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Biomedical subjects

R A Lew

Publications and source records attributed to R A Lew.

At least 109 records · Page 6Linked to original sources
PubMed1991

Prediction of alpha helices and T cell-presented sequences in proteins with algorithms based on strip-of-helix hydrophobicity index.

Recurrent aliphatic hydrophobic amino acids which occur in the sequence of a protein or a peptide at positions which form an axial, hydrophobic strip when the sequence is coiled as an alpha helix might stabilize coiling against hydrophobic surfaces. That effect can lead to helix formation against hydrophobic cores of nascent proteins or excised T cell-presented peptides and to protease protection and scavenging for presentation by MHC molecules. Such consensus sequences of recurrent hydrophobicity creating a scavenger "S" site might overlap to varying degrees the T cell-presented "T" epitope which actually sits in the antigen-binding site of a MHC molecules, as long as a cleavage "C" site does not fall between them when they are relatively separated. Cooperatively among the residues in an axial, hydrophobic strip to stabilize helix formation is reflected in the SOHHI, which is the mean hydrophobicity of residues in such potential strips. Algorithms based on the SOHHI, with additional considerations related to length and caps, lead to sensitive and efficient predictions of structural helices and of T cell-presented epitopes. In experimental tests of these ideas, the SOHHI was found to correlate to helical coiling of amphiphilic peptides in the presence of lipid vesicles. These principles lead to hypotheses to alter the potency and range of MHC restriction of peptide vaccines or to decrease the immunogenicity of therapeutic proteins.

Algorithms↗
PubMed1991

Common principles in protein folding and antigen presentation.

The regular recurrence of hydrophobic amino acid residues along a peptide sequence determines the formation of a longitudinal hydrophobic strip when the peptide forms an alpha-helix. An understanding of the ways this may affect both folding of nascent proteins and antigen presentation should facilitate vaccine and therapeutics design.

Amino Acid Sequence↗
PubMed1991

Who is being screened for melanoma/skin cancer? Characteristics of persons screened in Massachusetts.

We conducted a survey of persons who voluntarily attended melanoma/skin cancer screenings in Massachusetts in 1987. Of 1219 persons asked to fill out a questionnaire, 1116 (92%) completed it. Our study demonstrates that persons attending the melanoma/skin cancer screening program were, for the most part, at risk for the disease and appropriately selected themselves to be screened. Most were women, well educated (with college or advanced degrees), and white. More than 86% had at least one risk factor for melanoma/skin cancer whereas 78% had at least two risk factors. Future studies are necessary to determine whether our experience can be verified. Additional efforts should try to attract those who are at risk but perhaps are less willing to attend screening programs--men and those of lower socioeconomic status. These efforts can help target screening to those at highest risk and maximize the yield of these public health efforts.

Adolescent↗
PubMed1991

Quantitative ultraviolet skin exposure in children during selected outdoor activities.

We determined the cumulative exposure of 3 body sites to ultraviolet radiation from sunlight for 126 children observed from 1-3 d during a variety of common recreational activities at a girl scout camp, baseball camp and community baseball field. Median arm exposure to children playing baseball at a camp ranged from 27.6% to 33.2% of the possible ambient exposure. These exposures are similar to adult exposures reported for comparable activities. Median exposure to the arm at the girl scout camp during mixed activities ranged from 9.0% to 26.5% of possible ambient exposure. At the girl scout camp, exposure both within and between activity groups varied substantially and were more variable than the baseball players' exposure. Arm exposure was greater than cheek and forehead exposure for all subject groups, with an arm-to-cheek exposure ratio ranging from 1.7 to 2.3. For organized sports, such as baseball, it may be possible to assign a single exposure estimate for use in epidemiologic studies or risk estimates. However, for less uniform outdoor activities, wide variability in exposure makes it more difficult to predict an individual's exposure.

Adolescent↗
PubMed1991

Epidemiology of cutaneous melanoma. An update.

