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J N Weinstein

Publications and source records attributed to J N Weinstein.

At least 55 records · Page 3Linked to original sources
PubMed1998

Mining the National Cancer Institute Anticancer Drug Discovery Database: cluster analysis of ellipticine analogs with p53-inverse and central nervous system-selective patterns of activity.

The United States National Cancer Institute conducts an anticancer drug discovery program in which approximately 10,000 compounds are screened every year in vitro against a panel of 60 human cancer cell lines from different organs. To date, approximately 62,000 compounds have been tested in the program, and a large amount of information on their activity patterns has been accumulated. For the current study, anticancer activity patterns of 112 ellipticine analogs were analyzed with the use of a hierarchical clustering algorithm. A dramatic coherence between molecular structures and their activity patterns could be seen from the cluster tree: the first subgroup (compounds 1-66) consisted principally of normal ellipticines, whereas the second subgroup (compounds 67-112) consisted principally of N2-alkyl-substituted ellipticiniums. Almost all apparent discrepancies in this clustering were explainable on the basis of chemical transformation to active forms under cell culture conditions. Correlations of activity with p53 status and selective activity against cells of central nervous system origin made this data set of special interest to us. The ellipticiniums, but not the ellipticines, were more potent on average against p53 mutant cells than against p53 wild-type ones (i.e., they seemed to be "p53-inverse") in this short term assay. This study strongly supports the hypothesis that "fingerprint" patterns of activity in the National Cancer Institute in vitro cell screening program encode incisive information on the mechanisms of action and other biological behaviors of tested compounds. Insights gained by mining the activity patterns could contribute to our understanding of anticancer drugs and the molecular pharmacology of cancer.

Antineoplastic Agents↗
PubMed1998

A review of basic science issues in low back pain.

This review article is based on a workshop, "New Horizons in Low Back Pain" that was held in November 1995 in San Diego, California. The current article follows the 1995 workshop format of a series of three case study models. Three classical clinical profiles were presented for consideration: lumbar radiculopathy, idiopathic (degenerative disk) low back pain, and degenerative stenosis. This article summarizes the basic science perspectives that were presented and discussed on each topic.

Animals↗
PubMed1997

Identification of epidermal growth factor receptor and c-erbB2 pathway inhibitors by correlation with gene expression patterns.

BACKGROUND: Growth factor receptor-signaling pathways are potentially important targets for anticancer therapy. The interaction of anticancer agents with specific molecular targets can be identified by correlating target expression patterns with cytotoxicity patterns. We sought to identify new agents that target and inhibit the activity of the epidermal growth factor (EGF) receptor and of c-erbB2 (also called HER2 or neu), by correlating EGF receptor, transforming growth factor (TGF)-alpha (a ligand for EGF receptor), and c-erbB2 messenger RNA (mRNA) expression levels with the results of cytotoxicity assays of the 49000 compounds in the National Cancer Institute (NCI) drug screen database. METHODS: The levels of mRNAs were measured and used to generate a molecular target database for the 60 cell lines of the NCI anticancer drug screen. The computer analysis program, COMPARE, was used to search for cytotoxicity patterns in the NCI drug screen database that were highly correlated with EGF receptor, TGF-alpha, or c-erbB2 mRNA expression patterns. The putative EGF receptor-inhibiting compounds were tested for effects on basal tyrosine phosphorylation, in vitro EGF receptor tyrosine kinase activity, and EGF-dependent growth. Putative ErbB2-inhibiting compounds were tested for effects on antibody-induced ErbB2 tyrosine kinase activity. RESULTS: EGF receptor mRNA and TGF-alpha mRNA levels were highest in cell lines derived from renal cancers, and c-erbB2 mRNA levels were highest in cells derived from breast, ovarian, and colon cancers. Twenty-five compounds with high correlation coefficients (for cytotoxicity and levels of the measured mRNAs) were tested as inhibitors of the EGF receptor or c-erbB2 signaling pathways; 14 compounds were identified as inhibitors of these pathways. The most potent compound, B4, inhibited autophosphorylation (which occurs following activation) of ErbB2 by 50% in whole cells at 7.7 microM. CONCLUSIONS: Novel EGF receptor or c-erbB2 pathway inhibitors can be identified in the NCI drug screen by correlation of cytotoxicity patterns with EGF receptor or c-erbB2 mRNA expression levels.

Antineoplastic Agents↗
PubMed1997

Characterization of the p53 tumor suppressor pathway in cell lines of the National Cancer Institute anticancer drug screen and correlations with the growth-inhibitory potency of 123 anticancer agents.

