Cynthia Melinda Boyd, M.D., M.P.H.
https://www.hopkinsmedicine.org/profiles/results/directory/profile/0007719/cynthia-boyd
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Thus, these data support the existence, at least in the proximal small bowel, of self-renewing stem cells with multilineage capacity generic 50 mg glyset amex. Mushashi-1 is also strongly expressed in developing crypts (2-day-old mice), which would be predicted to be enriched with stem cells. Moreover, even with the more promising markers, a potential problem is that neither the function nor the expression mechanism is as yet understood, which makes definitive conclusions difficult in some cases. Apart from the apparent contradiction between these two models, there have been early attempts to integrate both concepts. There has been a move by several groups to propose a general hypothesis that states renewal systems have evolved two types of stem cell - fast and slow cycling. There is a "reserve" pool of quiescent stem cells, corresponding to the 4 label retaining stem cells, possibly including the label retaining cells, with the active cycling crypt base lgr5 positive stem cells that divide about every 24 hours. Certainly, as Fuchs66 pointed out, stem cells face great challenges; for example, during pregnancy, the mammary epithelium undergoes a massive remodeling as hair follicles undergo destruction, dormancy, and regeneration. In the gut, in addition to the constant need for cell renewal, inflammation or other damage can place enormous demands on the epithelium and, consequently, on the stem cell niches, emphasizing the need to adjust swiftly to maintain homeostasis. Implicitly, stem cells will need to change the rate at which they renew themselves or cycle. Certainly, about two-thirds of the long-term hemopoietic stem cells are in the G0 phase at any one time,66 whereas in the hair follicle, early in development, a population of infrequently cycling cells with many molecular characteristics of stem cells appears within the bulge that later drives the hair cycle. In comparison, cells in the mid region of the crypt had cycle times closer to 12 hours. However, labeled progeny were generated within a day, which can only happen if the Bmi1 cells are actively dividing. They appear resistant to tissue injury, and lineage-tracing studies showed that these mTert cells produced all differentiated intestinal cell types, persisted long term, and made a contribution to the regenerative response following injury. If indeed such cells exist, it is interesting to speculate what their function is in the maintenance of crypt homeostasis - whether they divide infrequently to renew the more rapidly cycling lgr5-positive stem cells, or constitute a reserve population that will enter the cell cycle in instances of intestinal injury. The inter-relationships between the cells bearing several lineage-labeling markers will be interesting. Whatever the case, the migration dynamics, with lgr5 daughters migrating upward differentiating Paneth cells migrating downward, and a potential long-lived stem cell seated further up in the crypt, are likely to be very complex indeed. These cells have an age-structure and cells with a longer mitotic history showed an increased probability of differentiation.
Liver regeneration and hepatocarcinogenesis in transforming growth factor-alpha-targeted mice discount glyset 50 mg visa. Evolution of neoplastic development in the liver of transgenic mice co-expressing c-myc and transforming growth factor-alpha. Transforming growth factoralpha and epidermal growth factor receptor in chronic liver disease and hepatocellular carcinoma. Differential binding and biological activities of epidermal growth factor and transforming growth factor alpha in a human pancreatic cancer cell line. Trophic action of epidermal growth factor on the pancreas and gastroduodenal mucosa in rats. Insulin, transforming growth factors, and substrates modulate growth of guinea pig pancreatic duct cells in vitro. Production of transforming growth factor alpha in human pancreatic cancer cells: evidence for a superagonist autocrine cycle. Serum levels of transforming growth factor alpha in gastrointestinal cancer patients. Malignant transformation of duct-like cells originating from acini in transforming growth factor transgenic mice. Transforming growth factor alpha dramatically enhances oncogene-induced carcinogenesis in transgenic mouse pancreas and liver. A murine tumor progression model for pancreatic cancer recapitulating the genetic alterations of the human disease. Expansion of Pdx1-expressing pancreatic epithelium and islet neogenesis in transgenic mice overexpressing transforming growth factor alpha. Analysis of expression profiles of islet-associated transcription and growth factors during beta-cell neogenesis from duct cells in partially duct-ligated mice. Transgenic expression of epidermal growth factor and keratinocyte growth factor in beta-cells results in substantial morphological changes. Transforming growth factor-alpha and epidermal growth factor expression in human fetal gastrointestinal tract. Immunohistochemical localization of transforming growth factor alpha in the developing rat colon. Developmental expression of transforming growth factor-alpha and epidermal growth factor receptor proteins in the human pancreas and digestive tract. Paracrine action of transforming growth factor-alpha in rectal crypt epithelium of humans. Increased expression of transforming growth factor-alpha and epidermal growth factor receptors in rat chronic reflux esophagitis.
