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Biomedical subjects

J C Steele

Publications and source records attributed to J C Steele.

At least 19 recordsLinked to original sources
PubMed2006

The polycomb group proteins, BMI-1 and EZH2, are tumour-associated antigens.

We used SEREX technology to identify novel tumour-associated antigens in patients with primary hepatocellular carcinoma and found serological responses to the polycomb group (PcG) protein BMI-1, which is overexpressed in a range of different tumour types. Further studies identified T-cell responses to both BMI-1 and another PcG protein, EZH2, in cancer patients and at relatively lower levels in some normal donors. We next identified several CD8+ T-cell epitopes derived from BMI-1 and EZH2 and demonstrated that EZH2-derived peptides elicited more significant interferon-gamma (IFN-gamma) release than BMI-1-derived peptides. That CD8(+) T cells were responsible for the observed responses was confirmed for EZH2 by both IFN-gamma capture assays and tetramer staining using an HLA-A0201-restricted, EZH2-derived YMSCSFLFNL (aa 666-674) epitope. The ability of YMSCSFLFNL (aa 666-674) to stimulate the in vitro expansion of specific T cells from peripheral blood lymphocytes was greatly enhanced when the CD25(+) T-cell population was depleted. EZH2-specific cytotoxic T lymphocyte clones specific for two HLA-A0201 epitopes were generated and found to recognise endogenously processed EZH2 in both HLA-matched fibroblasts and tumour cell lines. Given the widespread overexpression of PcG proteins in cancer and their critical role in oncogenesis, these data suggest that they may be useful targets for cancer immunotherapy.

Amino Acid Sequence↗
PubMed2005

T-cell responses to human papillomavirus type 16 among women with different grades of cervical neoplasia.

Infection with high-risk genital human papillomavirus (HPV) types is a major risk factor for the development of cervical intraepithelial neoplasia (CIN) and invasive cervical carcinoma. The design of effective immunotherapies requires a greater understanding of how HPV-specific T-cell responses are involved in disease clearance and/or progression. Here, we have investigated T-cell responses to five HPV16 proteins (E6, E7, E4, L1 and L2) in women with CIN or cervical carcinoma directly ex vivo. T-cell responses were observed in the majority (78%) of samples. The frequency of CD4+ responders was far lower among those with progressive disease, indicating that the CD4+ T-cell response might be important in HPV clearance. CD8+ reactivity to E6 peptides was dominant across all disease grades, inferring that E6-specific CD8+ T cells are not vitally involved in disease clearance. T-cell responses were demonstrated in the majority (80%) of cervical cancer patients, but are obviously ineffective. Our study reveals significant differences in HPV16 immunity during progressive CIN. We conclude that the HPV-specific CD4+ T-cell response should be an important consideration in immunotherapy design, which should aim to target preinvasive disease.

Adult↗
PubMed2005

Pyodermatitis-pyostomatitis vegetans complicated by methicillin-resistant Staphylococcus aureus infection.

Pyodermatitis-pyostomatitis vegetans (PPV), a rare disorder of the skin and oral mucosa, is considered a highly specific marker for inflammatory bowel disease, especially ulcerative colitis (UC). Oral lesions (pyostomatitis vegetans) are seen without skin involvement but rarely without gastrointestinal symptoms. Bowel symptoms may be minimal and precede the onset of other lesions by months or years. Dermatologically, PPV is characterized by annular, pustular lesions, which may precede or appear at the same time as the oral lesions. We report a case of PPV and UC in which presentation was confused by acneiform lesions and methicillin-resistant Staphylococcus aureus colonization. Management was complicated because of the patient's job commitments and need to travel, and the involvement of a number of different specialties at different locations.

Adult↗
PubMed2004

Occurrence of beta-methylamino-l-alanine (BMAA) in ALS/PDC patients from Guam.

