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Biomedical subjects

A L Cox

Publications and source records attributed to A L Cox.

At least 19 recordsLinked to original sources
PubMed2006

[Diffuse panbronchiolitis in an Asian woman with severely obstructed pulmonary disease].

A 41-year-old woman was referred for severely obstructed pulmonary disease 4 years after she stopped smoking. Treatment for chronic obstructive pulmonary disease (COPD) had no effect and lung function worsened in the following years. The clinical, radiological and pathological characteristics led us to the diagnosis of diffuse panbronchiolitis. She was treated with clarithromycin. After 1 year, major improvement was seen in clinical, radiological and spirometric features. Diffuse panbronchiolitis is a rare obstructive disorder that is usually seen in people of Japanese descent. Patients respond well to treatment with low-dose macrolide treatment.

Adult↗
PubMed2006

An investigation of auto-reactivity after head injury.

Murine models of CNS injury show auto-reactive T cell responses directed at myelin antigens, associated with improved neuronal survival and functional recovery. This pilot study shows, for the first time, that similar immune responses against myelin occur in human traumatic brain injury (TBI), with an expansion of lymphocytes recognising myelin basic protein observed in 40% of patients studied. "Reactive" patients did not have greater contusion volume on imaging, but were younger than the "unreactive" subgroup and tended towards a more favorable outcome. These findings are consistent with the concept of "beneficial autoimmunity".

Adult↗
PubMed2004

FDG-PET in staging lung cancer: how does it change the algorithm?

BACKGROUND: In patients with lung cancer, positron emission tomography (PET) using fluor-18-fluorodesoxyglucose (FDG) may be used both to detect extrathoracic metastases (ETM) and for mediastinal lymph node staging (MLS), potentially reducing the need for mediastinoscopy. We assessed the added value of FDG-PET in detecting ETM and focused on the reliability of FDG-PET and mediastinoscopy for MLS. PATIENTS AND METHODS: In 72 consecutive patients with non-small cell lung cancer, the impact of adding FDG-PET to full conventional clinical staging was prospectively analyzed. The predictive value of FDG-PET findings and tumor location for pathologic mediastinal lymph node status were assessed in a logistic regression analysis. RESULTS: Unexpected extrathoracic metastases were detected by FDG-PET in 15% of patients. In MLS overall negative and positive predictive values were 71 and 83% for FDG-PET, and 92 and 100% for mediastinoscopy. However, the negative predictive value of FDG-PET was only 17% in case of FDG-PET positive N1 nodes and/or a centrally located primary tumor, whereas it was 96% in case of FDG-PET negative N1 nodes and a non-centrally located primary tumor. CONCLUSION: By incorporating FDG-PET in clinical staging, 15% of patients with lung cancer are upstaged due to unexpected extrathoracic metastases. In case of a negative mediastinal FDG-PET, mediastinoscopy can only be omitted in the presence of a non-centrally located primary tumor and without FDG-PET positive N1 nodes.

Adolescent↗
PubMed2001

Use of the vicinal element effect for regiochemical control of quinone substitutions and its implication for convergent mitomycin construction.

[reaction--see text] Nucleophilic substitution reactions of 2-methoxy-3-alkyl-p-benzoquinones are described as they relate to the construction of the mitomycin backbone. Normally controlled by activating groups attached to the olefin, the observed regioselection in these cases is determined by the deactivating substituent. Approximation of carbonyl activating ability would not have predicted the behavior of two systems investigated in which the poorer of two leaving groups is substituted in each case.

Alkenes↗
PubMed1999

[Diagnosis of malignant pleural mesothelioma and asbestosis].

The incidence of malignant mesothelioma, the main consequence of exposure to asbestos, will increase considerably in the Netherlands in the coming decades. In the next 35 year, some 20,000 people will die from malignant mesothelioma. The diagnosis of malignant pleural mesothelioma in practice is based on histological examination in about 80%, on cytological examination in 15% and on other forms of examination, e.g., high resolution computer tomography (HRCT), in 6% of the cases. Using a combination of various noninvasive methods, such as anamnesis, physical and röntgenologic examination, HRCT and spirometry, the diagnosis of asbestosis is made erroneously in 5% of the patients examined. With regard to allowance of financial compensation to patients with pleural mesothelioma and asbestosis, a part is played by the fact that views differ internationally concerning the criteria on which the diagnosis should be based. For mesothelioma cytologic and histologic examination are the most important. For asbestosis, the Health Council considers HRCT as crucial, if necessary supplemented by histological examination, plus a history of exposure to asbestos and pulmonary dysfunction. In mesothelioma cytological and histological examination are the most important.