Resection significantly increased the rate of apoptosis in the control group; however, the apoptotic index in the Bax-null mice was unchanged purchase glyset 50 mg amex. These data supported the conclusion that increased apoptosis following small bowel resection is Bax dependent, and that enterocyte proliferation and apoptosis are regulated via different mechanisms during intestinal adaptation. They also found significant increased levels of caspase 8 and Fas protein following resection of Bax/ mice. In the adapting Bax/ intestine, increased apoptosis was confined to the crypts and was accompanied by increased cell proliferation. Bax/ mice exhibited an adaptive response similar in magnitude to the Bax/ animals; however, it occurred without an increase in cell proliferation and with an actual decrease in apoptosis. The authors concluded from these data that adaptation-induced, Bax-dependent apoptosis may be the limiting factor determining the magnitude of the adaptive response. Thus, these data and conclusions are in disagreement with those described by Tang et al. They reported only modest changes in these parameters, which did not correlate with the histological appearance of apoptosis. Crossing the animals prevented the increased apoptosis observed in the waved-2 mice. To summarize the studies, apoptosis following massive small bowel resection appears to be independent of p53 and dependent on Bax. Following transient occlusion of the superior mesenteric artery, apoptosis occurred in the undifferentiated epithelial cells of the proliferative compartment as well as in the differentiated cells of the villus. The response in the villous cells was sevenfold over baseline, compared to twofold in the crypt cells. The greatest increase in apoptosis occurred at the villous tip, perhaps reflecting the possibility that hypoxia was greatest in this region. Comparisons of p53/ and p53/ mice also indicated that apoptosis following ischemia reperfusion is p53 independent. These investigators used a fatty acid binding protein promoter to produce transgenic mice that overexpressed Bcl-2 fivefold in both crypt and villous cells. Forced expression of Bcl-2 reduced apoptosis by approximately 50% in both crypts and villi compared to normal littermates. The authors suggested that these data indicated that both mature and immature cells undergo a commitment phase that is sensitive to Bcl-2. They also found that forced expression of Bcl-2 caused a similar reduction of p53-dependent apoptosis of crypt epithelial cells in response to -irradiation. Thus, the ability of Bcl-2 to inhibit apoptosis occurs independently of whether p53 is involved in the response.
Keratinocyte growth factor ameliorates mucosal injury in an experimental model of colitis in rats cheap 50 mg glyset. Preclinical and early clinical development of keratinocyte growth factor, an epithelial-specific tissue growth factor. Keratinocyte growth factor protects mice from chemotherapy and radiation-induced gastrointestinal injury and mortality. Modification of oral mucositis by keratinocyte growth factor: single radiation exposure. The observation of angiogenin and basic fibroblast growth factor gene expression in human colonic adenocarcinomas, gastric adenocarcinomas, and hepatocellular carcinomas. Fibroblast growth factor 1 and fibroblast growth factor 2 immunoreactivity in gastrointestinal tumours. Signal transduction through extracellular signal-regulated kinase-like pp57 blocked in differentiated colon carcinoma cells having low levels of c-src kinase. Immunocytochemical localization of basic fibroblast growth factor in carcinomas and inflammatory lesions of the human digestive tract. Hedgehop pathway-regulated gene networks in cerebellum development and tumorigenesis. Signaling from Smo to Ci/Gli: conservation and divergence of hedgehog pathways from Drosophila to vertebrates. Sonic hedgeho directs specialized mesoderm differentiation in the intestine and pancreas. Sonic hedgehog in gastric physiology and neoplastic transformation: friend or foe. Direct repression of sonic hedgehog expression in the stomach by Cdx2 leads to intestinal transformation. Hedgehog signaling pathway and gastrointestinal stem cell signaling network (review). Localization of the human hedgehog-interacting protein (Hip) in the normal and diseased pancreas. As such, understanding how the deregulated pathways contribute to altered phenotypes in cancer cells can provide important clues into the function of the pathway in normal cells, complementing other investigations that might be carried out to explore the function of the pathway in normal cell physiology. The cellular gene whose expression was inappropriately activated by these integrations was termed Int-1, as an abbreviation for integration site 1. As noted previously, Wg mutants in Drosophila were associated with major defects in wing morphogenesis.
