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J Martin

Publications and source records attributed to J Martin.

At least 19 recordsLinked to original sources
PubMed2026

Multiregion profiling of genomic and transcriptional heterogeneity in head and neck squamous-cell carcinoma.

BACKGROUND: Intratumoral heterogeneity (ITH) is thought to contribute to tumour evolution and treatment resistance but its biological and clinical significance in localised head and neck squamous-cell carcinoma (HNSCC) remains incompletely understood. PATIENTS AND METHODS: In the prospective SCANDARE study, we analysed 87 patients with resectable HNSCC treated with upfront surgery. Two to five spatially distinct tumour regions per patient underwent pathological evaluation, targeted DNA sequencing, and bulk RNA sequencing. Genomic ITH (gITH) was quantified using clonal deconvolution and Shannon diversity indices, whereas transcriptional heterogeneity (tITH) was assessed using the intratumour expression distance metric. Associations between ITH, molecular features, tumour microenvironment composition, and clinical outcomes were explored using multivariable statistical models. RESULTS: Pathology-based spatial heterogeneity showed limited prognostic value. gITH was common, with 37% of tumours displaying regionally heterogeneous pathogenic variants, including spatially actionable alterations in 10% of patients. In an initial multivariable Cox model, higher gITH was associated with shorter disease-free survival. However, after Ridge-penalised modelling and bootstrap internal validation, the effect size was attenuated [corrected hazard ratio 1.42, 95% confidence interval (CI) 0.91-2.75]. The overall model retained moderate discriminative performance (optimism-corrected C-index 0.69, 95% CI 0.59-0.79). gITH was associated with tumour cellularity, reduced estimated endothelial cell infiltration, and alterations in KMT2C and PIK3CA. tITH differed according to human papillomavirus (HPV) status, with lower tITH in HPV-positive tumours, and was associated with distinct biological pathways and genomic alterations. Genomic and tITH were not correlated. CONCLUSIONS: This prospective multiregion study provides a comprehensive characterisation of genomic and tITH in localised HNSCC. Our findings highlight substantial spatial molecular diversity within primary tumours and suggest potential associations between heterogeneity, tumour biology, and clinical outcome that warrant validation in independent cohorts.

head and neck squamous-cell carcinoma (HNSCC)↗
PubMed2007

Observations from the UK Supra-Regional Assay Service laboratory for the measurement of Vitamin D metabolites.

As a Supra-Regional Assay Service (SAS) laboratory, we receive samples from all over the UK. Of these some are sent frozen and others by post or courier. We have examined transport and storage conditions to see whether they affect the measurement of Vitamin D metabolites and potentially contribute to the variation in measurement of 25-hydroxyvitamin D (25OHD) seen in the DEQAS scheme. We have also examined the samples received during 2005. We found that different transport and storage conditions did not contribute significantly to the normal variation seen in measuring Vitamin D metabolites (CV% (+/-S.E.) for stored versus assay controls: 5.1+/-0.06% versus 4.5+/-0.04% for 25OHD and 10.8+/-1.0% versus 12.3+/-1.0% for 1,25D). A review of the service showed a 240% increase in samples received over the last 5 years. Despite an increased awareness of the need to measure Vitamin D status, in this cross-section of patient samples 92% of Asian and 86% of white patients were found to be Vitamin D-insufficient (<30 ng/ml) and 27% of Asian and 14% of white patients were profoundly deficient (<5 ng/ml) and at risk of bone disease.

Humans↗
PubMed2006

Structure and thermoelectric characterization of Ba8Al14Si31.

A molten Al flux method was used to grow single crystals of the type I clathrate compound Ba8Al14Si31. Single-crystal neutron diffraction data for Ba8Al14Si31 were collected at room temperature using the SCD instrument at the Intense Pulsed Neutron Source, Argonne National Laboratory. Single-crystal neutron diffraction of Ba8Al14Si31 confirms that the Al partially occupies all of the framework sites (R1 = 0.0435, wR2 = 0.0687). Stoichiometry was determined by electron microprobe analysis, density measurements, and neutron diffraction analysis. Solid-state (27)Al NMR provides additional evidence for site preferences within the framework. This phase is best described as a framework-deficient solid solution Ba8Al14Si31, with the general formula, Ba(8)Al(x)Si(42-3/4x)[](4-1/4x) ([] indicates lattice defects). DSC measurements and powder X-ray diffraction data indicate that this is a congruently melting phase at 1416 K. Temperature-dependent resistivity reveals metallic behavior. The negative Seebeck coefficient indicates transport processes dominated by electrons as carriers.

Journal Article↗
PubMed2006

Carboplatin/cyclophosphamide or carboplatin/paclitaxel in elderly patients with advanced ovarian cancer? Analysis of two consecutive trials from the Groupe d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens.