We tested the brain tissues of the Chamorro people of Guam who died of amyotrophic lateral sclerosis/Parkinsonism dimentia complex (ALS/PDC) for the neurotoxin beta-methylamino-l-alanine (BMAA). We used validated high-pressure liquid chromatography and liquid chromatography-mass spectrometry analyses to test well-characterized archival tissues of the superior frontal gyrus from eight Chamorros from Guam and a comparison group of 15 Canadians. BMAA was found as a free amino acid in 83% of Chamorro ALS/PDC patients (3-10 microg/g) as a protein-associated amino acid in 100% of the Chamorro individuals (149-1190 microg/g). Both forms of BMAA were also found at comparable levels in two Canadians who died of progressive neurodegenerative disease. BMAA, which is produced by cyanobacteria, may be associated with some cases of neurodegenerative disease.

Adult↗
PubMed2004

Lingual striated muscle hamartoma or herniation?

Three grouped, small polypoid lesions were removed from the right lateral border of tongue of a healthy male aged 12 years. They were composed of packed, mature striated muscle fibres covered by oral epithelium and thinned lamina propria. Hamartomatous growth of striated muscle, or herniation through underdeveloped lamina propria is postulated to explain the exceedingly rare clinicopathological features.

Basement Membrane↗
PubMed2001

A clinical and pathological study of motor neurone disease on Guam.

Despite over 40 years of intensive study, the cause of the high incidence of motor neurone disease (MND) on Guam, and the relationship between this disease and MND seen in the rest of the world are still uncertain. We present a series of 45 cases of Guamanian MND, which reaffirm the clinical similarity between this disease and MND seen in other countries. However, the occurrence of MND among the indigenous Chamorros of Guam is distinguished by four factors: (i) high prevalence; (ii) frequent familial occurrence; (iii) co-occurrence with the parkinsonism-dementia complex (PDC); and (iv) association with an unusual and distinctive linear retinopathy termed Guam retinal pigment epitheliopathy (GRPE). These distinguishing factors were not present in four non-Chamorros who resided on Guam when their MND symptoms occurred. Pathologically, the classical features of MND were seen in Guamanian Chamorro cases including ubiquitin inclusions. Neurofibrillary tangles were frequently seen. The neurofibrillary tangles appeared in the same distribution as described in the PDC but, unlike classical PDC, they were not usually associated with cell loss and occurred less frequently. While neurofibrillary tangle formation and the clinicopathological syndrome of MND may occur in parallel, observations from this series suggest that pathologically classical MND on Guam may occur independently of neurofibrillary degeneration and the clinical features of PDC.

Adult↗
PubMed1999

Neurodegenerative diseases of Guam: analysis of TAU.

Mutations in the tau gene have been described in families affected by frontotemporal dementia with parkinsonism linked to chromosome 17. The authors performed a genetic and biochemical analysis of this gene and its product in the parkinsonism dementia complex of Guam, a disorder characterized by the extensive formation of neurofibrillary tangles. The tau gene is not a primary cause of the parkinsonism dementia complex of Guam.

Aged↗
PubMed1999

In vitro and in vivo evaluation of betulinic acid as an antimalarial.

The lupane-type triterpene betulinic acid was isolated from an ethanol extract of the root bark of the Tanzanian tree Uapaca nitida Müll-Arg. (Euphorbiaceae). The in vitro antiplasmodial IC50 values of betulinic acid against chloroquine resistant (K1) and sensitive (T9-96) Plasmodium falciparum were found to be 19.6 micrograms/mL and 25.9 micrograms/mL, respectively. The in vitro activities of several related triterpenes were also evaluated. Betulin was found to be inactive at 500 micrograms/mL for both K1 and T9-96. Ursolic acid exhibited IC50 values of 36.5 micrograms/mL and 28 micrograms/mL, and oleanolic acid exhibited IC50 values of 88.8 micrograms/mL and 70.6 micrograms/mL against K1 and T9-96, respectively. When betulinic acid was tested for in vivo activity in a murine malaria model (P. berghei) the top dosage employed of 250 mg/kg/day was ineffective at reducing parasitaemia and exhibited some toxicity. Betulinic acid has not previously been evaluated for in vivo activity. This is believed to be the first compound to be isolated from U. nitida.

Animals↗
PubMed1999

Evaluation of the anti-plasmodial activity of bisbenzylisoquinoline alkaloids from Abuta grandifolia.