Asbestosis↗
PubMed1995

Integrating parallelization strategies for linkage analysis.

We describe a second parallel implementation of the ILINK program from the LINKAGE package that improves on our previous implementation. To improve running time we integrated the strategy of parallel estimation of the gradient at a candidate recombination fraction vector with a previously implemented strategy for evaluating in parallel the likelihood at one vector. We also integrated an adaptive loadbalancing strategy in conjunction with our previous static loadbalancing strategy. We implemented a strategy for partitioning input pedigrees, but this slowed down the program; we give some evidence for what the problems are. To best exploit parallelism at all levels of the program and to take advantage of both coarse-grain and fine-grain parallelism it is necessary to combine multiple algorithmic strategies.

Algorithms↗
PubMed1994

Cytotoxic T-lymphocyte response to autologous human squamous cell cancer of the lung: epitope reconstitution with peptides extracted from HLA-Aw68.

Cytotoxic T-lymphocytes (CTLs) specific for autologous human squamous cell cancer of the lung were generated by stimulation of peripheral blood lymphocytes with autologous tumor cells in vitro. The CTL line was >97% CD3+, CD8+, CD16- and produced tumor necrosis factor-alpha, gamma-interferon, and granulocyte-macrophage colony-stimulating factor after stimulation with autologous tumor. The CTLs lysed autologous tumor but failed to recognize autologous or histocompatibility leukocyte antigen-matched lymphoid cells, K562, or allogeneic tumor cells of several histological types. Antibody-blocking studies suggested that the CTLs recognized one or more antigens presented by the class I major histocompatibility complex molecule Aw68. To characterize these antigens further, histocompatibility leukocyte antigen Aw68 molecules were extracted from the squamous cell cancer of the lung tumor line by immunoaffinity chromatography, and the associated peptides were eluted in acid and separated by reversed-phase high-performance liquid chromatography. Reconstitution of the CTL epitope was evaluated by adding these peptides to autologous Epstein-Barr virus-transformed B-cells. Two peaks of reconstituting activity were observed, suggesting that these CTLs recognize at least two Aw68-associated peptides. This study confirms the existence of a CTL response against autologous human squamous cell cancer of the lung and suggests that this CTL response is directed against peptide epitopes presented by the class I major histocompatibility complex molecules. It is anticipated that this approach will permit identification of peptide epitopes for lung cancer-specific CTLs.

Carcinoma, Squamous Cell↗
PubMed1994

Identification of a peptide recognized by five melanoma-specific human cytotoxic T cell lines.

Of several thousand peptides presented by the major histocompatibility molecule HLA-A2.1, at least nine are recognized by melanoma-specific cytotoxic T lymphocytes (CTLs). Tandem mass spectrometry was used to identify and to sequence one of these peptide epitopes. Melanoma-specific CTLs had an exceptionally high affinity for this nine-residue peptide, which reconstituted an epitope for CTL lines from each of five different melanoma patients tested. Recognition by multiple CTL lines suggests that this may be a promising candidate for use in peptide-based melanoma vaccines.

Amino Acid Sequence↗
PubMed1994

Naturally processed peptides longer than nine amino acid residues bind to the class I MHC molecule HLA-A2.1 with high affinity and in different conformations.

