Biomedical subjects

D T Jones

Publications and source records attributed to D T Jones.

At least 19 recordsLinked to original sources

PubMed1998

Do transmembrane protein superfolds exist?

A reliable and widely used transmembrane protein structure prediction algorithm was applied to five representative genomic sequence data sets in order to re-examine the hypothesis that in contrast to globular proteins there are no favored transmembrane protein fold families. When the number of predicted membrane spanning segments and the topology of these segments is taken into account then definite biases are observed which suggest that certain transmembrane topologies are significantly more common than others.

Algorithms↗

PubMed1997

CATH--a hierarchic classification of protein domain structures.

BACKGROUND: Protein evolution gives rise to families of structurally related proteins, within which sequence identities can be extremely low. As a result, structure-based classifications can be effective at identifying unanticipated relationships in known structures and in optimal cases function can also be assigned. The ever increasing number of known protein structures is too large to classify all proteins manually, therefore, automatic methods are needed for fast evaluation of protein structures. RESULTS: We present a semi-automatic procedure for deriving a novel hierarchical classification of protein domain structures (CATH). The four main levels of our classification are protein class (C), architecture (A), topology (T) and homologous superfamily (H). Class is the simplest level, and it essentially describes the secondary structure composition of each domain. In contrast, architecture summarises the shape revealed by the orientations of the secondary structure units, such as barrels and sandwiches. At the topology level, sequential connectivity is considered, such that members of the same architecture might have quite different topologies. When structures belonging to the same T-level have suitably high similarities combined with similar functions, the proteins are assumed to be evolutionarily related and put into the same homologous superfamily. CONCLUSIONS: Analysis of the structural families generated by CATH reveals the prominent features of protein structure space. We find that nearly a third of the homologous superfamilies (H-levels) belong to ten major T-levels, which we call superfolds, and furthermore that nearly two-thirds of these H-levels cluster into nine simple architectures. A database of well-characterised protein structure families, such as CATH, will facilitate the assignment of structure-function/evolution relationships to both known and newly determined protein structures.

Databases, Factual↗

PubMed1997

Successful ab initio prediction of the tertiary structure of NK-lysin using multiple sequences and recognized supersecondary structural motifs.

A simple approach to protein tertiary structure prediction is described, based on the assembly of recognized supersecondary structural fragments taken from highly resolved protein structures by using a simulated annealing algorithm. The results of blind-testing this method on CASP2 target T0042 (pig NK-lysin) are presented. The predicted structure had a C alpha root-mean-square deviation of only 6.2 A from the experimental structure (and less than 5.0 A over the first 66 residues), and clearly had the correct fold when judged by using a number of objective measures. Despite the significant degree of success in this case, there is clearly much more development required before predictions with the accuracy of a good homology model can be made with this kind of approach.

Anti-Infective Agents↗

PubMed1997

Closure of a bronchopleural fistula using decalcified human spongiosa and a fibrin sealant.

Bronchopleural fistulas associated with empyema can occur as a life-threatening sequelae after pulmonary resection, most frequently occurring after pneumonectomy. With the use of the flexible bronchoscope, the bronchopleural fistula of a 62-year-old critically ill woman was permanently sealed with a fibrin sealant and a small section of demineralized human spongiosa. Closure of bronchopleural fistulas with the application of fibrin sealant plus human spongiosa may offer a valuable addition to the armament of therapeutic alternatives.

Adenocarcinoma↗

PubMed1997

RBE variation as a function of depth in the 200-MeV proton beam produced at the National Accelerator Centre in Faure (South Africa).

