Gene/Protein Disease Symptom Drug Enzyme Compound
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Acute lymphoblastic leukemia (ALL) is predominantly a disease of the bone marrow that disseminates to multiple organ sites throughout the body and, without aggressive treatment, eventually results in multiorgan failure and death. Experimental models that mimic the dissemination of ALL have been difficult to establish, principally due to the poor engraftment efficiency of normal and malignant human hematopoietic cells in various strains of immune-deficient mice. The recent availability of mouse strains that are even more immunocompromised than established strains such as the nude (nu/nu) or severe combined immunodeficient (SCID) mouse has presented opportunities to establish improved experimental models of human leukemia. In this chapter we outline the methodology to (1) establish continuous xenografts from primary childhood ALL biopsies in nonobese diabetic/SCID (NOD/SCID) mice and (2) utilize these xenograft models of systemic disease to test established and experimental drugs while monitoring leukemia progression in "real time" by serial monitoring of murine peripheral blood. These experimental models will be useful for the preclinical evaluation of novel therapies.
Methods Mol Med 2005
PMID:Preclinical testing of antileukemic drugs using an in vivo model of systemic disease. 1591 88

Cartilage-hair hypoplasia (CHH), also known as metaphyseal chondrodysplasia McKusick type (OMIM no. 250250), is an autosomal recessive, multi-systemic disease characterized by disproportionate short stature, fine and sparse hair, deficient cellular immunity and a predisposition to malignancy. It is caused by mutations in RMRP, the RNA component of the ribonucleoprotein complex RNase MRP, and, thus, CHH represents one of few Mendelian disorders caused by mutations in a nuclear encoded, non-coding RNA. While studies in yeast indicate that RMRP contributes to diverse cellular functions, the pathogenesis of the human condition is unknown. Studies of our CHH patient cohort revealed mutations in both the promoter and the transcribed region of RMRP. While mutations in the promoter abolished transcription in vitro, RMRP RNA levels in patients with transcribed mutations were also decreased suggesting an unstable RNA. RMRP mutations introduced into the yeast ortholog, NME1, exhibited normal mitochondrial function, chromosomal segregation and cell cycle progression, while a CHH fibroblast cell line exhibited normal mitochondrial content. However, the most commonly found mutation in CHH patients, 70A>G, caused an alteration in ribosomal processing by altering the ratio of the short versus the long form of the 5.8S rRNA in yeast. Transcriptional profiling of CHH patient RNAs showed upregulation of several cytokines and cell cycle regulatory genes, one of which has been implicated in chondrocyte hypertrophy. These data suggest that alteration of ribosomal processing in CHH is associated with altered cytokine signalling and cell cycle progression in terminally differentiating cells in the lymphocytic and chondrocytic cell lineages.
Hum Mol Genet 2005 Dec 01
PMID:Consequences of mutations in the non-coding RMRP RNA in cartilage-hair hypoplasia. 1625 2

Klebsiella pneumoniae is a Gram-negative enterobacterium that has historically been, and currently remains, a significant cause of human disease. It is a frequent cause of urinary tract infections and pneumonia, and subsequent systemic infections can have mortality rates as high as 60%. Despite its clinical significance, few virulence factors of K. pneumoniae have been identified or characterized. In this study we present a mouse model of acute K. pneumoniae respiratory infection using an intranasal inoculation method, and examine the progression of both pulmonary and systemic disease. Wild-type infection recapitulates many aspects of clinical disease, including significant bacterial growth in both the trachea and lungs, an inflammatory immune response characterized by dramatic neutrophil influx, and a steady progression to systemic disease with ensuing mortality. These observations are contrasted with an infection by an isogenic capsule-deficient strain that shows an inability to cause disease in either pulmonary or systemic tissues. The consistency and clinical accuracy of the intranasal mouse model proved to be a useful tool as we conducted a genetic screen to identify novel virulence factors of K. pneumoniae. A total of 4800 independent insertional mutants were evaluated using a signature-tagged mutagenesis protocol. A total of 106 independent mutants failed to be recovered from either the lungs or spleens of infected mice. Small scale independent infections proved to be helpful as a secondary screening method, as opposed to the more traditional competitive index assay. Those mutants showing verified attenuation contained insertions in loci with a variety of putative functions, including a large number of hypothetical open reading frames. Subsequent experiments support the premise that the central mechanism of K. pneumoniae pathogenesis is the production of a polysaccharide-rich cell surface that provides protection from the inflammatory response.
Mol Microbiol 2005 Nov
PMID:Identification of Klebsiella pneumoniae virulence determinants using an intranasal infection model. 1626 90

