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At least 1,045 records · Page 58Linked to original sources
PubMed2003

Identification of a third Protein 4.1 tumor suppressor, Protein 4.1R, in meningioma pathogenesis.

Meningiomas are common central nervous system tumors; however, the mechanisms underlying their pathogenesis are largely undefined. In this report, we demonstrate that a third Protein 4.1 family member, Protein 4.1R, functions as a meningioma tumor suppressor. We observed loss of Protein 4.1R expression in two meningioma cell lines (IOMM-Lee, CH157-MN) by Western blotting as well as in 6 of 15 sporadic meningiomas by immunohistochemistry and fluorescence in situ hybridization. In support of a meningioma tumor suppressor function, Protein 4.1R overexpression resulted in reduced IOMM-Lee and CH157-MN cell proliferation. Similar to the Protein 4.1B and merlin tumor suppressors, Protein 4.1R membrane localization increased significantly under conditions of growth arrest in vitro. Lastly, we show that Protein 4.1R interacted with a subset of merlin/Protein 4.1B interactors including CD44 and betaII-spectrin. Collectively, these results suggest that Protein 4.1R functions as an important tumor suppressor in the molecular pathogenesis of meningioma.

Animals↗
PubMed2000

Genetic alterations and biological pathways in human bladder cancer pathogenesis.

Human bladder cancers are heterogeneous. For example, at first presentation papillary transitional cell carcinomas (TCCs) are typically superficial and often multifocal. Papillary TCCs frequently recur, but most never progress to invasive TCC. In contrast, bladder carcinoma in situ (CIS) usually presents as a solitary flat lesion and, if left untreated, invariably progresses to invasive TCC. Some TCC are already invasive at the time of presentation. Squamous cell carcinoma (SCC) tends to present at a later stage than most TCCs and has a relatively aggressive clinical course. Multiple genetic alterations have been identified in invasive human bladder cancers and are present in different combinations and in different frequencies in the different manifestations of bladder cancer described above. A high percentage ( approximately 67%) of superficial papillary TCCs show early losses involving chromosome 9q, while very few show either a TP53 or a CDKN2/16 mutation. Thus, loss of 9q may be the earliest event in initiation of papillary TCC. In contrast, bladder CIS and SCC show relatively low percentages of 9q loss. However, approximately 65% of bladder CIS contain a TP53 alteration and approximately 67% of bladder SCC contain a CDKN2/p16 alteration. Mutations in these two tumor suppressor genes have powerful implications for loss of genome stability and cell growth regulation, respectively, consistent with the aggressive phenotypes of these cancers. Thus, these data suggest a model of bladder cancer pathogenesis in which the predominant genetic alteration may be the "initiating event" in cancer pathogenesis and may play a role in determining the biological potential of the tumor.

Journal Article↗
PubMed2001

Understanding the pathogenesis of allergic asthma using mouse models.

OBJECTIVE: This paper reviews the current views of the pathogenesis of airway eosinophilic inflammation and airway hyperresponsiveness (AHR) in allergic asthma based on mouse models of the disease. The reader will also encounter new treatment strategies that have arisen as this knowledge is applied in practice. DATA SOURCES: MEDLINE searches were conducted with key words asthma, mouse model, and murine. Additional articles were identified from references in articles and book chapters. STUDY SELECTION: Original research papers and review articles from peer-reviewed journals were chosen. RESULTS: Although the mouse model does not replicate human asthma exactly, the lessons learned about the pathogenesis of allergic airway inflammation and AHR are generally applicable in humans. Type 2 T helper lymphocytes (Th2) orchestrate the inflammation and are crucial for the development of AHR. Cells and molecules involved in T cell activation (dendritic cells, T cell receptor, major histocompatibility complex molecule, and costimulatory molecules) are also vital. Besides these, no other cell or molecule could be shown to be indispensable for the establishment of the model under all experimental conditions. There are at least three pathways that lead to AHR. One is dependent on immunoglobulin E and mast cells, one on eosinophils and interleukin-5 (IL-5), and one on IL-13. Eosinophils are probably the most important effector cells of AHR. Radical methods to treat asthma have been tested in the animal model, including modifying the polarity of lymphocyte response and antagonizing IL-5. CONCLUSIONS: AHR, the hallmark of asthma, is attributable to airway inflammation ultimately mediated by helper T cells via three pathways, at least. The mouse model is also a valuable testing ground for new therapies of asthma.

