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PubMed2006

Towards the identification of essential genes using targeted genome sequencing and comparative analysis.

BACKGROUND: The identification of genes essential for survival is of theoretical importance in the understanding of the minimal requirements for cellular life, and of practical importance in the identification of potential drug targets in novel pathogens. With the great time and expense required for experimental studies aimed at constructing a catalog of essential genes in a given organism, a computational approach which could identify essential genes with high accuracy would be of great value. RESULTS: We gathered numerous features which could be generated automatically from genome sequence data and assessed their relationship to essentiality, and subsequently utilized machine learning to construct an integrated classifier of essential genes in both S. cerevisiae and E. coli. When looking at single features, phyletic retention, a measure of the number of organisms an ortholog is present in, was the most predictive of essentiality. Furthermore, during construction of our phyletic retention feature we for the first time explored the evolutionary relationship among the set of organisms in which the presence of a gene is most predictive of essentiality. We found that in both E. coli and S. cerevisiae the optimal sets always contain host-associated organisms with small genomes which are closely related to the reference. Using five optimally selected organisms, we were able to improve predictive accuracy as compared to using all available sequenced organisms. We hypothesize the predictive power of these genomes is a consequence of the process of reductive evolution, by which many parasites and symbionts evolved their gene content. In addition, essentiality is measured in rich media, a condition which resembles the environments of these organisms in their hosts where many nutrients are provided. Finally, we demonstrate that integration of our most highly predictive features using a probabilistic classifier resulted in accuracies surpassing any individual feature. CONCLUSION: Using features obtainable directly from sequence data, we were able to construct a classifier which can predict essential genes with high accuracy. Furthermore, our analysis of the set of genomes in which the presence of a gene is most predictive of essentiality may suggest ways in which targeted sequencing can be used in the identification of essential genes. In summary, the methods presented here can aid in the reduction of time and money invested in essential gene identification by targeting those genes for experimentation which are predicted as being essential with a high probability.

Animals↗
PubMed2003

The phase III trial in the era of targeted therapy: unraveling the "go or no go" decision.

PURPOSE: To review characteristics of contemporary phase III oncology trials and create an explicit framework to help clinical researchers prioritize novel therapies for phase III testing. METHODS: We searched the MEDLINE and EMBASE databases for all reviews of phase III trials; cataloged all phase III trials in two national clinical trial databases; and reviewed approval criteria of recently approved oncology drugs from public data provided by the US Food and Drug Administration. Industry data not available elsewhere in the medical literature were obtained from a sourcebook published by a large contract research organization. RESULTS: Phase III oncology trials are the most expensive and time-consuming aspect of the drug development process. The results of these trials continue to exert the greatest influence on the treatment decision of oncologists and remain pivotal to the granting of drug approval. Making optimal decisions about which agents to advance to phase III testing may decrease the overall cost of cancer drug development and limit the number of patients exposed to ineffective drugs. A conceptual decision model for prioritizing novel therapies for phase III testing is presented. CONCLUSION: Cancer drug development has become more complex and expensive, whereas overall clinical progress remains slow. The transition from phase II to phase III requires a strategic decision that is based on new considerations. A greater investment in phase I and II drug trials may be required to provide the information necessary for phase III planning.

Antineoplastic Agents↗
PubMedDate not supplied

[Competition for the promotion of essential generic drugs in Africa].

STATEMENT OF THE PROBLEM: in most sub-Saharan countries, an extensive economic crisis coupled with a low level of existing resources has put most pharmaceuticals beyond the reach of the general public. This situation was worsened by the devaluation of the Franc CFA in 1994. The supply of lowprice drugs and the improvement of rational drug use is now a priority. Unfortunately, essential generic drugs are little known and used in Africa. OBJECTIVE: 1. To improve the knowledge of and confidence in essential and generic drugs among providers, prescribers and consumers, through the participation of the general public in an incentive-based, creative competition; 2. To collect locally-adapted promotional material, to be used in the future promotion of essential and generic drugs in Africa. Design, setting and method: a competition was announced in June 1995, via various networks, in French-speaking Africa: the population was invited to create one or several items promoting essential generic drugs. These items included slogans, posters, songs and short plays. Over 550 entries were received before the deadline (15 October 1995), from 22 countries (mostly Sub-Saharan and French-speaking). The entries included 387 slogans, 94 posters, 22 plays, and various (photos, comic strips, songs, poems). RESULTS: 1. Greater awareness of essential generic drugs in Western Africa, through the publicity given to the competition; 2. Selection of a pool of approximately 200 promotional items, produced by the target populations, to be published in a catalog and distributed in African countries; 3. Insights into popular practices and representations of Western medications, and local re-interpretation of the concept. CONCLUSION: this public competition was effective at achieving three important goals: 1. Dynamic promotion (the competition was the opportunity for school projects, radio talkshows, etc. on generic drugs); 2. Re appropriation of a policy, thanks to a participative approach; 3. Analysis of the population's general comprehension of pharmaceuticals, through analysis of competition entries.

Advertising↗
PubMed1984

PSRO, quality review and mental health--a political and practical guide.