BACKGROUND AND PURPOSE: Thorough knowledge of the RBE of clinical proton beams is indispensable for exploiting their full ballistic advantage. Therefore, the RBE of the 200-MeV clinical proton beam produced at the National Accelerator Centre of Faure (South Africa) was measured at different critical points of the depth-dose distribution. MATERIAL AND METHODS: RBEs were determined at the initial plateau of the unmodulated and modulated beam (depth in Perspex = 43.5 mm), and at the beginning, middle and end of a 7-cm spread-out Bragg peak (SOBP) (depths in Perspex = 144.5, 165.5 and 191.5 mm, respectively). The biological system was the regeneration of intestinal crypts in mice after irradiation with a single fraction. RESULTS: Using 60Co gamma-rays as the reference, the RBE values (for a gamma-dose of 14.38 Gy corresponding to 10 regenerated crypts) were found equal to 1.16 +/- 0.04, 1.10 +/- 0.03, 1.18 +/- 0.04, 1.12 +/- 0.03 and 1.23 +/- 0.03, respectively. At all depths, RBEs were found to increase slightly (about 4%) with decreasing dose, in the investigated dose range (12-17 Gy). No significant RBE variation with depth was observed, although RBEs in the SOBP were found to average a higher value (1.18 +/- 0.06) than in the entrance plateau (1.13 +/- 0.04). CONCLUSION: An RBE value slightly larger than the current value of 1.10 should be adopted for clinical application with a 200-MeV proton beam.

Animals↗

PubMed1997

Progress in protein structure prediction.

If protein structure prediction methods are to make any impact on the impending onerous task of analyzing the large numbers of unknown protein sequences generated by the ongoing genome-sequencing projects, it is vital that they make the difficult transition from computational 'gedankenexperiments' to practical software tools. This has already happened in the field of comparative modelling and is currently happening in the threading field. Unfortunately, there is little evidence of this transition happening in the field of ab initio tertiary-structure prediction.

Algorithms↗

PubMed1997

A novel method of tear collection: comparison of glass capillary micropipettes with porous polyester rods.

PURPOSE: To develop a rapid, user-friendly method of tear collection to facilitate tear-protein analysis. METHODS: Tears were collected from a total of 19 normal volunteers without evidence of ocular-surface disease with either porous polyester rods or glass-capillary micropipettes. Tear-collection rate and recovery of two tear proteins, epidermal growth factor (EGF, low abundance) and lactoferrin (LFR, high abundance) were compared between polyester rods and glass-capillary micropipettes. The recovery of LFR and EGF and the stability of these proteins after storage at -70 degrees C were quantitated by specific monoclonal enzyme-linked immunosorbent assay (ELISA). RESULTS: Polyester rods collected tears an average of 3.9-fold faster than glass-capillary micropipettes (p < 0.001). Both methods were comparable in efficacy of protein recovery. The polyester rods demonstrated a trend toward enhanced recovery, but this difference was not statistically significant (p = 0.12, LFR; p = 0.055, EGF). Analysis of the reliability and reproducibility of the tear-collection assay system revealed that ELISA analysis is highly reproducible, but there is significant day-to-day variation in tear-protein levels of both LFR and EGF for a given volunteer. Both LFR and EGF displayed a trend toward enhanced detection by ELISA shortly after freezing at -70 degrees C and slow decay after storage at -70 degrees C for up to 72 and 105 days, respectively. After stimulation of reflex tearing via the nasolacrimal reflex, LFR levels remained relatively constant, whereas EGF levels for most patients declined and then plateaued. CONCLUSIONS: Polyester rods provide a more rapid, user-friendly alternative to glass-capillary micropipettes for the collection and analysis of tear fluid and tear proteins. Polyester rods may have greater clinical utility, facilitating routine analysis of the preocular tear film.

Enzyme-Linked Immunosorbent Assay↗

PubMed1996

Using evolutionary trees in protein secondary structure prediction and other comparative sequence analyses.

Previously proposed methods for protein secondary structure prediction from multiple sequence alignments do not efficiently extract the evolutionary information that these alignments contain. The predictions of these methods are less accurate than they could be, because of their failure to consider explicitly the phylogenetic tree that relates aligned protein sequences. As an alternative, we present a hidden Markov model approach to secondary structure prediction that more fully uses the evolutionary information contained in protein sequence alignments. A representative example is presented, and three experiments are performed that illustrate how the appropriate representation of evolutionary relatedness can improve inferences. We explain why similar improvement can be expected in other secondary structure prediction methods and indeed any comparative sequence analysis method.