Molecular diagnostics offers the promise of accurately matching patient with treatment, and a resultant significant effect on improved disease outcome. More specifically, the real-time reverse transcription polymerase chain reaction (qRT-PCR), with its combination of conceptual simplicity and technical utility, has the potential to become a valuable analytical tool for the detection of mRNA targets from tissue biopsies and body fluids. Its potential is particularly promising in cancer patients, both as a prognostic assay and for monitoring response to therapy. Colorectal cancer provides an instructive paradigm for this potential as well as the problems associated with its use as a clinical assay. Currently, histopathological staging, which provides a static description of the anatomical extent of tumour spread within a surgical specimen, defines patient prognosis. The detection of lymph node (LN) metastasis constitutes the most important prognostic factor in colorectal cancer and as the primary indicator of systemic disease spread, LN status determines the choice of postoperative adjuvant chemotherapy. However, its limitations are emphasised by the considerable prognostic heterogeneity of patients within a given tumour stage: not all patients with LN-negative cancers are cured and not all patients with LN-positive tumours die from their disease. This has resulted in a search for more accurate staging protocols and has seen the introduction of the concept of "molecular staging", the incorporation of molecular parameters into clinical tumour staging. Quantification of disease-associated mRNA is one such parameter that utilises the qRT-PCR assay's potential for generating quantitative results. These are not only more informative than qualitative data, but contribute to assay standardisation and quality management. This review provides an assessment of the practical value to the clinician of RT-PCR-based molecular diagnostics. It points out reasons for the many contradictory results encountered in the literature and concludes that there is an urgent need for standardisation at every level, starting with pre-assay sample acquisition and template preparation, assay protocols and post-assay analysis.
Mol Aspects Med
PMID:Real-time reverse transcription PCR and the detection of occult disease in colorectal cancer. 1644 74

An essential requirement for adequate organ performance is the formation of permeability barriers that separate and maintain compartments of distinctive structure. The endothelial cell lining of the vasculature defines a semipermeable barrier between the blood and the interstitial spaces of all organs. Disruption of the endothelial cell barrier can result in increased permeability and vascular leak. These effects are associated with multiple systemic disease states. The mechanisms that control barrier function are complex and their full understanding requires a multidisciplinary approach. In vivo permeability data often complement molecular findings and add power to the studies. The interaction of multiple cell types and tissues present only on mammalian models allow for testing of hypothesis and to establish the physiological significance of the results. In this chapter, we describe methods that can be used systematically to measure the permeability characteristics of several organs.
Methods Mol Biol 2006
PMID:Methods to assess tissue permeability. 1679 93

Diabetes mellitus type 2 is a systemic disease characterized by imbalance of energy metabolism, which is mainly caused by inadequate insulin action. Recent data have revealed a surprising role for estradiol in regulating energy metabolism and opened new insights into the role of the two estrogen receptors, ERalpha and ERbeta, in this context. New findings on gene modulation by ERalpha and ERbeta of insulin-sensitive tissues indicate that estradiol participates in glucose homeostasis by modulating the expression of genes that are involved in insulin sensitivity and glucose uptake. Drugs that can selectively modulate the activity of either ERalpha or ERbeta in their interactions with target genes represent a promising frontier in diabetes mellitus coadjuvant therapy.
Trends Mol Med 2006 Sep
PMID:Estrogen receptors: new players in diabetes mellitus. 1689 Apr 92

Histoplasma capsulatum is a dimorphic fungus that causes respiratory and systemic disease and is capable of surviving and replicating within macrophages. The virulence of Histoplasma has been linked to cell wall alpha-(1,3)-glucan; however, the role of this polysaccharide during infection, its organization within the cell wall, and its synthesis and regulation remain poorly understood. To identify genes involved in the biosynthesis of alpha-(1,3)-glucan, we employed a forward genetics strategy to isolate physically marked mutants with reduced alpha-(1,3)-glucan. Insertional mutants were generated in a virulent strain of H. capsulatum by optimization of Agrobacterium tumefaciens-mediated transformation. Approximately 90% of these mutants possessed single insertions with no chromosomal rearrangements or deletions in the host genome. To confirm the role and specificity of identified candidate genes, we phenocopied the disrupted locus by either RNA interference or targeted gene deletion. Our findings indicate alpha-(1,3)-glucan production requires the function of the AMY1 gene product, a novel protein with homology to the alpha-amylase family of glycosyl hydrolases, and UGP1, a UTP-glucose-1-phosphate uridylyltransferase which synthesizes UDP-glucose monomers. Loss of AMY1 function attenuated the ability of Histoplasma to kill macrophages and to colonize murine lungs.
Mol Microbiol 2006 Nov
PMID:An alpha-(1,4)-amylase is essential for alpha-(1,3)-glucan production and virulence in Histoplasma capsulatum. 1703 19

