA in intestinal secretions were studied in a group of children (between 3 months and 5 years of age) during diarrhea, convalescence and in normals. The method of simple radial immunodiffusion according to Mancini was employed. IgA is the immunoglobulin which suffers the greastest alteration in acute diarrhea. The precipitation halos (the average values), were lower during the diarrhea than in convalescence and in normals.

  5. Teleost intestinal immunology.

    PubMed

    Rombout, Jan H W M; Abelli, Luigi; Picchietti, Simona; Scapigliati, Giuseppe; Kiron, Viswanath

    2011-11-01

    Teleosts clearly have a more diffuse gut associated lymphoid system, which is morphological and functional clearly different from the mammalian GALT. All immune cells necessary for a local immune response are abundantly present in the gut mucosa of the species studied and local immune responses can be monitored after intestinal immunization. Fish do not produce IgA, but a special mucosal IgM isotype seems to be secreted and may (partly) be the recently described IgZ/IgT. Fish produce a pIgR in their mucosal tissues but it is smaller (2 ILD) than the 4-5 ILD pIgR of higher vertebrates. Whether teleost pIgR is transcytosed and cleaved off in the same way needs further investigation, especially because a secretory component (SC) is only reported in one species. Teleosts also have high numbers of IEL, most of them are CD3-ɛ+/CD8-α+ and have cytotoxic and/or regulatory function. Possibly many of these cells are TCRγδ cells and they may be involved in the oral tolerance induction observed in fish. Innate immune cells can be observed in the teleost gut from first feeding onwards, but B cells appear much later in mucosal compartments compared to systemic sites. Conspicuous is the very early presence of putative T cells or their precursors in the fish gut, which together with the rag-1 expression of intestinal lymphoid cells may be an indication for an extra-thymic development of certain T cells. Teleosts can develop enteritis in their antigen transporting second gut segment and epithelial cells, IEL and eosinophils/basophils seem to play a crucial role in this intestinal inflammation model. Teleost intestine can be exploited for oral vaccination strategies and probiotic immune stimulation. A variety of encapsulation methods, to protect vaccines against degradation in the foregut, are reported with promising results but in most cases they appear not to be cost effective yet. Microbiota in fish are clearly different from terrestrial animals. In the past decade a fast

  6. Synthetic Small Intestinal Scaffolds for Improved Studies of Intestinal Differentiation

    PubMed Central

    Costello, Cait M.; Hongpeng, Jia; Shaffiey, Shahab; Yu, Jiajie; Jain, Nina K.; Hackam, David

    2014-01-01

    In vitro intestinal models can provide new insights into small intestinal function, including cellular growth and proliferation mechanisms, drug absorption capabilities, and host-microbial interactions. These models are typically formed with cells cultured on 2D scaffolds or transwell inserts, but it is widely understood that epithelial cells cultured in 3D environments exhibit different phenotypes that are more reflective of native tissue. Our focus was to develop a porous, synthetic 3D tissue scaffold with villous features that could support the culture of epithelial cell types to mimic the natural microenvironment of the small intestine. We demonstrated that our scaffold could support the co-culture of Caco-2 cells with a mucus-producing cell line, HT29-MTX, as well as small intestinal crypts from mice for extended periods. By recreating the surface topography with accurately sized intestinal villi, we enable cellular differentiation along the villous axis in a similar manner to native intestines. In addition, we show that the biochemical microenvironments of the intestine can be further simulated via a combination of apical and basolateral feeding of intestinal cell types cultured on the 3D models. PMID:24390638

  7. Microbiota Plays a Key Role in Non-Steroidal Anti-Inflammatory Drug-Induced Small Intestinal Damage.

    PubMed

    Otani, Koji; Tanigawa, Tetsuya; Watanabe, Toshio; Shimada, Sunao; Nadatani, Yuji; Nagami, Yasuaki; Tanaka, Fumio; Kamata, Noriko; Yamagami, Hirokazu; Shiba, Masatsugu; Tominaga, Kazunari; Fujiwara, Yasuhiro; Arakawa, Tetsuo

    2017-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) damage the small intestine by causing multiple erosions and ulcers. However, to date, no established therapies and prophylactic agents are available to treat such damages. We reviewed the role of intestinal microbiota in NSAID-induced intestinal damage and identified potential therapeutic candidates. The composition of the intestinal microbiota is an important factor in the pathophysiology of NSAID-induced small intestinal damage. Once mucosal barrier function is disrupted due to NSAID-induced prostaglandin deficiency and mitochondrial malfunction, lipopolysaccharide from luminal gram-negative bacteria and high mobility group box 1 from the injured epithelial cells activate toll-like receptor 4-signaling pathway and nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 inflammasome; this leads to the release of proinflammatory cytokines such as tumor necrosis factor-α and interleukin-1β. Proton pump inhibitors (PPIs) are often used for the prevention of NSAID-induced injuries to the upper gastrointestinal tract. However, several studies indicate that PPIs may induce dysbiosis, which may exacerbate the NSAID-induced small intestinal damage. Our recent research suggests that probiotics and rebamipide could be used to prevent NSAID-induced small intestinal damage by regulating the intestinal microbiota. Key Messages: Intestinal microbiota plays a key role in NSAID-induced small intestinal damage, and modulating the composition of the intestinal microbiota could be a new therapeutic strategy for treating this damage. © 2016 S. Karger AG, Basel.

  8. Recurrent intestinal intussusception in an adult due to intestinal pseudopolyps not associated with inflammatory bowel disease: a case report.

    PubMed

    Martínez-Ubieto, Fernando; Jiménez-Bernadó, Teresa; Bueno-Delgado, Alvaro; Martínez-Ubieto, Javier; Pascual-Bellosta, Ana

    2015-11-23

    Intestinal intussusception is very rare in adults and, unlike in children, it is due to an organic cause, mainly benign or malignant tumors, in 90 % of cases. Recurrent intussusception in an adult is even more exceptional, and in the case reported it was due to repeated occurrence of intestinal pseudopolyps, which is exceptional according to the literature. Preoperative diagnosis is difficult, and surgery is always indicated because a tumor is usually present. The surgical procedure may be controversial, as some would prefer desintussusception before resection, while others would advocate initial resection because of the risk of dissemination if a malignant lesion exists. We report the case of a 34-year-old Caucasian man who underwent emergency laparoscopic surgery for intestinal obstruction and was found to have a jejunal intussusception. Polyps or pseudopolyps, some of them large and causing the intussusception, were seen in the surgical specimen. Our patient had also undergone surgery for intussusception 10 years before, after which the pathological report also noted the presence of these formations. Recurrent intussusception in adults due to the presence of intestinal pseudopolyps is exceptional and, to the best of our knowledge, this is the first such case reported.

  9. Burden of serious fungal infections in Tanzania.

    PubMed

    Faini, Diana; Maokola, Werner; Furrer, Hansjakob; Hatz, Christoph; Battegay, Manuel; Tanner, Marcel; Denning, David W; Letang, Emilio

    2015-10-01

    The incidence and prevalence of fungal infections in Tanzania remains unknown. We assessed the annual burden in the general population and among populations at risk. Data were extracted from 2012 reports of the Tanzanian AIDS program, WHO, reports, Tanzanian census, and from a comprehensive PubMed search. We used modelling and HIV data to estimate the burdens of Pneumocystis jirovecii pneumonia (PCP), cryptococcal meningitis (CM) and candidiasis. Asthma, chronic obstructive pulmonary disease and tuberculosis data were used to estimate the burden of allergic bronchopulmonary aspergillosis (ABPA) and chronic pulmonary aspergillosis (CPA). Burdens of candidaemia and Candida peritonitis were derived from critical care and/or cancer patients' data. In 2012, Tanzania's population was 43.6 million (mainland) with 1,500,000 people reported to be HIV-infected. Estimated burden of fungal infections was: 4412 CM, 9600 PCP, 81,051 and 88,509 oral and oesophageal candidiasis cases respectively. There were 10,437 estimated post-tuberculosis CPA cases, whereas candidaemia and Candida peritonitis cases were 2181 and 327 respectively. No reliable data exist on blastomycosis, mucormycosis or fungal keratitis. Over 3% of Tanzanians suffer from serious fungal infections annually, mostly related to HIV. Cryptococcosis and PCP are major causes of mycoses-related deaths. National surveillance of fungal infections is urgently needed.

