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Chris Jones

Publications and source records attributed to Chris Jones.

At least 37 records · Page 2Linked to original sources
PubMed2005

Pleomorphic lobular carcinoma of the breast: role of comprehensive molecular pathology in characterization of an entity.

Immunohistochemical analysis of E-cadherin has changed the way lobular neoplasia is perceived. It has helped to classify difficult cases of carcinoma in situ with indeterminate features and led to the identification of new variants of lobular carcinoma. Pleomorphic lobular carcinoma (PLC) and pleomorphic lobular carcinoma in situ (PLCIS), recently described variants of invasive and in situ classic lobular carcinoma, are reported to be associated with more aggressive clinical behaviour. Although PLC/PLCIS show morphological features of classic lobular neoplasia and lack E-cadherin expression, it is still unclear whether these lesions evolve through the same genetic pathway as lobular carcinomas or are high-grade ductal neoplasms that have lost E-cadherin. Here we have analysed a case of extensive PLCIS and invasive PLC associated with areas of E-cadherin-negative carcinoma in situ with indeterminate features, using immunohistochemistry, chromogenic in situ hybridization, high-resolution comparative genomic hybridization (CGH) and array-based CGH. We observed that all lesions lacked E-cadherin and beta-catenin and showed gain of 1q and loss of 16q, features that are typical of lobular carcinomas but are not seen in high-grade ductal lesions. In addition, amplifications of c-myc and HER2 were detected in the pleomorphic components, which may account for the high-grade features in this case and the reported aggressive clinical behaviour of these lesions. Taken together, these data suggest that at least some PLCs may evolve from the same precursor or through the same genetic pathway as classic lobular carcinomas.

Adult↗
PubMed2005

Columnar cell lesions of the breast: the missing link in breast cancer progression? A morphological and molecular analysis.

Columnar cell lesions (CCLs) of the breast are a spectrum of lesions that have posed difficulties to pathologists for many years, prompting discussion concerning their biologic and clinical significance. We present a study of CCL in context with hyperplasia of usual type (HUT) and the more advanced lesions ductal carcinoma in situ (DCIS) and invasive ductal carcinoma. A total of 81 lesions from 18 patients were subjected to a comprehensive morphologic review based upon a modified version of Schnitt's classification system for CCL, immunophenotypic analysis (estrogen receptor [ER], progesterone receptor [PgR], Her2/neu, cytokeratin 5/6 [CK5/6], cytokeratin 14 [CK14], E-cadherin, p53) and for the first time, a whole genome molecular analysis by comparative genomic hybridization. Multiple CCLs from 3 patients were studied in particular detail, with topographic information and/or showing a morphologic spectrum of CCL within individual terminal duct lobular units. CCLs were ER and PgR positive, CK5/6 and CK14 negative, exhibit low numbers of genetic alterations and recurrent 16q loss, features that are similar to those of low grade in situ and invasive carcinoma. The molecular genetic profiles closely reflect the degree of proliferation and atypia in CCL, indicating some of these lesions represent both a morphologic and molecular continuum. In addition, overlapping chromosomal alterations between CCL and more advanced lesions within individual terminal duct lobular units suggest a commonality in molecular evolution. These data further support the hypothesis that CCLs are a nonobligate, intermediary step in the development of some forms of low grade in situ and invasive carcinoma.

Biomarkers, Tumor↗
PubMed2004

Frequency and heritability of WT1 mutations in nonsyndromic Wilms' tumor patients: a UK Children's Cancer Study Group Study.