BACKGROUND: To determine the feasibility of two chemotherapy regimens in elderly patients with advanced ovarian carcinoma (AOC). PATIENTS AND METHODS: Eighty-three patients >or=70 years were previously enrolled in a trial evaluating carboplatin and cyclophosphamide (CC). On the basis of identical eligibility criteria, 75 further patients were enrolled in a trial evaluating carboplatin and paclitaxel (Taxol) (CP). The primary end point of these studies was the feasibility of six courses of chemotherapy. Comprehensive geriatric assessment (CGA) parameters were assessed in terms of prognostic factors. RESULTS: More patients in the CC group presented with performance status of two or more, depression symptoms, use of co-medications, hypoalbuminemia, abnormal Mini-Mental Status score, or sub-optimal surgery. Both regimens appeared feasible: 75.6% in the CC group and 68.1% in the CP group completed six courses. CC and CP groups had similar overall survival (OS). Independent prognostic factors of poorer OS were the following: increasing age (P = 0.013), depression symptoms at baseline (P < 0.001), International Federation of Gynecology and Obstetrics stage IV (P = 0.001), and use of paclitaxel (P = 0.025). CONCLUSION: As this is a non-randomised retrospective review of two consecutive studies, no firm conclusion can be drawn. It seems, however, that in elderly patients with AOC the use of paclitaxel results in more toxicity. CGA parameters and particularly emotional disorders might help to determine a priori the risk/benefit ratio of chemotherapy in this patient population.

Aged↗
PubMed2006

Genetic basis of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a clinically heterogeneous condition with a complex aetiology in which environmental and genetic factors are implicated. The contribution of human leukocyte antigen (HLA) genes, particularly the HLA-DRB1 gene, to RA genetic predisposition was the first described, and remains as the best characterised single genetic risk factor contributing to RA. However, it has been estimated that only 30% of the genetic contribution to RA can be attributed to HLA genes and it is suggested that other non-HLA genes may play a relevant role in RA susceptibility. Linkage studies and association studies are the two main strategies used in the investigation of genetic factors contributing to complex genetic traits. In this work we review the progress made in the field of RA genetics, focusing mainly on the contribution of candidate gene association studies to the dissection of RA genetic risk factors.

Antigens, CD↗
PubMed2006

The pluripotent cytokine pleiotrophin is induced by wounding in human mesangial cells.

Mesangial re-modeling and mesangial cell (MC) migration are features of several glomerular diseases including mesangiocapillary glomerulonephritis. In vitro investigations have recently identified ADAM-15, a multidomain adamalysin, as central to the migration of MC. The current study used array technology to investigate the expression of other genes in migrating cells and identified pleiotrophin (PTN), platelet-derived growth factor alpha polypeptide chain, colony stimulating factor, and four members of the tumor necrosis factor-alpha superfamily as major genes that were upregulated. Transcriptional induction of PTN was confirmed by reverse transcription-polymerase chain reaction and Northern blotting and induction of the protein by Western blotting and immunohistochemical localization. PTN was observed associated with mesangial 'hillocks' in confluent MC cultures. In contrast, in models of migration, migrating cells had the highest expression of cell-associated PTN. PTN protein was less evident, however, in the conditioned medium of MCs. Treatment of MC with heparanase removed PTN from the cells suggesting that its localization was owing to an association with heparan sulfates on the cell surface or in the extracellular matrix. This is the first description of the expression of PTN by human MCs and the data suggest that it is rapidly induced in cells that are triggered to migrate. The result of this induction is currently under investigation.

Carrier Proteins↗
PubMed2006

Formation of C7F15COOH (PFOA) and other perfluorocarboxylic acids during the atmospheric oxidation of 8:2 fluorotelomer alcohol.

Calculations using a three-dimensional global atmospheric chemistry model (IMPACT) indicate that n-C8F17CH2CH2OH (widely used in industrial and consumer products) degrades in the atmosphere to give perfluorooctanoic acid (PFOA) and other perfluorocarboxylic acids (PFCAs). PFOA is persistent, bioaccumulative, and potentially toxic. Molar yields of PFOA depend on location and season, are in the range of 1-10%, and are of the correct order of magnitude to explain the observed levels in Arctic fauna. Fluorotelomer alcohols such as n-C8F17CH2CH2OH appear to be a significant global source of persistent bioaccumulative perfluorocarboxylic acid pollution. This is the first modeling study of the atmospheric chemistry of a fluorotelomer alcohol.

Alcohols↗
PubMed2006

The role of few-asperity contacts in adhesion.