  10. Burden of childhood-onset arthritis

    PubMed Central

    2010-01-01

    Juvenile arthritis comprises a variety of chronic inflammatory diseases causing erosive arthritis in children, often progressing to disability. These children experience functional impairment due to joint and back pain, heel pain, swelling of joints and morning stiffness, contractures, pain, and anterior uveitis leading to blindness. As children who have juvenile arthritis reach adulthood, they face possible continuing disease activity, medication-associated morbidity, and life-long disability and risk for emotional and social dysfunction. In this article we will review the burden of juvenile arthritis for the patient and society and focus on the following areas: patient disability; visual outcome; other medical complications; physical activity; impact on HRQOL; emotional impact; pain and coping; ambulatory visits, hospitalizations and mortality; economic impact; burden on caregivers; transition issues; educational occupational outcomes, and sexuality. The extent of impact on the various aspects of the patients', families' and society's functioning is clear from the existing literature. Juvenile arthritis imposes a significant burden on different spheres of the patients', caregivers' and family's life. In addition, it imposes a societal burden of significant health care costs and utilization. Juvenile arthritis affects health-related quality of life, physical function and visual outcome of children and impacts functioning in school and home. Effective, well-designed and appropriately tailored interventions are required to improve transitioning to adult care, encourage future vocation/occupation, enhance school function and minimize burden on costs. PMID:20615240

  11. General Information about Small Intestine Cancer

    MedlinePlus

    ... Health Professional Small Intestine Cancer Treatment Research Small Intestine Cancer Treatment (PDQ®)–Patient Version General Information About Small Intestine Cancer Go to Health Professional Version Key Points ...

  12. Treatment Option Overview (Small Intestine Cancer)

    MedlinePlus

    ... Health Professional Small Intestine Cancer Treatment Research Small Intestine Cancer Treatment (PDQ®)–Patient Version General Information About Small Intestine Cancer Go to Health Professional Version Key Points ...

  13. How Is Small Intestine Adenocarcinoma Staged?

    MedlinePlus

    ... Early Detection, Diagnosis, and Staging How Is Small Intestine Adenocarcinoma Staged? Staging is a process that tells ... distant m etastasis (M). T categories for small intestine adenocarcinoma T categories of small intestine cancer describe ...

  14. Work productivity in brain tumor survivors.

    PubMed

    Feuerstein, Michael; Hansen, Jennifer A; Calvio, Lisseth C; Johnson, Leigh; Ronquillo, Jonne G

    2007-07-01

    To determine the association of symptom burden to work limitation among working survivors of malignant brain tumors. Working adults with malignant brain tumors (n = 95) and a non-cancer comparison (n = 131) group completed a web-based questionnaire. Measures of demographics, tumor type and treatment, fatigue, emotional distress, cognitive limitations, and factors that can positively impact work, including health behaviors and problem solving, were obtained. Survivors of malignant brain tumors reported higher levels of work limitations and time off from work than the non-cancer group. Higher levels of symptom burden, lower levels of health behaviors, and more negative problem solving orientation were characteristic of the brain tumor survivor group. These variables were not differentially associated with work limitations among brain cancer survivors or the comparison group. Depressive symptoms, fatigue, cognitive limitations, sleep, and negative problem solving orientation were independently associated with work limitations, accounting for 65% of the variance in work limitations. Despite higher levels of burden, poorer health behaviors, and negative problem solving coping style, modifiable factors account for most of the variance in work limitations for both groups. Efforts to modify these variables should be evaluated.

  15. Intestinal adenocarcinoma in a herd of farmed Sika deer (Cervus nippon): a novel syndrome.

    PubMed

    Kelly, P A; Toolan, D; Jahns, H

    2015-01-01

    Intestinal adenocarcinomas were identified in 76 adult deer from a closed herd of 193 breeding animals grazing pasture heavily infested with bracken fern (Pteridium aquilinum). Tumors were observed postmortem in 32 animals with rapid weight loss, and similar neoplasms were detected in a further 44 clinically normal deer at "cull." Tumors were located in distal ileum, cecum, and proximal colon and presented as single (26%) or multiple (74%), variably sized, pale-gray, firm, poorly circumscribed neoplasms with associated intestinal strictures. Histopathologically tumors were well-differentiated, locally infiltrative, low-grade adenocarcinomas of tubular (51%), mucinous (33.5%), or mixed (15.5%) types. Extraintestinal metastases were not observed. The high incidence of intestinal adenocarcinoma within this herd suggests a specific and novel syndrome, and genetic and/or environmental factors may be involved in the pathogenesis. © The Author(s) 2014.

  16. Pituitary Tumors

    MedlinePlus

    ... National Brain Tumor Society 55Chapel Street Suite 200 Newton MA Newton, MA 02458 questions@braintumor.org http://www.braintumor. ... National Brain Tumor Society 55Chapel Street Suite 200 Newton MA Newton, MA 02458 questions@braintumor.org http:// ...

  17. Pituitary Tumors

    MedlinePlus

    ... pituitary is the "master control gland" - it makes hormones that affect growth and the functions of other glands in the body. Pituitary tumors are common, but often they don't cause health ... tumor produces hormones and disrupts the balance of hormones in your ...

  18. Carcinoid Tumors

    MedlinePlus

    Carcinoid tumors are rare, slow-growing cancers. They usually start in the lining of the digestive tract or in the lungs. They grow ... trouble breathing. Surgery is the main treatment for carcinoid tumors. If they haven't spread to other parts of the body, surgery can cure the cancer.

  19. Hypothalamic tumor

    MedlinePlus

    ... occur at any age. They are often more aggressive in adults than in children. In adults, tumors ... The treatment depends on how aggressive the tumor is, and whether it is a glioma or another type of cancer. Treatment may involve combinations of surgery, radiation , ...

  20. Pindborg tumor

    PubMed Central

    Caliaperoumal, Santhosh Kumar; Gowri, S.; Dinakar, J.

    2016-01-01

    Calcifying epithelial odontogenic tumor (CEOT), also known as Pindborg tumor, is a rare odontogenic epithelial neoplasm. So far, nearly 200 cases have been reported in the literature. We are reporting a case of CEOT in a 42-year-old male patient with painless bony swelling in the mandible. The clinical, radiographic, and histopathologic features are discussed with relevant references. PMID:27041911

  1. 40 CFR 22.24 - Burden of presentation; burden of persuasion; preponderance of the evidence standard.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 1 2011-07-01 2011-07-01 false Burden of presentation; burden of persuasion; preponderance of the evidence standard. 22.24 Section 22.24 Protection of Environment... complaint and any response or evidence with respect to the appropriate relief. The respondent has...

  2. GAD Antibodies as Key Link Between Chronic Intestinal Pseudoobstruction, Autonomic Neuropathy, and Limb Stiffness in a Nondiabetic Patient

    PubMed Central

    Maier, Andrea; Mannartz, Vera; Wasmuth, Hermann; Trautwein, Christian; Neumann, Ulf-Peter; Weis, Joachim; Grosse, Joachim; Fuest, Matthias; Hilz, Max-J.; Schulz, Joerg B.; Haubrich, Christina

    2015-01-01

    Abstract Chronic intestinal pseudoobstruction (CIP) can be a severe burden and even a life-threatening disorder. Typically, several years of uncertainty are passing before diagnosis. We are reporting the case of a young woman with a decade of severe, progressive gastrointestinal dysmotility. Unusually, she had also developed an autonomic neuropathy, and a stiff limb syndrome. In addition to achalasia and CIP the young woman also developed neuropathic symptoms: orthostatic intolerance, urinary retention, a Horner syndrome, and lower limb stiffness. Careful interdisciplinary diagnostics excluded underlying infectious, rheumatoid, metabolic or tumorous diseases. The detection of GAD (glutamic acid decarboxylase) antibodies, however, seemed to link CIP, autonomic neuropathy, and limb stiffness and pointed at an autoimmune origin of our patient's complaints. This was supported by the positive effects of intravenous immunoglobulin. In response to this therapy the body weight had stabilized, orthostatic tolerance had improved, and limb stiffness was reversed. The case suggested that GAD antibodies should be considered in CIP also in nondiabetic patients. This may support earlier diagnosis and immunotherapy. PMID:26252289

  3. Ion channel TRPV1-dependent activation of PTP1B suppresses EGFR-associated intestinal tumorigenesis

    PubMed Central

    de Jong, Petrus R.; Takahashi, Naoki; Harris, Alexandra R.; Lee, Jihyung; Bertin, Samuel; Jeffries, James; Jung, Michael; Duong, Jen; Triano, Amy I.; Lee, Jongdae; Niv, Yaron; Herdman, David S.; Taniguchi, Koji; Kim, Chang-Whan; Dong, Hui; Eckmann, Lars; Stanford, Stephanie M.; Bottini, Nunzio; Corr, Maripat; Raz, Eyal

