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Biomedical subjects

D L Weaver

Publications and source records attributed to D L Weaver.

At least 37 records · Page 2Linked to original sources
PubMed1995

Minimal-access surgery for staging of malignant melanoma.

OBJECTIVE: To develop a simple, minimally invasive technique of determining whether regional node metastasis has occurred in patients with melanoma. SETTING: Teaching hospital tertiary care and private practice settings. PATIENTS: Between February 1993 and October 1994, 121 patients with invasive malignant melanoma and clinically negative lymph nodes were enrolled in this clinical trial. DESIGN: Consecutive sample clinical trial. Within 24 hours prior to lymph node resection, a radioactive tracer was injected into the dermis around the site of the primary melanoma. Forty-four patients also had blue dye injected immediately prior to surgical resection. Measurement of radioactivity in the lymph nodes and surgical localization were made using a handheld gamma detector. Radiolabeled nodes were selectively removed with the least dissection possible. In patients with pathologically positive radiolabeled nodes, regional lymphadenectomy was performed. OUTCOME MEASURES: Successful identification of radiolabeled sentinel lymph nodes, correlation of radiolabeling with injection of blue dye, and regional node recurrence rate. RESULTS: Surgeons successfully resected the radiolabeled sentinel lymph nodes in 118 (98%) of 121 patients. One hundred percent of blue-stained lymph nodes were successfully radiolabeled. Fifteen patients had pathologically positive sentinel lymph nodes. In 10 patients, the sentinel node was the only node with metastasis. Two systemic and one regional node recurrences occurred during a mean follow-up of 220 days. CONCLUSIONS: Selective gamma probe-guided resection of the radiolabeled sentinel lymph node is possible in over 95% of patients with melanoma. This technique offers a simple and reliable method of staging of regional lymph nodes in these patients without performing a regional lymphadenectomy.

Adolescent↗
PubMed1995

Strategies and rationales for the de novo design of a helical hairpin peptide.

The de novo design of alpha t alpha, a helical hairpin peptide, is described, alpha t alpha (alpha-helix/turn/alpha-helix) was developed to provide a model system for protein folding at the level of secondary structure association and stabilization. According to the prevailing models of protein folding, the second step in the folding process is the association and stabilization of secondary structural elements or microdomains. A brief description of the design, along with CD and NMR evidence confirming the conformation of the peptide in solution, has been published (Fezoui Y, Weaver DL, Osterhout JJ, 1994, Proc Natl Acad Sci USA 91:3675-3679). The present work includes a full description of the design process, including the trade-offs that were made during the development of the peptide, a discussion of recent experimental results that were not available at the time of the original design, indications of areas where, in retrospect, the design might have been done differently, and a discussion of how the present work fits into the field of de novo protein design.

Amino Acid Sequence↗
PubMed1995

Von Hippel-Lindau disease presenting as pancreatic neuroendocrine tumour.

A 21-year-old woman with a family history of von Hippel-Lindau disease presented with a mass in the head of the pancreas. Light microscopic features of the tumour suggested neuroendocrine differentiation and although it displayed positive immunostaining for the antigens expected in a neuroendocrine neoplasm, S-100 staining was also present. This unusual feature prompted further evaluation by routine and post-embedding protein-A gold immunoelectron microscopy, which demonstrated the presence of neuroendocrine granules. Tumour cell DNA content was normal by flow cytometry. Although this patient exhibited no other signs of von Hippel-Lindau disease, the presence of a pancreatic tumour with neuroendocrine differentiation demonstrated that she was affected. Future surveillance and genetic counselling will be influenced by this diagnosis.

Adult↗
PubMed1995

Comparison of DNA content, S-phase fraction, and survival between medullary and ductal carcinoma of the breast.

Medullary carcinoma (MC) of the breast has been regarded as a subtype of breast carcinoma with a relatively favorable prognosis despite its high nuclear grade and high mitotic index. High nuclear grade and high mitotic index have been correlated with DNA aneuploidy and high S-phase fraction (SPF) by flow cytometry. Generally in breast cancer, these histologic and DNA content features predict a less favorable prognosis. To address this paradox, all cases of MC of the breast (20 of 1,365 carcinomas [1.5%]) diagnosed between 1968 and 1982 were compared to age- and stage-matched cases of infiltrating ductal carcinoma (IDC) diagnosed during the same time period. All of the MC and 80% of the IDC had one or more DNA aneuploid stem lines. Average total SPF was 8.1% for MC and 4.8% for IDC. DNA analysis was performed from paraffin blocks (average CV: 4.5% DNA diploid; 4.1% DNA aneuploid), and subjected to computer modeled analysis. Statistically significant differences between presence or absence of DNA aneuploidy (P = .035) and total SPF (P = .029) were demonstrated between the two groups. Thirteen of 20 patients (65%) with MC (average followup 130 months) were alive at the end of the study period compared to 12 of 20 patients (60%) with IDC (average follow-up 160 months). The difference in crude survival was not statistically significant (P = .867). However, there was a tendency toward early death in MC and late death in IDC. Within the TNM stage-matched patients, no significant difference was demonstrated for tumor size or nodal status when these variables were examined separately. In conclusion, statistically significant differences in DNA content and proliferative fraction exist between medullary carcinoma of the breast and ductal carcinoma. The biologic and clinical differences demonstrated in this analysis warrant careful consideration before including cases of medullary carcinoma in studies evaluating newer prognostic variables in breast cancer.