The surface roughness of a few asperities and their influence on the work of adhesion is of scientific interest. Macroscale and nanoscale adhesion data have seemingly given inconsistent results. Despite the importance of bridging the gap between the two regimes, little experimental work has been done, presumably due to the difficulty of the experiment needed to determine how small amounts of surface roughness might influence adhesion data lying in between the two scales. To investigate the role of few-asperity contacts in adhesion, the pull-off force was measured between different sized atomic-force microscope (AFM) tips (with different roughnesses) and sample surfaces that had well-controlled material properties. There were seventeen tips of four different types, with radii from 200 nm to 60 microm. The samples were unpatterned single crystal silicon with a chemical silicon dioxide surface resulting from a standard silicon wafer clean. Some of the samples were treated with a few angstroms of vapor deposited diphenylsiloxane. We observed that the uncorrected (for surface roughness) pull-off force was independent of the radius of the AFM tip, which was contrary to all continuum-mechanics model predictions. To explain this behavior, we assumed that the interactions between the AFM tip and sample were additive, material properties were constant, and that the AFM tip, asperities, and sample surfaces were of uniform density. Based on these assumptions, we calculated a simple correction due to the measured root mean square (RMS) surface roughness of the AFM tips. The simple correction for the RMS surface roughness resulted in the expected dependence of the pull-off force on radius, but the magnitudes were higher than expected. Commercial and heat-treated AFM tips have minimal surface roughness and result in magnitudes that are more reliable. The relative uncertainty for the pull-off force was estimated to be 10%. In this paper, we derive how the cantilever and tip parameters contribute to the measured pull-off force and show how the corrected results compare with theory. Although much work is still needed, the work presented here should advance the understanding of adhesion between the macroscale and nanoscale regimes.

Journal Article↗
PubMed2006

A new large CFTR rearrangement illustrates the importance of searching for complex alleles.

The p.Val754Met variant, described in 1996 in a CF patient, has been considered a CF mutation. However, biochemical aspects, results of functional studies and, finally, the identification of a complex deletion removing exons 3 to 10 and 14b to 16 in cis of p.Val754Met in a CF patient, argue against a strong deleterious effect. An inventory through the French CF network of patients carrying p.Val754Met led to the registration of seven patients (CF: n=4; idiopathic chronic pancreatitis: n=3) and six healthy individuals, all heterozygous for the variation. Extensive CFTR gene analysis was carried out, including the search for large rearrangements and other possible mutations. The complex deletion, whose breakpoints are described here, was found only in the four CF patients, in association with the same haplotype. This data, added to the fact that the p.[Phe508del]+[Val754Met] genotype was found in a healthy individual, bring further arguments against the association of p.Val754Met with CF. We thus suggest looking for a possible complex allele whenever p.Val754Met is detected and considering it neutral regarding genetic counseling when found in isolation.

Adolescent↗
PubMed2006

[Protein kinase C isoforms in corneal epithelium and endothelium].

BACKGROUND: Protein kinase C (PKC) plays a key role in cell metabolism. Three subgroups and 12 isoforms have been isolated so far, catalysing specific functions in cell metabolism. The demonstration of PKC subtypes in corneal tissue has been inconsistent. The aim of this study was to verify the expression of several PKC subgroups and isoforms in human and bovine corneal epithelial and endothelial cells. MATERIALS AND METHODS: PKC subgroups and isoforms were studied using polyclonal antibodies. RESULTS: Antibodies to PKC-alpha, -delta, -epsilon and -zeta, representing all three PKC subgroups, bound in human and bovine corneal epithelium and endothelium. No binding was found for antibodies to PKC-beta2. CONCLUSIONS: For the first time the presence of all three PKC subgroups was demonstrated in human and bovine corneal epithelial and endothelial cells. Further studies are needed to show the role of these subgroups in cellular functions such as cell proliferation and differentiation.

Adult↗
PubMed2006

Secondary prevention of fragility fractures: are we following the guidelines? Closing the audit loop.

INTRODUCTION: The aim of this study was to determine whether orthopaedic surgeons follow the British Orthopaedic Association (BOA) guidelines for secondary prevention of fragility fractures. PATIENTS AND METHODS: A retrospective audit was conducted on patients with neck of femur fractures treated in our hospital between October and November 2003. A re-audit was conducted during the period August to October 2004. RESULTS: There were 27 patients in the initial study period. Twenty-six patients (96%)had full blood count measured with LFT and bone-profile measured in 18 patients (66%). Only nine patients (30%)had treatment for osteoporosis (calcium and vitamin D). Only one patient was referred for DEXA scan. Steps were taken in the form of creating better awareness among the junior doctors and nurse practitioners of the BOA guidelines. In patients above 80 years of age, it was decided to use abbreviated mental score above 7 as a clinical criteria for DEXA referral. A hospital protocol based on BOA guidelines was made. A re-audit was conducted during the period August to October 2004. There were 37 patients. All had their full blood count and renal profile checked (100%). The bone-profile was measured in 28 (75.7%) and LFT in 34 (91.9%) patients. Twenty-four patients (65%) received treatment in the form of calcium + vitamin D (20) and bisphosphonate (4). DEXA-scan referral was not indicated in 14 patients as 4 were already on bisphosphonates and for 10 patients their abbreviated mental score was less than 7. Among the remaining 23 patients, 9 patients (40%) were referred for DEXA scan. This improvement is statistically significant (P = 0.03, chi square test). DISCUSSION AND CONCLUSIONS: The re-audit shows that, although there is an improvement in the situation, we are still below the standards of secondary prevention of fragility fractures with 60% of femoral fragility fracture patients not being referred for DEXA scan. A pathway lead by a fracture liaison nurse dedicated to osteoporotic fracture patients should improve the situation.

Aged↗