    2014-01-01

    The intestinal epithelium has a high rate of turnover, and dysregulation of pathways that regulate regeneration can lead to tumor development; however, the negative regulators of oncogenic events in the intestinal epithelium are not fully understood. Here we identified a feedback loop between the epidermal growth factor receptor (EGFR), a known mediator of proliferation, and the transient receptor potential cation channel, subfamily V, member 1 (TRPV1), in intestinal epithelial cells (IECs). We found that TRPV1 was expressed by IECs and was intrinsically activated upon EGFR stimulation. Subsequently, TRPV1 activation inhibited EGFR-induced epithelial cell proliferation via activation of Ca2+/calpain and resulting activation of protein tyrosine phosphatase 1B (PTP1B). In a murine model of multiple intestinal neoplasia (ApcMin/+ mice), TRPV1 deficiency increased adenoma formation, and treatment of these animals with an EGFR kinase inhibitor reversed protumorigenic phenotypes, supporting a functional association between TRPV1 and EGFR signaling in IECs. Administration of a TRPV1 agonist suppressed intestinal tumorigenesis in ApcMin/+ mice, similar to — as well as in conjunction with — a cyclooxygenase-2 (COX-2) inhibitor, which suggests that targeting both TRPV1 and COX-2 has potential as a therapeutic approach for tumor prevention. Our findings implicate TRPV1 as a regulator of growth factor signaling in the intestinal epithelium through activation of PTP1B and subsequent suppression of intestinal tumorigenesis. PMID:25083990

  4. Regenerative Inflammation: Lessons from Drosophila Intestinal Epithelium in Health and Disease

    PubMed Central

    Panayidou, Stavria; Apidianakis, Yiorgos

    2013-01-01

    Intestinal inflammation is widely recognized as a pivotal player in health and disease. Defined cytologically as the infiltration of leukocytes in the lamina propria layer of the intestine, it can damage the epithelium and, on a chronic basis, induce inflammatory bowel disease and potentially cancer. The current view thus dictates that blood cell infiltration is the instigator of intestinal inflammation and tumor-promoting inflammation. This is based partially on work in humans and mice showing that intestinal damage during microbially mediated inflammation activates phagocytic cells and lymphocytes that secrete inflammatory signals promoting tissue damage and tumorigenesis. Nevertheless, extensive parallel work in the Drosophila midgut shows that intestinal epithelium damage induces inflammatory signals and growth factors acting mainly in a paracrine manner to induce intestinal stem cell proliferation and tumor formation when genetically predisposed. This is accomplished without any apparent need to involve Drosophila hemocytes. Therefore, recent work on Drosophila host defense to infection by expanding its main focus on systemic immunity signaling pathways to include the study of organ homeostasis in health and disease shapes a new notion that epithelially emanating cytokines and growth factors can directly act on the intestinal stem cell niche to promote “regenerative inflammation” and potentially cancer. PMID:25437036

  5. Intestinal microbiota and obesity.

    PubMed

    Blaut, Michael; Klaus, Susanne

    2012-01-01

    The human gut harbors a highly diverse microbial ecosystem of approximately 400 different species, which is characterized by a high interindividual variability. The intestinal microbiota has recently been suggested to contribute to the development of obesity and the metabolic syndrome. Transplantation of gut microbiota from obese mice to nonobese, germ-free mice resulted in transfer of metabolic syndrome-associated features from the donor to the recipient. Proposed mechanisms for the role of gut microbiota include the provision of additional energy by the conversion of dietary fiber to short-chain fatty acids, effects on gut-hormone production, and increased intestinal permeability causing elevated systemic levels of lipopolysaccharides (LPS). This metabolic endotoxemia is suggested to contribute to low-grade inflammation, a characteristic trait of obesity and the metabolic syndrome. Finally, activation of the endocannabinoid system by LPS and/or high-fat diets is discussed as another causal factor. In conclusion, there is ample evidence for a role of gut microbiota in the development of obesity in rodents. However, the magnitude of its contribution to human obesity is still unknown.

  6. The Homeodomain Transcription Factor Cdx1 Does Not Behave as an Oncogene in Normal Mouse Intestine1

    PubMed Central

    Crissey, Mary Ann S; Guo, Rong-Jun; Fogt, Franz; Li, Hong; Katz, Jonathan P; Silberg, Debra G; Suh, Eun Ran; Lynch, John P

    2008-01-01

    The Caudal-related homeobox genes Cdx1 and Cdx2 are intestine-specific transcription factors that regulate differentiation of intestinal cell types. Previously, we have shown Cdx1 to be antiproliferative and to promote cell differentiation. However, other studies have suggested that Cdx1 may be an oncogene. To test for oncogenic behavior, we used the murine villin promoter to ectopically express Cdx1 in the small intestinal villi and colonic surface epithelium. No changes in intestinal architecture, cell differentiation, or lineage selection were observed with expression of the transgene. Classic oncogenes enhance proliferation and induce tumors when ectopically expressed. However, the Cdx1 transgene neither altered intestinal proliferation nor induced spontaneous intestinal tumors. In a murine model for colitis-associated cancer, the Cdx1 transgene decreased, rather than increased, the number of adenomas that developed. In the polyps, the expression of the endogenous and the transgenic Cdx1 proteins was largely absent, whereas endogenous Villin expression was retained. This suggests that transgene silencing was specific and not due to a general Villin inactivation. In conclusion, neither the ectopic expression of Cdx1 was associated with changes in intestinal cell proliferation or differentiation nor was there increased intestinal cancer susceptibility. Our results therefore suggest that Cdx1 is not an oncogene in normal intestinal epithelium. PMID:18231635

  7. [Burden of disease in Latin America].

    PubMed

    Gómez Dantés, Héctor; Castro, Ma Victoria; Franco-Marina, Francisco; Bedregal, Paula; Rodríguez García, Jesús; Espinoza, Azalea; Valdez Huarcaya, William; Lozano, Rafael

    2011-01-01

    To describe the burden of disease studies made in the region, identify the main priorities in health from the indicator Disability Adjusted Life Years (DALYs). By the use of DALYs identify the burden of disease in the countries in the network. DALYs emphasize the emergency of mental disorders, diabetes mellitus in women and the disorders associated with alcohol consumption and injuries in men. Latin America is the region with more national studies of burden of disease, using a standardized methodology, that allows identifying new health priorities which are pressing to the health services; for that reason these results constitute an element to take into account in the establishment of public policies in each country.

  8. The unrecognized burden of typhoid fever.

    PubMed

    Obaro, Stephen K; Iroh Tam, Pui-Ying; Mintz, Eric Daniel

    2017-03-01

    Typhoid fever (TF), caused by Salmonella enterica serovar Typhi, is the most common cause of enteric fever, responsible for an estimated 129,000 deaths and more than 11 million cases annually. Although several reviews have provided global and regional TF disease burden estimates, major gaps in our understanding of TF epidemiology remain. Areas covered: We provide an overview of the gaps in current estimates of TF disease burden and offer suggestions for addressing them, so that affected communities can receive the full potential of disease prevention offered by vaccination and water, sanitation, and hygiene interventions. Expert commentary: Current disease burden estimates for TF do not capture cases from certain host populations, nor those with atypical presentations of TF, which may lead to substantial underestimation of TF cases and deaths. These knowledge gaps pose major obstacles to the informed use of current and new generation typhoid vaccines.

  9. The Burden of Human African Trypanosomiasis

    PubMed Central

    Fèvre, Eric M.; Wissmann, Beatrix v.; Welburn, Susan C.; Lutumba, Pascal

    2008-01-01

    Human African trypanosomiasis (HAT, or sleeping sickness) is a protozoan parasitic infection caused by Trypanosoma brucei rhodesiense or Trypanosoma brucei gambiense. These are neglected tropical diseases, and T.b. rhodesiense HAT is a zoonosis. We review current knowledge on the burden of HAT in sub-Saharan Africa, with an emphasis on the disability-adjusted life year (DALY), data sources, and methodological issues relating to the use of this metric for assessing the burden of this disease. We highlight areas where data are lacking to properly quantify the impact of these diseases, mainly relating to quantifying under-reporting and disability associated with infection, and challenge the HAT research community to tackle the neglect in data gathering to enable better evidence-based assessments of burden using DALYs or other appropriate measures. PMID:19104653

  10. Double burden of malnutrition: the Vietnamese perspective.

    PubMed

    Khan, Nguyen Cong; Khoi, Ha Huy

    2008-01-01

    In addition to the burden of undernutrition, many recent studies in Vietnam demonstrate that overweight/obesity and a number of nutritionally- related chronic diseases (NRCD) (hypertension, diabetes, cardio-vascular diseases) are on the rise at an alarming rate. This could be the result of dietary and life style changes. The double burden of malnutrition (DBM) - a typical phenomenon during nutrition transition in developing countries, has been clearly reported in our country. Controlling nutritional deficiencies and newly emerging nutrition problems to reduce the double burden of malnutrition in Vietnam requires comprehensive and appropriate measures as set out in the National Nutrition Strategy 2001 - 2010, as well as a greater research effort on transitional nutrition.