Adult↗
PubMed1995

Mature teratoma of the uterine cervix with pulmonary differentiation.

Teratomas of the uterus are very rare, and a uterine teratoma with pulmonary differentiation has not, to our knowledge, been described previously. In this article, we report such a case in a 33-year-old woman, who presented with heavy vaginal bleeding and a polypoid mass of the uterine cervix. The cervical lesion was composed entirely of mature lung tissue, including bronchial, bronchiolar, and alveolar structures. The presence of well-differentiated respiratory epithelial cells, ie, Clara cells and alveolar type II cells, is confirmed by immunohistochemistry. The patient had no history of dilatation and curettage; therefore, implantation of fetal tissue could be excluded from the differential diagnoses. Since this is a newly developed mass in an adult individual, we favor a neoplastic process over heterotopia and interpret the lesion as unilateral lung development in an extragonadal mature teratoma.

Adult↗
PubMed1994

De novo design and structural characterization of an alpha-helical hairpin peptide: a model system for the study of protein folding intermediates.

The de novo design and structural characterization of an alpha-helical hairpin peptide (alpha-helix/turn/alpha-helix, alpha t alpha) are reported. The peptide is intended to provide a model system for the study of the interactions of secondary structural elements during protein folding. Both the diffusion-collision and framework models of protein folding envision that the earliest intermediates in protein folding are transient secondary structures or microdomains which interact and become mutually stabilizing. Design principles for the alpha t alpha peptide were drawn from the large body of work on the structure of peptides in solution. Computer modeling was not used in the design process. Study of alpha t alpha by circular dichroism and two-dimensional nuclear magnetic resonance indicates that the designed peptide is monomeric, helical, and stable in aqueous solution at room temperature. Analysis of two-dimensional nuclear magnetic resonance experiments indicates that the two helices and the turn form in the intended positions and that the helices associate in the designed orientation. Development of alpha t alpha represents an advance in protein design in that both the secondary structural elements and designed tertiary interactions have been realized and can be detected in solution by nuclear magnetic resonance. The resulting model system resembles a protein folding intermediate and will allow the study of interacting helices in a context that approximates an early stage in protein folding.

Amino Acid Sequence↗
PubMed1994

Protein folding dynamics: the diffusion-collision model and experimental data.

The diffusion-collision model of protein folding is assessed. A description is given of the qualitative aspects and quantitative results of the diffusion-collision model and their relation to available experimental data. We consider alternative mechanisms for folding and point out their relationship to the diffusion-collision model. We show that the diffusion-collision model is supported by a growing body of experimental and theoretical evidence, and we outline future directions for developing the model and its applications.

Diffusion↗
PubMed1994

MacMolecular: a program for visualization of molecular structures on the Macintosh.

MacMolecular displays small- to medium-sized biomolecules, with particular emphasis on peptides. It has been developed to run on color Macintosh computers. The display can be stick, ball and stick, depth cued by thickness stick, or several types of space-filling representations. The program takes input from standard PDB files, simple Cartesian coordinate files, and, in addition, from Kinemage files in which atom information has been included. The program allows color changes of various types as well as the normal functions of translation, rotation, and zooming. In addition, animation files may be produced for subsequent display. Bonding of atoms is done by a distance algorithm (standard) or sequentially to properly display C alpha traces and traces of peptides containing simplified representations of amino acids. Stereo viewing is available, and manipulated structures which were drawn from PDB files can be written out to new PDB files. In addition, PICT files of the drawing window can be generated.

Alanine↗
PubMed1993

Simulation of alpha-helix-coil transitions in simplified polyvaline: equilibrium properties and Brownian dynamics.

A quantitative understanding of helix-coil dynamics will help explain their role in protein folding and in folded proteins. As a contribution to the understanding, the equilibrium and dynamical aspects of the helix-coil transition in polyvaline have been studied by computer simulation using a simplified model of the polypeptide chain. Each amino acid residue is treated as a single quasi-particle in an effective potential that approximates the potential of mean force in solution. The equilibrium properties examined include the helix-coil transition and its dependence on chain position and well depth at the coil-helix interface. A stochastic simulation of the Brownian motion of the chain in its solvent surroundings has been used to investigate dynamical properties. Time histories of the dihedral angles have been used to study the behavior of the helical structure. Auto and cross-correlation functions have been calculated from the time histories and from the state (helix or coil) functions of the residues with relaxation times of tens to hundreds of picoseconds. Helix-coil rate constants of tens of ns-1 were found for both directions of the transition.

Amino Acid Sequence↗
PubMed1993

Surgical resection and radiolocalization of the sentinel lymph node in breast cancer using a gamma probe.

