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At least 199 records · Page 11Linked to original sources
PubMed2002

Novel variant isoform of G-CSF receptor involved in induction of proliferation of FDCP-2 cells: relevance to the pathogenesis of myelodysplastic syndrome.

Recent studies have shown that point mutations in granulocyte colony-stimulating factor receptor (G-CSFR) are involved in the pathogenesis of severe congenital neutropenia (SCN) and in the transformation of SCN to acute myelogenous leukemia (AML). It is reasonably speculated that the abnormalities in the signal transduction pathways for G-CSF could be partly responsible for the pathogenesis and the development to AML in patients with myelodysplastic syndromes (MDS). Therefore, we investigated the structural and functional abnormalities of the G-CSFR in 14 patients with MDS and 10 normal subjects. In in vitro colony forming assay, MDS samples showed reduced response to growth factors. However, G-CSF, but not GM-CSF and IL-3, enhanced clonal growth in three cases of high risk patients with MDS (RAEB, RAEB-t, and MDS having progressed to acute myeloid leukemia (AML)) and one low risk patient (RA). Eight out of 14 patients including above 4 patients demonstrated a common deletion of the G-CSFR cDNA; a deletion of three nucleotides (2128-2130) in the juxtamembrane domain of the G-CSFR, which resulted in a conversion of Asn(630)Arg(631) to Lys(630). To assess the functional activities of this deletion in the G-CSFR isoform, a mutant with the same three-nucleotide deletion was constructed by site-directed mutagenesis. FDCP-2 cells expressing the G-CSFR isoform responded to G-CSF, and exhibited proliferative responses than did those cells having wild-type G-CSFR. Moreover, these isoforms showed prolonged activation of STAT3 in response to G-CSF than did the wild-type. These results suggest that the deletion in the juxtamembrane domain of the G-CSFR gives a growth advantage to abnormal MDS clones and may contribute to the pathogenesis of MDS.

Amino Acid Sequence↗
PubMed1986

Effect of bacterial flora and mouse genotype (euthymic or athymic) on scrapie pathogenesis.

Euthymic and athymic female BALB/c mice, reared under either germfree or defined flora conditions, were used to investigate the pathogenesis of scrapie after intracerebral or intraperitoneal inoculation. Time in days to onset of clinical signs (Stage I), to endstage (Stage II), and the time interval between Stage I and Stage II were compared among groups. In addition, scrapie agent titers in spleen were determined at 28 and 90 days after infection, as were agent titers in spleen and brain at Stage II. Three-way analysis of variance indicated that the bacterial flora, the presence or absence of a thymus, and the route of agent inoculation interact to produce significant differences in the pathogenesis of disease. The three factors in the experimental design also influenced the spleen titers of scrapie infectivity. The variation in scrapie pathogenesis among the groups of mice is likely to be mediated by differences in their reticuloendothelial systems. These differences may alter the agent's adsorption in spleen and/or route of transport from spleen to brain.

Animals↗
PubMed2004

Exploring the pathogenesis of severe acute respiratory syndrome (SARS): the tissue distribution of the coronavirus (SARS-CoV) and its putative receptor, angiotensin-converting enzyme 2 (ACE2).

Severe acute respiratory syndrome (SARS) is an emerging infectious disease associated with a new coronavirus, SARS-CoV. Pulmonary involvement is the dominant clinical feature but extra-pulmonary manifestations are also common. Factors that account for the wide spectrum of organ system involvement and disease severity are poorly understood and the pathogenesis of SARS-CoV infection remains unclear. Angiotensin converting enzyme 2 (ACE2) has recently been identified as the functional cellular receptor for SARS-CoV. Studies of the tissue and cellular distribution of SARS-CoV, and ACE2 protein expression, reveal new insights into the pathogenesis of this deadly disease. ACE2 is expressed at high level in the primary target cells of SARS-CoV, namely pneumocytes and surface enterocytes of the small intestine. Despite the fact that SARS-CoV can infect the lung and intestine, the tissue responses in these two organs are different. All other tissues and cell types expressing ACE2 may be potential targets of SARS-CoV infection. Remarkably, endothelial cells, which express ACE2 to a high level, have not been shown to be infected by SARS-CoV. There is also evidence that cell types without detectable ACE2 expression may also be infected by the virus. Furthermore, studies in a new human cell culture model have indicated that the presence of ACE2 alone is not sufficient for maintaining viral infection. Therefore, other virus receptors or co-receptors may be required in different tissues. Moreover, the interaction between SARS-CoV and the immunological or lymphoid system remains to be defined. It is clear that we are only at the dawn of our understanding of the pathogenesis of SARS. As our knowledge of the pathogenic mechanisms improves, a more rational approach to therapeutic and vaccine development can be designed in order to combat this new and fatal human disease.