  11. The Global Burden of Occupational Disease.

    PubMed

    Rushton, Lesley

    2017-07-21

    Burden of occupational disease estimation contributes to understanding of both magnitude and relative importance of different occupational hazards and provides essential information for targeting risk reduction. This review summarises recent key findings and discusses their impact on occupational regulation and practice. New methods have been developed to estimate burden of occupational disease that take account of the latency of many chronic diseases and allow for exposure trends and workforce turnover. Results from these studies have shown in several countries and globally that, in spite of improvements in workplace technology, practices and exposures over the last decades, occupational hazards remain an important cause of ill health and mortality worldwide. Major data gaps have been identified particularly regarding exposure information. Reliable data on employment and disease are also lacking especially in developing countries. Burden of occupational disease estimates form an important part of decision-making processes.

  12. Influenza Burden and Transmission in the Tropics.

    PubMed

    Ng, Sophia; Gordon, Aubree

    Each year, influenza causes substantial mortality and morbidity worldwide. It is important to understand influenza in the tropics because of the significant burden in the region and its relevance to global influenza circulation. In this review, influenza burden, transmission dynamics, and their determinants in the tropics are discussed. Environmental, cultural, and social conditions in the tropics are very diverse and often differ from those of temperate regions. Theories that account for and predict influenza dynamics in temperate regions do not fully explain influenza epidemic patterns observed in the tropics. Routine surveillance and household studies have been useful in understanding influenza dynamics in the tropics, but these studies have been limited to only some regions; there is still a lack of information regarding influenza burden and transmission dynamics in many tropical countries. Further studies in the tropics will provide useful insight on many questions that remain.

  13. Targeting communication interventions to decrease caregiver burden.

    PubMed

    Wittenberg-Lyles, Elaine; Goldsmith, Joy; Oliver, Debra Parker; Demiris, George; Rankin, Anna

    2012-11-01

    To describe family communication patterns that give shape to four types of family caregivers: Manager, Carrier, Partner, and Loner. Case studies of oncology family caregivers and hospice patients selected from data collected as part of a larger, randomized controlled trial aimed at assessing family participation in interdisciplinary team meetings. Each caregiver type demonstrates essential communication traits with nurses and team members; an ability to recognize these caregiver types will facilitate targeted interventions to decrease family oncology caregiver burden. By becoming familiar with caregiver types, oncology nurses will be better able to address family oncology caregiver burden and the conflicts arising from family communication challenges. With an understanding of family communication patterns and its impact on caregiver burden, nurses can aid the patient, family, and team to best optimize all quality-of-life domains for patient and family caregiver. Copyright © 2012 Elsevier Inc. All rights reserved.

  14. Addressing the burden of epilepsy: Many unmet needs.

    PubMed

    Beghi, Ettore

    2016-05-01

    Epilepsy is a heterogeneous clinical condition characterized by recurrent unprovoked seizures, their causes and complications. The incidence, prevalence and mortality of epilepsy vary with age, place and time contributing to a variable extent to the burden of the disease. Diagnostic misclassification may have strong impact on personal and societal reflections of the disease in light of its clinical manifestations and the need for chronic treatment. Epilepsy accounts for a significant proportion of the world's disease burden ranking fourth after tension-type headache, migraine and Alzheimer disease. Among neurological diseases, it accounts for the highest disability-adjusted life year rates both in men and in women. Although epilepsy is self-remitting in up to 50% of cases, variable long-term prognostic patterns can be identified based on the response to the available treatments. Epilepsy carries an overall increased risk of premature mortality with variable estimates across countries. Premature mortality predominates in patients aged less than 50 years, with epilepsies due to structural/metabolic conditions, with generalized tonic-clonic seizures, and seizures not remitting under treatment. Among deaths directly attributable to epilepsy or seizures, included are sudden unexpected death in epilepsy (SUDEP), status epilepticus, accidents, drowning, unintentional injuries, and suicide. Somatic and psychiatric disorders prevail in patients with epilepsy than in people without epilepsy. Asthma, migraine and cerebral tumors tend to occur more frequently in younger adults while cardiovascular disorders, stroke, dementia and meningioma predominate in the elderly. As being a fairly common clinical condition affecting all ages and requiring long-term (sometimes lifelong) treatment, epilepsy carries high health care costs for the society. Direct costs peak in the first year after diagnosis and then vary according to the severity of the disease, the response to treatment, and

  15. Burden attributable to child maltreatment in Australia.

    PubMed

    Moore, Sophie E; Scott, James G; Ferrari, Alize J; Mills, Ryan; Dunne, Michael P; Erskine, Holly E; Devries, Karen M; Degenhardt, Louisa; Vos, Theo; Whiteford, Harvey A; McCarthy, Molly; Norman, Rosana E

    2015-10-01

    Child maltreatment is a complex phenomenon, with four main types (childhood sexual abuse, physical abuse, emotional abuse, and neglect) highly interrelated. All types of maltreatment have been linked to adverse health consequences and exposure to multiple forms of maltreatment increases risk. In Australia to date, only burden attributable to childhood sexual abuse has been estimated. This study synthesized the national evidence and quantified the burden attributable to the four main types of child maltreatment. Meta-analyses, based on quality-effects models, generated pooled prevalence estimates for each maltreatment type. Exposure to child maltreatment was examined as a risk factor for depressive disorders, anxiety disorders and intentional self-harm using counterfactual estimation and comparative risk assessment methods. Adjustments were made for co-occurrence of multiple forms of child maltreatment. Overall, an estimated 23.5% of self-harm, 20.9% of anxiety disorders and 15.7% of depressive disorders burden in males; and 33.0% of self-harm, 30.6% of anxiety disorders and 22.8% of depressive disorders burden in females was attributable to child maltreatment. Child maltreatment was estimated to cause 1.4% (95% uncertainty interval 0.4-2.3%) of all disability-adjusted life years (DALYs) in males, and 2.4% (0.7-4.1%) of all DALYs in females in Australia in 2010. Child maltreatment contributes to a substantial proportion of burden from depressive and anxiety disorders and intentional self-harm in Australia. This study demonstrates the importance of including all forms of child maltreatment as risk factors in future burden of disease studies. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. Chemopreventive Action of Anthocyanin-rich Black Soybean Fraction in APCMin/+ Intestinal Polyposis Model

    PubMed Central

    Park, Mi-Young; Kim, Jung-Mi; Kim, Jong-Sang; Choung, Myoung-Gun; Sung, Mi-Kyung

    2015-01-01

    Background: Anthocyanins have been shown to inhibit cancer cell growth by suppressing oxidative stress and inflammatory responses. The purpose of this study was to investigate the effects of an anthocyanin-rich extract (AE) from black soybean coat on intestinal carcinogenesis. Methods: ApcMin/+ mice were fed a diet of 0.2% or 0.5% AE for 7 weeks. We analyzed the number of intestinal tumors, oxidative stress and inflammatory markers associated with β-catenin and cytosolic phospholipase A2 (cPLA2) signals. The number of intestinal tumors, and cellular expression of β-catenin were determined. Results: The number of intestinal tumors was significantly lower in mice fed a 0.5% AE diet compared to those of the other groups. Cytosolic β-catenin expression was significantly decreased in the AE supplemented groups compared to that of the control animals. In addition, mucosa expression of cyclooxygenase-2 and cPLA2 were also significantly decreased in the 0.5% AE group, by 32% and 62%, respectively, compared to the control group. Conclusions: These results suggest that dietary AE reduced the development of intestinal tumors, possibly through the ability to suppress oxidative stresses, decreasing inflammatory responses mediated by β-catenin associated signals. PMID:26473158

  17. Effect of various doses of chalone-containing alcohol precipitate from Ehrlich's ascites tumor on mitotic activity and DNA synthesis in that tumor

    SciTech Connect

    Matsak, N.Ya.; Romanov, Yu.A.; Antokhin, A.I.

