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Biomedical subjects

B A Jennings

Publications and source records attributed to B A Jennings.

17 recordsLinked to original sources
PubMed2002

HFE mutations in an inflammatory arthritis population.

OBJECTIVES: To determine the value of screening patients with inflammatory arthritis for haemochromatosis-associated mutations in the HFE gene. METHODS: We screened 1000 patients with inflammatory arthritis and 1000 controls for the HFE gene mutations that are associated with haemochromatosis. The arthritis patients were diagnosed between 1989 and 1995 and their blood DNA was archived as part of the Norfolk Arthritis Register project. RESULTS: Five out of 1000 (0.005) patients in the arthritis group were homozygous for the HFE C282Y mutation. This frequency is the same as the frequency of 5/1000 (0.005) for C282Y homozygosity observed in the normal population. It is slightly above the predicted frequency of homozygosity of 0.0044 derived from the gene frequency in the normal population. CONCLUSIONS: These data suggest that most of the C282Y homozygotes occurred in this arthritis group by chance and that their arthritis was incidental to their HFE genotype. This implies that screening for HFE mutations among patients with inflammatory arthritis would infrequently identify patients whose arthritis might benefit from additional treatment.

Adult↗
PubMed2000

Prevalence of HFE (hemochromatosis gene) mutations in unselected male patients with type 2 diabetes.

To assess the prevalence of mutations in the HFE (hemochromatosis) gene in unselected male patients with type 2 diabetes, we examined 220 white men without known diabetes and 220 age-matched white men with type 2 diabetes for mutations in the HFE gene. Nucleotide 845 (C282Y) and 187(H63D) alleles were amplified by polymerase chain reaction (PCR) with lymphocyte DNA. The PCR products were analyzed by restriction enzyme digestion. One of the 220 patients (0.45%) with diabetes was homozygous for the HFE 845A (C282Y) mutation and 25 (11.3%) were heterozygous for the same mutation, of whom 3 (1.3%) were compound heterozygotes also carrying the HFE 187G (H63D) mutation. These frequencies did not differ significantly from the control population without diabetes. There is no evidence that HFE mutations are found in excess in unselected male patients with type 2 diabetes, and there is no indication for a population-based search for an excess of these alleles in type 2 diabetes.

Adult↗
PubMed2000

Incidence of liver disease in people with HFE mutations.

BACKGROUND: Most patients with haemochromatosis have mutations of the HFE gene. However, the risk to people with HFE mutations of developing disease manifestations of haemochromatosis is not known. AIMS: To determine the risk of developing cirrhosis and liver cancer in individuals with HFE mutations in a population where few people were being treated for haemochromatosis. METHODS: 215 archive biopsy specimens of liver cancer (n=34) and cirrhosis (n=190) were retrieved from histology archives. Blood samples from 1000 individuals from the normal population were also collected. DNA was extracted from the biopsy specimens and exons 2 and 4 of the HFE gene were amplified using polymerase chain reaction. The products were analysed for the C282Y (845A) and H63D (187G) mutations. RESULTS: Three (8.8%) patients from the liver cancer group were homozygous for the C282Y mutation. Five (2.6%) patients from the cirrhosis group were homozygous for the C282Y mutation. One case fell in both the liver cancer and cirrhosis groups. C282Y homozygosity was thus significantly more frequent in both groups than in the normal population. These 215 cases are representative of a population of about 250 000 over 20 years. During this period we estimate that about 260 births or deaths of C282Y homozygous individuals occurred within this population. CONCLUSIONS: A diagnosis of liver cancer or cirrhosis is rare in the lifetime of individuals from this population who are homozygous for the C282Y mutation (2.5%; upper 95% confidence interval (CI) = 8%). Similarly liver disease is rare among C282Y/H63D compound heterozygotes (1%; upper 95% CI = 3.5%).

Adolescent↗
PubMed1998

Consistent fusion of ZNF198 to the fibroblast growth factor receptor-1 in the t(8;13)(p11;q12) myeloproliferative syndrome.