Animals↗
PubMed1997

New concepts in the pathogenesis of portal hypertension: hepatic wounding and stellate cell contractility.

The pathogenesis of portal hypertension is multifactorial, and appears to result from interplay between fixed and dynamically modulable elements; the stellate cell is a newly recognized example of the latter. This perisinusoidal, pericyte-like cell has contractile features that are most prominent after liver injury, concomitant with their activation. These data imply an exaggerated contractile phenotype in the cirrhotic liver. This cell may contribute to increased intrahepatic portal hypertension via perisinusoidal constriction of the sinusoid or by contraction of fibrous extracellular matrix rich in type I collagen with concomitant disruption of lobular architecture. Endothelins and NO play a major role in the modulation of stellate cell contractility, and are therefore important in the pathogenesis of intrahepatic portal hypertension. These new data provide potential areas for therapeutic intervention in this clinical entity.

Carbon Monoxide↗
PubMed1997

Cytomegalovirus infection in the liver transplant recipient. Epidemiology, pathogenesis, and clinical management.

The effects of cytomegalovirus (CMV) on the liver transplant patient can be divided into two general categories: the direct infectious disease effects (e.g. CMV mononucleosis, hepatitis, pneumonitis, GI infection) and the indirect effects that are mediated by cytokines elaborated as a consequence of the infection. These indirect effects include an immunosuppressive effect that contributes to the development of superinfection with fungi, bacteria, and Pneumocystis carinii; a role in the pathogenesis of allograft injury; and a role in the development of post-transplant lymphoproliferative disease. The two key steps in the pathogenesis of CMV infection-reactivation of the virus from latency and systemic spread-are modulated by the immunosuppressive therapy administered. New antiviral programs, primarily those involving ganciclovir, have resulted in considerable progress in the prevention and treatment of CMV disease among liver transplant recipients.

Cytomegalovirus↗
PubMedDate not supplied

Role of the lower esophageal sphincter and hiatal hernia in the pathogenesis of gastroesophageal reflux disease.

The relative importance of the lower esophageal sphincter (LES) and hiatal hernia in the pathogenesis of gastroesophageal reflux disease is controversial. To identify the role of hiatal hernia and LES in reflux disease, 375 consecutive patients with foregut symptoms and no previous foregut surgery were evaluated. All patients underwent upper endoscopy, stationary manometry, and 24-hour esophageal pH monitoring. Hiatal hernia was diagnosed endoscopically, when the distance between the crural impression and the gastroesophageal junction was >/=2 cm. The LES was considered structurally defective when the resting pressure was </=6 mm Hg, the overall length was less than 2 cm, and/or the abdominal length was less than 1 cm. Factors predicting abnormal esophageal acid exposure (composite score >14.7) were analyzed using multivariate analysis. The presence of a hiatal hernia and a defective LES were identified as independent predictors of abnormal esophageal acid exposure. LES pressure and abdominal length were reduced in patients with hiatal hernia by 4 mm Hg and 0.4 cm, irrespective of the presence of gastroesophageal reflux disease. It is concluded that both a structurally defective LES and hiatal hernia are important factors in the pathogenesis of reflux disease. It is hypothesized that in the presence of a structurally normal LES, the altered geometry of the cardia imposed by a hiatal hernia facilitates the ability of gastric wall tension to pull open the sphincter.

Adolescent↗
PubMed2001

A point of view: quantitative and qualitative imbalance in disease pathogenesis; pulmonary surfactant protein A genetic variants as a model.

