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Biomedical subjects

J N Weinstein

Publications and source records attributed to J N Weinstein.

At least 37 records · Page 2Linked to original sources
PubMed2000

A gene expression database for the molecular pharmacology of cancer.

We used cDNA microarrays to assess gene expression profiles in 60 human cancer cell lines used in a drug discovery screen by the National Cancer Institute. Using these data, we linked bioinformatics and chemoinformatics by correlating gene expression and drug activity patterns in the NCI60 lines. Clustering the cell lines on the basis of gene expression yielded relationships very different from those obtained by clustering the cell lines on the basis of their response to drugs. Gene-drug relationships for the clinical agents 5-fluorouracil and L-asparaginase exemplify how variations in the transcript levels of particular genes relate to mechanisms of drug sensitivity and resistance. This is the first study to integrate large databases on gene expression and molecular pharmacology.

Antineoplastic Agents↗
PubMed2000

Designing an ambulatory clinical practice for outcomes improvement: from vision to reality--the Spine Center at Dartmouth-Hitchcock, year one.

Development of a new program for diagnosis and treatment of spine-related problems provided a unique opportunity to design and implement a new model for delivery of health care incorporating outcomes measurement and improvement. Key features include: application of microsystem thinking and interdisciplinary practice; integration of a uniform outcomes measurement tool, the Dartmouth Clinical Value Compass; and touch pad technology for data collection. This, for the first time, provided clinically meaningful point-of-service data and aggregated information for improvement. A further advantage was the ability to integrate a clinical research program within this microsystem. A multisite clinical research trial, the Spine Patient Outcomes Research Trial (SPORT), modeled on the Spine Center microsystem and funded by The National Institute of Arthritis, Musculoskeletal and Skin Diseases and the Office of Research on Woman's Health, the National Institutes of Health, and the National Institute of Occupational Safety and Health, the Centers for Disease Control and Prevention, is currently underway. The significant problems we face today cannot be solved by the same level of thinking that created them.

Ambulatory Care↗
PubMed2000

EDGAR: extraction of drugs, genes and relations from the biomedical literature.

EDGAR (Extraction of Drugs, Genes and Relations) is a natural language processing system that extracts information about drugs and genes relevant to cancer from the biomedical literature. This automatically extracted information has remarkable potential to facilitate computational analysis in the molecular biology of cancer, and the technology is straightforwardly generalizable to many areas of biomedicine. This paper reports on the mechanisms for automatically generating such assertions and on a simple application, conceptual clustering of documents. The system uses a stochastic part of speech tagger, generates an underspecified syntactic parse and then uses semantic and pragmatic information to construct its assertions. The system builds on two important existing resources: the MEDLINE database of biomedical citations and abstracts and the Unified Medical Language System, which provides syntactic and semantic information about the terms found in biomedical abstracts.

Algorithms↗
PubMed2000

Molecular targets in cancer drug discovery: cell-based profiling.

The phrase "molecular target-based drug discovery" usually implies an in vitro biochemical assay or battery of assays. One portion of the U.S. National Cancer Institute's drug discovery program, to the contrary, examines molecular targets for cancer therapy in a cell-based format. That approach has a number of significant limitations, but it has produced databases of significant utility on the activities and structures of tested compounds, as well as on molecular characteristics of the cell types used for testing.

Animals↗
PubMed1999

Predictors of surgical outcome in degenerative lumbar spinal stenosis.

STUDY DESIGN: A prospective, observational study. OBJECTIVES: To identify outcome predictors of surgery for degenerative lumbar spinal stenosis. SUMMARY OF BACKGROUND DATA: Degenerative lumbar spinal stenosis is the most frequent indication for spine surgery in the elderly. More than 25% of surgical patients have a poor outcome, yet little is known about factors that predict the outcome of surgery. METHODS: Surgery was performed on 199 patients with degenerative lumbar spinal stenosis, and they were observed for 2 years after surgery in four referral centers. Surgery consisted of decompressive laminectomy with or without arthrodesis. Outcomes included validated measures of symptom severity, walking capacity, and satisfaction with the results of surgery. Potential predictors of outcome included sociodemographic factors and physical examination, as well as radiographic, psychological, social, and clinical history variables. RESULTS: The proportion of patients with severe pain decreased from 81% before surgery to 31% by 2 years afterward. The most powerful preoperation predictor of greater walking capacity, milder symptoms, and greater satisfaction was the patient's report of good or excellent health before surgery. Low cardiovascular comorbidity also predicted a favorable outcome. CONCLUSIONS: Patient's assessments of their own health and comorbidity are the most cogent outcome predictors of surgery for spinal stenosis.