Dramatic increases in melanoma incidence and more moderate increases in the death rate have been observed. Although paradoxes exist, most, but not all, melanomas appear to be related in some way to solar exposure and genetic factors. No other exogenous factor has been strongly implicated.

Age Factors↗
PubMed1991

Can screening for melanoma and skin cancer save lives?

Although screening for melanoma and skin cancer is theoretically appealing, too few data exist to evaluate its effectiveness. The rising incidence and mortality rates of melanoma and the continued incurability of metastatic disease underscore the desperate need for effective screening. The extraordinary incidence of NMSC is a public health problem, but the value of screening for NMSC has not been established. The AAD screening program offers an opportunity to obtain critical data. Further research must make our screenings more effective and efficient. We need rigorous design and evaluation of all screening efforts. In the absence of a randomized controlled trial, other design measures, with careful tracking of incidence and mortality, are critical to assessing whether screening for melanoma and skin cancer can reduce morbidity and save lives.

Humans↗
PubMed1990

Role of recurrent hydrophobic residues in catalysis of helix formation by T cell-presented peptides in the presence of lipid vesicles.

We tested the hypothesis that the recurrence of hydrophobic amino acids in a polypeptide at positions falling in an axial, hydrophobic strip if the sequence were coiled as an alpha helix, can lead to helical nucleation on a hydrophobic surface. The hydrophobic surface could anchor such residues, whereas the peptide sequence grows in a helical configuration that is stabilized by hydrogen bonds among carbonyl and amido NH groups along the peptidyl backbone of the helix, and by other intercycle interactions among amino acid side chains. Such bound, helical structures might protect peptides from proteases and/or facilitate transport to a MHC-containing compartment and thus be reflected in the selection of T cell-presented segments. Helical structure in a series of HPLC-purified peptides was estimated from circular dichroism measurements in: 1) 0.01 M phosphate buffer, pH 7.0, 2) that buffer with 45% trifluoroethanol (TFE), and 3) that buffer with di-O-hexadecyl phosphatidylcholine vesicles. By decreasing the dielectric constant of the buffer, TFE enhances intrapeptide interactions generally, whereas the lipid vesicles only provide a surface for hydrophobic interactions. The peptides varied in their strip-of-helix hydrophobicity indices (SOHHI; the mean Kyte-Doolittle hydrophobicities of residues in an axial strip of an alpha helix) and in proline content. Structural order for peptides with helical circular dichroism spectra was estimated as percentage helicity from circular dichroism theta 222 nm values and peptide concentration. A prototypic alpha helical peptide with three cycles plus two amino acids and an axial hydrophobic strip of four leucyl residues (SOHHI = 3.8) was disordered in phosphate buffer, 58% helical in that buffer with 48% TFE, and 36% helical in that buffer with vesicles. Percentage helicity in the presence of vesicles of the subset of peptides without proline followed their SOHHI values. Peptides with multiple prolyl residues had circular dichroism spectra with strong signals, but since they did not have altered spectra in the presence of vesicles relative to phosphate buffer alone, the hydrophobic surface of the vesicle did not appear to stabilize those structures.

Amino Acid Sequence↗
PubMed1990

The prognosis in Alzheimer's disease. 'How far' rather than 'how fast' best predicts the course.