PURPOSE: Constitutional WT1 mutations in patients with Wilms' tumor (WT) have specifically been associated with genitourinary abnormalities, such as cryptorchidism and hypospadias. We sought to ascertain the frequency and heritability of constitutional WT1 mutations in nonsyndromic WT patients. PATIENTS AND METHODS: Constitutional DNA from 282 patients treated at seven United Kingdom Children's Cancer Study Group centers was screened for WT1 mutations using heteroduplex analysis. Bidirectional sequencing was used to confirm the mutation and to analyze the corresponding parental DNA samples. RESULTS: Five different constitutional WT1 mutations were identified in six children. Mutations in four patients were confirmed to be de novo, and all five mutations are predicted to produce truncated protein. The WT1 mutation group had a young median age at diagnosis of 13.8 months, compared with 34.9 months in the group in whom no WT1 mutations were found; four were female and two were male; and all tumors were of favorable histology. The three tumors with known histologic subtype were stromal-predominant. Contrary to expectation, four of six mutations occurred in children with unilateral tumors without any associated genitourinary abnormality. CONCLUSION: Constitutional WT1 mutations occur with a low frequency (2.1%; 95% CI, 0.8% to 4.6%) in nonsyndromic WT patients. Most mutations occurred in children with unilateral WT without associated genitourinary abnormalities, creating difficulties in identifying individuals with germline mutations on phenotype alone. Two factors that may indicate that an individual is carrying a germline WT1 mutation are an early age of onset and stromal-predominant histology of the WT.

Child, Preschool↗
PubMed2004

Molecular cytogenetic identification of subgroups of grade III invasive ductal breast carcinomas with different clinical outcomes.

Tumor grade is an established indicator of breast cancer outcome, although considerable heterogeneity exists even within-grade. Around 25% of grade III invasive ductal breast carcinomas are associated with a "basal" phenotype, and these tumors are reported to be a distinct subgroup. We have investigated whether this group of breast cancers has a distinguishing pattern of genetic alterations and which of these may relate to the different clinical outcome of these patients. We performed comparative genomic hybridization (CGH) analysis on 43 grade III invasive ductal breast carcinomas positive for basal cytokeratin 14, as well as 43 grade- and age-matched CK14-negative controls, all with up to 25 years (median, 7 years) of clinical follow-up. Significant differences in CGH alterations were seen between the two groups in terms of mean number of changes (CK14+ve - 6.5, CK14-ve - 10.3; P = 0.0012) and types of alterations at chromosomes 4q, 7q, 8q, 9p, 13q, 16p, 17p, 17q, 19p, 19q, 20p, 20q and Xp. Supervised and unsupervised algorithms separated the two groups on CGH data alone with 76% and 74% accuracy, respectively. Hierarchical clustering revealed distinct subgroups, one of which contained 18 (42%) of the CK14+ve tumors. This subgroup had significantly shorter overall survival (P=0.0414) than other grade III tumors, regardless of CK14 status, and was an independent prognostic marker (P=0.031). These data provide evidence that the "basal" phenotype on its own does not convey a poor prognosis. Basal tumors are also heterogeneous with only a subset, identifiable by pattern of genetic alterations, exhibiting a shorter overall survival. Robust characterization of this basal group is necessary if it is to have a major impact on management of patients with breast cancer.

Algorithms↗
PubMed2004

Expression profiling of purified normal human luminal and myoepithelial breast cells: identification of novel prognostic markers for breast cancer.

The normal duct-lobular system of the breast is lined by two epithelial cell types, inner luminal secretory cells and outer contractile myoepithelial cells. We have generated comprehensive expression profiles of the two normal cell types, using immunomagnetic cell separation and gene expression microarray analysis. The cell-type specificity was confirmed at the protein level by immunohistochemistry in normal breast tissue. New prognostic markers for survival were identified when the luminal- and myoepithelial-specific molecules were evaluated on breast tumor tissue microarrays. Nuclear expression of luminal epithelial marker galectin 3 correlated with a shorter overall survival in these patients, and the expression of SPARC (osteonectin), a myoepithelial marker, was an independent marker of poor prognosis in breast cancers as a whole. These data provide a framework for the interpretation of breast cancer molecular profiling experiments, the identification of potential new diagnostic markers, and development of novel indicators of prognosis.

Breast↗
PubMed2004

Distribution and significance of 14-3-3sigma, a novel myoepithelial marker, in normal, benign, and malignant breast tissue.