Three alkaloids were isolated from the bark of the traditional medicinal plant Abuta grandifolia (Mart.) Sandw. (Menispermaceae) and tested for in vitro anti-plasmodial activity. Two of them were identified as the Type VIII bisbenzylisoquinoline alkaloids, krukovine (1) and limacine (2), while the least abundant compound (3) could only be characterised to Type I of the same class. Krukovine exhibited potent anti-plasmodial activity with IC50 values of 0.44 microgram/ml and 0.022 microgram/ml against K1 (chloroquine-resistant) and T9-96 (chloroquine-sensitive) Plasmodium falciparum, respectively. Both limacine and compound 3 exhibited moderate anti-plasmodial activity against K1 with IC50 values of 1.35 micrograms/ml and 1.58 micrograms/ml, respectively. Limacine gave an IC50 value of 0.24 microgram/ml against T9-96. Krukovine and limacine showed greater activity against T9-96 than against K1, exhibiting similar activity profiles to that of chloroquine diphosphate (0.187 microgram/ml and 0.013 microgram/ml against K1 and T9-96, respectively). This indicates that krukovine and limacine may be affected by the mechanism of chloroquine resistance present in K1 P. falciparum.

Alkaloids↗
PubMed1999

Antiplasmodial activity of extracts and alkaloids of three Alstonia species from Thailand.

Methanol extracts prepared from various parts of Alstonia scholaris, A. macrophylla and A. glaucescens, collected from Thailand, have been assessed for antiplasmodial activity against multidrug-resistant K1 strain of Plasmodium falciparum cultured in human erythrocytes. Pronounced antiplasmodial activity was exhibited by methanol extract of the root bark of A. macrophylla with an IC50 value of 5.7 micrograms/ml. Thirteen indole alkaloids were isolated from the active extract. These alkaloids and a semisynthetic bisindole O-acetylmacralstonine were subsequently tested against the K1 strain of P. falciparum. Pronounced antiplasmodial activity was observed mainly among the bisindole alkaloids, particularly villalstonine and macrocarpamine with IC50 values of 0.27 and 0.36 microM, respectively. The potent alkaloids were further tested against T9-96, the chloroquine-sensitive strain of P. falciparum. It has been found that the active alkaloids, in contrast to chloroquine, have significantly higher affinity to the K1 strain than to the T9-96 strain.

Animals↗
PubMed1999

Rotavirus.

Rotavirus is the leading cause of nonbacterial gastroenteritis in young children and may infect neonates, older children, and adults as well. A large number of serogroups and types complicates the study, epidemiology, diagnosis, and prevention of rotaviral illness. Currently, routine diagnostic methods are satisfactory only for group A rotaviruses, and most commercially available kits in widespread use detect only this serogroup. Rehydration therapy and electrolyte management remain the primary treatment modalities. Recent vaccine developments offer the promise of a reduced burden of the viral pathogen worldwide.

Gastroenteritis↗
PubMed1998

Structural aspects of the interaction between heterogeneic human papillomavirus type 1 E4-specific T cell receptors and the same peptide/HLA-DQ8 complex.

TCR usage has been studied in a panel of Th cell clones specific for the same peptide epitope (P N S Q D R G R P R R S D), derived from the human papillomavirus type 1 (HPV1) E4 protein, and restricted through HLA-DQ8. After identifying the V, D, and J genes used by the TCRs and sequencing across the V(D)J junctions, five different alpha-chain sequences and five different beta-chain sequences, comprising six independent clones, were identified. A structural model of our E4 peptide/HLA-DQ8 complex predicted that the guanidinyl side chain on the arginine residue at position 6 of the peptide could exist in different orientations. An intramolecular interaction between this arginine and the glutamine residue at position four appeared to control this orientation. Interacting HPV1 E4-specific TCRs would therefore have to recognize the complex in different conformations, and molecular modeling of the TCRs suggested that this could be achieved by changing the dimensions of the central pocket formed where the CDR3 loops of the TCR alpha- and beta-chains converge. It is known that interactions between bound peptide and amino acid residues lining the peptide-binding cleft of HLA molecules are important for determining the conformation and orientation of the peptide/MHC complex. The suggestion here that intramolecular interactions between amino acids of close proximity on the bound peptide are also important adds a further level of complexity to the mechanism by which TCRs interact with Ag.

Amino Acid Sequence↗
PubMed1998

Pyramidal neuron loss is matched by ghost tangle increase in Guam parkinsonism-dementia hippocampus.

