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1.
Mol Pathol ; 52(1): 32-6, 1999 Feb.
Article in English | MEDLINE | ID: mdl-10439837

ABSTRACT

AIMS: Human herpesvirus 8 (HHV-8) is now acknowledged as the infective cofactor in the pathogenesis of Kaposi's sarcoma. The mode by which HHV-8 causes Kaposi's sarcoma is unresolved and it is probable that it acts in conjunction with other factors including cytokines, anti-apoptosis proteins, and cell surface receptors. CD40, a cell membrane receptor belonging to the tumour necrosis factor receptor super family, promotes B cell survival and is expressed constitutively on endothelial cells. It is upregulated on cytokine treatment and has been documented recently in Kaposi's sarcoma. Because the HHV-8 genome contains cytokine homologues, this study investigated whether CD40 expression in Kaposi's sarcoma correlated with HHV-8 status, using a unique set of HHV-8 positive and negative specimens. METHODS: Twenty one paraffin wax embedded samples of Kaposi's sarcoma were selected, of which 18 were screened for the presence of HHV-8 using both conventional solution phase and TaqMan polymerase chain reaction (PCR). CD40 immunohistochemistry was assessed using a biotinylated amplification system. Staining was scored semiquantitatively. RESULTS: The results indicated that the expression of CD40 is independent of viral status, being present in both HHV-8 positive and negative specimens. CONCLUSIONS: This suggests that HHV-8 promotes Kaposi's sarcoma cell survival following infection by mechanisms other than those involving CD40.


Subject(s)
Antigens, Neoplasm/metabolism , CD40 Antigens/metabolism , Herpesvirus 8, Human/isolation & purification , Sarcoma, Kaposi/immunology , Up-Regulation , Female , Humans , Immunoenzyme Techniques , Male , Polymerase Chain Reaction , Sarcoma, Kaposi/virology
2.
J Clin Pathol ; 52(8): 569-73, 1999 Aug.
Article in English | MEDLINE | ID: mdl-10645225

ABSTRACT

BACKGROUND: Human herpesvirus 8 (HHV8) appears to be the agent responsible for Kaposi sarcoma. The mechanism remains undetermined but may involve cell cycle regulating genes including D type cyclins which are pivotal in cell cycle progression. Recent HHV8 genetic analysis has revealed the presence of a v-cyclin which is homologous to D type cyclins. AIMS: First, to assess whether there is an independent relation between endogenous cyclin D1 expression in Kaposi sarcoma and HHV8 status; second to determine whether v-cyclin mRNA expression varies with Kaposi sarcoma stage. METHODS: Cyclin D1 immunohistochemistry was performed on 17 paraffin embedded Kaposi sarcoma samples from 16 patients. HHV8 status was assessed in 15 of these using nested polymerase chain reaction (PCR) to ORF 26 and the newly described technique of TaqMan PCR. An additional 10 fresh Kaposi sarcoma samples (early and nodular) were examined for HHV8 v-cyclin RNA. RESULTS: One case, which did not contain amplifiable HHV8, showed strong cyclin D1 staining. The remaining cases were negative or weakly staining; v-cyclin transcript load was higher in early Kaposi sarcoma. CONCLUSIONS: While endogenous cyclin D1 expression is independent of HHV8 status, v-cyclin transcription is higher in early lesions, supporting the "viral hit" hypothesis.


Subject(s)
Cyclin D1/metabolism , Herpesvirus 8, Human/isolation & purification , Neoplasm Proteins/metabolism , Sarcoma, Kaposi/virology , Female , Gene Expression , Humans , Immunoenzyme Techniques , Male , Polymerase Chain Reaction , RNA, Messenger/genetics , RNA, Viral/genetics , Sarcoma, Kaposi/metabolism , Viral Proteins/metabolism
3.
Mol Pathol ; 51(3): 155-9, 1998 Jun.
Article in English | MEDLINE | ID: mdl-9850339