Angiotensin-Converting Enzyme 2↗
PubMed1995

Apolipoprotein E interaction with the neurofibrillary tangles and senile plaques in Alzheimer disease: implications for disease pathogenesis.

Apolipoprotein E (ApoE) genotype is a significant risk factor for the development of Alzheimer disease (AD) and the ApoE protein is associated with senile plaques (SP) and neurofibrillary tangles (NFT), the pathological lesions of AD. Despite this data, the relevance of ApoE to the disease pathogenesis is unknown. In this study we sought to understand the role that ApoE protein could play in the pathogenesis of AD. Using an in situ binding technique, we showed that ApoE bound avidly to SP and NFT in diseased brain. Molecular characterization of ApoE binding suggested that binding to NFT was mediated by tau, the main protein component of NFT, and that ApoE binding to SP was mediated by amyloid-beta, the main protein component of SP. There was no significant difference in binding or binding characteristics between the different ApoE isoforms, ApoE3 and ApoE4. These findings suggest that the interaction of ApoE with tau and amyloid-beta proteins in AD could play a important role in the formation of NFT and SP, respectively, contributing to the pathogenesis of AD.

Alzheimer Disease↗
PubMed1997

Re-assessing the virological approach to HIV pathogenesis: can it explain AIDS as an immunological disease?

Over 10 years after the discovery of HIV, its molecular virology still fails to explain the clinical immunology of AIDS. The prevailing paradigm of AIDS pathogenesis, called here the "virological hypothesis", argues that viral attributes such as cytopathicity, replicability, syncytiality, cell tropism, emergent virulence, and viral load explain why infection develops to a life-threatening immunodeficiency. However, these attributes-singly and in combination-are shown here to be inadequate to explain the latency, immunological damage, and clinical dynamics of the disease of AIDS. The virological paradigm cannot explain the disease-free period (clinical latency); the mechanism and dynamics of CD4 T cell loss; the reason for the onset of disease at a given time-point; the relationship of CD4 T cell loss to AIDS-type disease; nor the idiosyncratic constellation of immunological and clinical phenomena that comprise AIDS as a unique syndrome. HIV as it is currently understood does not have the virological characteristics necessary to create a disease such as AIDS through direct classical (i.e. cytopathic) mechanisms. It is clear that the pathogenesis of AIDS remains unknown. Therefore, treatment based solely on inhibiting viral mechanisms-as with antivirals-is very likely to be insufficient. In addition, the molecular epidemiology of pathogenesis has been very poor; there is an enormous amount that is not known about the clinical immunology of AIDS, and the central question remains of how CD4 cell loss relates to clinical immunodeficiency. The conclusion drawn is that the virology of HIV has been pursed at the cost of understanding AIDS itself; that an emphasis on AIDS as an immunological disease is long overdue; and that appropriate treatment of AIDS will not be possible until the clinical immunology of AIDS is understood.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Expression of hemagglutinin/esterase by a mouse hepatitis virus coronavirus defective-interfering RNA alters viral pathogenesis.