Amino Acid Sequence↗

PubMed1996

Angiofibroma. Changes in staging and treatment.

OBJECTIVE: To identify specific preoperative tumor characteristics and potential surgical decisions that ultimately place a patient at a greater risk for tumor recurrence. DESIGN: The clinical presentation, management, and prognosis of 23 consecutive cases of juvenile nasopharyngeal angiofibroma were reviewed retrospectively from January 1, 1977, to June 30, 1993. A minimum follow-up of 12 months was necessary for study inclusion. SETTING: A single, tertiary care pediatric facility. INTERVENTIONS: All available preoperative imaging studies were reevaluated to ensure consistency in reporting. Preoperative computed tomography was performed in 21 patients, but only 18 scans were available for review. Preoperative angiography with embolization was performed in 21 of 23 patients. Surgical excision was the primary mode of treatment in 22 of 23 patients, and complete surgical excision was possible in 21 of 23 patients. MAIN OUTCOME MEASURES: The rate of recurrence was examined with respect to time of presentations, initial tumor stage, intraoperative blood loss, and surgical approach. RESULTS: When compared with patients without a recurrent tumor, there was no difference in age at presentation, primary symptom, or duration of symptoms before diagnosis. Preoperative tumor stage was found to be the primary factor affecting tumor recurrence. A recurrence rate of 21.7% (five of 23 patients) was identified after an average 6-year follow-up. A trend toward use of the midfacial degloving approach for surgical exposure was identified and was not associated with an increased risk of recurrence. All patients were ultimately cured of their tumor without the need for open craniotomy despite a 32% incidence of stage IIIA and IIIB tumors. No deaths were reported during the study. CONCLUSIONS: Juvenile nasopharyngeal angiofibromas are benign tumors occurring almost exclusively in adolescent males. Recent advances in radiographic imaging techniques allow for more accurate preoperative staging, especially in regard to skull base involvement. Recognition of the extent of the tumor before surgical extirpation reduces the risk of recurrence.

Adolescent↗

PubMed1996

Towards meeting the Paracelsus Challenge: The design, synthesis, and characterization of paracelsin-43, an alpha-helical protein with over 50% sequence identity to an all-beta protein.

In response to the Paracelsus Challenge (Rose and Creamer, Proteins, 19:1-3, 1994), we present here the design, synthesis, and characterization of a helical protein, whose sequence is 50% identical to that of an all-beta protein. The new sequence was derived by applying an inverse protein folding approach, in which the sequence was optimized to "fit" the new helical structure, but constrained to retain 50% of the original amino acid residues. The program utilizes a genetic algorithm to optimize the sequence, together with empirical potentials of mean force to evaluate the sequence-structure compatibility. Although the designed sequence has little ordered (secondary) structure in water, circular dichroism and nuclear magnetic resonance data show clear evidence for significant helical content in water/ethylene glycol and in water/methanol mixtures at low temperatures, as well as melting behavior indicative of cooperative folding. We believe that this represents a significant step toward meeting the Paracelsus Challenge.

Algorithms↗

PubMed1996

RBE variation between fast neutron beams as a function of energy. Intercomparison involving 7 neutrontherapy facilities.