ABSTRACT

AIMS: Human herpes virus 8 (HHV-8) is the infectious agent implicated in the pathogenesis of Kaposi's sarcoma, although its mode of action is unclear. Recent work indicates that the HHV-8 genome encodes a viral Bcl-2 homologue (v-Bcl-2). The aim of this study was to explore Bcl-2 expression in Kaposi's sarcoma using a unique set of HHV-8 positive and negative cases, and to determine whether there is a relation with p53 expression. METHODS: Up to 18 specimens from 17 patients were selected. HHV-8 status was determined using nested polymerase chain reaction (PCR) to the open reading frame (ORF) 26, with further confirmation by TaqMan PCR. In addition, Bcl-2 and p53 immunohistochemistry were performed using standard protocols. RESULTS: The results suggest that Bcl-2 and p53 expression is independent of HHV-8 status. In addition, there does not appear to be a direct correlation with disease stage. CONCLUSIONS: HHV8 histopathogenesis is likely to be a multifactorial complex process, which may be mediated in part by viral genes and apoptosis regulating homologues.


Subject(s)
Herpesvirus 8, Human/isolation & purification , Neoplasm Proteins/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , Sarcoma, Kaposi/virology , Tumor Suppressor Protein p53/metabolism , Female , Humans , Immunoenzyme Techniques , Male , Polymerase Chain Reaction , Sarcoma, Kaposi/metabolism
4.
Mol Pathol ; 51(1): 14-20, 1998 Feb.
Article in English | MEDLINE | ID: mdl-9624414

ABSTRACT

AIMS: Kaposi's sarcoma is a vascular tumour of uncertain pathogenesis possibly caused by an infectious agent, identified in high risk groups. Accumulating solution phase polymerase chain reaction (PCR) and seroepidemiological data suggest that a previously undescribed herpes DNA virus (human herpesvirus 8 (HHV8)) is the causative agent. Using a unique cohort of early Kaposi's sarcoma, the precise cell type infected with HHV8 in such lesions was identified to elucidate further the role of HHV8 in the pathobiology of Kaposi's sarcoma. METHODS: Sixteen cases of early Kaposi's sarcoma (derived from skin and lymph node) were assessed for the presence of HHV8 using both standard solution phase PCR and TaqMan PCR to the KS330 Bam region of HHV8. In situ amplification was also performed on a selected group in an attempt to identify the candidate infected cells. RESULTS: Using both conventional solution phase and TaqMan PCR, 87% of cases were positive. In addition, HHV8 amplicons were localised in situ to endothelial and spindle cell proliferations in early Kaposi's sarcoma. The HHV8 viral load varied from lesion to lesion. CONCLUSIONS: The presence of HHV8 in early lesions supports a role for HHV8 in the pathogenesis of Kaposi's sarcoma. Coupled with recent seroepidemiological studies, these results suggest that HHV8 is the aetiological agent of Kaposi's sarcoma. Its precise interaction with other factors known to be involved in the development of Kaposi's sarcoma, including cytokines and anti-apoptosis genes, requires elucidation.


Subject(s)
Herpesvirus 8, Human/isolation & purification , Lymphatic Diseases/virology , Sarcoma, Kaposi/virology , Skin Neoplasms/virology , Adolescent , Adult , Blotting, Southern , Cell Transformation, Neoplastic , Cell Transformation, Viral , Female , Humans , In Situ Hybridization , Lymph Nodes , Male , Middle Aged , Polymerase Chain Reaction/methods
5.
Mol Pathol ; 50(2): 96-100, 1997 Apr.
Article in English | MEDLINE | ID: mdl-9231158

ABSTRACT

AIMS: The recent finding that human herpes virus 8 (HHV8) is found in the majority of Kaposi's sarcoma (KS) cases supports the epidemiological observation that the tumour may be caused by an infectious agent. This study aimed to address when and how HHV8 evolved. METHODS: A cohort of African endemic KS (49 samples from 45 patients) and European KS (18 samples from 13 patients), spanning 27 years, was assessed for the presence of HHV8 by both standard solution phase polymerase chain reaction (PCR) and the newly described technique of TaqMan PCR. RESULTS: HHV8 was present in approximately 49% (24 of 49 tissue samples) of the African cases and in more than 90% (16 of 18 tissue samples) of the European cohort, in keeping with recent seroepidemiological data. CONCLUSIONS: HHV8 is strongly linked to the development of KS; however, in some patients, other factors may operate. The utility and flexibility of TaqMan PCR in detecting low copy viral target in human tissues was demonstrated.