The 8p11 myeloproliferative syndrome is a rare, aggressive condition associated with reciprocal translocations of chromosome band 8p11, most commonly the t(8;13)(p11;q12). To identify the genes involved in this translocation, we used fluorescence in situ hybridization (FISH) analysis to show that the chromosome 8 breakpoints fell within YAC 899e2 and that the chromosome 13 breakpoints are clustered in a region flanked by YACs 929f11 and 911h8. FISH using chromosome 13 PAC clones indicated that the t(8;13) is not simply a reciprocal translocation but also involves an inversion of 13q11-12. Exon trapping of a PAC that spanned the chromosome 13 translocation breakpoints led to the identification of a gene, ZNF198, that detected rearranged bands when used as a probe against Southern blots of patient DNA. Conceptual translation of the full-length ZNF198 cDNA sequence predicts a protein of 1377 amino acids that shows significant homology to the DXS6673E/KIAA0385 and KIAA0425 proteins. Alignment of these three proteins revealed a novel, conserved Zn-finger-related motif (MYM domain) of the general form CX2C19-22CX3CX13-19CX2CX19-25FCX3CX3F/Y that is repeated five times in each protein. To identify the translocation partner gene on chromosome 8, 5' and 3' RACE polymerase chain reactions (PCRs) were performed on patient RNA with several combinations of ZNF198 primers. Clones were identified in which the ZNF198 was fused to exon 9 of the fibroblast growth factor receptor-1 (FGFR1), a gene known to map to 8p11. An identical ZNF198-FGFR1 fusion was detected in the three patients with a t(8;13) for whom RNA was available; reciprocal FGFR1-ZNF198 transcripts were not detected. Rearrangements of both ZNF198 and FGFR1 were found in two further patients by Southern blotting. ZNF198-FGFR1 includes the five MYM domains of ZNF198 and the intracellular tyrosine kinase domain of FGFR1. We hypothesize that this fusion leads to constitutive activation of the FGFR1 tyrosine kinase in a manner analogous to the activation of ABL by BCR in chronic myeloid leukemia.

Amino Acid Sequence↗
PubMed1998

c-myc locus amplification and the acquisition of trisomy 8 in the evolution of chronic myeloid leukaemia.

The biological progression of chronic myeloid leukaemia is often associated with secondary cytogenetic abnormalities but the molecular mechanisms underlying this progression are poorly understood. This study explores the association of c-myc gene amplification with the progression of chronic myeloid leukaemia in fourteen individuals. Three of these cases showed amplification of c-myc during the course of their disease. Cytogenetic and molecular analysis of serial samples from some patients suggested the successive expansion of distinct clones of malignant cells. Our findings also suggest that trisomy 8 and locus amplification could represent alternative mechanisms for increasing c-myc gene dosage.

Chromosome Mapping↗
PubMed1997

A high prevalence of HLA-H 845A mutations in hemochromatosis patients and the normal population in eastern England.

We have examined normal individuals and all the patients currently being treated for hemochromatosis at the Norfolk and Norwich hospital for mutations in the HLA-H gene. We found a gene frequency in 200 normal subjects for teh 845A (C282Y) allele of 0.085, corresponding to a carrier frequency of 17% which is among the highest reported anywhere in the world. The frequency for the less penetrant 187G (H63D) allele was 0.16 among 58 of the normal subjects, which corresponds to a carrier frequency of 32%. All 18 hemochromatosis patients were homozygous for the 845A allele which is not significantly different from other reports in our subset of 12 unrelated patients. These findings present a snapshot of a relatively stable population containing a predicted 3,500 individuals homozygous for the 845A allele but not diagnosed with hemochromatosis. This population will be an excellent model for studies on the penetrance of the 845A homozygous genotype and population screening.

Alleles↗
PubMed1997

A differential PCR assay for the detection of c-erbB 2 amplification used in a prospective study of breast cancer.

AIMS: To establish a robust differential polymerase chain reaction (PCR) assay for the detection of c-erbB 2 amplification in breast cancer that can be used in a routine pathology laboratory. Once established, the assay was used in a prospective study of breast tumours to investigate the relation between c-erbB 2 amplification and both recognised prognostic features and short term clinical outcome. METHODS: The differential PCR was used for the co-amplification of c-erbB 2 and a reference gene from 48 tumour DNA samples and control DNA samples. The ratio of the two genes was determined by image analysis of the PCR products electrophoresed on a highly resolving agarose gel. RESULTS: The differential PCR assay was shown to be accurate and reproducible using the conditions outlined. Twenty six per cent of the breast cancer patients were shown to have c-erbB 2 amplification in their tumour biopsies. Twenty eight per cent of the patients died of their disease or had disease recurrence during the follow up period and 73% of these patients had amplification of c-erbB 2. CONCLUSIONS: A significant association was found between c-erbB 2 amplification and early disease recurrence. This assay could be used to provide a marker for poor prognosis in breast cancer.