A defective-interfering (DI) RNA of mouse hepatitis virus (MHV) was developed as a vector for expressing MHV hemagglutinin/esterase (HE) protein. The virus containing an expressed HE protein (A59-DE-HE) was generated by infecting cells with MHV-A59, which does not express HE, and transfecting the in vitro-transcribed DI RNA containing the HE gene. A similar virus (A59-DE-CAT) expressing the chloramphenicol acetyltransferase (CAT) was used as a control. These viruses were inoculated intracerebrally into mice, and the role of the HE protein in viral pathogenesis was evaluated. Results showed that all mice infected with parental A59 or A59-DE-CAT succumbed to infection by 9 days postinfection (p.i.), demonstrating that inclusion of the DI did not by itself alter pathogenesis. In contrast, 60% of mice infected with A59-DE-HE survived infection. HE- or CAT-specific subgenomic mRNAs were detected in the brains at days 1 and 2 p.i. but not later, indicating that the genes in the DI vector were expressed only in the early stage of viral infection. No significant difference in virus titer or viral antigen expression in brains was observed between A59-DE-HE- and A59-DE-CAT-infected mice, suggesting that virus replication in brain was not affected by the expression of HE. However, at day 3 p.i. there was a slight increase in the extent of inflammatory cell infiltration in the brains of the A59-DE-HE-infected mice. Surprisingly, virus titers in the livers of A59-DE-HE-infected mice were 3 log10 lower than that of the A59-DE-CAT-infected mice at day 6 p.i. Also, substantially less necrosis and viral antigen were detected in the livers of the A59-DE-HE-infected mice. This may account for the reduced mortality of these mice. The possible contribution of the host immune system to this difference in pathogenesis was analyzed by comparing the expression of four cytokines. Results showed that both tumor necrosis factor-alpha and interleukin-6 mRNAs increased in the brains of the A59-DE-HE-infected mice at day 2 p.i., whereas interferon-gamma and interleukin-1 alpha mRNAs were similar between A59-DE-HE- and A59-DE-CAT-infected mice. These data suggest that the transient expression of HE protein enhances an early innate immune response, possibly contributing to the eventual clearance of virus from the liver. This study indicates the feasibility of the DI expression system for studying roles of viral proteins during MHV infection.

Animals↗
PubMed2002

The role of endothelial cell-derived inflammatory and vasoactive mediators in the pathogenesis of bluetongue.

Bluetongue is an insect-transmitted disease of sheep and wild ruminants that is caused by bluetongue virus (BTV). Cattle are asymptomatic reservoir hosts of BTV. Infection of lung microvascular endothelial cells (ECs) is central to the pathogenesis of BTV infection of both sheep and cattle, but it is uncertain as to why sheep are highly susceptible to BTV-induced microvascular injury, whereas cattle are not. Thus, to better characterize the pathogenesis of bluetongue, the transcription of genes encoding a variety of vasoactive and inflammatory mediators was quantitated in primary ovine lung microvascular ECs (OLmVECs) exposed to BTV and/or inflammatory mediators. BTV infection of OLmVECs increased the transcription of genes encoding interleukin- (IL) 1 and IL-8, but less so IL-6, cyclooxygenase-2, and inducible nitric oxide synthase. In contrast, we previously have shown that transcription of genes encoding all of these same mediators is markedly increased in BTV-infected bovine lung microvascular ECs and that BTV-infected bovine ECs produce substantially greater quantities of prostacyclin than do sheep ECs. Thus, sheep and cattle were experimentally infected with BTV to further investigate the role of EC-derived vasoactive mediators in the pathogenesis of bluetongue. The ratio of thromboxane to prostacyclin increased during BTV infection of both sheep and cattle, but was significantly greater in sheep (P = 0.001). Increases in the ratio of thromboxane to prostacyclin, indicative of enhanced coagulation, coincided with the occurrence of clinical manifestations of bluetongue in BTV-infected sheep. The data suggest that inherent species-specific differences in the production and activities of EC-derived mediators contribute to the sensitivity of sheep to BTV-induced microvascular injury.

Animals↗
PubMed1997

Pathogenesis of O157:H7 Escherichia coli infection in neonatal calves.

Cattle have been implicated as an important reservoir of Shiga-like toxin-producing Escherichia coli (SLTEC) O157:H7, enterohemorrhagic E. coli (EHEC) that cause hemorrhagic colitis and hemorrhagic uremic syndrome in humans. Naturally- or experimentally-infected cattle can shed low levels of E. coli O157:H7 long-term, but little is known about the pathogenesis of E. coli O157:H7 infection in cattle. E. coli O157:H7 induce characteristic attaching and effacing (A/E) mucosal lesions in ceca and colons of 1-day-old gnotobiotic piglets and this model is used to study the pathogenesis of SLTEC infections. A/E lesions were not detected in histologic sections of the intestines from adult cattle or 3- to 14-week-old calves infected with E. coli O157:H7. Our objective was to determine if E. coli O157:H7 induce A/E lesions in neonatal calves. Colostrum-deprived calves (< 12-h-old) were bottle-fed with antibiotic-free milk replacer containing 10(10) colony forming units (CFU) of O157:H7 (SLT-I+, SLT-II+) or nonpathogenic E. coli, necropsied 18 h postinfection and their intestines examined histologically. Bacterial attachment, effacement of microvillous borders, and destruction of epithelium were observed in the intestines of the neonatal calves inoculated with E. coli O157:H7. No lesions were observed in calves inoculated with nonpathogenic E. coli. The distribution of intestinal lesions in neonatal calves resembled that in gnotobiotic pigs. Neonatal calves are apparently more susceptible to A/E lesions induced by E. coli O157:H7 than are older calves or adult cattle and provide a model for studying the pathogenesis of E. coli O157:H7 infections in cattle.