We have recently reported on a technique of gamma probe localization of radiolabelled lymph nodes to identify the sentinel node in malignant melanoma. In order to determine whether this technique is applicable to assist in staging breast cancer, a pilot study was begun to address two questions: (i) can the sentinel lymph node draining a breast cancer be identified for selective resection; and (ii) is the sentinel lymph node predictive of the status of the entire axillary lymph nodes? One to four hours prior to axillary lymph node dissection, 22 consecutive patients had approximately 0.4 mCi of technetium sulfur colloid in 0.5 ml saline injected around the perimeter of the breast lesion. A hand-held gamma counter was used at surgery to locate the lymph node(s) receiving drainage from the breast. A sentinel lymph node was identified in 18 of 22 patients. Of these 18 patients, the sentinel lymph node was positive in seven of seven patients, with pathologically verified metastatic breast cancer to at least one lymph node. In three out of seven patients, the sentinel lymph node was the only lymph node with metastatic cancer. In this pilot study of breast cancer patients, we conclude that: (i) radiolocalization and selective resection of sentinel lymph nodes is possible; and (ii) the sentinel lymph node appears to predict correctly the status of the remaining axilla. These data justify a larger clinical trial to verify the value of this technique.

Adult↗
PubMed1993

Gamma-probe-guided lymph node localization in malignant melanoma.

The initial draining lymph node (sentinel node) has been successfully localized using intraoperative vital dye mapping and reportedly is predictive of regional nodal metastases in Clinical- Stage 1 melanoma. In an animal model, we previously established the technique of gamma-probe-guided localization of the technetium-99 sulfur colloid labelled sentinel node and found its sensitivity equal to vital dye mapping. We now report our initial experience using gamma-probe-guided localization to identify and then surgically remove the first draining lymph node(s) in 10 malignant melanoma patients. Lymphoscintigraphy was used to confirm localization. We conclude that this technique: (a) reliably localizes the sentinel node draining the site of a primary melanoma, (b) allows the lymphatic bed to be checked intraoperatively verifying complete sentinel node biopsy, and (c) is relatively simple and can be performed under local anaesthesia.

Adult↗
PubMed1992

Hydrophobic interaction between globin helices.

The interhelical interfaces have been examined in seven high-resolution globin chains. The profiles of hydrophobic contact, as measured by the residue solvent-accessible area loss upon folding, have been calculated. The seven globins studied differ in their overall loss of solvent-accessible area upon packing of their helices, the order being 1MBD greater than 1LH1 greater than 1ECD greater than 2MHBB greater than 2HHBB greater than 2HHBA greater than 2MHBA, which gives a measure of the difference in stability due to the hydrophobic interaction. The five helix-pair packings (AH, BE, BG, FH and GH) examined in detail have qualitative similarities. There are, however, substantial quantitative differences both at the equivalent residue level and at the level of overall helix-helix contact, which has significance in some models of folding. The AH pair has the most uniform area loss over the seven globins and the largest variation in accessible area loss on packing among the five helix pairs is the GH pair. The set of residues required to produce the globin fold has been deduced from the residue area losses.

Animals↗
PubMed1992

DNA signal splitting improves detection and analysis of tetraploid populations.

Detection of DNA tetraploid populations requires a high index of suspicion at the time of data acquisition and frequently requires subsequent off-line analysis for confirmation, including evaluation of the hypertetraploid region. To analyze these specimens, the flow cytometer operator must run all specimens with the G0G1 peak in low channels or rerun specimens in which tetraploidy is suspected with a lower photomultiplier tube (PMT) voltage or lower amplifier gain setting. Re-analysis may not be possible in specimens with few cells. A simple modification to the cytometer allows PMT signal splitting with simultaneous processing of the signal by two different amplifiers. This allows simultaneous acquisition of histograms optimized for both the hypotetraploid and hypertetraploid regions.

DNA, Neoplasm↗
PubMed1992

Beta-sheet coil transitions in a simple polypeptide model.

A simplified model of a polypeptide chain is used to study the dynamics of the beta-sheet-coil transition. Each amino acid residue is treated as a single quasiparticle in an effective potential that approximates the potential of mean force in solution. The model is used to study the equilibrium and dynamic aspects of the sheet-coil transition. Systems studied include ones with both strands free to move (two-strand sheet), and ones with either strand fixed in position (multistrand sheet). The equilibrium properties examined include sheet-coil equilibrium constants and their dependence on chain position. Dynamic properties are investigated by a stochastic simulation of the Brownian motion of the chain in its solvent surroundings. Time histories of the dihedral angles and residue-residue cross-strand distances are used to study the behavior of the sheet structure. Auto- and cross-correlation functions are calculated from the time histories with relaxation times of tens to hundreds of picoseconds. Sheet-coil rate constants of tens of ns-1 were found for the fixed strand cases.

Models, Molecular↗
PubMed1992

Modeling microdomains: the surface area of globin helices.

The accessible surface areas of 53 high-resolution globin helices are correlated with molecular weight. The linear fit is assessed for statistical accuracy using a boot-strap analysis, and by comparison to the areas of 13 ideal polyalanine alpha-helices. The accessible area of the unfolded helices is compared with the folded values before helix-helix packing. An analytical physical model is presented to explain the correlation, and to provide an analytical value for the surface area parameter in the diffusion-collision model of protein folding.

Animals↗