RESUMEN
Colorectal cancer (CRC) is one of the leading causes of cancer related-deaths. The risk of development of CRC is complex and multifactorial, and includes disruption of homeostasis of the intestinal epithelial layer mediated though dysregulations of tumor suppressing/promoting signaling pathways. Guanylate cyclase 2C (GUCY2C), a membrane-bound guanylate cyclase receptor, is present in the apical membranes of intestinal epithelial cells and maintains homeostasis. GUCY2C is activated upon binding of paracrine hormones (guanylin and uroguanylin) that lead to formation of cyclic GMP from GTP and activation of downstream signaling pathways that are associated with normal homeostasis. Dysregulation/suppression of the GUCY2C-mediated signaling promotes CRC tumorigenesis. High-calorie diet-induced obesity is associated with deficiency of guanylin expression and silencing of GUCY2C-signaling in colon epithelial cells, leading to tumorigenesis. Thus, GUCY2C agonists, such as linaclotide, exhibit considerable role in preventing CRC tumorigenesis. However, phosphodiesterases (PDEs) are elevated in intestinal epithelial cells during CRC tumorigenesis and block GUCY2C-mediated signaling by degrading cyclic GMP to 5`-GMP. PDE5-specific inhibitors, such as sildenafil, show considerable anti-tumorigenic potential against CRC by amplifying the GUCY2C/cGMP signaling pathway, but cannot achieve complete anti-tumorigenic effects. Hence, dual targeting the elevation of cGMP by providing paracrine hormone stimuli to GUCY2C and by inhibition of PDEs may be a better strategy for CRC prevention than alone. This review delineates the involvement of the GUCY2C/cGMP/PDEs signaling pathway in the homeostasis of intestinal epithelial cells. Further, the events are associated with dysregulation of this pathway during CRC tumorigenesis are also discussed. In addition, current updates on targeting the GUCY2C/cGMP/PDEs pathway with GUCY2C agonists and PDEs inhibitors for CRC prevention and treatment are described in detail.
Asunto(s)
Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/prevención & control , GMP Cíclico/metabolismo , Hormonas/metabolismo , Comunicación Paracrina , Hidrolasas Diéster Fosfóricas/metabolismo , Receptores de Enterotoxina/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Transformación Celular Neoplásica/efectos de los fármacos , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Quimioprevención , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/etiología , Susceptibilidad a Enfermedades , Hemostasis , Humanos , Terapia Molecular Dirigida , Comunicación Paracrina/efectos de los fármacosRESUMEN
INTRODUCTION: Various methods are deployed by an oral and maxillofacial surgeon to control the osteotomised/ fractured bony segments intraoperatively till the time a stable fixation in the desired position is achieved. Few of these include the use of bone holding crocodile forceps, towel clips, reduction forceps, wires, digital control (Thota and Mitchell in Br J Orthod 26(4):325, 1999). In our technique, we present the use of an IMF screw to manipulate bony segments intraoperatively. MATERIALS AND METHODS: We used this novel technique in a series of 12 patients. An IMF screw was fixed in the greatest bulk of the bony fragment so as to control it and hold it in the desired position in various surgical procedures. CONCLUSION: This technique was found to be minimally invasive and easy to perform to achieve a good hold and control of the bony segments.
RESUMEN
Bacillus thuringiensis is an insect pathogen that is widely used as a biopesticide (E. Schnepf, N. Crickmore, J. Van Rie, D. Lereclus, J. Baum, J. Feitelson, D. R. Zeigler, and D. H. Dean, Microbiol. Mol. Biol. Rev. 62:775-806, 1998). Here we report the finished, annotated genome sequence of B. thuringiensis Al Hakam, which was collected in Iraq by the United Nations Special Commission (L. Radnedge, P. Agron, K. Hill, P. Jackson, L. Ticknor, P. Keim, and G. Andersen, Appl. Environ. Microbiol. 69:2755-2764, 2003).