The parkinsonism dementia complex of Guam (bodig disease) is characterized by severe neurofibrillary tangle (NFT) development without the senile plaques which characterize Alzheimer's disease. Here we analyze eight cases of bodig and three control cases from Guam, for the numbers of unaffected pyramidal neurons, intracellular NFTs (iNFTs), and extracellular NFTs (eNFTs) in hippocampal sectors CA1 and CA4. We utilized Alz50 immunostaining to identify iNFTs, amyloid P immunostaining to identify eNFTs, and cresyl violet staining to identify the surviving pyramidal neurons. We developed a modification of the Bielschowsky silver staining method which distinguished iNFTs from eNFTs and found the numbers of iNFTs and eNFTs identified by this method to be comparable to those obtained by immunohistochemical staining. In CA4, the combined total of unaffected pyramidal neurons, iNFTs and eNFTs was found to be remarkably constant in all the cases studied. The density of eNFTs correlated significantly and negatively with the density of surviving neurons, which included unaffected neurons and iNFTs. CA1 was more intensely affected than CA4. The combined total of unaffected pyramidal neurons, iNFTs and eNFTs was still relatively constant, although greater variability was recorded. Our results suggest that loss of pyramidal neurons is proportional to the appearance of eNFTs. The eNFTs accumulate, without evidence of disappearance through phagocytosis.

Adult↗
PubMed1997

Amyloid P immunoreactivity precedes C4d deposition on extracellular neurofibrillary tangles.

Extracellular neurofibrillary tangles (eNFTs) are the insoluble cytoskeletal debris left behind when neurons with intracellular neurofibrillary tangles (iNFTs) die. Reactive microglia and reactive astrocytes gather around eNFTs. Many inflammatory proteins are deposited in their vicinity, including activated components of the classical complement pathway. Agents which are potential activators of the pathway include beta-amyloid protein (A beta) and amyloid P (AP), since these in vitro activators have been reported to be associated with both senile plaques (SPs) and eNFTs. To investigate the apparent order in which these proteins are deposited, we studied by immunohistochemistry the relative association of AP, A beta, and the classical complement protein C4d with eNFTs in Alzheimer's disease (AD), parkinsonism-dementia complex of Guam (lytico-bodig, LB), and elderly non-demented cases. In normal elderly cases with mild tangle development, most but not all eNFTs were AP positive. Substantially fewer eNFTs were C4d positive, and in two of the three cases no eNFTs were A beta positive. In AD and mild LB cases with more extensive tangle development, a high portion of eNFTs were AP positive, and most of them were C4d positive. Only a few were A beta positive. In severe LB cases, with dense tangle development, almost all eNFTs were AP and C4d positive, and a significant number were also A beta positive. AP seems to be deposited early in eNFT exposure and could therefore be a potential activator of the complement pathway, while A beta deposition occurs relatively late in the process, and is therefore unlikely to be responsible.

Aged↗
PubMed1997

Dystrophic neurites are associated with early stage extracellular neurofibrillary tangles in the parkinsonism-dementia complex of Guam.

We found tangle-associated neuritic clusters (TANCs), previously reported as being present in Alzheimer's disease (AD), to be common in early and mild cases of the parkinsonism-dementia complex of Guam (PDC, bodig disease). These entities were observed around extracellular neurofibrillary tangles (eNFTs), apparently as a transient phenomenon. They were not observed around normal neurons, or neurons with intracellular neurofibrillary tangles (iNFTs). They were also not observed around late stage eNFTs. The TANCs contained both type 1 (elongated) and type 2 (globular) dystrophic neurites, as well as small, granular structures. The type 1 dystrophic neurites in TANCs were immunostained by antibodies to neuroskeletal proteins, while type 2 dystrophic neurites were immunostained by antibodies to amyloid precursor protein (APP). The eNFTs surrounded by TANCs were almost all immunopositive for amyloid P, while only some were immunopositive for C4d, and only a minority had beta-amyloid protein (A beta) associated with them. We hypothesize that the eNFTs are a source of complement activation which results in destruction of surrounding neurites. We further hypothesize that the degenerating neurites are a source of A beta which forms long-term deposits around eNFTs.

Aged↗