Clinical features at the initial examination of 42 patients with probable Alzheimer's disease were tested for prognostic value at subsequent follow-up of 54 +/- 25 months. These potential prognostic features were of three types: degree of severity features (eg, IQ scores); variable clinical features (eg, extrapyramidal signs); and individual distinguishing features (eg, gender, education, and age). The power of these potential prognostic features to predict prognosis was assessed using the Kaplan-Meier life-tables method and the Cox proportional hazards model. Three clinical end points were considered: total dependence in activities of daily living; incontinence; and institutionalization at follow-up. Degree of severity features (subtests of the Wechsler Adult Intelligence Scale-Revised and the Wechsler Memory Scale, and the Clinical Severity Score) predicted subsequent dependence in activities of daily living, incontinence, and institutionalization. Historical disease duration, age, gender, family history of dementia, retrospective rate of progression, anxiety, psychosis, depression, and extrapyramidal signs did not influence prognosis. These results suggest that initial degree of severity ("how far") rather than variation in the rate of progression ("how fast") best predicts prognosis in the early to intermediate stages of Alzheimer's disease. The relationship of disease severity to prognosis should be taken into account before concluding that there are subtypes of Alzheimer's disease that have different rates of progression.

Activities of Daily Living↗
PubMed1990

Comparison of three related methods to select T cell-presented sequences of protein antigens.

A comparison of three methods to predict T cell-presented sequences within antigenic proteins led to the view that recurrent hydrophobic residues might nucleate excised peptides as alpha-helices against hydrophobic surfaces. Such helices could be protease-protected structures on their way to desetope binding. The compared methods were: the amphipathicity algorithm of DeLisi and Berzofsky [Proc. natn. Acad. Sci. U.S.A. 82, 7048-7052. (1985)] as modified by Margalit et al. [J. Immun. 138, 2213-2229. (1987)] the strip of-helix hydrophobicity algorithm (SOHHA) of Stille et al. [Molec. Immun. 24, 1021-1027. (1987)] and the motifs algorithm of Rothbard and Taylor [EMBO J. 7, 93-100. (1988)]. Correct prediction was defined at two levels of stringency: (1) the predicted sequence overlapped the experimentally reported sequence when the ratio of the intersection of both to the union of both greater than or equal to 0.5 or (2) the sequences touched when there was a non-empty intersection of both sequences. We determined the sensitivity (correct predictions/number of reported T cell-presented sequences) and efficiency (correct predictions/number of predictions) at each level of stringency. In terms of overlap, the SOHHA was more sensitive (0.43) than the amphipathicity (0.29) (not significant) and motifs (0.0, 0.0) (p less than 0.05) predictions and more efficient (0.35) than the amphipathicity (0.14) and motifs (0.0, 0.0) predictions. At the less stringent criterion touching, the amphipathicity method (0.71) was as sensitive as motif Rothbard-4 (0.79) and more sensitive than SOHHA (0.57) and motif Rothbard-5 (0.43). At that criterion, the SOHHA was more efficient (0.47) than the amphipathicity (0.36) and motifs (0.25, 0.40) methods. We hypothesize that the comparability of these approaches reflected the common, predominant influence of recurrent hydrophobicity in their predictions.

Algorithms↗
PubMed1990

Years of potential life lost: another indicator of the impact of cutaneous malignant melanoma on society.

Years of potential life lost (YPLL) is an indicator of premature mortality that complements traditional incidence and mortality rates and that facilitates comparisons among different cancers. We calculated YPLL from cutaneous melanoma and 11 other cancers routinely recorded and tracked by Surveillance, Epidemiology and End Results (SEER). YPLL from cutaneous melanoma ranked eighth for persons younger than 65 years of age and fourth for those 20 to 49 years of age. An average of 17.1 YPLL per death were due to melanoma, one of the highest rates for adult-onset cancers. The results of our study, the first to apply YPLL to cutaneous melanoma, emphasize the disproportionate impact of this cancer on young and middle-aged adults and reemphasize the importance of this cancer as a public health priority.

Adult↗
PubMed1990

Advances in screening protocols for the detection of early bladder cancer.

Bladder cancer screening faces several obstacles, including low yield, numerous false-positive results, and the absence of a single effective screening test. We present a model of a screening program that (1) targets an occupational cohort exposed to a putative carcinogen, to increase the detection of disease, (2) uses four screening tests in parallel to maximize case detection, and (3) defines a diagnostic protocol that minimizes the number of invasive procedures by utilizing both flexible and rigid cystoscopy. In a hypothetical cohort of 1000 men aged 45 to 74 years potentially exposed to a bladder carcinogen, the model would find eight of the nine detectable cancers, with a sensitivity of 89% and a specificity of 78%. In addition, the model allows the sensitivities, specificities, and predictive values of the individual screening tests to be compared and evaluated in a single cohort.