Asunto(s)
Bacillus thuringiensis/genética , Genoma Bacteriano , Secuencia de Bases , Datos de Secuencia Molecular , Análisis de Secuencia de ADNRESUMEN
Bacillus anthracis, Bacillus cereus, and Bacillus thuringiensis are closely related gram-positive, spore-forming bacteria of the B. cereus sensu lato group. While independently derived strains of B. anthracis reveal conspicuous sequence homogeneity, environmental isolates of B. cereus and B. thuringiensis exhibit extensive genetic diversity. Here we report the sequencing and comparative analysis of the genomes of two members of the B. cereus group, B. thuringiensis 97-27 subsp. konkukian serotype H34, isolated from a necrotic human wound, and B. cereus E33L, which was isolated from a swab of a zebra carcass in Namibia. These two strains, when analyzed by amplified fragment length polymorphism within a collection of over 300 of B. cereus, B. thuringiensis, and B. anthracis isolates, appear closely related to B. anthracis. The B. cereus E33L isolate appears to be the nearest relative to B. anthracis identified thus far. Whole-genome sequencing of B. thuringiensis 97-27and B. cereus E33L was undertaken to identify shared and unique genes among these isolates in comparison to the genomes of pathogenic strains B. anthracis Ames and B. cereus G9241 and nonpathogenic strains B. cereus ATCC 10987 and B. cereus ATCC 14579. Comparison of these genomes revealed differences in terms of virulence, metabolic competence, structural components, and regulatory mechanisms.
Asunto(s)
Bacillus anthracis/genética , Bacillus cereus/genética , Bacillus thuringiensis/genética , Genoma Bacteriano , Análisis de Secuencia , Aminoácidos/metabolismo , Animales , Bacillus cereus/patogenicidad , Bacillus cereus/fisiología , Cápsulas Bacterianas/biosíntesis , Cápsulas Bacterianas/genética , Metabolismo de los Hidratos de Carbono , Evolución Molecular , Humanos , Esporas Bacterianas/crecimiento & desarrollo , Virulencia/genéticaRESUMEN
The intestinal transport of chlorpyrifos (CPF), an organothiophosphate pesticide, was investigated using the single-pass intestinal perfusion (SPIP) technique in male, Sprague-Dawley rats. SPIP was performed in each isolated region of the small intestine (i.e. duodenum, jejunum and ileum) with three concentrations of CPF (0.1, 2.0 and 10 microM) at a flow rate of 0.25 ml/min. Preliminary binding and stability studies were conducted to ensure that the loss of CPF in the SPIP study can be attributed to intestinal absorption. The effective permeability (P(eff)) of CPF was determined for each segment and concentration. CPF exhibits a high intestinal permeability over the length of the small intestine indicative of compounds that are well absorbed. Decreases in permeability values at the highest CPF concentration studied in the duodenum and ileum suggest a saturable transport process. Based on these results, passive, transcellular diffusion dominates the intestinal transport mechanism of CPF, with a saturable transport process evident in the duodenum and ileum. The P(eff) of CPF is in the range of drugs with high intestinal permeability and high fraction of dose absorbed indicating that CPF readily crosses the intestine. The dependence of CPF's P(eff) on concentration in the duodenum and ileum suggests that CPF is transported by a combination of mechanisms across the intestine. Using established relationships, the human fraction dose absorbed for CPF was estimated to be >99%. The permeability values obtained from this study may be useful in models of exposure assessment.
Asunto(s)
Cloropirifos/farmacocinética , Insecticidas/farmacocinética , Absorción Intestinal/fisiología , Algoritmos , Animales , Cloropirifos/administración & dosificación , Cromatografía Líquida de Alta Presión , Técnicas In Vitro , Insecticidas/administración & dosificación , Masculino , Perfusión , Unión Proteica , Ratas , Ratas Sprague-Dawley , Espectrofotometría UltravioletaRESUMEN
The stability of calcitonin salmon in calcitonin salmon nasal spray at elevated temperatures was studied. Vials of calcitonin salmon nasal spray (2200 IU/mL) were stored for three days at 25, 40, or 60 degrees C or for three days at the same temperatures followed by two weeks at 5 degrees C and two additional weeks at 25 degrees C. Concentrations of calcitonin salmon and calcitonin C (a degradation product) were determined relative to a calcitonin salmon reference standard by high-performance liquid chromatography. Calcitonin salmon was stable under all study conditions except initial storage at 60 degrees C followed by two weeks at 5 degrees C and two weeks at 25 degrees C. The stability results were the same when determinations were made in terms of calcitonin C, which exceeded a 5% concentration only for samples stored for the extended period after initial storage at 60 degrees C. Calcitonin salmon remained stable in nasal spray after being stored for three days at 25 or 40 degrees C followed by two weeks at 5 degrees C and two weeks at 25 degrees C. Stability was lost during extended storage after initial storage at 60 degrees C.