Subject(s)
Herpesvirus 8, Human/isolation & purification , Sarcoma, Kaposi/virology , Adolescent , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , Cohort Studies , Europe , Female , HIV Infections/complications , Humans , Infant , Infant, Newborn , Malawi , Male , Middle Aged , Polymerase Chain Reaction/methods , Sarcoma, Kaposi/complications
6.
J Pathol ; 183(4): 447-52, 1997 Dec.
Article in English | MEDLINE | ID: mdl-9496262

ABSTRACT

Kaposi's sarcoma (KS) is an enigmatic tumour of uncertain histogenesis. Epidemiological data have long suggested that KS may be caused by an infectious agent, possibly sexually transmitted. Following the documentation of human herpesvirus 8 (HHV8) and its strong association with all forms of KS, it now appears that the putative agent has at last been identified. As KS is rare in females, a unique group was screened for the presence of HHV8 using both conventional solution-phase polymerase chain reaction (PCR) and the newly described technique of TaqMan PCR. The presence of HHV8 was demonstrated in 10/12 of these female patients. This further supports the direct role of HHV8, in conjunction with cytokines and other factors, in the pathogenesis of KS.


Subject(s)
Herpesvirus 8, Human/isolation & purification , Sarcoma, Kaposi/virology , Adolescent , Adult , Aged , Electrophoresis, Agar Gel , Female , Humans , Middle Aged , Polymerase Chain Reaction/methods , Retrospective Studies , Taq Polymerase
9.
Scand J Gastroenterol ; 23(9): 1063-71, 1988 Nov.
Article in English | MEDLINE | ID: mdl-3247588

ABSTRACT

After the observation of a low incidence of gastric carcinoid tumours in rats, but not in mice, given ciprofibrate for 2 years, ciprofibrate and related compounds were investigated for gastric antisecretory activity. A significant inhibition of gastric secretion, similar to that induced by comparable doses of cimetidine, was observed in the fischer rat 1.5 h after a single oral (200 or 500 mg kg-1) or intraduodenal (100 or 300 mg kg-1) administration of ciprofibrate, bezafibrate, and clofibric acid. Ciprofibrate had prolonged antisecretory activity when compared with bezafibrate or ranitidine. Prolonged inhibition of gastric secretion is proposed as the primary cause of gastric carcinoids in the rat, since in a comparative evaluation, antisecretory activity was observed in the rat but not in the mouse.


Subject(s)
Bezafibrate/pharmacology , Clofibrate/analogs & derivatives , Clofibrate/pharmacology , Clofibric Acid/analogs & derivatives , Gastric Juice/metabolism , Administration, Oral , Animals , Carcinoid Tumor/chemically induced , Clofibric Acid/pharmacology , Fibric Acids , Gastric Juice/drug effects , Male , Mice , Mice, Inbred Strains , Rats , Rats, Inbred F344 , Species Specificity , Stomach Neoplasms/chemically induced , Time Factors
10.
Toxicol Appl Pharmacol ; 95(2): 328-38, 1988 Sep 15.
Article in English | MEDLINE | ID: mdl-3138789

ABSTRACT

Comparative oral toxicity studies with ciprofibrate have been undertaken in the mouse, rat, and marmoset for up to 26 weeks. Chronic administration of ciprofibrate (20 mg/kg/day) produced a prolonged, modest, but statistically significant hypergastrinemia in the rat. Morphological changes in the rat stomach included increased eosinophilia and hypertrophy of oxyntic cells after 2 or more weeks treatment and hyperplasia of the neuroendocrine (NE) cells after 8 weeks treatment. In contrast, only a transient hypergastrinemia was induced, but not sustained in the mouse at the same dose level over an 8-week time period. No morphological changes were detected in the stomach of this species. In the marmoset treatment, up to 80 mg/kg/day for 26 weeks failed to induce hypergastrinemia and no significant alterations in gastric NE cells were detected.