In the present study, we report the characterization of the p53 tumor suppressor pathway in the 60 cell lines of the National Cancer Institute (NCI) anticancer drug screen, as well as correlations between the integrity of this pathway and the growth-inhibitory potency of 123 anticancer agents in this screen. Assessment of p53 status in these lines was achieved through complete p53 cDNA sequencing, measurement of basal p53 protein levels and functional assessment of (a) transcriptional activity of p53 cDNA from each line in a yeast assay, (b) gamma-ray-induced G1 phase cell cycle arrest, and (c) gamma-ray-induced expression of CIP1/WAF1, GADD45, and MDM2 mRNA. Our investigations revealed that p53 gene mutations were common in the NCI cell screen lines: 39 of 58 cell lines analyzed contained a mutant p53 sequence. cDNA derived from almost all of the mutant p53 cell lines failed to transcriptionally activate a reporter gene in yeast, and the majority of mutant p53 lines studied expressed elevated basal levels of the mutant p53 protein. In contrast to most of the wild-type p53-containing lines, cells containing mutant p53 sequence were also deficient in gamma-ray induction of CIP1/WAF1, GADD45, and MDM2 mRNA and the ability to arrest in G1 following gamma-irradiation. Taken together, these assessments provided indications of the integrity of the p53 pathway in the 60 cell lines of the NCI cell screen. These individual p53 assessments were subsequently used to probe a database of growth-inhibitory potency for 123 "standard agents," which included the majority of clinically approved anticancer drugs. These 123 agents have been tested against these lines on multiple occasions, and a proposed mechanism of drug action had previously been assigned to each agent. Our analysis revealed that cells with mutant p53 sequence tended to exhibit less growth inhibition in this screen than the wild-type p53 cell lines when treated with the majority of clinically used anticancer agents: including DNA cross-linking agents, antimetabolites, and topoisomerase I and II inhibitors. Similar correlations were uncovered when we probed this database using most of the other indices of p53 status we assessed in the lines. Interestingly, a class of agents that differed in this respect was the antimitotic agents. Growth-inhibitory activity of these agents tended, in this assay, to be independent of p53 status. Our characterization of the p53 pathway in the NCI cell screen lines should prove useful to researchers investigating fundamental aspects of p53 biology and pharmacology. This information also allows for the large-scale analysis of the more than 60,000 compounds tested against these lines for novel agents that might exploit defective p53 function as a means of preferential toxicity.

Antineoplastic Agents↗
PubMed1997

A system for surgical staging and management of spine tumors. A clinical outcome study of giant cell tumors of the spine.

STUDY DESIGN: This study developed and independently applied a spine tumor classification system, referred to as the Weinstein-Boriani-Biagini system, in a retrospective analysis of a series of patients with spinal giant cell tumors from three institutions. OBJECTIVE: To evaluate factors of potential prognostic significance for recurrence of spinal giant cell tumors. SUMMARY OF BACKGROUND DATA: No prior reviews of patients treated with modern surgical techniques are available. METHODS: Charts and radiographs for 36 cases of spinal giant cell tumors were reviewed by an independent investigator. All patients had had recent clinical follow-up examinations. All patients were classified according to the Enneking system. A subgroup of 24 patients for whom preoperative computed tomography scans were available were classified using the Weinstein-Boriani-Biagini staging system. Outcome measures included pain, neurologic status, and tumor recurrence. RESULTS: Recurrence rates were substantially higher among patients treated with attempted surgical excision before referral to a tertiary care center (83% vs. 18%). There was a higher recurrence rate for tumors that involved the vertebral body and posterior elements in comparison with lesions residing in only anterior elements (24% vs. 0%). Tumors that had extra-osseous extension into the canal and into the paraspinous musculature had a higher recurrence rate than tumors either confined to the osseous compartment or with extension either into the spinal canal or externally into paraspinous planes, but not both (21% vs. 10%). CONCLUSIONS: These results indicate that the Weinstein-Boriani-Biagini system may prove useful in developing treatment algorithms and in assessing outcome for these rare and difficult lesions. At least in the case of giant cell tumors, the musculoskeletal tumor staging system as developed by Enneking for long bones suggests the ideal surgical margin and may provide information relevant to tumor recurrence rates. Additional aspects of tumor extent and location, however, may berelevant to primary tumor recurrence rates when the selesions occur in the spine.

Adolescent↗
PubMed1997

The role of phospholipase A2 and nitric oxide in pain-related behavior produced by an allograft of intervertebral disc material to the sciatic nerve of the rat.