Mice harboring a defective epidermal growth factor receptor (waved-2) have an increased susceptibility to acute dextran sulfateinduced colitis order 50 mg glyset visa. Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor. Colonic epithelial expression of ErbB2 is required for postnatal maintenance of the enteric nervous system. Employment of the epidermal growth factor receptor in growth factor-independent signaling pathways. Phosphorylation of beta-catenin and epidermal growth factor receptor by intestinal trefoil factor. Expression of somatomedin/insulin-like growth factor messenger ribonucleic acids in the human fetus: identification, characterization, and tissue distribution. Insulin/insulin-like growth factor I hybrid receptors have different biological characteristics depending on the insulin receptor isoform involved. Insulin-like growth factor I rapidly stimulates tyrosine phosphorylation of a Mr 185,000 protein in intact cells. Coupling of the insulin-like growth factor-I receptor tyrosine kinase to Gi2 in human intestinal smooth muscle: G-dependent mitogen-activated protein kinase acitvation and growth. Demonstration of tumor suppression by mannose 6-phosphate/insulin-like growth factor 2 receptor. Insulin-like growth factor-binding protein-5 stimulates growth of human intestinal muscle cells by activation of Gi3. Nuclear import of insulin-like growth factor-binding protein-3 and -5 is mediated by the importin beta subunit. Insulinlole growth factor binding protein-5 interacts with the vitamin D receptor and modulates the vitamin D response in osteoblasts. Determination of the histological distribution of insulin like growth factor 1 receptors in the rat gut. Tissue and development specific regulation of a complex family of rat insulin-like growth factor I messenger ribonucleic acids. Insulin-like growth factor I messenger ribonucleic acids with alternative 5-untranslated regions are differentially expressed during development of the rat. Relative expression and localization of the insulin-like growth factor system components in the fetal, child and adult intestine. Expression of two types of receptor for insulinlike growth factors in human colonic epithelium. Regulation and localization of the insulin-like growth factor system in small bowel during altered nutrient status. Expression and regulation of the insulin-like growth factor axis components in rat liver myofibroblasts. Insulin-like growth factors and the developing and mature rat small intestine: receptors and biological actions.
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With fiirther development, extensions of the superior and infe rior endocardial cushions grow along the edge of the septum primum, closing the ostium primum glyset 50 mg sale. Before closure is complete, however, cell death produces perforations in the upper portion of the septum primum. Coalescence of these perforations forms the ostium secundum, ensuring free blood flow from the right to the left primitive atrium. When the lumen of the right atrium expands as a result of incorporation of the sinus horn, a new crescent-shaped fold appears. At this stage, the central portion of the mesocardium breaks down such that oniy the tw o ends of the heart tube remain attached. Initially, oniy the main stem of the pulmonary vein enters the left atrium, but, as the atrlal walls expand, this stem is incorporated into the left atrium to the polnt where its four branches diverge to go to the lungs. Both the wall of the right sinus horn [blue] and the pulmonary vein [red] are incorpo rated Into the heart to form the sm ooth-w ailed parts of the atria. In the fully developed heart, the original em bryonic right atrium becom es the trabeculated right atrial appendage containing the pectinate muscles, whereas the smooth-walled sinus venarum originates from the right horn of the sinus ve nosus. The original em bryonic left atrium is represented by little m ore than the trabeculated atrial appendage, whereas the At the end of the fourth week, four atrioven tricular endocardial cushions appear: one on each side plus one at the dorsal (superior) and one at the ventral (inferior) border of the atrioventricular canal. Initially, the atrioventricular canal gives access only to the primitive left ventricle and is separated from the bulbus cordis by the bulbo (cono) ventricular flange. Near the end of the fifth week, however, the posterior extremity of the flange terminates almost midway along the base of the dorsal endocardial cushion and is much less prom inent than before. Because the atrioventricular canal enlarges to the right, blood passing through the atrioventricular orifice now has direct access to the primitive left as well as the primitive right ventricle. In addition to the dorsal and ventral endo cardial cushions, two lateral atrioventricular cushions appear on the right and left borders of the canal. At this stage of development, blood from the atrial cavity enters the prim itive left ventricle as well as the prim itive right ventrlcle. Finally, muscular tissue in the cords degenerates and is replaced by dense connective tissue. They are connected to thick muscular trabeculae in the wall of the ventricle, the papillary muscles, by means of chordae tendineae.