Adult↗
PubMed1996

Cyclin D1 amplification and expression in human breast carcinoma: correlation with histological prognostic markers and oestrogen receptor expression.

Aims-To study the amplification of the Cyclin D1 gene (CCND1) in human breast carcinoma; to relate this to Cyclin D1 protein expression; to relate these parameters to recognised pathological prognostic factors, including oestrogen receptor (ER) status.Methods-DNA extracted from frozen sections of breast tumours (n = 36) was used for Southern blotting. Probes for CCND1, c-myc and the immunoglobulin heavy chain locus (IgH) were hybridised to tumour DNA. Immunocytochemical expression of Cyclin D1 protein and ER was studied in paraffin wax sections from the same tumours.Results-Amplification of CCND1 was observed in 11% (four of 36) of tumours studied. Over expression of Cyclin D1 protein was observed in 73% (30/41) of tumours. There was no correlation between recognised histological prognostic markers and either gene amplification or expression. However, a weak association was seen between Cyclin D1 expression and ER status.Conclusions-A disparity exists between locus amplification and over expression of Cyclin D1, suggesting the existence of another mechanism for raised protein expression. No significant correlation was detected between either Cyclin D1 amplification or over expression and established prognostic markers.

Journal Article↗
PubMed1992

Zinc binding by retroviral integrase.

Zinc binding by integrase from Moloney murine leukaemia virus and a protein A fusion protein containing integrase from human immunodeficiency virus type 1 was demonstrated by a zinc blotting technique using 65ZnCl2. Autoradiography revealed a clear band that was absent from the appropriate controls. This band co-migrated with the major band in Coomassie-stained gels and in immunoblots. This binding activity was retained in the presence of competing divalent cations and was sensitive to oxidation. This is the first demonstration of zinc binding by intact retroviral integrase.

Amino Acid Sequence↗
PubMed1991

Herpes simplex virus type 1 that exhibits herpes simplex virus type 2 sensitivity to (E)-5-(2-bromovinyl)-2'-deoxyuridine.

A clinical isolate, designated 145, of herpes simplex virus (HSV) had type 1 characteristics as determined by monoclonal antibody immunofluorescence, heat stability of viral thymidine kinase (TK), BamHI restriction endonuclease pattern, and absence of the HSV-2-specific 38-kD protein. However, instead of being sensitive to E-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) like HSV-1, isolate 145 displayed a resistance pattern like HSV-2 to the drug as determined by viral replication and viral DNA synthesis. Because BVDU is activated by viral TK phosphorylation, we cloned the TK-containing DNA region from isolate 145 and compared it by restriction mapping using several endonucleases to similar regions of HSV-1 and HSV-2. In each instance, the patterns for HSV-1 and isolate 145 were identical to each other, but distinct from the patterns for the corresponding region of HSV-2, suggesting that the genome TK region of isolate 145 was HSV-1-like.

Animals↗
PubMed1983

The formula frenzie.

Explore the source record for details and available documents.

Aphakia, Postcataract↗
PubMedDate not supplied

Clinicopathological features and molecular markers of breast cancer in Jos, Nigeria.

BACKGROUND: Several studies have suggested that breast cancer in black women is associated with aggressive features and poor survival. This study examines molecular markers along with clinical stage and pathological grade in breast cancer material from Jos, Nigeria. STUDY DESIGN: The histological diagnoses of 178 consecutive Nigerian patients with breast cancer were retrieved from their hospital records. A subset of 36 patients was staged and their tumours typed and graded. Immunohistochemical staining of sections from paraffin wax embedded tissues from these cases for the expression of oestrogen receptor (ER), progesterone receptor (PGR), Human ERBB2 (or HER2/neu), p53 and cyclin D1 (CCND1) was carried out using the avidin biotin complex (ABC) procedure. RESULTS: A majority of the cases were invasive ductal carcinoma (92.7%), high grade (grade 3, 70.6%) and of late clinical stage (stages III and IV, 58.3%). Only 25% and 27.8% of cases expressed ER and PGR respectively. The ERBB2 and CCND1 antigens were expressed in 25%, and 5.7% of cases respectively. The p53 protein was the most frequently expressed in this study (47.2% of cases). High grade tumours were significantly more likely to be ER and PGR negative (P = 0.006 and P = 0.002 respectively). CONLCLUSION: There is predominance of high grade, invasive ductal carcinomas which are likely to be ER and PGR negative but p53 positive. These features suggest a biologically aggressive form of breast cancer in Nigerian women with the possibility of poor response to both hormonal therapy and chemotherapy.

Adolescent↗