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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
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↗
PubMed1993

Surgical treatment of Pancoast tumor.

The treatment of superior pulmonary sulcus (Pancoast) tumor is not uniform and is still discussed. Literature data and our retrospective study are presented. Fourteen patients were operated for a Pancoast tumor. Nine patients underwent mediastinoscopy followed by preoperative radiotherapy. Five patients received adjuvant radiotherapy after incomplete resection. Five patients who did not have preoperative radiotherapy, received postoperative irradiation. All three patients who survived five years or more, had preoperative radiotherapy and two of them underwent a complete resection. Literature data are discussed and emphasis is laid on the importance of preoperative staging, including mediastinoscopy, preoperative radiotherapy and complete "en bloc" resection.

Adult↗
PubMed1992

Peptides presented to the immune system by the murine class II major histocompatibility complex molecule I-Ad.

Between 650 and 2000 different peptides are associated with the major histocompatibility complex class II molecule I-Ad. Sequences for nine of these were obtained by a combination of automated Edman degradation and tandem mass spectrometry. All of the peptides are derived from secretory or integral membrane proteins that are synthesized by the antigen-presenting cell itself. Peptides were 16 to 18 residues long, had ragged NH2-and COOH-termini, and contained a six-residue binding motif that was variably placed within the peptide chain. Binding data on truncated peptides suggest that the peptide binding groove on class II molecules can be open at both ends.

Amino Acid Sequence↗
PubMed1992

[Generalized sarcoidosis in combination with a malignancy in 3 patients; the value of mediastinoscopy].

Two male patients with a testicular carcinoma and a female with a mammary carcinoma, all associated with pulmonary sarcoidosis are described. This coincidence is very rare, but clinically relevant as enlarged mediastinal and hilar lymph nodes might suggest metastatic disease or metastasis after a curative treatment. The role of mediastinoscopy in obtaining a histological diagnosis is stressed. A causal relationship between sarcoidosis and malignant diseases has not yet been established.

Adult↗
PubMed1992

Characterization of peptides bound to the class I MHC molecule HLA-A2.1 by mass spectrometry.

Antigens recognized by T cells are expressed as peptides bound to major histocompatibility complex (MHC) molecules. Microcapillary high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry was used to fractionate and sequence subpicomolar amounts of peptides isolated from the MHC molecule HLA-A2.1. Of 200 different species quantitated, eight were sequenced and four were found in cellular proteins. All were nine residues long and shared a distinct structural motif. The sensitivity and speed of this approach should enhance the analysis of peptides from small quantities of virally infected and transformed cells as well as those associated with autoimmune disease states.

Amino Acid Sequence↗
PubMed1992

Pectus excavatum. A clinical study with long-term postoperative follow-up.

Between 1972 and 1987, 192 patients have been operated upon for pectus excavatum of which 152 patients were included in the study (79%). Mean age at operation was 15.3 +/- 5.5 years; 117 were male. Mean follow-up was 8.1 +/- 3.6 years. The deformity was noted before the age of 5 in 90%. Type I symmetrical and localized deformity was seen in 33.2%, type II symmetrical but diffuse depression in 23.7% and type III localized or diffuse asymmetrical deformity in 43.1%. It was considered severe in 68.9%, fair in 16.9% and mild in 14.2%. There were significantly more asymmetrical defects in the older age groups. The operation consisted of subperichondral chondrectomy, transverse sternotomy and division of the intercostal bundles at the outer limit of the chondrectomy and suturing the edge of this broad sheet of muscle and perichondrium to the anterior surface of the chest wall more laterally and under tension, elevating and stabilizing the sternum. Results were satisfactory in 83.6% (excellent 44.1%, good 39.5%). Results were not significantly influenced by age, sex, severity, type, symmetry, the extent of cartilage resection or follow-up. Results were inversely influenced by the occurrence of wound problems. The optimal age for operation is considered to be between 5 and 10 years. Both physical as well as psychological cosmetic factors may serve as an indication for operation.

Adolescent↗