14-3-3sigma is a candidate tumour suppressor gene transactivated by p53 in response to DNA damage. In gene expression analysis of normal luminal and myoepithelial cells, 14-3-3sigma was preferentially expressed by myoepithelial cells. This study has analysed the immunohistochemical distribution and subcellular localization of 14-3-3sigma in normal breast tissue and in a large series of benign and malignant breast lesions on whole tissue sections and by tissue microarray. Immunohistochemistry demonstrated that 14-3-3sigma was consistently expressed in the cytoplasmic compartment and occasionally in the nuclei of myoepithelial cells arranged as a continuous layer around normal ducts and lobular units, whereas luminal epithelial, stromal, endothelial, pericytic, lipomatous, and neural cells showed no staining. Myoepithelial cells of benign proliferations and pre-invasive lesions were consistently positive for 14-3-3sigma. Strong expression of 14-3-3sigma was evident in one case of ductal carcinoma in situ (5.5%) and in 105/554 invasive cancers (18.9%). Survival data were available for 452 patients with invasive breast carcinoma. 14-3-3sigma cytoplasmic subcellular localization was a statistically significant prognostic factor for the whole series of invasive carcinomas, as well as for those positive for oestrogen (ER) or progesterone receptors (PR). This analysis demonstrates the utility of 14-3-3sigma as a new adjunct antibody for characterization of myoepithelial cells and myoepithelial lesions and it may be a novel prognostic factor for breast cancer patients.

14-3-3 Proteins↗
PubMed2004

Immunoglobulin heavy chain genes somatic hypermutations and chromosome 11q22-23 deletion in classic mantle cell lymphoma: a study of the Swiss Group for Clinical Cancer Research.

Mantle cell lymphoma (MCL) shares immunophenotypic and karyotypic features with chronic lymphocytic leukaemia. The latter comprises two distinct entities with prognosis dependent upon immunoglobulin heavy chain (IgH) gene mutational status and the presence of 11q deletion. We evaluated the relevance of IgH gene mutational status, IgV gene family usage and presence of 11q deletion in a series of 42 histologically reviewed classical MCL cases to determine the prognostic impact. VH3 was the most common VH family, with VH3-21 being the most frequent individual VH gene. Approximately 30% of the cases had a IgH somatic mutation rate higher than 2%, but was only higher than 4% in <10% of cases. Half of the cases had deletion of chromosome 11q21-telomere (11q21->ter), with two minimal deleted regions, at 11q22.2 and 11q23.2. There was no association between 11q loss and IgH gene somatic mutation rate; the use of VH3-21 gene could be associated with a better prognosis.

Aged↗
PubMed2004

Simulation model of renal replacement therapy: predicting future demand in England.

BACKGROUND: The demand for renal replacement therapy (RRT) in England has risen steadily, although from a lower base than many other developed countries. Predicting the future demand for RRT and the impact of factors such as the acceptance rate, transplant supply and patient survival, is required in order to inform the planning of such services. METHODS: A discrete event simulation model estimates the future demand for RRT in England in 2010 for a range of scenarios. The model uses current prevalence and current and projected future acceptance rates, survival rates and the transitions between modalities to predict future patient numbers. National population and mortality data, published literature and data from the UK Renal Registry and UK Transplant, are used to estimate unmet need for RRT, the impact of changing demography and incidence of Type 2 diabetes, patient haemodialysis (HD) survival and transplant supply. RESULTS: By 2010 the predicted prevalence will have increased from about 30,000 in 2000 to between 42 and 51,000 (900-1000 p.m.p.), an average annual growth of 4.5-6%. Changing transplant supply has a small effect on overall numbers but changes the proportion of patients with functioning graft by up to 8%. Even with an optimistic increase in transplant supply (11% p.a. for 5 years), numbers on HD will continue to rise substantially, especially in the elderly. The factors most influencing future patient numbers are the acceptance rate and dialysis survival. CONCLUSION: This model predicts a substantial growth in the RRT population to 2010 to a rate approaching 1000 p.m.p., particularly in the elderly and those on HD, with a steady state not being reached for at least 25 years.

Adolescent↗
PubMed2003

cDNA microarray analysis of genes associated with ERBB2 (HER2/neu) overexpression in human mammary luminal epithelial cells.