STUDY DESIGN: To elucidate the pathomechanisms of radicular pain secondary to lumbar disc herniation. OBJECTIVES: To evaluate whether intervertebral disc material applied to the sciatic nerve produces hyperalgesia, and if the hyperalgesia in influenced by inhibitors of phospholipase A2 and nitric oxide synthase. SUMMARY OF BACKGROUND DATA: Previously, the authors reported that application of nucleus pulposus and anulus fibrosus material to the lumbar epidural space produces different forms of hyperalgesia (mechanical versus thermal), with different and distinct histologic changes. Additional pharmacologic studies showed that phospholipase A2 and nitric oxide are involved in the mechanisms that produce the mechanical and thermal hyperalgesia, respectively, N omega-nitro-L-arginine methyl ester and mepacrine are relatively selective inhibitors of nitric oxide synthase and phospholipase A2, respectively. However, it is not known what the relation is between the hyperalgesia produced and the activation and involvement of phospholipase A2 and production of nitric oxide, or why the application of nucleus pulposus and nucleus pulposus with anulus fibrosus produces different types of hyperalgesia. METHODS: Experiments were performed in five groups of rats: The control group (no treatment), the sham group (exposure of the sciatic nerve only), the fat group (allografted fat on the sciatic nerve), the nucleus pulposus group (allografted nucleus pulposus) and the nucleus pulposus + anulus fibrosus group (allografted nucleus pulposus and anulus fibrosus). Withdrawal threshold and latency from mechanical pressure and a radiant heat to hind paws were measured preoperatively and postoperatively. After local sciatic nerve administration of N theta-nitro-L-arginine methyl ester or mepacrine into the operated site, sensitivities to noxious stimuli were reevaluated after treatment. RESULTS: Only rats in the nucleus pulposus group showed evidence of mechanical hyperalgesia. However, injection of N theta-nitro-L-arginine methyl ester resulted in evidence of mechanical hyperalgesia in the nucleus pulposus + anulus fibrosus group. Mechanical hyperalgesia was produced in the nucleus pulposus group and after injection of N theta-nitro-L-arginine methyl ester in the nucleus pulposus+anulus fibrosus group, both of which returned to normal after mepacrine injection. There were no significant changes in sensitivity to thermal stimuli in any of the experimental groups. CONCLUSION: It appears that phospholipase A2 and nitric oxide play important but different roles in pathomechanisms of radicular pain in lumbar disc herniation.

Animals↗
PubMed1997

Lumbar laminectomy alone or with instrumented or noninstrumented arthrodesis in degenerative lumbar spinal stenosis. Patient selection, costs, and surgical outcomes.

DESIGN: A prospective, multicenter observational study. OBJECTIVES: 1) Identify correlates of the decision to perform arthrodesis in patients undergoing laminectomy for lumbar spinal stenosis. 2) Compare symptoms, walking capacity, and satisfaction 6 and 24 months after laminectomy alone and laminectomy with noninstrumented and with instrumented arthrodesis. BACKGROUND DATA: Few prospective studies have compared outcomes of laminectomy alone or laminectomy with noninstrumented or with instrumented arthrodesis in patients with degenerative lumbar spinal stenosis. There is uncertainty regarding the optimal use of arthrodesis and instrumentation. METHODS: Two hundred seventy--two patients undergoing--surgery for degenerative lumbar stenosis by eight surgeons at four centers were included in the study cohort. Of these, 37 had noninstrumented and 41 had instrumented arthrodesis. Logistic regression identified factors associated with arthrodesis. The principal outcomes-health status, walking capacity, back and leg pain, and satisfaction with surgery-were assessed 6 and 24 months postoperatively with univariate and multivariate techniques. Outcomes also were assessed in a restricted cohort of patients with at least 5 mm spondylolisthesis and/or 15 degrees scoliosis. Hospital costs were obtained from a computerized hospital cost accounting system. RESULTS: The major predictor of the decision to perform arthrodesis was the individual surgeon (P = 0.0001). Noninstrumented arthrodesis was associated with superior relief of low back pain at 6 months (P = 0.004) and 24 months (P = 0.01). This difference persisted in multivariate analyses, with borderline statistical significance. There were no significant differences in the other outcomes across treatment groups. Mean hospital costs of laminectomy alone and noninstrumented and instrumented arthrodesis were $12,615, $18,495, and $25,914, respectively (P = 0.0001). CONCLUSION: Findings were limited by the small number of participating surgeons, modest sample size that produced P values of borderline significance, and nonrandomized design. With these caveats in mind, the authors conclude: (1) The individual surgeon was a more important correlate of the decision to perform arthrodesis than clinical variables such as spondylolisthesis. (2) Noninstrumented arthrodesis resulted in superior relief of back pain after 6 and 24 months. (3) Instrumented arthrodesis was the most costly option. These results highlight the need for randomized controlled trials and cost effectiveness analyses of lumbar arthrodesis and instrumentation in patients with degenerative lumbar spinal stenosis.