In fast neutron therapy, the relative biological effectiveness (RBE) of a given beam varies to a large extent with the neutron energy spectrum. This spectrum depends primarily on the energy of the incident particles and on the nuclear reaction used for neutron production. However, it also depends on other factors which are specific to the local facility, eg, target, collimation system, etc. Therefore direct radiobiological intercomparisons are justified. The present paper reports the results of an intercomparison performed at seven neutrontherapy centres: Orléans, France (p(34)+Be), Riyadh, Saudi Arabia (p(26)+Be), Ghent, Belgium (d(14.5)+Be), Faure, South Africa (p(66)+Be), Detroit, USA (d(48)+Be), Nice, France (p(65)+Be) and Louvain-la-Neuve, Belgium (p(65)+Be). The selected radiobiological system was intestinal crypt regeneration in mice after single fraction irradiation. The observed RBE values (ref cobalt-60 gamma-rays) were 1.79 +/- 0.10, 1.84 +/- 0.07, 2.24 +/- 0.11, 1.55 +/- 0.04, 1.51 +/- 0.03, 1.50 +/- 0.04 and 1.52 +/- 0.04, respectively. When machine availability permitted, additional factors were studied: two vs one fraction (Ghent, Louvain-la-Neuve), dose rate (Detroit), influence of depth in phantom (Faure, Detroit, Nice, Louvain-la-Neuve). In addition, at Orléans and Ghent, RBEs were also determined for LD50 at 6 days after selective abdominal irradiation and were found to be equal to the RBEs for crypt regeneration. The radiobiological intercomparisons were always combined with direct dosimetric intercomparisons and, when possible in some centres, with microdosimetric investigations.

Abdomen↗

PubMed1996

The neutron therapy clinical programme at the National Accelerator Centre (NAC).

A total of 721 patients were treated in the neutron therapy programme at NAC from February 1989-March 1995 with a p(66)/Be isocentric unit. The preliminary results showed: 3-year local control and survival probabilities of 57 and 79% respectively for advanced salivary gland tumours; increased local control for twice-daily neutron therapy for advanced head and neck cancer compared with photon therapy; local control rates of 68 and 83% for locally advanced breast cancer treated with 17 and 19 Gy respectively; complete response rates of 67% for macroscopic residual soft tissue sarcomas and those with irresectable disease of less than 10 cm; complete response rate of 56% for macroscopic residual uterine sarcoma with a median follow up of 38 months; 2-year local control rate and survival of 44 and 38% respectively for advanced squamous carcinoma of the maxillary antrum; complete response rate of 38% for advanced osteosarcomas and chondrosarcomas.

Breast Neoplasms↗

PubMed1996

Potential energy functions for threading.

Despite little progress in ab initio solutions to the problem of predicting a protein's tertiary structure, over the past four years or so the development of fold-recognition methods for tertiary structure prediction has been the source of some encouragement in this difficult field. Despite promising initial results, these methods are clearly not yet fully mature and many groups are now working on different aspects of the methods involved in the hope of increasing the reliability and sensitivity of these tools.

Protein Folding↗

PubMed1996

Combining protein evolution and secondary structure.

An evolutionary model that combines protein secondary structure and amino acid replacement is introduced. It allows likelihood analysis of aligned protein sequences and does not require the underlying secondary (or tertiary) structures of these sequences to be known. One component of the model describes the organization of secondary structure along a protein sequence and another specifies the evolutionary process for each category of secondary structure. A database of proteins with known secondary structures is used to estimate model parameters representing these two components. Phylogeny, the third component of the model, can be estimated from the data set of interest. As an example, we employ our model to analyze a set of sucrose synthase sequences. For the evolution of sucrose synthase, a parametric bootstrap approach indicates that our model is statistically preferable to one that ignores secondary structure.

Amino Acid Sequence↗

PubMed1996

Protein fold recognition by sequence threading: tools and assessment techniques.

Protein fold recognition has been approached by threading an amino acid sequence onto a library of folds, calculating a sequence-structure compatibility score, and ranking these scores. Due to imperfections in the empirically derived pairwise potential functions and the necessarily heuristic approach to the sequence-structure alignment problem, the method benefits from the assessment of threaded models to evaluate the most probable structures among the list of possible folds. THREADER and ANALYST, software tools available through the Internet, facilitate the alignment and assessment steps of a threading prediction. No process has been found to be universally reliable for the detection of folds related to the structure of a known input sequence, but several useful steps and approaches are discussed.