    1987-06-01

    Experiments were carried out on noninbred male albino mice to assess the effects of varying doses of chalone-containing alcohol precipitates on mitotic activity and DNA synthesis in Ehrlich ascites tumor. Histological preparations of the tumor and small intestine were made by standard methods. Hydrolysis of the tumor in HCl was carried out before application of the nuclear photographic emulsion in order to prepare autoradiographs of the tumor. Tritium-labelled thymidine was injected as the radioactive marker.

  18. What Happens After Treatment for Small Intestine Adenocarcinoma?

    MedlinePlus

    ... After Treatment What Happens After Treatment for Small Intestine Adenocarcinoma? For some people with small intestine cancer, ... Small Intestine Adenocarcinoma Stops Working More In Small Intestine Cancer About Small Intestine Cancer Causes, Risk Factors, ...

  19. [Adipocytic tumors].

    PubMed

    Stock, Nathalie

    2015-01-01

    Adipocytic tumors are the most common mesenchymal neoplasms, liposarcoma accounting for approximately 20% of soft tissue sarcomas. The differential diagnosis between benign and malignant tumors is often problematic and represents a significant proportion of consultation cases. The goal of this article is to review liposarcoma subtypes, the main benign adipocytic neoplasms: lipoblastoma, hibernoma, spindle/pleomorphic cell lipoma, chondroid lipoma, as well as non adipocytic neoplasms with a lipomatous component such as lipomatous solitary fibrous tumor, emphasizing on practical differential diagnosis issues, and immunohistochemical and molecular tools allowing their resolution.

  20. Vascular Tumors

    PubMed Central

    Sepulveda, Abel; Buchanan, Edward P.

    2014-01-01

    Vascular anomalies are divided into two main groups: tumors and malformations. Vascular tumors are a large and complex group of lesions, especially for clinicians with none or little experience in this field. In the past, these lesions caused a great deal of confusion because many appear analogous to the naked eye. Thankfully, recent advances in diagnostic techniques have helped the medical community to enhance our comprehension, accurately label, diagnose, and treat these lesions. In this article, we will review the most frequent vascular tumors and provide the reader with the tools to properly label, diagnose, and manage these complex lesions. PMID:25045329

  1. Infectious disease burden and vaccination needs among asylees versus refugees, district of columbia.

    PubMed

    Chai, Shua J; Davies-Cole, John; Cookson, Susan T

    2013-03-01

    Unlike US-bound refugees, asylum seekers (asylees) apply for asylum while residing in the United States and are not provided a medical screening. Infectious disease burden and vaccination needs have not been described among US asylees. We conducted a retrospective cohort study of 630 asylees and 151 refugees referred to the District of Columbia (DC) Department of Health screening program for an initial US medical screening during September 2003-August 2007. We assessed the prevalence of latent tuberculosis infection (tuberculin skin test reactivity ≥10 mm), human immunodeficiency virus (HIV) and hepatitis B seropositivity, intestinal parasite test positivity, need for vaccinations, and time from date of US arrival to receipt of screening. Asylees in DC had a similar prevalence as refugees of latent tuberculosis infection (39% vs 38%, respectively, P = .83), pathogenic intestinal parasites (4% vs 2%, P = .36), and need for adult vaccinations (80% vs 80%, P = .95). Asylees were screened significantly later after US arrival compared with refugees (55 weeks vs 1 week, P < .001). Asylees had higher prevalence of latent tuberculosis infection, hepatitis B and HIV seropositivity, and child and adult vaccination needs than the US population (P < .001). This study of the infectious disease concerns of a US asylee population suggests that in DC, asylees have similar infectious disease burden and prevention needs as refugees and should be screened with the same urgency. Because applicants for US asylum are not linked to prompt medical screenings, DC asylees are typically screened much later, placing them and US communities at risk.

  2. Pseudomyxoma peritonei originating from an intestinal duplication.

    PubMed

    Lemahieu, Julie; D'Hoore, André; Deloose, Stijn; Sciot, Raf; Moerman, Philippe

    2013-01-01

    Alimentary tract duplications are rare congenital anomalies. They most often become symptomatic in childhood and rarely undergo malignant transformation. Pseudomyxoma peritonei (PMP) is an equally uncommon condition, most frequently originating from a primary appendiceal mucinous neoplasm. We report an extremely unusual case of PMP arising from an intestinal duplication. A 67-year-old woman presented with vague upper abdominal pain, and, unexpectedly, explorative laparoscopy revealed diffuse jelly-like peritoneal implants. The histopathological diagnosis of a low-grade PMP or "disseminated peritoneal adenomucinosis" was made. At that moment, no primary tumor was found. During later surgery, a cystic lesion located in the mesentery of the small bowel could be resected. Histologically, the cyst wall clearly showed the concentric layering of a normal bowel wall. The mucosa, however, displayed a diffuse low-grade villous adenoma. We concluded that this histological picture was most consistent with a small intestinal duplication, containing a low-grade villous adenoma. The adenoma caused a mucocele, which subsequently leaked or ruptured, giving rise to noninvasive mucinous peritoneal implants or low-grade PMP, also known as "disseminated peritoneal adenomucinosis" (DPAM).

  3. Pseudomyxoma Peritonei Originating from an Intestinal Duplication

    PubMed Central

    Lemahieu, Julie; D'Hoore, André; Deloose, Stijn; Sciot, Raf; Moerman, Philippe

    2013-01-01

    Alimentary tract duplications are rare congenital anomalies. They most often become symptomatic in childhood and rarely undergo malignant transformation. Pseudomyxoma peritonei (PMP) is an equally uncommon condition, most frequently originating from a primary appendiceal mucinous neoplasm. We report an extremely unusual case of PMP arising from an intestinal duplication. A 67-year-old woman presented with vague upper abdominal pain, and, unexpectedly, explorative laparoscopy revealed diffuse jelly-like peritoneal implants. The histopathological diagnosis of a low-grade PMP or “disseminated peritoneal adenomucinosis” was made. At that moment, no primary tumor was found. During later surgery, a cystic lesion located in the mesentery of the small bowel could be resected. Histologically, the cyst wall clearly showed the concentric layering of a normal bowel wall. The mucosa, however, displayed a diffuse low-grade villous adenoma. We concluded that this histological picture was most consistent with a small intestinal duplication, containing a low-grade villous adenoma. The adenoma caused a mucocele, which subsequently leaked or ruptured, giving rise to noninvasive mucinous peritoneal implants or low-grade PMP, also known as “disseminated peritoneal adenomucinosis” (DPAM). PMID:24024058

  4. Hospitalization Burden among Individuals with Autism

    ERIC Educational Resources Information Center

    Lokhandwala, Tasneem; Khanna, Rahul; West-Strum, Donna

    2012-01-01

    The objective of this study was to assess the inpatient care burden among individuals with autism using the 2007 Health Care Utilization Project Nationwide Inpatient Sample [HCUP NIS]). There were approximately 26,000 hospitalizations among individuals with autism in 2007, with an overall rate of 65.6/100,000 admissions. Rates of hospitalizations…

  5. Fear of future terrorism: Associated psychiatric burden.

    PubMed

    Abiola, T; Udofia, O; Sheikh, T L; Yusuf, D A

    2017-02-04

    The mental health burden from fear of future terrorism has not been given much research attention compared to the immediate mental distress such as post-traumatic stress disorder (PTSD). Such neglected ongoing mental health morbidity associated with threats of terrorism had been described as pre-traumatic stress syndrome (PTSS). The study highlighted this phenomenon (PTSS) in Nigeria by examining the catastrophic burden of the fear of future terrorism and associated psychiatric burden among adult population in Kaduna city. Participants were students and staff of Kaduna State University (KASU), Kaduna Polytechnic, and students awaiting admission into Kaduna State University. They responded to the following instruments after obtaining their informed consents: a sociodemographic questionnaire, the Terrorism Catastrophising Scale (TCS), and the depression and Generalised Anxiety Disorder (GAD) portion of Mini International Neuropsychiatric Interview (MINI). The TCS showed that 78.8% of the participants had from moderate to severe clinical distress on fear of terrorism. The TCS has a Cronbach's alpha of 0.721 and also had significant moderate correlation with depression (r=0.278; p<0.01) and GAD (r=0.201; p<0.01) scales of MINI. The study illustrated that the mental health burden from the fear of terrorism was high and this was relatively related to depression and GAD. This highlighted the need for ongoing monitoring and called for their effective prevention from the identified underlying cognitive mechanisms. Copyright © 2017. Published by Elsevier B.V.