To investigate changes in gene expression associated with ERBB2, expression profiling of immortalized human mammary luminal epithelial cells and variants expressing a moderate and high level of ERBB2 has been carried out using cDNA microarrays corresponding to approximately 6000 unique genes/ESTs. A total of 61 significantly up- or downregulated (2.0-fold) genes were identified and further validated by RT-PCR analysis as well as microarray comparisons with a spontaneously ERBB2- overexpressing breast cancer cell line and ERBB2-positive primary breast tumors. The expression and clinical relevance of proteins predicted to be associated with ERBB2 overexpression in breast cancers were analysed together with their clinical relevance by antibody screening using a tissue array. Differentially regulated genes include those involved in cell-matrix interactions including proline 4-hydroxylase (P4HA2), galectin 1 (LGALS1) and galectin 3 (LGALS3), fibronectin 1 (FN1) and p-cadherin (CDH3), and cell proliferation (CRIP1, IGFBP3) and transformation (S100P, S100A4). A number of genes associated with MYC signalling were also differentially expressed, including NDRG1, USF2 and the epithelial membrane proteins 1 and 3 (EMP1, EMP3). These data represent profiles of the transcriptional changes associated with ERBB2-related pathways in the breast, and identify novel and potentially useful targets for prognosis and therapy.

Breast↗
PubMed2003

Comparative genomic hybridization analysis of bilateral hyperplasia of usual type of the breast.

Hyperplasia of usual type (HUT) is part of the spectrum of benign proliferative disease in the breast and confers an increased risk of developing invasive cancer. Its role as a putative precursor of invasive ductal carcinomas in the breast is, however, controversial. HUT is occasionally seen bilaterally but it is not clear whether there is a genetic predisposition to the process. This study has analysed 14 cases of bilateral HUT in the breast (28 independent lesions) by comparative genomic hybridization (CGH) analysis to define DNA copy number changes and to investigate any commonality in these genetic alterations. The mean number of alterations seen was 1.6 (46/28) in all lesions, with common losses at chromosomes 1p, 16p, 17q, and 22q. Bilaterally, only five alterations were seen in common across both lesions in both breasts, but no single locus was altered preferentially. These data indicate that a proportion of HUT in the breast are indeed clonal, neoplastic proliferations which exhibit genetic alterations in common with invasive breast cancer, albeit at very low levels. The limited data from these experiments do not reveal a specific predisposition locus.

Breast↗
PubMed2003

Tightropes and tragedies: 25 years of Tarasoff.

In 1976 the California Supreme Court decided the case of Thrasoff v Regents of the University of California. That case has had very significant effects on psychiatric practice on both sides of the Atlantic, and its very name is instantly recognizable to most psychiatrists. Yet the details of the case are often misunderstood or misquoted; as a legal precedent it was rapidly superceded, and is now largely redundant. Twenty-five years on it seems appropriate to revisit the case itself, and its impact on contemporary psychiatric practice. English law has yet to impose a similar duty, but two leading cases raising similar issues are also described.

Adult↗
PubMed2002

Detection of residual pertussis toxin in vaccines using a modified ribosylation assay.

Pertussis toxin (PTx) in its detoxified form is an important component of both whole cell and acellular pertussis vaccines (ACVs). For safety reasons, it is imperative to ensure that the quantity of residual PTx in vaccines does not exceed permissible levels. The majority of the toxic effects of PTx have been attributed to the consequences of PTx-catalyzed ribosylation of the alpha-subunits of signal-transducing guanine-nucleotide-binding proteins. In this report PTx ribosylation activity was determined by an improved enzymatic-high performance liquid chromatography coupled assay using a fluorescein labeled Galpha(i3)C20 peptide. The effect of aluminum salts and other vaccine components on the assay system were also studied. The enzymatic assay system was shown to be a convenient, sensitive method and correlate well with the toxicity observed in vivo by the histamine sensitization assay. This method forms the basis of a new assay which could replace the unsatisfactory animal test currently used in pertussis vaccines control.

Animals↗
PubMed2002

Reelin and ApoE receptors cooperate to enhance hippocampal synaptic plasticity and learning.