Aged↗
PubMed1990

Ultraviolet exposure to children from sunlight: a study using personal dosimetry.

Childhood exposure to ultraviolet (UV) radiation in sunlight may be an important risk factor for later development of skin diseases. We quantified the UVB radiant exposure on the wrist and face of children performing mixed outdoor activities at a summer camp. Polysulfone film badges were attached directly to the skin for several hours and simultaneously were used to measure ambient UVB levels. The results for the ratio of site-specific exposure to ambient exposure indicate a high degree of intersubject variability, a parity of samples taken in right and left positions, and a significantly higher exposure on the wrist compared with the face. The technique was well accepted by the subjects but some badges could not be read because of loss or damage. Measurement of exposure ratios in additional settings as well as data on childhood activity patterns are needed for an overall assessment of childhood exposure.

Cheek↗
PubMed1989

Endothelial cells stimulate ANF secretion from atrial myocytes in co-culture.

Using a novel in vitro co-culture system, we investigated the possible influence of vascular endothelial cells on the secretion of atrial natriuretic factor (ANF) from atrial myocytes. Co-culture of bovine aortic endothelial cells grown on Cytodex-3 microcarrier beads with primary monolayer cultures of neonatal rat myocytes induced a 2.1-fold increase in immunoreactive ANF (irANF) in the medium, compared with irANF in medium from atrial cultures alone. This increase did not appear to be the result of processing of prohormone to more immunoreactive species, and could be inhibited by 47% with 10 microM acetylcholine. The endothelium-derived vasoconstrictor peptide, endothelin, elicited a dose-dependent increase in ANF secretion from atrial cultures, but, contrary to vasopressin, was incapable of further stimulating release from atrial-endothelial co-cultures. These experiments suggest that endothelium stimulates the release of ANF from myocytes, possibly by the action of the peptide endothelin.

Animals↗
PubMed1989

Prediction of protein helices with a derivative of the strip-of-helix hydrophobicity algorithm.

The strip-of-helix hydrophobicity algorithm was devised to identify protein sequences which, when coiled as alpha or 3(10) helices, had one axial, hydrophobic strip and otherwise variably hydrophilic residues. The strip-of-helix hydrophobicity algorithm also ranked such sequences according to an index, the mean hydrophobicity of amino acids in the axial strip. This algorithm well predicted T cell-presented fragments of antigenic proteins. A derivative of this algorithm (the structural helices algorithm (SHA] was tested for the prediction of helices in crystallographically defined proteins. For the SHA, eight amino acid sequences, 2 cycles plus one amino acid in an alpha helix, with strip-of-helix hydrophobicity indices greater than 2.5, were selected with overlapping segments joined. These selections were terminated according to simple "capping rules," which took into account the roles of N-terminal Asn or Pro and C-terminal Gly in the stability of helices. In analyses of 35 crystallographically defined proteins with known alpha and 3(10) helices, the predictions with the SHA overlapped (had overlap indices x greater than or equal to 0.5) with 34% of known helices, touched (had overlap indices 0.5 greater than x greater than 0) or overlapped with 66% of known helices, or were neighboring (came within 6 residues) or touched or overlapped with 82% of known helices. At each level of judging the quality of prediction, the SHA was usually less sensitive (correct predictions/total number of known helices) and more efficient (correct predictions/total number of predictions) than the Chou-Fasman and Garnier-Robson methods. It was simpler in design and calculation. The chemical mechanisms underlying these algorithms appear to apply both to protein folding and to selection of T cell-presented antigenic sequences.

Algorithms↗