Animals↗
PubMed1993

Pathogenesis of Borna disease.

Borna disease represents a unique model of a virus-induced immunological disease of the brain. Naturally occurring in horses and sheep, the mechanisms of pathogenesis have been studied in experimental animals, namely in the rat. Many investigations have revealed that the infection of the natural hosts principally follows the same pathogenic pathways as observed in rats, leading to a severe encephalomyelitis. This affliction of the central nervous system results in severe neurological disorders that again, are fully comparable in laboratory animals to those in the natural and the different experimental hosts. In addition, alterations have been reported which are also based on the infection of the brain and do not result in the classical encephalitic clinical picture but rather in alterations of behavior. However, to all of our knowledge, the various clinical pictures of Borna disease are not caused by the infecting virus itself but rather by the hosts immune response towards it, i.e. by a virus-induced cell-mediated immunopathological reaction. The importance of virus-specific CD4+ T cells as exemplified by a cultured T cell line and of CD8+ T cells as shown by immunomodulatory substances and specific antibody treatment in vivo for the pathogenesis of acute Borna disease will be elucidated here. In addition, evidence will be provided that virus-specific CD8+ T cells are also responsible for the dramatic brain atrophy in the chronic phase of the disease in rats. Therefore, Borna disease not only lends itself exquisitely well to the study of the pathogenesis of an immunopathological disease of the brain but also represents one of the few models for immune-mediated tissue destruction that eventually leads to brain atrophy and clinically to dementia.

Animals↗
PubMed1994

A molecular genetic approach to the study of Venezuelan equine encephalitis virus pathogenesis.

Viral pathogenesis can be described as a series of steps, analogous to a biochemical pathway, whose endpoint is disease of the infected host. Distinct viral functions may be critical at each required step. Our genetic approach is to use Venezuelan equine encephalitis virus (VEE) mutants blocked at different steps to delineate the process of pathogenesis. A full-length cDNA clone of a virulent strain of VEE was used as a template for in vitro mutagenesis to produce attenuated single-site mutants. The spread of molecularly cloned parent or mutant viruses in the mouse was monitored by infectivity, immunocytochemistry, in situ hybridization and histopathology. Virulent VEE spread through the lymphatic system, produced viremia and replicated in several visceral organs. As virus was being cleared from these sites, it began to appear in the brain, frequently beginning in the olfactory tracts. A single-site mutant in the E2 glycoprotein appeared to block pathogenesis at a very early step, and required a reversion mutation to spread beyond the site of inoculation. The feasibility of combining attenuating mutations to produce a stable VEE vaccine strain has been demonstrated using three E2 mutations.

Amino Acid Sequence↗
PubMed1990

Models for studying the role of fungal attachment in colonization and pathogenesis.

Fungal adhesion and aggregation is considered an important event in human, animal and plant disease as well as in the ecology of fungi in nature (e.g., in mating reactions and the dispersion of fungal propagules). Because of this, numerous models have been developed to study fungal adhesion and aggregation mechanisms over the last decade. Unfortunately, however, nearly all of the work in this area has been carried out in simple in vitro models and has focused its attention on that of the attachment process alone, while realitively little effort has been made toward understanding the role adhesion and aggregation plays in colonization or pathogenesis. The emphasis on adhesion and aggregation mechanisms appears, therefore, to have somewhat obscured the study of the interaction of adhesion with other factors that may be of equal or greater importance in these processes and to the development of more complex adhesion models to explore the relationship between adhesion and colonization. Moreover, because it has not generally been appreciated that several methodologic pitfalls accompany the use of simple in vitro adhesion models, there is now emerging a confused literature base with regard to: (i) the nature of the cell wall component(s) of Candida albicans that mediates its attachment to, for example, epithelial cells; (ii) the mechanism(s) of invasion of mucosal and endothelial surfaces; and (iii) the role certain adhesive reactions observed in vitro play in colonization and pathogenesis by this fungus. Therefore, with an emphasis on C. albicans, this paper will attempt to put into perspective the uses and limitations of models for studying the role of fungal attachment in colonization and pathogenesis. In addition, factors that can modify fungal adhesion data will be discussed and the beginnings of a standardized assay to study the adhesion of C. albicans to buccal epithelial cells will be described.