Hemolytic uremic syndrome (HUS) is a systemic disease characterized by damage to endothelial cells, erythrocytes and kidney glomeruli. A "typical" form of HUS follows gastrointestinal infection with enterohemorrhagic E. coli (e.g. O157:H7). Atypical HUS (aHUS) is not associated with gastrointestinal infections but is sporadic or familial in nature. Approximately 50% of aHUS cases are associated with a mutation in one or more genes coding for proteins involved in regulation or activation of the alternative pathway of complement. The link between the disease and the mutations shows the important balance of the alternative pathway between activation and regulation on host cell surfaces. It also demonstrates the power of this pathway in destroying cellular targets in general. In this review we discuss the current knowledge on pathogenesis, classification, diagnostics and management of this disease. We indicate a comprehensive diagnostic approach for aHUS based on the latest knowledge on complement dysregulation to gain both immediate and future patient benefit by assisting in choosing more appropriate therapy for each patient. We also indicate directions in which therapy of aHUS might improve and indicate the need to re-think the terminology and categorisation of the HUS-like diseases so that any advantage in the understanding of complement regulatory problems can be applied to patients accurately.
Mol Immunol 2007 Sep
PMID:Where next with atypical hemolytic uremic syndrome? 1776 7

Hepatitis C virus (HCV) infection is a global health problem, being the second most common chronic viral infection in the world with a global prevalence of about 3% (about 180 million people). HCV is both an hepatotropic and a lymphotropic virus; and chronic infection could cause, on one hand, chronic hepatitis, cirrhosis and hepatocellular carcinoma and on the other hand several extrahepatic diseases including, first, mixed cryoglobulinemia and lymphoma. The association between hepatic (hepatocellular carcinoma) and extrahepatic (lymphoma, thyroid cancer) malignancies has justified the inclusion of HCV among human cancer viruses. The pathogenesis of HCV-related sequelae (hepatic or extrahepatic) is not fully understood representing a challenge of prime importance in light of the optimization of clinico-therapeutic management of these patients. Combined treatment with pegylated interferon plus ribavirin is presently the first-line, gold standard treatment of most HCV-related diseases. However, mainly in the case of extrahepatic manifestations, a cautious approach to the patient, with a case to case accurate tailoring of therapy is frequently requested. The present review will outline the principal aspects of such HCV-induced systemic disease focusing on extrahepatic manifestations.
Mol Aspects Med
PMID:Hepatitis C virus (HCV) infection: a systemic disease. 1817

Abstract Rats transgenic for HLA-B27 and human beta2microglobulin (B27TR) develop a multi-systemic disease resembling inflammatory bowel disease (IBD) and spondyloarthritis. TNFalpha has a crucial role in chronic inflammation. Our objective was to evaluate the effect of anti-TNFalpha treatment on spontaneous IBD in B27TR. Nine-week-old B27TR received monoclonal anti-TNFalpha or an isotypic IgG2a,k up to age of 18 weeks. A second group was monitored up to 18 weeks and then randomly assigned to anti-TNFalpha or IgG2 a,k treatment. Each rat was monitored for clinical IBD manifestations. After sacrifice, the colon was examined for pathological changes. TNFalpha receptors (TNF-R1, TNF-R2), Fas/Fas-L expression and apoptosis were evaluated. IgG2a,k-treated and untreated B27TR presented signs of IBD at 11 weeks, whereas in anti-TNFalpha-treated B27TR no IBD signs were detected. In the late treatment, IBD signs improved after 1 week. Histopathological analysis of IgG2a,k-treated B27TR colon showed inflammatory signs that were widely prevented by early anti-TNFalpha treatment. Late treatment did not significantly reduce inflammation. TNF-R1 was weakly expressed in intestinal epithelial cells of IgG2a,k-treated B27TR, while it was comparable to controls in anti-TNFalpha-treated animals. TNF-R2 immunopositivity was strongly evident in IgG2a,k-treated B27TR, whereas was absent in anti-TNFalpha-treated rats. RT-PCR confirmed these results. IgG2a,k-treated B27TR showed, at 18 weeks, few Fas-positive cells and an increase of Fas-L-positive cells. At 27 weeks, Fas-/Fas-L-positive cell number was significantly low. Anti-TNFalpha treatment increased Fas-L expression, whereas Fas increased only with the early treatment. TNFalpha blockade is effective in preventing inflammation in early phase of IBD, maintaining the homeostatic balance of apoptosis.
J Cell Mol Med 2009 Jan
PMID:TNFalpha blockade prevents the development of inflammatory bowel disease in HLA-B27 transgenic rats. 1836 45


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