An equilibrium binding assay was used to directly measure the relative affinities of naturally processed 9-mer, 10-mer, and 12-mer peptides for the human class I MHC molecule HLA-A2.1. The peptides exhibited a range of affinities with IC50 values of 11 to 214 nM. The mode of interaction between these peptides and HLA-A2.1 was examined using peptides in which Asp had been substituted for suspected anchor residues. Regardless of length, the previously identified Leu at position 2 relative to the amino terminus was critical for peptide binding. While the carboxyl terminal residue was also critical for the binding of a 9-mer peptide, it was much less important in the binding of longer peptides. Additional residues close to the carboxyl terminus that contained aliphatic hydrocarbon side chains were of similar or greater importance in peptide binding. In addition, residue at position 3 also appeared to be important for the binding of longer peptides. The data suggest that different naturally occurring longer peptides can bind in different conformations to class I MHC molecules. While one of these is similar to the kinked conformation described by others, another conformation would involve an extension of the carboxyl terminus out of the class I binding site. The ability of MHC molecules to accommodate the same peptide in different conformations would appear to have distinct advantages to the immune system.

Amino Acid Sequence↗
PubMed1994

Multiple primary lung cancers.

Between 1970 and 1990, of 1287 patients undergoing resection for primary lung cancer, we considered 55 (4.3%) to have a second primary lung cancer, being synchronous in 15 cases (1.2%) and metachronous in 40 (3.1%). Two patients had a third primary lung cancer. The 15 patients with synchronous cancers were all treated surgically: ten underwent a two-stage procedure and 5 patients a one-stage. In 6 patients the cancers were located bilaterally and in 4 patients both synchronous cancers had a different histology. There were 3 postoperative deaths (20%). The 3- and 5-year actuarial survival rates were 26% and 15%. Of the 40 patients with metachronous cancers the mean interval between treatment of their first and second cancer was 5 years and 11 months. It was longer for the 21 patients having a contralateral second localization (7 years) than for those having an ipsilateral localization (4 years). There was no dependence of the intervals on whether or not the second cancer had the same histology as the first cancer. In 7 patients the second cancer was treated by chemo- and/or radiotherapy and in 33 patients by surgery. There were 5 postoperative deaths in this group (15.2%). The 3- and 5-year actuarial survival rates were 33% and 18%. For 25 patients with a stage I or II second cancer these rates were 42% and 27%; all 8 patients with a stage III second cancer died within 14 months. Survival was positively affected by: histological type differing between both cancers, an interval of more than 3 years, a bilateral localization, and a stage I or II second cancer.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenocarcinoma↗
PubMed1994

Exercise cardiorespiratory function before and one year after operation for pectus excavatum.

In 35 patients with pectus excavatum (aged 17.9 +/- 5.6 years) pulmonary function and maximal exercise test results were compared before and at 1 year after operation. The lower posteroanterior chest diameter on the lateral x-ray film was significantly smaller than normal (p < 0.0001) and increased significantly after operation (p < 0.0001). Preoperatively, total lung capacity (86.0% +/- 14.4%; p = 0.0001) and inspiratory vital capacity (79.7% +/- 16.2; p = 0.0001) were significantly smaller than predicted and further decreased after operation (-9.2% +/- 9.2%; p = 0.0001 and -6.6% +/- 10.7%; p = 0.0012, respectively). Arterial blood gas values displayed normal patterns with increasing exercise both before and after operation. Only the arterial pH decreased more after operation than before (p = 0.0026). After operation there was a significant increase in maximal oxygen uptake (oxygen uptake; p = 0.0002 and oxygen uptake per kilogram; p = 0.0025) and oxygen pulse (oxygen uptake/heart rate approximates an indirect parameter for stroke volume; p = 0.0333) during exercise, whereas the maximal work performed was unchanged. Efficiency of breathing (ratio of tidal volume/inspiratory vital capacity) at maximal exercise improved significantly after operation (p = 0.0005). Ventilatory limitation of exercise (defined by an increase in carbon dioxide tension during exercise) was found in 43.9% of the patients before operation. A tendency of improvement was noted (not significant) after operation (difference in carbon dioxide tension 0.6 +/- 0.4 kPa before versus 0.3 +/- 0.5 kPa after operation). However, the group with normal preoperative carbon dioxide elimination had a ventilatory limitation of exercise after operation (difference in carbon dioxide tension -0.4 +/- 0.3 kPa before versus -0.1 +/- 0.3 kPa after operation; p = 0.0128) with a significant increase in oxygen consumption (p = 0.0007). In conclusion the subjective physical improvement after operation is not explained by changes in cardiorespiratory function at exercise. The data suggest a higher work of breathing after operation.