Animals↗
PubMed2005

Role of stem cell factor and its receptor in the pathogenesis of pediatric aplastic anemia.

In order to investigate the levels of stem cell factor (SCF) and its receptor c-kit protein and mRNA in pediatric aplastic anemia (AA) and their relevance to the pathogenesis, immunocytochemical and in situ hybridization were utilized to detect the expression of SCF and its receptor c-kit gene protein and mRNA, respectively in 59 children with AA and 51 normal controls. The relationship between SCF and c-kit and the pathogenesis of AA was analyzed subsequently. The results showed that the positive rate of SCF protein and mRNA expression in children with AA was significantly lower than that in healthy controls (P < 0.05). However, there was no significant difference in the positive rate of c-kit protein and mRNA expression between children with AA and control group (P > 0.05). It was concluded that the expression of SCF is significantly decreased in children with AA, which may be closely associated with the pathogenesis of the AA. c-kit may be unrelated to the development of pediatric AA. Therefore, AA in children may have abnormalities at SCF/c-kit signal transduction levels.

Adolescent↗
PubMed1997

[Pathogenesis of rheumatoid arthritis].

BACKGROUND: Despite ongoing intensive research using sophisticated new molecular tools and methods, the pathogenesis of autoimmune diseases such as rheumatoid arthritis (RA) is still not completely understood. HYPOTHESES: In this paper the two favorite hypotheses of the pathogenesis of rheumatoid arthritis currently discussed are introduced and compared. Hypothesis 1 is focussing on the central role of the T cells and T cell dependent phenomena in the pathogenetic scenario of RA. In contrast, hypothesis 2 stresses the role of altered synovial fibroblasts and their specific features critical for the destruction of inflamed joints. Both hypotheses are thoroughly discussed and suggestions for further research activities are made. CONCLUSION: Insights in the pathogenesis of RA provide options to develop new therapeutic strategies aimed at the inhibition of pathogenetic relevant processes.

Animals↗
PubMed2004

[Hereditary tumor syndromes. Cutaneous manifestations and molecular pathogenesis of Gorlin and Cowden syndromes].

Several hereditary tumor syndromes are associated with characteristic skin lesions which may facilitate an early diagnosis. We summarize clinical features and recent progress in understanding the etiology and pathogenesis of two selected tumor syndromes, namely nevoid basal cell carcinoma syndrome (Gorlin syndrome) and Cowden syndrome. Both are autosomal dominantly inherited disorders. Nevoid basal cell carcinoma syndrome is characterized by the early onset of multiple basal cell carcinomas as as well as developmental defects and a predisposition for other benign and malignant tumors. The syndrome is caused by germline mutations in the PTCH tumor suppressor gene. Cowden syndrome is associated with pathognomonic mucocutaneous lesions, such as facial trichilemmomas, acral keratoses, and mucocutaneous papillomatosis. In addition, Cowden patients are predisposed to carcinomas of the thyroid, breast and endometrium. Cowden syndrome is caused by germline mutations in the PTEN tumor suppressor gene. Identification of the genes causing hereditary tumor syndromes as well as generation of genetically engineered mouse models have greatly advanced our understanding of the molecular pathogenesis of these diseases. Furthermore, novel pathogenesis-based pharmacological strategies are being developed that promise to improve prevention and therapy.

Animals↗
PubMed2004

Spinal and bulbar muscular atrophy: ligand-dependent pathogenesis and therapeutic perspectives.