Aged↗
PubMed1999

Gadd45, a p53-responsive stress protein, modifies DNA accessibility on damaged chromatin.

This report demonstrates that Gadd45, a p53-responsive stress protein, can facilitate topoisomerase relaxing and cleavage activity in the presence of core histones. A correlation between reduced expression of Gadd45 and increased resistance to topoisomerase I and topoisomerase II inhibitors in a variety of human cell lines was also found. Gadd45 could potentially mediate this effect by destabilizing histone-DNA interactions since it was found to interact directly with the four core histones. To evaluate this possibility, we investigated the effect of Gadd45 on preassembled mononucleosomes. Our data indicate that Gadd45 directly associates with mononucleosomes that have been altered by histone acetylation or UV radiation. This interaction resulted in increased DNase I accessibility on hyperacetylated mononucleosomes and substantial reduction of T4 endonuclease V accessibility to cyclobutane pyrimidine dimers on UV-irradiated mononucleosomes but not on naked DNA. Both histone acetylation and UV radiation are thought to destabilize the nucleosomal structure. Hence, these results imply that Gadd45 can recognize an altered chromatin state and modulate DNA accessibility to cellular proteins.

Animals↗
PubMed1999

MedMiner: an Internet text-mining tool for biomedical information, with application to gene expression profiling.

The trend toward high-throughput techniques in molecular biology and the explosion of online scientific data threaten to overwhelm the ability of researchers to take full advantage of available information. This problem is particularly severe in the rapidly expanding area of gene expression experiments, for example, those carried out with cDNA microarrays or oligonucleotide chips. We present an Internet-based hypertext program, MedMiner, which filters and organizes large amounts of textual and structured information returned from public search engines like GeneCards and PubMed. We demonstrate the value of the approach for the analysis of gene expression data, but MedMiner can also be extended to other areas involving molecular genetic or pharmacological information. More generally still, MedMiner can be used to organize the information returned from any arbitrary PubMed search.

Databases, Factual↗
PubMed1998

Molecular modeling studies of the DNA-topoisomerase I ternary cleavable complex with camptothecin.

The present studies provide a three-dimensional model for the postulated ternary cleavable complex of topoisomerase I (top1), DNA, and camptothecin (CPT). Molecular simulations were done using the AMBER force field. The results suggest that a ternary cleavable complex might be stabilized by several hydrogen bonds in the binding site. In this proposed "drug-stacking" model, CPT is pseudointercalated in the top1-linked DNA cleavage site and interacts with the protein near its catalytic tyrosine through hydrogen bonding and stacking. The structural model is consistent with the following experimental observations: (i) the N3 position of the 5' terminal purine of the cleaved DNA strand is readily alkylated by 7-chloromethyl 10,11-methylenedioxy CPT; (ii) CPT generally tolerates substituents at positions 7, 9, and 10 but is inactivated by additions at position 12; (iii) 10,11-methylenedioxy (MDO) CPT is much more potent than 10,11-dimethoxy (DMO) CPT; (iv) the lactone portion of CPT is essential for top1 inhibitory activity; (v) 20S derivatives of CPT are much more potent than the 20R analogues; (vi) a catalytic tyrosine hydroxyl in top1 covalently links to the 3' terminal base, T, of the cleaved DNA strand; and (vii) top1 mutation Asn722Ser leads to CPT resistance. A total of 18 camptothecin derivatives with different DNA cleavage potencies were docked into the hypothetical cleavable complex binding site to test and refine the model. These studies provide insight into a possible mechanism of top1 inhibition by CPT derivatives and suggest rational approaches for the design of new CPT derivatives.

Amino Acid Substitution↗
PubMed1998

The role of steroids and their effects on phospholipase A2. An animal model of radiculopathy.