  6. Acute Gastroenteritis and Recreational Water: Highest Burden ...

    EPA Pesticide Factsheets

    OBJECT I VES : To provide summary estimates of gastroenteritis risks and illness burden associated with recreational water exposure and determine whether children have higher risks and burden.METHODS: We combined individual participant data from 13 prospective cohorts at marine and freshwater beaches throughout the United States (n = 84 411). We measured incident outcomes within 10 days of exposure: diarrhea, gastrointestinal illness, missed daily activity (work, school, vacation), and medical visits. We estimated the relationship between outcomes and 2 exposures: body immersion swimming and Enterococcus spp. fecal indicator bacteria levels in the water. We also estimated the population-attributable risk associated with these exposures.RESULTS: Water exposure accounted for 21% of diarrhea episodes and 9% of missed daily activities but was unassociated with gastroenteritis leading to medical consultation. Children aged 0 to 4 and 5 to 10 years had the most water exposure, exhibited stronger associations between levels of water quality and illness, and accounted for the largest attributable illness burden.CONCLUSIONS: The higher gastroenteritis risk and associated burden in young children presents important new information to inform future recreational water quality guidelines designed to protect public health. Meta-analysis of 13 beach sites and nearly 90,000 subjects found that swimming at the beach increased diarrhea incidence and individuals who swam in water

  7. Hospitalization Burden among Individuals with Autism

    ERIC Educational Resources Information Center

    Lokhandwala, Tasneem; Khanna, Rahul; West-Strum, Donna

    2012-01-01

    The objective of this study was to assess the inpatient care burden among individuals with autism using the 2007 Health Care Utilization Project Nationwide Inpatient Sample [HCUP NIS]). There were approximately 26,000 hospitalizations among individuals with autism in 2007, with an overall rate of 65.6/100,000 admissions. Rates of hospitalizations…

  8. Burden of neurological conditions in Canada.

    PubMed

    Gaskin, J; Gomes, J; Darshan, S; Krewski, D

    2016-05-03

    Neurological conditions are among the leading causes of disability in the Canadian population and are associated with a large public health burden. An increase in life expectancy and a declining birth rate has resulted in an aging Canadian population, and the proportion of age-adjusted mortality due to non-communicable diseases has been steadily increasing. These conditions are frequently associated with chronic disability and an increasing burden of care for patients, their families and caregivers. The National Population Health Study of Neurological Conditions (NPHSNC) aims to improve knowledge about neurological conditions and their impacts on individuals, their families, caregivers and health care system. The Systematic Review of Determinants of Neurological Conditions, a specific objective within the NPHSNC, is a compendium of systematic reviews on risk factors affecting onset and progression of the following 14 priority neurological conditions: Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), brain tumours (BT), cerebral palsy (CP), dystonia, epilepsy, Huntington's disease (HD), hydrocephalus, multiple sclerosis (MS), muscular dystrophies (MD), neurotrauma, Parkinson's disease (PD), spina bifida (SB), and Tourette's syndrome (TS). The burden of neurological disease is expected to increase as the population ages, and this trend is presented in greater detail for Alzheimer's and Parkinson's disease because the incidence of these two common neurological diseases increases significantly with age over 65 years. This article provides an overview of burden of neurological diseases in Canada to set the stage for the in-depth systematic reviews of the 14 priority neurological conditions presented in subsequent articles in this issue.

  9. Shift Would Add Burden on Principals

    ERIC Educational Resources Information Center

    Killion, Joellen

    2004-01-01

    In this article, the author describes how the transition from district-centered to school-based staff development can add to the burden on principals. This column first presents a brief review of the efforts of Braxton Hinsdale, a staff development director who advocated for moving professional development resources from the district level to the…

  10. OPERATOR BURDEN IN METAL ADDITIVE MANUFACTURING

    SciTech Connect

    Elliott, Amy M; Love, Lonnie J

    2016-01-01

    Additive manufacturing (AM) is an emerging manufacturing process that creates usable machine parts via layer-by-layer joining of a stock material. With this layer-wise approach, high-performance geometries can be created which are impossible with traditional manufacturing methods. Metal AM technology has the potential to significantly reduce the manufacturing burden of developing custom hardware; however, a major consideration in choosing a metal AM system is the required amount of operator involvement (i.e., operator burden) in the manufacturing process. The operator burden not only determines the amount of operator training and specialization required but also the usability of the system in a facility. As operators of several metal AM processes, the Manufacturing Demonstration Facility (MDF) at Oak Ridge National Labs is uniquely poised to provide insight into requirements for operator involvement in each of the three major metal AM processes. The paper covers an overview of each of the three metal AM technologies, focusing on the burden on the operator to complete the build cycle, process the part for final use, and reset the AM equipment for future builds.

  11. 78 FR 42893 - Statement on Regulatory Burden

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-07-18

    ... CREDIT ADMINISTRATION 12 CFR Chapter VI RIN 3052-AC88 Statement on Regulatory Burden AGENCY: Farm Credit Administration. ACTION: Notice of intent; request for comment. SUMMARY: The Farm Credit Administration (FCA, our... burdensome. We seek public comment on the appropriateness of the requirements we impose on Farm Credit System...

  12. Metabolomics of Apc Min/+ mice genetically susceptible to intestinal cancer

    PubMed Central

    2014-01-01

    Background To determine how diets high in saturated fat could increase polyp formation in the mouse model of intestinal neoplasia, Apc Min/+ , we conducted large-scale metabolome analysis and association study of colon and small intestine polyp formation from plasma and liver samples of Apc Min/+ vs. wild-type littermates, kept on low vs. high-fat diet. Label-free mass spectrometry was used to quantify untargeted plasma and acyl-CoA liver compounds, respectively. Differences in contrasts of interest were analyzed statistically by unsupervised and supervised modeling approaches, namely Principal Component Analysis and Linear Model of analysis of variance. Correlation between plasma metabolite concentrations and polyp numbers was analyzed with a zero-inflated Generalized Linear Model. Results Plasma metabolome in parallel to promotion of tumor development comprises a clearly distinct profile in Apc Min/+ mice vs. wild type littermates, which is further altered by high-fat diet. Further, functional metabolomics pathway and network analyses in Apc Min/+ mice on high-fat diet revealed associations between polyp formation and plasma metabolic compounds including those involved in amino-acids metabolism as well as nicotinamide and hippuric acid metabolic pathways. Finally, we also show changes in liver acyl-CoA profiles, which may result from a combination of Apc Min/+ -mediated tumor progression and high fat diet. The biological significance of these findings is discussed in the context of intestinal cancer progression. Conclusions These studies show that high-throughput metabolomics combined with appropriate statistical modeling and large scale functional approaches can be used to monitor and infer changes and interactions in the metabolome and genome of the host under controlled experimental conditions. Further these studies demonstrate the impact of diet on metabolic pathways and its relation to intestinal cancer progression. Based on our results, metabolic signatures

  13. Heparanase Mediates Intestinal Inflammation and Injury in a Mouse Model of Sepsis.

    PubMed

    Chen, Song; He, Ying; Hu, Ziwei; Lu, Siyu; Yin, Xiaohan; Ma, Xiaochun; Lv, Chuanzhu; Jin, Guiyun

    2017-04-01

    Heparanase, a heparan sulfate (HS)-specific endoglycosidase, plays an important role in inflammation and mediates acute pulmonary and renal injuries during sepsis. To explore its role in septic intestinal injury, a non-anticoagulant heparanase inhibitor, N-desulfated/re- N-acetylated heparin (NAH), was administrated to a mouse sepsis model induced by cecal ligation and puncture (CLP). Immunohistochemical staining revealed massive shedding of HS from the intestinal mucosal surfaces after CLP, and effective inhibition of heparanase by NAH was confirmed by markedly reduced HS shedding. Following CLP, intestinal expression of heparanase was increased, whereas pretreatment with NAH reduced the sepsis-induced upregulation of heparanase expression. Meanwhile, CLP led to shedding of syndecan-1 and upregulated expression of proteases such as matrix metalloprotease-9 and urokinase-type plasminogen activator in the intestine, whereas NAH markedly suppressed syndecan-1 shedding and protease upregulation following CLP. In addition, pretreatment with NAH attenuated intestinal injury, inhibited neutrophil infiltration and suppressed the production of inflammatory cytokines (tumor necrosis factor-α, interleukin-1β, and interleukin-6) in the intestine during sepsis, and it also significantly reduced the elevation of inflammatory cytokines in the serum 24 hr after CLP. Our findings demonstrate that the activation of intestinal heparanase contributes to intestinal injury during early sepsis by facilitating the destruction of mucosal epithelial glycocalyx and promoting inflammatory responses.