Spinal and bulbar muscular atrophy (SBMA) is a late-onset motor neuron disease characterized by proximal muscle atrophy, weakness, contraction fasciculations, and bulbar involvement. SBMA exclusively affects males, while females are usually asymptomatic. The molecular basis of SBMA is the expansion of a trinucleotide CAG repeat, which encodes the polyglutamine (polyQ) tract in the first exon of the androgen receptor (AR) gene. The histopathological hallmark is the presence of nuclear inclusions containing mutant truncated ARs with expanded polyQ tracts in the residual motor neurons in the brainstem and spinal cord, as well as in some other visceral organs. The AR ligand, testosterone, accelerates AR dissociation from heat shock proteins and thus its nuclear translocation. Ligand-dependent nuclear accumulation of mutant ARs has been implicated in the pathogenesis of SBMA. Transgenic mice carrying the full-length human AR gene with an expanded polyQ tract demonstrate neuromuscular phenotypes, which are profound in males. Their SBMA-like phenotypes are rescued by castration, and aggravated by testosterone administration. Leuprorelin, an LHRH agonist that reduces testosterone release from the testis, inhibits nuclear accumulation of mutant ARs, resulting in the rescue of motor dysfunction in the male transgenic mice. However, flutamide, an androgen antagonist promoting nuclear translocation of the AR, yielded no therapeutic effect. The degradation and cleavage of the AR protein are also influenced by the ligand, contributing to the pathogenesis. Testosterone thus appears to be the key molecule in the pathogenesis of SBMA, as well as main therapeutic target of this disease.

Animals↗
PubMed2003

[Inflammatory bowel diseases (IBD) -- critical discussion of etiology, pathogenesis, diagnostics, and therapy].

AIMS: Crohn's disease and ulcerative colitis are the most frequent inflammatory bowel diseases (IBD) with a prevalence of approximately one out of 500. Cytokine research opened new and potent treatment options and thus stimulated clinical and basic research.However, the IBD still remain a challenge for patients and physicians,demanding close cooperation between gastroenterologists,radiologists and surgeons. The basic understanding of IBD,which is necessary for efficient diagnostic and therapeutic concepts is reviewed. METHODS: Based upon recent publications and our clinical experience we discuss aspects of etiology,pathogenesis,diagnostics,and therapy of Crohn's disease and ulcerative colitis. RESULTS: A genetically influenced, exaggerated and sustained immune response against the own gut flora seems to be one of the most important factors in the pathogenesis of IBD. Not less important are environmental influences. For instance, cigarette smoking had been judged to have some negative influence on the natural course of Crohn's disease.Now,however, recent studies show that smoking is even a significant independent risk factor in the pathogenesis of IBD. Since IBD and especially Crohn's disease can effect the whole body, detailed analysis of inflammatory organ involvement is necessary before therapy. For instance, the MRI enteroclysis technique adds a necessary diagnostic tool for the exploration of those parts of the small bowel that cannot been reached by routine endoscopy like the upper ileum and the lower jejunum. In terms of therapy, a change of paradigms can be observed: patients will no longer be treated only when symptoms arise, but will early be integrated into a therapeutic concept, which is determined by site and extent of the disease and adapted to the abilities and needs of the patient.Furthermore,immunosuppressive agents like azathioprine and 6-mercaptopurine will establish as central concept in the medical treatment of IBD. DISCUSSION: IBD-therapy should rather be adapted to the patient's individual inflammatory pattern than be oriented to schematic treatment rules. New endoscopic and radiologic techniques provide the necessary diagnostic tools.

Adrenal Cortex Hormones↗
PubMed1998

[Molecular pathogenesis and prognostic factors in testicular tumor].

Aim of this review article was to critically analyse the recently described zytogenetic and molecular markers for testicular germ cell tumors with regard to their clinical utility. The isochromosome i(12p) represents the most common and characteristic cytogenetic finding which already appears in testicular carcinoma in situ. A number of proto-oncogenes (Cyclin D and PTHLH) as well as putative tumor suppressor genes are localized on 12p; however, their role in pathogenesis and prognosis of testicular germ cell tumors has not been defined yet. Clinical characteristics of patients with familial testicular germ cell tumors indicate a genetic background for the development of testicular tumors. Although a number of chromsomal loci encoding potential testicular tumor susceptibility genes have been identified, the genetic basis of testicular cancer pathogenesis is still unknown. With regard to molecular prognostic risk factors most of the reported data on proliferation markers, tumor suppressor genes, proteases and adhesion molecules have to be confirmed in prospective randomized trials prior to their widespread clinical use. Based on the available data on prospective studies percentage of embryonal carcinoma and vascular invasion appear to be the most significant prognosticators. Investigation and identification of those factors determining the aggressive biologic behavior of embryonal carcinoma compared to all other histological components appear to be most promising in research for prognosticators of metastatic disease. In conclusion, the increasing knowledge of molecular genetic events involved in pathogenesis and prognosis of testicular germ cell tumors will not only help to better understand development and progression of testicular cancer, but it also will define new approaches to classification and management of germ cell tumors.