Algorithms↗

PubMed1996

Modeling marrow damage from response data: evolution from radiation biology to benzene toxicity.

Consensus principles from radiation biology were used to describe a generic set of nonlinear, first-order differential equations for modeling toxicity-induced compensatory cell kinetics in terms of sublethal injury, repair, direct killing, killing of cells with unrepaired sublethal injury, and repopulation. This cellular model was linked to a probit model of hematopoietic mortality that describes death from infection and/or hemorrhage between 5 and 30 days. Mortality data from 27 experiments with 851 dose-response groups, in which doses were protracted by rate and/or fractionation, were used to simultaneously estimate all rate constants by maximum-likelihood methods. Data used represented 18,940 test animals: 12,827 mice, 2925 rats, 1676 sheep, 829 swine, 479 dogs, and 204 burros. Although a long-term, repopulating hematopoietic stem cell is ancestral to all lineages needed to restore normal homeostasis, the dose-response data from the protracted irradiations indicate clearly that the particular lineage that is critical to hematopoietic recovery does not resemble stemlike cells with regard to radiosensitivity and repopulation rates. Instead, the weakest link in the chain of hematopoiesis was found to have an intrinsic radioresistance equal to or greater than stromal cells and to repopulate at the same rates. Model validation has been achieved by predicting the LD50 and/or fractional group mortality in 38 protracted-dose experiments (rats and mice) that were not used in fitting of model coefficients.

Animals↗

PubMed1996

Radiosensitivity variations in human tumor cell lines exposed in vitro to p(66)/Be neutrons or 60Co gamma-rays.

BACKGROUND: Neutron therapy should be beneficial to patients with tumor types which are resistant to photons but relatively sensitive to high-LET radiation. In this work the potential therapeutic gain of a clinical neutron beam is evaluated by quantifying the variations in radiosensitivity of different cell lines to neutrons and photons. MATERIAL AND METHODS: Different cell lines were exposed in vitro to p(66)/Be neutrons or 60Co gamma-rays. Micronuclei frequencies in binucleated cells and surviving fractions were determined for each cell type. RESULTS: Following exposure to either 1 or 1.5 Gy neutrons, micronuclei frequencies were significantly correlated with that observed for 2 Gy photons. A weak but significant correlation between the variation in neutron RBE values, determined from survival curve inactivation parameters and the mean inactivation doses for photon exposures, was also established. CONCLUSION: It is concluded that although neutron and photon sensitivities are related, the use of this high energy neutron source may constitute a potential therapeutic gain for tumor types that can be identified as very resistant to photons. Considering that a definitive oxygen gain factor has been established for this neutron beam the observed therapeutic gain is expected to be further enhanced in tumors where hypoxia protects cells from conventional radiation damage.

Beryllium↗

PubMed1995

Tumor blood flow measurements using coincidence counting on patients treated with neutrons.

PURPOSE: The purpose of this work was to measure blood flow in tumors using a coincidence counting technique on patients undergoing treatment with neutrons. METHODS AND MATERIALS: The half-time, Tw, for the washout of 15O from neutron-activated tumors was measured with two 10 cm NaI(Tl) crystals coupled to a PC-based coincidence counting system. Blood flow measurements were made in 33 patients, 19 of whom had cancers of the head and neck region, 6 had breast cancer, 5 had sarcomas, and 3 patients had mesotheliomas. RESULTS: Blood flow as indicated by Tw of mobile 15O formed by neutron activation could be readily determined in tumors of patients undergoing neutron radiotherapy. The general reduction in the value for Tw was noted towards the end of treatment and did not seem to be dependent on the initial tumor volume. There was a tendency for larger lesions to be associated with longer half-times of 15O washout. CONCLUSION: It appears possible to obtain a reasonable estimate of tumor blood flow using a simple coincidence counting technique. In view of the large variation in blood flow between tumors, it did not appear to be possible to identify potentially hypoxic tumors that would respond to neutron therapy.

Breast Neoplasms↗