Two apolipoprotein E (apoE) receptors, the very low density lipoprotein (VLDL) receptor and apoE receptor 2 (apoER2), are also receptors for Reelin, a signaling protein that regulates neuronal migration during brain development. In the adult brain, Reelin is expressed by GABA-ergic interneurons, suggesting a potential function as a modulator of neurotransmission. ApoE receptors have been indirectly implicated in memory and neurodegenerative disorders because their ligand, apoE, is genetically associated with Alzheimer disease. We have used knockout mice to investigate the role of Reelin and its receptors in cognition and synaptic plasticity. Mice lacking either the VLDL receptor or the apoER2 show contextual fear conditioning deficits. VLDL receptor-deficient mice also have a moderate defect in long term potentiation (LTP), and apoER2 knockouts have a pronounced one. The perfusion of mouse hippocampal slices with Reelin has no effect on baseline synaptic transmission but significantly enhances LTP in area CA1. This Reelin-dependent augmentation of LTP is abolished in VLDL receptor and apoER2 knockout mice. Our results reveal a role for Reelin in controlling synaptic plasticity in the adult brain and suggest that both of its receptors are necessary for Reelin-dependent enhancement of synaptic transmission in the hippocampus. Thus, the impairment of apoE receptor-dependent neuromodulation may contribute to cognitive impairment and synaptic loss in Alzheimer disease.

Alzheimer Disease↗
PubMed2002

Late referral for end-stage renal disease: a region-wide survey in the south west of England.

BACKGROUND: The proportion of patients referred for renal replacement therapy (RRT) at a late stage of disease appears to be similar to that first described nearly 20 years ago. This study investigated the current scale of the problem in a large region in England, identifying the prior health care, patient characteristics, referral pattern, and outcomes of those accepted onto RRT. METHODS: Three hundred and sixty-one (88%) out of 411 patients accepted for RRT in six renal units in the South and West Region of the UK between 1 June 1996 and 31 May 1997 were studied retrospectively. We examined the history of chronic renal failure, referral path to nephrologist, management of chronic renal failure (CRF) and patient outcomes. Patients were categorized as 'late' if they were referred to the renal unit either within 4 months or within 1 month of requiring RRT. RESULTS: One hundred and twenty-four (35%) patients were referred within 4 months of RRT, and 84 (23%) within 1 month. The main differences between patients referred later and other patients was seen for those referred within 1 month. These patients were older and had more co-morbidity, significantly worse laboratory parameters at the start of RRT, were less likely to have received standard treatments for CRF, had less permanent dialysis access in place at the start of RRT (18% vs 47%, P=0.001), and had a significantly longer hospital stay (18 vs 10 days, P=0.001). Seventy-four (19%) patients died in the first 6 months: 27 (32%) in the 1-month group, 46 (16%) in all others (P=0.002). We found no evidence that patients referred late had defaulted from nephrology follow-up or had an excess of rapidly progressive disease. Though data were incomplete, there was evidence of prior CRF of over 1 year in all late referral groups. CONCLUSION: Nearly a quarter of patients are referred for specialist nephrology treatment at a very late stage, within 1 month of RRT. They are less likely to receive interventions that could alter the progression of CRF or reduce its associated co-morbidity, have a worse clinical state at the start of RRT, longer hospitalization and poorer survival. These differences were much less marked for those referred within 1-4 months of starting RRT, although this is an insufficient time to prepare for RRT. Further research is needed to determine the missed opportunities for more proactive diagnosis and management of CRF.

Aged↗
PubMed2002

Duration of untreated psychosis and pathways to care in first-episode psychosis. Investigation of help-seeking behaviour in primary care.

BACKGROUND: Studies have consistently found that many individuals with first-episode psychosis experience significant delays before receiving treatment. Current research investigating treatment delays has focused on the relationship between demographic factors and duration of untreated psychosis (DUP). However, treatment-seeking behaviours in this group have not been investigated. AIMS: To examine psychological processes that influence the decision-making process to contact primary care, in individuals with emerging psychosis. METHOD: The influence of coping style, health locus of control and past health help-seeking behaviour on DUP was investigated in clients with a first episode of psychosis. This involved scrutiny of general practitioner (GP) records in an average of 6 years before the first treatment. RESULTS: Shorter DUP was associated with more frequent GP attendance in the 6 years before the onset of psychosis and lower health threat avoidant coping scores. CONCLUSIONS: Patients with short DUP have history of higher contact with their GP and, as a group, tend not to avoid health threats. The study underlines the importance of engaging young people and their families with primary care as one of a series of strategies to reduce DUP.

Adaptation, Psychological↗