Subject(s)
Clofibrate/analogs & derivatives , Clofibric Acid/analogs & derivatives , Stomach/drug effects , Animals , Callitrichinae , Clofibric Acid/toxicity , Fibric Acids , Gastrins/blood , Male , Mice , Rats , Rats, Inbred F344 , Species Specificity , Stomach/pathology
11.
J Pharm Pharmacol ; 40(7): 512-3, 1988 Jul.
Article in English | MEDLINE | ID: mdl-2904995

ABSTRACT

The potential of ciprofibrate to inhibit gastric secretion has been investigated in the rat. A significant gastric antisecretory effect was observed following a single oral administration of 300 and 500 mg kg-1 and following a single intraduodenal dose of 100, 300 and 500 mg kg-1. The toxicological significance of this finding is discussed in the light of a spate of recent publications linking changes in gastric morphology with hypergastrinaemia produced as a secondary effect of inhibition of acid secretion.


Subject(s)
Clofibrate/analogs & derivatives , Clofibric Acid/analogs & derivatives , Gastric Mucosa/metabolism , Hypolipidemic Agents/pharmacology , Animals , Clofibric Acid/pharmacology , Dose-Response Relationship, Drug , Female , Fibric Acids , Gastric Mucosa/drug effects , Male , Mice , Rats , Rats, Inbred F344 , Reference Values
12.
J Appl Toxicol ; 8(1): 29-34, 1988 Feb.
Article in English | MEDLINE | ID: mdl-3356862

ABSTRACT

The effect of amrinone on platelet production was differentiated from that of a known bone-marrow cytotoxic agent (cyclophosphamide) and anti-platelet serum (APS). The rate of platelet production has been observed over a 4-day period in the Gunn rat using [75Se]selenomethionine cohort labelling of platelets following administration of either amrinone, 160 mg kg-1 day-1, cyclophosphamide, 30 mg kg-1 day-1 or APS, 0.75 ml. Platelet numbers were reduced by amrinone, cyclophosphamide and APS. The rate of platelet production was increased following APS and suppressed by cyclophosphamide, but the rate of platelet production when expressed as the selenomethionine incorporation in counts per minute (cpm) per 10(8) platelets appeared to be increased in amrinone-treated animals. When these values are expressed as radioactivity per unit platelet volume the difference between the control and the amrinone-treated group was reduced but the difference between the control, APS- and cyclophosphamide-treated groups remained unchanged. It is concluded that in the Gunn rat amrinone affects platelet production by producing fewer, larger platelets.


Subject(s)
Amrinone/toxicity , Blood Platelets/drug effects , Cyclophosphamide/toxicity , Hematopoiesis/drug effects , Immune Sera/toxicity , Animals , Blood Platelets/cytology , Blood Platelets/immunology , Female , Male , Methionine/blood , Platelet Count/drug effects , Rats , Rats, Gunn , Selenium Radioisotopes
13.
J Appl Toxicol ; 6(6): 437-41, 1986 Dec.
Article in English | MEDLINE | ID: mdl-3100606

ABSTRACT

Platelet counts are routinely assessed from whole blood samples and recent technical advances enable the total platelet counts to be complemented by additional information which fully profiles the platelet population. In this report the platelet count, mode and mean platelet volumes and platelet profile histograms are presented for eight mammalian species. Species and strain variation in platelet profiles and the degree of volume heterogeneity are presented, and a platelet profile is presented for the marmoset which is previously unreported. The significance of these parameters and their potential importance to the toxicologist are discussed in the light of an observation of a drug-induced alteration in a platelet population profile.


Subject(s)
Platelet Count , Adolescent , Adult , Animals , Blood Platelets/drug effects , Callitrichinae , Cricetinae , Dogs , Edetic Acid/pharmacology , Female , Guinea Pigs , Humans , Male , Mesocricetus , Mice , Mice, Inbred Strains , Middle Aged , Platelet Count/drug effects , Rabbits , Rats , Rats, Inbred Strains , Species Specificity
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