STUDY DESIGN: The possible role of phospholipase A2 in an animal model for lumbar radiculopathy and mechanisms of epidural steroid injections were studied. OBJECTIVES: To clarify the pathophysiologic mechanism of the recently proved animal model for lumbar radiculopathy and to characterize further the mechanisms of action of steroids. SUMMARY OF BACKGROUND DATA: There have been several reported animal models of peripheral neuropathy. Recently an animal model that shows reliable behavioral and neurochemical changes was proposed, and epidural steroid injections in this model were effective in the reduction of thermal hyperalgesia and allodynia. METHOD: In a behavioral study, 24 rats were divided into 4 groups: Group I, loose ligature of the left L4 and L5 nerve roots with 4-0 chromic gut sutures and an epidural injection of 0.1 mL of saline at 3 days after surgery; Group II, same as Group I but with an epidural injection of 0.1 mL of betamethasone on the day before the operation; Group II, same as Group II except injection at 1 day after surgery; Group IV, same as Group II except injection at 3 days after surgery. To test the phospholipase A2 activity in the nerve roots and dorsal root ganglia after the operation, eight rats were killed at given intervals. Analysis of variance techniques were used to test behavioral pattern changes and phospholipase A2 activity across time in each group. RESULTS: Thermal hyperalgesia reached its maximal point at 3 weeks after surgery in Group I, but in steroid injection groups, the recovery from hyperalgesia was faster than in Group I. However, there was no significant difference in recovery time among steroid injection groups. The level of phospholipase A2 activity was at its maximum at 1 week after surgery in Groups I and IV. It showed a steady reduction in the steroid group, whereas it remained relatively high and dropped rapidly after 3 weeks in the saline-treated group, and returned to the level of a normal nerve root at 6 weeks after surgery. CONCLUSION: These results suggest that the behavioral pattern changes observed in the irritated nerve root model are caused in part by a high level of phospholipase A2 activity initiated by inflammation, and that the mechanism of action of epidural steroid injection in this model is inhibition of phospholipase A2 activity.

Animals↗
PubMed1998

The effect of epidural injection of betamethasone or bupivacaine in a rat model of lumbar radiculopathy.

STUDY DESIGN: The effect of epidural injection of betamethasone or bupivacaine was investigated in an animal model of lumbar radiculopathy. OBJECTIVE: To investigate the effects of an epidural steroid (betamethasone) or a local anesthetic (bupivacaine) in an animal model of radiculopathy produced by nerve root irritation. SUMMARY OF BACKGROUND DATA: Epidural injections are commonly used for the treatment of low back pain and sciatica. However, efficacy remains controversial, and there is a paucity of basic information to support clinical use or the injections. METHODS: Fifty-one rats were used. The left L4 and L5 nerve roots were loosely ligated with chromic gut, and either betamethasone, bupivacaine, betamethasone in combination with bupivacaine, or saline was injected using an epidurally placed catheter. The effects of epidural injection were evaluated using response to noxious stimuli and immunohistochemical methods. RESULTS: In betamethasone-treated rats (either alone or in combination with bupivacaine), thermal hyperalgesia was significantly less (P < 0.010 after surgery than that in saline- or bupivacaine-treated groups, in which the hyperalgesia was maximum at 2-3 postoperative weeks before resolving 5 weeks after surgery. Immunohistochemical analysis did not correlate with these results. CONCLUSIONS: Epidural steroid injection has a significant effect on the thermal hyperalgesia produced in a model of radiculopathy, which may provide clinical support for advocates of epidural steroids.

Anesthetics, Local↗
PubMed1998

Historical perspective. Ernest Amory Codman, 1869-1940. A pioneer of evidence-based medicine: the end result idea.

Unappreciated during his career and largely uncelebrated today, Ernest A. Codman made profound contributions to medical practice and outcomes research. The origin of the present emphasis on evidence-based medicine began with Codman and his "end result" idea. Codman's ideas, courage, and persistence played a critical role in the transition from the 19th century artisan style of medical practice to the current scientific basis of medicine. This historical perspective is a tribute to Codman's contributions to medical science and highlights his remarkable career.

Evidence-Based Medicine↗