Adolescent↗
PubMed1993

Direct identification of an endogenous peptide recognized by multiple HLA-A2.1-specific cytotoxic T cells.

An endogenous peptide recognized by a murine T-cell clone specific for the human class I major histocompatibility complex-encoded molecule HLA-A2.1 was identified through the use of microcapillary high-performance liquid chromatography coupled with electrospray-ionization tandem mass spectrometry. The peptide was associated with HLA-A2.1 on both normal cells and the antigen-processing-mutant cell line T2. This observation demonstrates that a processing mechanism other than that involving the transporter associated with antigen processing (TAP) proteins 1 and 2 can produce peptides that can be recognized by T cells. The peptide was also recognized by four other independently derived murine HLA-A2.1-specific murine T-cell clones. This suggests that xenogeneic responses are directed at a restricted subset of major histocompatibility complex product-associated peptides. Finally, quantitation of this peptide in cell extracts using mass spectrometry showed it to be among the most dominant HLA-A2.1 associated species on human lymphoid cells. The potential relevance of this observation to models of alloreactivity will be discussed. The methodology described should be generally useful for the identification of peptide epitopes recognized by alloreactive, tumor-specific, and autoimmune T cells.

Amino Acid Sequence↗
PubMed1993

Recognition of human melanoma cells by HLA-A2.1-restricted cytotoxic T lymphocytes is mediated by at least six shared peptide epitopes.

HLA-A2.1-associated peptides were extracted from human melanoma cell lines and used to study epitopes for melanoma-specific HLA-A2.1-restricted CTL. CTL were generated from tumor-involved nodes by in vitro stimulation, initially with autologous melanoma cells and subsequently with allogeneic A2.1+ melanoma cells. These CTL lysed autologous melanoma plus four allogeneic HLA-A2.1+ melanomas, including an HLA-A2.1-transfected melanoma. K562, HLA-A2- melanomas and HLA-A2+ nonmelanomas were not lysed. HLA-A2.1 molecules were purified from human melanoma cell lines by immunoaffinity column chromatography of detergent-solubilized cell pellets. Peptides bound to the MHC molecules were acid eluted and fractionated by reversed phase HPLC. Individual fractions were assessed for their ability to reconstitute melanoma-specific epitopes by addition to the HLA-A2.1+ Ag-processing mutant, 721.174XCEM.T2 (T2). Five peaks of reconstitution were observed. Second dimension HPLC separations of reconstituting fractions revealed evidence for two distinct reconstituting peptides within one of these peaks. Based on these data, a minimum of six distinct peptides associated with HLA-A2.1 and recognized by melanoma-specific CTL are present on these different melanoma lines. These data document the presence of multiple peptide-defined CTL epitopes that are shared by at least three unrelated human melanoma cell lines.

Cell Line↗
PubMed1993

Prognosis of unsuspected but completely resectable N2 non-small cell lung cancer.

Of 111 patients with non-small cell lung cancer without clinically evident N2 disease 95 underwent mediastinoscopy between 1975 and 1985. In 63 cases mediastinoscopy was positive and in 32 negative. The patients with a positive mediastinoscopy were considered to have inoperable disease. Their 3- and 5-year survival rates were 5% and 0%, respectively. The patients with a negative mediastinoscopy and 16 patients in whom no mediastinoscopy was performed because of a peripheral tumor underwent operation. They underwent complete tumor resection and mediastinal lymph node dissection. Unsuspected N2 disease was found. Their 3- and 5-year survival rates were 19% and 10%, respectively. The better survival rate in the operated group was statistically significant and mainly due to a better survival of the lobectomy group. Multiple regression analysis showed no favorable prognostic factors in the nonoperated group, but in the operated group lobectomy and central location of the tumor significantly improved the prognosis. We conclude that patients with unsuspected stage IIIa non-small cell lung cancer discovered at thoracotomy benefit from complete tumor resection and mediastinal lymph node dissection, especially if the resection can be confined to lobectomy and if the tumor is located centrally.

Adult↗