The high degree of similarity at the molecular level, between humans and other species, has provided the rationale for the use of a variety of species as model systems in research, resulting in enormous advances in biological sciences and medicine. In contrast, the individual variability observed among humans, for example, in external physique, organ functionality and others, is accounted for, by only a fraction of 1% of differences at the DNA level. These small differences, which are essential for understanding disease pathogenesis, have posed enormous challenges in medicine, as we try to understand why patients may respond differently to drugs or why one patient has complications and another does not. Differences in outcome are most likely the result of interactions among genetic components themselves and/or the environment at the molecular, cellular, organ, or organismal level, or the macroenvironment. In this paper: (1) we consider some issues for multifactorial disease pathogenesis; (2) we provide a review of human SP-A and how the knowledge gained and the characteristics of the hSP-A system may serve as a model in the study of disease with multifactorial etiology; and (3) we describe examples where hSP-A has been used in the study of disease.

Alleles↗
PubMed2001

Pathogenesis of diabetes: our current understanding.

Understanding the pathogenesis of any disease is of prime importance when considering treatment. Recent breakthroughs in the evaluation and management of diabetes and the availability of new therapeutic regimens make it imperative that the primary care physician be aware of these advances to improve patient care. This article discusses our current understanding of the pathogenesis of both type 1 and type 2 diabetes mellitus. A glossary of pertinent genetic terms is included.

Aging↗
PubMed2005

Use of genome information for the study of the pathogenesis of fungal infections and the development of diagnostic tools.

One of the most exciting advances in Mycology is the application of genomic approaches. The advent of genomics, together with post-genomic studies, promises to revolutionize the studies on the pathogenesis of fungal infections. Approaches include comparative genomics to identify sequences that contribute to infection and disease and functional genomics and proteomics to analyze global patterns of gene and protein expression involved in fungal pathogenesis.

DNA, Fungal↗
PubMed2001

Insights into the epidemiology, natural history and pathogenesis of hepatitis C virus infection from studies of infected donors and blood product recipients.

Studies of patients with post-transfusion non-A, non-B hepatitis and their implicated donors were critical to the discovery of hepatitis C virus (HCV) and to the development and progressive enhancement of HCV immunoassays for donor screening and diagnostic applications. Post-transfusion HCV cases have also been used to define the time course of viral and immunological markers following acute infection. Even more precise data on the timing and characteristics of viremia and immune responses during primary HCV infection have been derived from studies of serial samples from source plasma donors who were identified while in the process of infection and seroconversion. Such data have been critical to the derivation of estimates for the viremic, pre-seroconversion window period, and hence projections of the yield of addition of nucleic acid amplification technology (NAT) or HCV core antigen enzyme immunoassays (Ag-EIAs) to antibody screening in donor and diagnostic settings. In addition to these implications for screening and diagnosis, studies of HCV in the blood donor and blood product recipient settings have yielded substantial insights into the epidemiology, pathogenesis and prognosis of HCV infection. In the future, prospective studies of blood and plasma donors detected in the primary phase of HCV infection by NAT screening, will be important for defining viral and host genetic and immunological determinants of clearance of acute viremia, as well as for investigating the benefits of early treatment. Thus, the findings from studies of HCV among donors and blood product recipients have yielded and should continue to provide important insights into HCV pathogenesis leading to novel diagnostic, therapeutic and vaccination strategies.

Antigenic Variation↗
PubMed2003

Identification of metabolites of importance in the pathogenesis of pulmonary cryptococcoma using nuclear magnetic resonance spectroscopy.