Aged↗
PubMed1997

Primary bone tumors of the spine. Terminology and surgical staging.

Appropriate application of an oncologic staging system is required to evaluate the relationship among histologic types, management, and outcome of primary bone tumors. A commonly accepted terminology for surgical procedures and for definition of tumor extent is needed for surgical planning and clinical reviews. The principles of the Enneking system for classifying stages of tumors are emphasized and applied to the spine using a practical approach for surgical staging.

Chondrosarcoma↗
PubMed1997

Artificial neural networks improve the accuracy of cancer survival prediction.

BACKGROUND: The TNM staging system originated as a response to the need for an accurate, consistent, universal cancer outcome prediction system. Since the TNM staging system was introduced in the 1950s, new prognostic factors have been identified and new methods for integrating prognostic factors have been developed. This study compares the prediction accuracy of the TNM staging system with that of artificial neural network statistical models. METHODS: For 5-year survival of patients with breast or colorectal carcinoma, the authors compared the TNM staging system's predictive accuracy with that of artificial neural networks (ANN). The area under the receiver operating characteristic curve, as applied to an independent validation data set, was the measure of accuracy. RESULTS: For the American College of Surgeons' Patient Care Evaluation (PCE) data set, using only the TNM variables (tumor size, number of positive regional lymph nodes, and distant metastasis), the artificial neural network's predictions of the 5-year survival of patients with breast carcinoma were significantly more accurate than those of the TNM staging system (TNM, 0.720; ANN, 0.770; P < 0.001). For the National Cancer Institute's Surveillance, Epidemiology, and End Results breast carcinoma data set, using only the TNM variables, the artificial neural network's predictions of 10-year survival were significantly more accurate than those of the TNM staging system (TNM, 0.692; ANN, 0.730; P < 0.01). For the PCE colorectal data set, using only the TNM variables, the artificial neural network's predictions of the 5-year survival of patients with colorectal carcinoma were significantly more accurate than those of the TNM staging system (TNM, 0.737; ANN, 0.815; P < 0.001). Adding commonly collected demographic and anatomic variables to the TNM variables further increased the accuracy of the artificial neural network's predictions of breast carcinoma survival (0.784) and colorectal carcinoma survival (0.869). CONCLUSIONS: Artificial neural networks are significantly more accurate than the TNM staging system when both use the TNM prognostic factors alone. New prognostic factors can be added to artificial neural networks to increase prognostic accuracy further. These results are robust across different data sets and cancer sites.

Breast Neoplasms↗
PubMed1997

An information-intensive approach to the molecular pharmacology of cancer.

Since 1990, the National Cancer Institute (NCI) has screened more than 60,000 compounds against a panel of 60 human cancer cell lines. The 50-percent growth-inhibitory concentration (GI50) for any single cell line is simply an index of cytotoxicity or cytostasis, but the patterns of 60 such GI50 values encode unexpectedly rich, detailed information on mechanisms of drug action and drug resistance. Each compound's pattern is like a fingerprint, essentially unique among the many billions of distinguishable possibilities. These activity patterns are being used in conjunction with molecular structural features of the tested agents to explore the NCI's database of more than 460,000 compounds, and they are providing insight into potential target molecules and modulators of activity in the 60 cell lines. For example, the information is being used to search for candidate anticancer drugs that are not dependent on intact p53 suppressor gene function for their activity. It remains to be seen how effective this information-intensive strategy will be at generating new clinically active agents.

Algorithms↗
PubMed1997

In vitro testing of a new transpedicular stabilization technique.

The rigidity of a pedicle screw implant is a critical biomechanical variable in lumbar spinal fusions. Sufficient rigidity is required for integration of bone grafts and to promote healing. Osteopenia, stress shielding, and compensatory hypermobility have been described as consequences of excessive rigidity. Little is known about the biomechanical characteristics of "semirigid" compared to "rigid" implants. A new implant, whose rigidity can be varied by selection of different implant components, was tested in vitro under well-defined loading conditions. The three-dimensional load-displacement behavior of all lumbar vertebrae involved in or adjacent to the two-level fusion was evaluated for two fusion modifications: bilateral rigid and bilateral semirigid. Cyclic fatigue loading was subsequently carried out under realistic conditions and motion testing repeated. The rigid device reduced the motion of the L3-4 transfixed segment in the primary movement planes by 87.3% with respect to the intact spine value in flexion/extension (FE), 86.3% in lateral bending (LB), and 76.8% in axial rotation (AR). The semirigid device achieved a reduction in motion of 79.6% (FE), 82.7% (LB), and 51.7% (AR). The semirigid implant was particularly easy to insert, because no bending of rods or plates was necessary. The implants showed no loosening or breakage after the fatigue testing. The results are compared to other available systems and the underlying biomechanics discussed.