  14. The burden of brain diseases in Europe.

    PubMed

    Olesen, J; Leonardi, M

    2003-09-01

    The burden [as defined by the World Health Organisation (WHO)] of brain diseases (neurological, neurosurgical and psychiatric diseases together) is very high and yet resources spent on these diseases are not necessarily commensurate with the extent of this burden. However, hard data on the burden of brain diseases in Europe have not previously been easily accessible. The Global Burden of Disease (GBD) 1990 study conducted jointly by the WHO, Harvard University and the World Bank provided new measures that are now becoming universally accepted and have been used also in a repeat study: The GBD 2000. The key parameter of the study is disability adjusted life years (DALY), which is the sum of years of life lost (YLL) caused by premature death and years of life lived with disability (YLD). In the present report, data from the GBD 2000 study and from the World Health Report 2001 on brain diseases is extracted for the territory of Europe. This territory corresponds roughly to the membership countries of the European Federation of Neurological Societies. The WHO's Report has a category called neuropsychiatric diseases, which comprises the majority but not all the brain diseases. In order to gather all brain diseases, stroke, meningitis, half of the burden of injuries and half of the burden of congenital abnormalities are added. Throughout Europe, 23% of the years of healthy life is lost and 50% of YLD are caused by brain diseases. Regarding the key summary measure of lost health, DALY, 35% are because of brain diseases. The fact that approximately one-third of all burden of disease is caused by brain diseases should have an impact on resource allocation to teaching, reasearch, health care and prevention. Although other factors are also of importance, it seems reasonable that one-third of the curriculum at medical school should deal with the brain and that one-third of life science funding should go to basic and clinical neuroscience. In addition, resource allocation to

  15. Low Mutation Burden in Ovarian Cancer May Limit the Utility of Neoantigen-Targeted Vaccines

    PubMed Central

    Brown, Scott D.; Wick, Darin A.; Nielsen, Julie S.; Kroeger, David R.; Twumasi-Boateng, Kwame; Holt, Robert A.; Nelson, Brad H.

    2016-01-01

    Due to advances in sequencing technology, somatically mutated cancer antigens, or neoantigens, are now readily identifiable and have become compelling targets for immunotherapy. In particular, neoantigen-targeted vaccines have shown promise in several pre-clinical and clinical studies. However, to date, neoantigen-targeted vaccine studies have involved tumors with exceptionally high mutation burdens. It remains unclear whether neoantigen-targeted vaccines will be broadly applicable to cancers with intermediate to low mutation burdens, such as ovarian cancer. To address this, we assessed whether a derivative of the murine ovarian tumor model ID8 could be targeted with neoantigen vaccines. We performed whole exome and transcriptome sequencing on ID8-G7 cells. We identified 92 somatic mutations, 39 of which were transcribed, missense mutations. For the 17 top predicted MHC class I binding mutations, we immunized mice subcutaneously with synthetic long peptide vaccines encoding the relevant mutation. Seven of 17 vaccines induced robust mutation-specific CD4 and/or CD8 T cell responses. However, none of the vaccines prolonged survival of tumor-bearing mice in either the prophylactic or therapeutic setting. Moreover, none of the neoantigen-specific T cell lines recognized ID8-G7 tumor cells in vitro, indicating that the corresponding mutations did not give rise to bonafide MHC-presented epitopes. Additionally, bioinformatic analysis of The Cancer Genome Atlas data revealed that only 12% (26/220) of HGSC cases had a ≥90% likelihood of harboring at least one authentic, naturally processed and presented neoantigen versus 51% (80/158) of lung cancers. Our findings highlight the limitations of applying neoantigen-targeted vaccines to tumor types with intermediate/low mutation burdens. PMID:27192170

  16. Neuroblastoma causes alterations of the intestinal microbiome, gut hormones, inflammatory cytokines, and bile acid composition.

    PubMed

    Castellani, Christoph; Singer, Georg; Kaiser, Margarita; Kaiser, Thomas; Huang, Jianfeng; Sperl, Daniela; Kashofer, Karl; Fauler, Guenter; Guertl-Lackner, Barbara; Höfler, Gerald; Till, Holger

    2017-08-01

    To assess the effect of neuroblastoma (NB) on the intestinal microbiome, metabolism, and inflammatory parameters in a murine model. Athymic Hsd:Fox1nu mice received subperitoneal implantation of human NB cells (MHH-NB11) (tumor group, TG) or culture medium (sham group). Following 10 weeks of tumor growth, all animals were sacrificed to collect total white adipose tissue (WAT). Luminex assays were performed for gut hormone and inflammation marker analysis. Bile acids were measured by high-performance liquid chromatography-mass spectrometry in feces and serum. The microbiome of the ileal content was determined by 16S rDNA next-generation sequencing. At 10 weeks, tumors masses in the TG reached a mean weight of 1.10 g (interquartile range 3.45 g) associated with a significant reduction in WAT. Furthermore, in the TG, there was a marked reduction in leptin and an increase in glucagon-like peptide 1 serum levels. Moreover, the TG mice displayed a pro-inflammatory profile, with significant increases in monocyte chemotactic protein 1, tumor necrosis factor alpha, and interleukin-10. Lithocholic acid, deoxycholic acid, and ursodeoxycholic acid were significantly decreased in the stool of TG mice. Significant alterations of the intestinal microbiome were found in the ileal contents of the TG. The present study provides a first glimpse that human NB in a murine model induces tumor cachexia associated with alterations in metabolic and inflammatory parameters, as well as changes in the intestinal microbiota. Since the intestinal microbiome is known to contribute to the host's ability to harvest energy, a favorable modulation of the intestinal microbiome in tumor patients could potentially represent a novel therapeutic target to prevent tumor-associated cachexia. © 2017 Wiley Periodicals, Inc.

  17. [Surgical therapy of obstructive tumors of the large intestine].

    PubMed

    Mandrioli, M; Accorsi, D; Carbonari, A; Berardi, M; Lecce, F

    1993-10-15

    Current option in managing obstructive colorectal carcinoma is a one stage procedure. Between 1987 and 1991, 47 cases of obstructive colorectal cancer were managed. A statistical analysis showed no significant difference in mortality, morbidity and hospital stay when comparing elective and emergency one staged resection and reconstruction.

  18. Bone tumor

    MedlinePlus

    ... primary bone tumors include: Chondrosarcoma Ewing sarcoma Fibrosarcoma Osteosarcomas Cancers that most often spread to the bone are cancers of the: Breast Kidney Lung Prostate Thyroid These forms of cancer usually affect ...

  19. Spinal tumor

    MedlinePlus

    ... Livingstone; 2014:chap 49. Read More Brain tumor - children Hodgkin lymphoma Metastasis Spinal cord trauma Review Date 8/15/2016 Updated by: Todd Gersten, MD, Hematology/Oncology, Florida Cancer Specialists & Research Institute, Wellington, FL. Review ...

  20. Wilms' Tumor

    MedlinePlus

    ... team and have training in child development, recreation, psychology or social work. If your child must remain ... conditions/wilms-tumor/basics/definition/CON-20043492 . Mayo Clinic Footer Legal Conditions and Terms Any use of ...

  1. Tumor Grade

    MedlinePlus

    ... Other Funding Find NCI funding for small business innovation, technology transfer, and contracts Training Cancer Training at ... much of the tumor tissue has normal breast (milk) duct structures Nuclear grade : an evaluation of the ...

  2. Wilms tumor

    MedlinePlus

    ... a type of kidney cancer that occurs in children. Causes WT is the most common form of childhood kidney cancer. The exact cause of this tumor in most children is unknown. A missing iris of the eye ( ...

  3. Pituitary tumor

    MedlinePlus

    ... enough of its hormones. This condition is called hypopituitarism . The causes of pituitary tumors are unknown. Some ... Cyst Endocrine glands Gigantism Growth hormone test Hyperthyroidism Hypopituitarism Multiple endocrine neoplasia (MEN) I Prolactin blood test ...

  4. The Intestinal Microbiome and Health

    PubMed Central

    Tuddenham, Susan; Sears, Cynthia L.