Cell Transformation, Neoplastic↗
PubMed2001

[Rheumatoid arthritis: new developments in the pathogenesis with special reference to synovial fibroblasts].

Rheumatoid arthritis (RA) is a chronic inflammatory disease, which is mainly characterized by synovial hyperplasia, pathological immune phenomena and progressive destruction of the affected joints. Various cell types are involved in the pathogenesis of RA including T cells, antigen presenting cells, and endothelial cells. Recent experimental evidence suggests that the CD40/CD154 system might play an important role in the development of RA. Our experimental approach focuses on RA synovial fibroblasts (RA-SF) that are able to destroy articular cartilage independent of inflammation. To elucidate the specific role of those cells in RA pathophysiology the following questions are currently addressed: 1. Which mechanisms do activate the RA-SF? 2. How do the activated RA-SF attach to the cartilage? 3. How do RA-SF destroy cartilage and bone? Which mechanisms do activate the RA-SF? The process of activation is poorly understood. It is unclear, how far the synovial hyperplasia of RA resembles tumor diseases. Along this line some contradictory results exist concerning the role of the tumor suppressor protein p53. Some investigations could show the expression of p53 in the synovial lining including p53 mutations in RA synovium and in RASF, while other research groups could not confirm these data. Our group has demonstrated that the tumor suppressor PTEN was less expressed in the synovial lining of RA than in normal synovium, but no PTEN mutations could be found in the RA-SF. In addition, the in vivo and in vitro expression of the anti-apoptotic molecule sentrin suggests a functional resistance of RA-SF to undergo apoptosis. Although it is still unclear, whether certain viruses or viral elements are involved in the pathogenesis of RA (cause, consequence or coincidence?), certain viruses could play a role in the pathogenesis of RA. The endogenous retroviral element L1 was found to be expressed in the synovial lining, at sites of invasion as well as in RA-SF grown in vitro. Moreover, the data indicate that after the initial activation of L1 downstream molecules such as the SAP kinase 4, the met-protoonocogene and the galectin-3 binding protein are upregulated. How do the activated RA-SF attach to the cartilage? It has been suggested that integrins mediate the attachment of RA-SF to fibronectin rich sites of cartilage. Intriguingly, other adhesion molecules such as the vascular cellular adhesion molecule-1 (VCAM) and CS-1, a splice variant of fibronectin, are synthesized by RA-SF. By binding to these adhesion molecules, lymphocytes that express the integrin VLA-4 could be stimulated and thereby maintain the inflammatory process. Osteopontin is an extracellular matrix protein, which is associated with matrix adhesion and metastasis in tumors. In RA synovium, osteopontin was detectable in the synovial lining and at sites of invasion. How do RA-SF destroy cartilage and bone? The destruction of cartilage and bone in RA is mediated by matrix metalloproteinases (MMPs) and cathepsins. MMPs exist as secreted and as membrane bound forms. In vitro models are being developed to simulate the invasive process of RA-SF. In an in vitro model developed in our laboratory, the treatment of RA-SF with anti-CD44 or anti-interleukin-1 (IL-1) minimized matrix degradation of RA-SF. On the other hand, co-culture of RA-SF and U937 cells as well as application of interleukin-1 beta (IL-1 beta) or tumor necrosis factor alpha (TNF alpha) increased the invasiveness of RA-SF. Gene transfer of bovine pancreas trypsin inhibitor (BPMI) or interleukin-10 (IL-10) reduced the invasion of RA-SF, while transduction of interleukin-1 receptor antagonist (IL-1Ra) was chondroprotective. Double gene transfer of IL-10 and IL-1Ra resulted in both inhibition of invasion and chondroprotection.

Arthritis, Rheumatoid↗