Aged↗
PubMed1996

Disc herniation.

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Humans↗
PubMed1996

Consensus summary of the diagnosis and treatment of lumbar disc herniation.

Clinicians must not simply decide that a patient with symptoms and a positive diagnostic test has a reason for a specific treatment, and likewise clinicians must not decide that a patient with symptoms and a negative test does not have a clinically important problem. We must also consider the sensitivity, specificity and predictive value of the diagnostic test and the individual characteristics of the patient. Treatment outcome depends on many factors. Point of service decisions vs population based decisions are obviously different. Each patient presents to the treating practitioner on a given day, at a given time, and it is this picture upon which a plan of care is formulated.

Humans↗
PubMed1996

Effects of muscle dysfunction on lumbar spine mechanics. A finite element study based on a two motion segments model.

STUDY DESIGN: A combined finite element and optimization approach was developed to investigate the clinically relevant biomechanical parameters of the muscular lumbar spine under five quasistatic back-lifting conditions. OBJECTIVES: To quantify the effects of muscle "dysfunction" on the mechanical behavior of the lumbar spine. SUMMARY OF BACKGROUND DATA: Trunk muscles have been proven to play an important role in the normal functioning of the spine. Although passive structures of the spine are believed to be subjected increasingly to mechanical stresses when muscular support is inadequate, supportive quantitative data have been lacking. METHODS: External loads at L3-L4 for various lifting tasks were estimated experimentally and partitioned to the disc and muscles across the L3-L4 segment using an optimization scheme. These forces were incorporated into a finite element model of the ligamentous L3-L5 lumbar spine. Muscle "dysfunction" was simulated by decreasing the computed muscle forces. RESULTS: The range of motion intradiscal pressure forces in ligaments, and load across facets increased nonlinearly with the increases in trunk flexion and the load held in hands. At higher loads or at larger flexed postures, muscles were found to play a more crucial role in stabilizing the spine compared with the passive structures. Muscle "dysfunction" destabilized the spine, reduced the role of facet joints in transmitting load, and shifted loads to the discs and ligaments. CONCLUSIONS: Muscle dysfunction disturbs the normal functioning of other spinal components and may cause spinal disorders.

Biomechanical Phenomena↗
PubMed1996

Pathomechanism of pain-related behavior produced by allografts of intervertebral disc in the rat.

STUDY DESIGN: This study was designed to evaluate whether allografts of intervertebral disc materials produce hyperalgesia in the rat and whether an immune response, pH, or chemicals correlate with the induced hyperalgesia. OBJECTIVE: To elucidate the pathomechanisms of radicular pain secondary to lumbar disc herniation. SUMMARY OF BACKGROUND DATA: It has been reported that a low pH, an autoimmune reaction, or chemical radiculitis is likely responsible for radicular pain associated with lumbar disc herniation. In animal studies, it has been shown that hyperalgesia (an increased sensitivity to painful stimuli) involves activation of phospholipase A2 and nitric oxide synthase. METHODS: Fat, nucleus pulposus, and anulus fibrosus were allografted into the epidural space at L6 in the rat. Withdrawal response thresholds to mechanical stimuli and withdrawal response latencies to thermal stimuli on the tail and pH in the applied tissues were measured after surgery. Interleukin-1, phospholipase A2, and nitric oxide synthase were examined in the applied tissues using immunohistochemistry, nicotineamide adenine dinucleotide phosphate-diaphorase histochemistry, and in situ hybridization. RESULTS: Allografted fat did not produce hyperalgesia. Allografts of nucleus pulposus and nucleus pulposus plus anulus fibrosis showed evidence of mechanical and thermal hyperalgesia, respectively. There were no observed changes in pH over time. Although interleukin-1 was demonstrated in all applied tissues, phospholipase A2 was only observed around the applied nucleus A2 was only observed around the applied nucleus pulposus and nucleus pulposus plus anulus fibrosus. Nitric oxide synthase was only markedly increased around the applied tissues. CONCLUSION: The nucleus pulposus and anulus fibrosus produce different forms of hyperalgesia (mechanical vs. thermal) associated with different and distinct immunohistochemical changes. It is possible that radicular pain of a lumbar disc herniation results from chemicals, such as phospholipase A2 and nitric oxide.

Adipose Tissue↗