    2015-01-01

    Purpose of Review A diverse array of microbes colonizes the human intestine. In this review we seek to outline the current state of knowledge on what characterizes a “healthy” or “normal” intestinal microbiome, what factors modify the intestinal microbiome in the healthy state and how the intestinal microbiome affects normal host physiology Recent Findings What constitutes a “normal” or “healthy” intestinal microbiome is an area of active research, but key characteristics may include diversity, richness and a microbial community’s resilience and ability to resist change. A number of factors, including age, the host immune system, host genetics, diet and antibiotic use appear to modify the intestinal microbiome in the normal state. New research shows that the microbiome likely plays a critical role in the healthy human immune system and metabolism. Summary It is clear that there is a complicated bi-directional relationship between the intestinal microbiota and host which is vital to health. An enhanced understanding of this relationship will be critical not only to maximize and maintain human health but also to shape our understanding of disease and to foster new therapeutic approaches. PMID:26237547

  5. Intestinal flora, probiotics, and cirrhosis.

    PubMed

    Guerrero Hernández, Ignacio; Torre Delgadillo, Aldo; Vargas Vorackova, Florencia; Uribe, Misael

    2008-01-01

    Intestinal microflora constitutes a symbiotic ecosystem in permanent equilibrium, composed mainly of anaerobic bacteria. However, such equilibrium may be altered by daily conditions as drug use or pathologies interfering with intestinal physiology, generating an unfavorable environment for the organism. Besides, there are factors which may cause alterations in the intestinal wall, creating the conditions for translocation or permeation of substances or bacteria. In cirrhotic patients, there are many conditions that combine to alter the amount and populations of intestinal bacteria, as well as the functional capacity of the intestinal wall to prevent the permeation of substances and bacteria. Nowadays, numerous complications associated with cirrhosis have been identified, where such mechanisms could play an important role. There is evidence that some probiotic microorganisms could restore the microbiologic and immunologic equilibrium in the intestinal wall in cirrhotic patients and help in the treatment of complications due to cirrhosis. This article has the objective to review the interactions between intestinal flora, gut permeability, and the actual role of probiotics in the field of cirrhotic patients.

  6. Financial Burden of Health Care Expenditures: Turkey

    PubMed Central

    Sulku, S Nur; Bernard, D Minbay

    2012-01-01

    In this study, we examine whether and to what extent the health insurance system in Turkey provided adequate protection against high out of pocket expenditures in the period prior to “The Health Transformation Programme”. Furthermore, we examine the distribution of out of pocket expenditures by demographic characteristics, poverty status, health service type, access to health care and self-reported health status. We employ the 2002/03 National Household Health Expenditure Survey data to analyze financial burden of health care expenditure. Following the literature, we define high burdens as expenses above 10 and 20% of income. We find that 19% of the nonelderly population were living in families spending more than 10% of family income and that 14% of the nonelderly population were living in families spending more than 20% of family income on health care. Furthermore, the poor and those living in economically less developed regions had the greatest risk of high out of pocket burdens. The risk of high financial burdens varied by the type of insurance among the insured due to differences in benefits among the five separate public schemes that provided health insurance in the pre-reform period. Our results are robust to three alternative specifications of the burden measure and including elderly adults in the sample population. We see that prior to the reforms there were not adequate protection against high health expenditures. Our study provides a baseline against which policymakers can measure the success of the health care reform in terms of providing financial protection. PMID:23113149

  7. The burden of Duchenne muscular dystrophy

    PubMed Central

    Landfeldt, Erik; Lindgren, Peter; Bell, Christopher F.; Schmitt, Claude; Guglieri, Michela; Straub, Volker; Lochmüller, Hanns

    2014-01-01

    Objective: The objective of this study was to estimate the total cost of illness and economic burden of Duchenne muscular dystrophy (DMD). Methods: Patients with DMD from Germany, Italy, United Kingdom, and United States were identified through Translational Research in Europe–Assessment & Treatment of Neuromuscular Diseases registries and invited to complete a questionnaire online together with a caregiver. Data on health care use, quality of life, work status, informal care, and household expenses were collected to estimate costs of DMD from the perspective of society and caregiver households. Results: A total of 770 patients (173 German, 122 Italian, 191 from the United Kingdom, and 284 from the United States) completed the questionnaire. Mean per-patient annual direct cost of illness was estimated at between $23,920 and $54,270 (2012 international dollars), 7 to 16 times higher than the mean per-capita health expenditure in these countries. Indirect and informal care costs were substantial, each constituting between 18% and 43% of total costs. The total societal burden was estimated at between $80,120 and $120,910 per patient and annum, and increased markedly with disease progression. The corresponding household burden was estimated at between $58,440 and $71,900. Conclusions: We show that DMD is associated with a substantial economic burden. Our results underscore the many different costs accompanying a rare condition such as DMD and the considerable economic burden carried by affected families. Our description of the previously unknown economic context of a rare disease serves as important intelligence input to health policy evaluations of intervention programs and novel therapies, financial support schemes for patients and their families, and the design of future cost studies. PMID:24991029

  8. How to measure the burden of mortality?

    PubMed Central

    Bonneux, L

    2002-01-01

    Objectives: To explore various methods to quantify the burden of mortality, with a special interest for the more recent method at the core of calculations of disability adjusted life years (DALY). Design: Various methods calculating the age schedule at death are applied to two historical life table populations. One method calculates the "years of life lost", by multiplying the numbers of deaths at age x by the residual life expectancy. This residual life expectancy may be discounted and age weighted. The other method calculates the "potential years of life lost" by multiplying the numbers of deaths at age x by the years missing to reach a defined threshold (65 years or 75 years). Methods: The period life tables describing the mortality of Dutch male populations from 1900–10 (high mortality) and from 1990–1994 (low mortality). Results: A standard life table with idealised long life expectancy increases the burden of death more if mortality is lower. People at old age, more prevalent if mortality is low, lose more life years in an idealised life table. The discounted life table decreases the burden of death strongly if mortality is high: the life lost by a person dying at a young age is discounted. Age weighting the discounted life table balances the effect of discounting. Conclusions: For the purpose of description of the burden of mortality, the aggregate life table of the studied populations gives the better description of the age schedule at death. Discounting and the use of idealised lifetables as a standard increase the burden of mortality of degenerative disease at the end of life. The age weighted discounted life table violates the principle of parsimony. PMID:11812812

  9. [Phyllodes tumors].

    PubMed

    Cabaret, V; Delobelle-Deroide, A; Vilain, M O

    1995-01-01

    A review of mammary phyllodes tumors is presented. Clinical, radiological and cytological features are treated, with special emphasis on the histopathological grading system and prognostic indicators. Other analytical methods are described: immunohistochemistry, hormonal receptors study, flow cytometry and electron microscopy. A large place is also given to differential diagnosis, clinical course, histogenesis and originality of some phyllodes tumors. The authors stress the importance of wide excision and the contribution of frozen sections in surgical treatment.

  10. Protective effects of dexmedetomidine on intestinal ischemia-reperfusion injury

    PubMed Central

    SUN, YONG; GAO, QIANG; WU, NAN; LI, SHENG-DE; YAO, JING-XIN; FAN, WEN-JIE

    2015-01-01

    Dexmedetomidine (DEX) has been hypothesized to possess anti-oxidative properties that may mitigate the damage caused by ischemia-reperfusion (IR) injury. The aim of the present study was to examine the effects of DEX on intestinal contractile activity, inflammation and apoptosis following intestinal IR injury. Intestinal IR injury was induced in rats by complete occlusion of the superior mesenteric artery for 60 min, followed by a 60-min reperfusion period. Rats received an intraperitoneal injection of 25 µg/kg DEX at 30 min prior to the mesenteric IR injury. Following reperfusion, segments of the terminal ileum were rapidly extracted and transferred into an isolated organ bath. The contractile responses to receptor-mediated acetylcholine (Ach) and non-receptor-mediated potassium chloride (KCl) were subsequently examined. Nitric oxide (NO) levels were determined and the expression levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, Bax and Bcl-2 were measured using an enzyme-linked immunosorbent assay. The levels of telomerase and caspase-3 were determined using reverse transcription-quantitative polymerase chain reaction. The results indicated that DEX treatment produced a significant reduction in the IR-induced contractile response to Ach and KCl in the intestinal tissue. Furthermore, DEX appeared to significantly ameliorate intestinal IR injury, in addition to reducing the production of NO. Similar reductions were observed in the intestinal expression levels of TNF-α and IL-6. In addition, DEX treatment resulted in a reduction in the expression levels of Bax in the intestinal tissues, while increasing those of Bcl-2, in addition to significantly increasing the mRNA levels of telomerase and caspase-3. Therefore, the present study indicated that NO, TNF-α and IL-6 may partially contribute to the pathogenesis of intestinal IR injury in addition to the increased expression levels of Bax, Bcl-2, telomerase and caspase-3. These findings suggest that DEX

  11. Hemangiopericytoma in the Small Intestine: A Case Report

    PubMed Central

    Coha, B.; Krizanovic, D.; Perusinovic, Z.; Marinic, S.; Jakovina, K.

    2008-01-01

    Hemangiopericytoma is a rare