Primary lung infection with Cryptococcus neoformans is characterised by circumscribed lesions (cryptococcomas). To identify cryptococcal and/or host products of importance in pathogenesis, we applied proton nuclear magnetic resonance (NMR) spectroscopy, which identifies mobile compounds present in complex mixtures, to experimental pulmonary cryptococcomas from rats. Magnetic resonance experiments were performed on cryptococcomas (n = 10) and healthy lungs (n = 8). Signal assignment to key metabolites was confirmed by homo-nuclear and hetero-nuclear NMR correlation spectroscopy. Cryptococcal metabolites, dominating spectra from cryptococcomas included the stress protectants, trehalose and mannitol, acetate, and in some animals, ethanol. Glycerophosphorylcholine was also abundant in cryptococcomas, consistent with hydrolysis of phospholipids in vivo by the cryptococcal enzyme, phospholipase B (PLB). PLB has been identified by molecular studies as a cryptococcal virulence determinant. We propose that PLB secreted by cryptococci promotes tissue invasion by hydrolysing host phospholipids, such as dipalmitoyl phosphatidyl choline, which is abundant in pulmonary surfactant, and lung cell membrane phospholipids. Our results confirm the utility of NMR spectroscopy in studies of microbial pathogenesis.

Animals↗
PubMed2002

Vernal keratoconjunctivitis: pathogenesis and treatment.

Vernal keratoconjunctivitis (VKC) is a recurrent or chronic ocular allergic disease that affects mostly children and young adults living in warm climates worldwide. Understanding and treating VKC has been a challenge for ophthalmologists since the pathogenesis is unclear and anti-allergic therapy often unsuccessful. In this paper, the culmination of 11 years of research into the immunological characteristics of this disease in a group of 221 VKC patients will be presented. Cytological, biohumoral, immunohistological and molecular biological studies indicate that VKC is a Th2 lymphocyte-mediated disease. Mast cells, eosinophils and their mediators play major roles in the clinical manifestation of VKC. In addition to typical Th2-derived cytokines, IL-4, IL-5 and IL-13, other cytokines, chemokines, growth factors and enzymes are over-expressed in the conjunctiva of VKC patients. Furthermore, structural cells, such as epithelial cells and fibroblasts, are involved both in the inflammatory process and in the tissue remodeling phase, ultimately resulting in the formation of giant papillae. Interactions between specific (IgE- and Th2-mediated) and non-specific triggers and mechanisms may account for treatment failure. New insights into the pathogenesis of VKC should generate the means to better design the strategies for this complex disease.

Humans↗
PubMed2003

The molecular pathogenesis of hepatic encephalopathy.

Hepatic encephalopathy (HE) incorporates a spectrum of neuropsychiatric abnormalities seen in patients with liver dysfunction with a potential for full reversibility. Distinct syndromes are identified in acute liver failure and cirrhosis. Rapid deterioration in consciousness level and increased intracranial pressure that may result in brain herniation and death are a feature of acute liver failure whereas manifestations of HE in cirrhosis include psychomotor dysfunction, impaired memory, increased reaction time, sensory abnormalities, poor concentration and in severe forms, coma. For over a 100 years ammonia has been considered central to its pathogenesis. In the brain, the astrocyte is the main site for ammonia detoxification, during the conversion of glutamate to glutamine. An increased ammonia level raises the amount of glutamine within astrocytes, causing an osmotic imbalance resulting in cell swelling and ultimately brain oedema. The present review focuses upon the molecular mechanisms involved in the pathogenesis of HE. Therapy of HE is directed primarily at reducing ammonia generation and increasing its detoxification.

Ammonia↗
PubMed2003

Augmented mRNA expression of tissue inhibitor of metalloproteinase-1 in buccal mucosal fibroblasts by arecoline and safrole as a possible pathogenesis for oral submucous fibrosis.