The physiological action of motilin is mediated by motilin receptors located on enteric neurons, ultimately leading to activation of muscarinic cholinergic neurons in the gastric antrum generic glyset 50 mg buy on line. The actions of motilin can be mimicked by the macrolide antibiotic, erythromycin, and a group of motilin agonists known as motilides. The motilides may be useful clinically as prokinetic agents for treatment of patients with delayed gastric emptying and impaired colonic motility. Both the amino- and carboxyl-terminals of motilin are essential for full activity since neither amino- or carboxyl-terminal fragments stimulate gastric motor activity. This contractile activity starts in the stomach/ lower esophageal sphincter and moves down the small intestine. Other studies show that immunoneutralization of systemic motilin interrupts phase 7. As expected, erythromycin (a macrolide antibiotic) binds to the motilin receptor, which is also found in enteric neurons of the duodenum, jejunum, and colon. This dog was prepared with three force transducers that were implanted on the gastric antrum 3 cm proximal to the gastroduodenal junction, on the upper jejunum 20 cm distal to the ligament of Treitz, and on the mid-intestine just midway between the ligament of Treitz and the terminal ileum. During the interdigestive state, plasma motilin levels increased at constant intervals in close association with the occurrence of episodes of strong contractions in the stomach. However, when bands of strong contractions (indicated by arrows) reached the mid-intestine, plasma motilin levels had decreased. Motilin receptor agonists have been used successfully for delayed gastric, emptying especially in diabetic patients with gastroparesis. Findings for dogs and humans show that motilin can increase the gastric emptying rate. Findings show that the effects of erythromycin on prompting gastric emptying are associated with changes in systemic motilin levels. In pregnant subjects or patients with constipation and idiopathic gastroparesis, decreased plasma motilin levels were measured. In the dog, the duodenum, jejunum, and ileum were divided into three segments of equal length. The y6 receptor is given the lower case designation since it encodes for a truncated receptor. Y1 receptors are expressed only in nonepithelial colonic cells, whereas Y2 and Y4 receptors are found in epithelial and non-epithelial cells of either the small or large intestine. The Y4 receptor is found in the pancreas and mediates an inhibition of pancreatic exocrine secretion. In the colon, Y4 and Y2 receptors have been shown to play a role in propulsive colonic motor function and in reducing colonic anion transport. Unabsorbed nutrients, especially fats in the lumen of the distal small intestine (ileum), will inhibit upper gut motility.
At the end of the fourth week, sderotome ceUs become polymorphous and form loosely organized tissue, called mesenchyme, or embryonic connective tis sue buy 50 mg glyset overnight delivery. Itis characteristic for mesenchymal ceUs to migrate and to differentiate in many ways. This layer of meso derm forms bones of the pelvic and shoulder gir- dles, limbs, and sternum (see page 154). In some bones, such as the flat bones of the skull, mesenchyme in the dermis differentiates directly into bone, a process known as intram embranous ossification. The foUowing paragraphs discuss development of the most important bony structures and some of their abnormalities. As a result of further differentiatlon, cells in the ventromedial wall lose their epithelial arrangement and become mes enchymal. Cells in the ventrolateral and dorsomedial regions form muscle cells and also migrate beneath the remaining dorsal epithelium [the dermatome] to form the myotome. Blood vesseis in vade the center of the cartilaginous model, bringing osteoblasts [black cells] and restricting proliferating chondrocytic cells to the ends [epiphyses] of the bones. Later, as blood vesseis invade the epiphyses, secondary ossifica tion centers form. Growth of the bones is m aintained by proliferation of chondrocytes in the growth plates. With further growth during fetal and postnatal life, membranous bones enlarge by apposition of new layers on the outer surface and by simultaneous osteoclastic resorption from the inside. Newborn Skull At birth, the flat bones of the skull are separated from each other by narrow seams of connective tissue, the sutures.
Dawson, 35 years: In the next century, as Standard and colleagues noted,2 the diagnosis of cerebral aneurysms improved significantly when Moniz developed cerebral angiography.
Thorus, 56 years: This alternating policy created a random sample of two statistically well-matched groups of patients that were thereby assigned on "an intent to treat" basis to one modality or the other.
Falk, 54 years: Fortunately, multiple studies have demonstrated that morbidity from retreatment is low.
Esiel, 36 years: The surgical approach to arteriovenous malformations of the lateral and sigmoid dural sinuses.
Dimitar, 63 years: The middle ear, consisting of the tympanic cavity and auditory tube, is lined with epithelium of endodermal origin and is derived from the first pharyngeal pouch.
Tufail, 55 years: Kinase suppression of Ras determines survival of intestinal epithelial cells exposed to tumor necrosis factor.
Ningal, 52 years: Thus, it will be critical to define the specific components involved in Notch signaling in the intestine in order to facilitate the design of therapies that will spare the gut while targeting amyloid -peptide production in the brain or Notch activity in various human cancers.
Trano, 29 years: AngiopoietinandTie-2 Angiopoietins (Ang-1 and Ang-2) and their receptor Tie-2 play a critical role in angiogenesis and vascular stability.
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