Oral submucous fibrosis (OSF) is an oral precancerous condition, and is associated with betel quid (BQ) chewing habits. It is a disorder of excessive deposition of collagen in the connective tissues that results from disruption in the regulation of the equilibrium between matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs). Elevated TIMP-1 protein has been thought to be associated with oral fibrosis, however whether TIMP-1 expression in OSF is modulated at the transcriptional level is still unknown. The present study used arecoline, arecaidine and safrole, which are thought to be major toxic ingredients in BQ, as candidates to explore the role of TIMP-1 expression in OSF pathogenesis. Fresh tissue biopsies of oral mucosa from 20 OSF males were included in this study, and fibroblasts were cultured from one OSF buccal mucosa and one normal buccal mucosa of the same OSF patient. To quantify the TIMP-1 expression, enzyme-linked immunosorbent assay (ELISA) was used in the present study. The results indicated that OSF fibroblasts produced more TIMP-1 protein (569.2+/-79.5 ng/ml) than normal fibroblasts (303.0+/-59.3 ng/ml) from the same patients, and the mRNA expression of TIMP-1 in OSF fibroblasts was higher (1.76 fold) than normal fibroblasts of the same patients. Arecoline and safrole significantly elevated TIMP-1 protein and mRNA expression. We concluded that increased mRNA expression of TIMP-1 in buccal mucosal fibroblasts by arecoline and safrole is a possible pathogenesis for oral submucous fibrosis.

Adult↗
PubMed2001

Toward a genome-scale understanding of group A Streptococcus pathogenesis.

Recent significant contributions have been made to the understanding of Group A Streptococcus (GAS) pathogenesis. New regulatory pathways have been discovered, insight into the molecular basis of epidemics of serotype M1 disease has been obtained, the crystal structures of four toxins have been reported and a genome sequence of one GAS strain has been determined. Genome-scale approaches to the study of GAS pathogenesis are now rapidly emerging and will advance our fundamental understanding of the molecular basis of host-pathogen interactions.

Antigens, Bacterial↗
PubMed2001

Is oxidative stress central to the pathogenesis of chronic obstructive pulmonary disease?

There is now considerable evidence for an increased oxidant burden in patients with chronic obstructive pulmonary disease (COPD). Oxidative stress is a critical feature in the pathogenesis of COPD, since it results in inactivation of antiproteinases, airspace epithelial injury, MUCUS HYPERSECRETION, increased influx of neutrophils into the lungs, transcription factor activation and gene expression of pro-inflammatory mediators. Antioxidants should therefore not only protect against the direct injurious effects of oxidants, but also may fundamentally alter the inflammatory events which have a central role in the pathogenesis of COPD.

Antioxidants↗
PubMed2002

Reciprocal products of chromosomal translocations in human cancer pathogenesis: key players or innocent bystanders?

Chromosomal translocations are frequently involved in the pathogenesis of leukemias, lymphomas and sarcomas. They can lead to aberrant expression of oncogenes or the generation of chimeric proteins. Classically, one of the products is thought to be oncogenic. For example, in acute promyelocytic leukaemia (APL), reciprocal chromosomal translocations involving the retinoic acid receptor alpha (RARalpha) gene lead to the formation of two fusion genes: X-RARalpha and RARalpha-X (where X is the alternative RARalpha fusion partner: PML, PLZF, NPM, NuMA and STAT 5b). The X-RARalpha fusion protein is indeed oncogenic. However, recent data indicate that the RARalpha-X product is also critical in determining the biological features of this leukemia. Here, we review the current knowledge on the role of reciprocal products in cancer pathogenesis, and highlight how their expression might impact on the biology of their respective tumour types.

Animals↗
PubMed2002

New methods to investigate infectious disease transmission and pathogenesis--Staphylococcus aureus disease in drug users.

Staphylococcus aureus is the single most important bacterial pathogen in infections among drug users. It is responsible for several diseases, ranging from superficial cutaneous abscesses to life-threatening intravascular infections. Although the nature of these infections is well described in published work, there is limited understanding of their epidemiology and pathogenesis. This limitation is in part due to the difficulty of studying disease transmission among drug users in the community, and the limitations of the investigative tools that have so far been used. We review the current understanding of the pathogenesis of staphylococcal disease in drug users and argue for the integration of molecular epidemiological techniques and social network methodology to increase our understanding of the basis for the persistence, distribution, and transmission dynamics of S aureus among drug users. Finally, we propose a framework for investigating the transmission of pathogens in community-based settings.

HIV Infections↗