Quality assessment of mental health care is distinguished by it defensive character. The field has been sensitive to the criticisms of outside agencies and groups to the point of studying the quality of care it provides far more than other health providers have done. The result has been productive leadership in matters of practical evaluation. The author details the impact of PSRO, the JCAH, DRGS, and other formal review mechanisms upon the quality assessment process. He catalogs a shift in emphasis to take into account organizational dynamics and concludes that the JCAH seems to be propelling alcohol, drug, and mental health treatment programs into creative new directions.

Alcoholism↗
PubMed2006

Global mapping of pharmacological space.

We present the global mapping of pharmacological space by the integration of several vast sources of medicinal chemistry structure-activity relationships (SAR) data. Our comprehensive mapping of pharmacological space enables us to identify confidently the human targets for which chemical tools and drugs have been discovered to date. The integration of SAR data from diverse sources by unique canonical chemical structure, protein sequence and disease indication enables the construction of a ligand-target matrix to explore the global relationships between chemical structure and biological targets. Using the data matrix, we are able to catalog the links between proteins in chemical space as a polypharmacology interaction network. We demonstrate that probabilistic models can be used to predict pharmacology from a large knowledge base. The relationships between proteins, chemical structures and drug-like properties provide a framework for developing a probabilistic approach to drug discovery that can be exploited to increase research productivity.

Computational Biology↗
PubMedDate not supplied

Analysis of methamphetamine-induced changes in the expression of integrin family members in the cortex of wild-type and c-fos knockout mice.

Methamphetamine (METH) is an illicit drug that is also neurotoxic. Recent studies suggest that in addition to dopamine terminal degeneration in the striatum, METH causes apoptosis in cortical neurons. Earlier, we showed that c-fos knockout mice are more susceptible to the toxic effects of the drug. In order to identify possible pathways related to these differences, we have used cDNA array that provided us with a comprehensive catalog of METH affected genes. In the present study, we report on the effects of METH on the integrin family members that were shown to be involved in intracellular signaling cascades effecting cell survival. We found that, in comparison to wild type animals, c-fos knockout mice have lower baseline levels of the integrins in the cortex. Moreover, METH caused time-dependent decreases in their transcripts in both strains of mice. Quantitative RT-PCR confirmed the changes obtained in cDNA array. These findings are discussed in view of the possible role of integrins in METH-induced toxic effects on the cortical neurons.

Journal Article↗
PubMed1999

Implementing a multiple-isolator unit for centralized preparation of cytotoxic drugs in a cancer center pharmacy.

Due to numerous reasons: assuring safety (technicians, patients, nurses, environment), preventing medication errors, cost, maintaining pharmaceutical quality, rules and regulations, it was decided to create a dedicated room within the pharmacy for the preparation of intravenous cytotoxic drugs. After a preliminary study, the following choices were made: isolator unit instead of a vertical laminar air-flow hood, rigid surface instead of flexible film, a multiple-unit structure (one half suit unit for storage and one isolator unit for passthrough, two preparation units, each with four double-gloving portals) instead of a single-unit structure. After the equipment was installed, the physical and microbiological processes were validated and a medical/pharmaceutical catalog of protocols was created. Then the technicians were trained and the standard operating procedures were written. Updated every six months, they describe the general organization, gaseous sterilization of the isolators, the drugs and the medical devices, prescription analysis and circuit, preparation of nominative forms and labels, double checking the preparations delivery, cleaning and maintenance, documentation and reports, waste disposal, safety and protection and instructions for emergency. The pharmacists, pharmacy staff, physicians and nurses were all included in a work group responsible for the isolator unit project. The unit was opened in January 1997.

Antineoplastic Agents↗
PubMed1988

Antibiotic prophylaxis in vascular and interventional radiology: a rational approach.

The current medical and surgical literature was reviewed to determine the rationale for the use of prophylactic antibiotics during surgical procedures. Specifically, the experimental basis for the timing and duration of administration of the antibiotics was considered, and the expected pathogens in each type of surgery were cataloged. High-risk patient groups were identified. The risk of infectious complications during interventional radiologic procedures was reviewed, and appropriate choices of drugs were determined by analogy to the corresponding surgical procedures.

Angiography↗
PubMed1998

Chromosomal abnormalities in secondary MDS and AML. Relationship to drugs and radiation with specific emphasis on the balanced rearrangements.

BACKGROUND AND OBJECTIVE: In therapy-related myelodysplasia (t-MDS) or acute myeloid leukemia (t-AML) balanced chromosome aberrations to bands 11q23 and 21q22 have been significantly related to previous chemotherapy with DNA topoisomerase II inhibitors. The purpose of the present study was to evaluate to what extent other balanced chromosome aberrations show the same association, and to evaluate a possible relationship to patient age and subgroups of drugs. DESIGN AND METHODS: All previously published cases of t-MDS and t-AML with any type of balanced aberration identified from Felix Mitelman's Catalog of Chromosome Aberrations in Cancer were analyzed for age and type of previous therapy, and the results were evaluated in univariate and multivariate analyses. RESULTS: A total of 422 cases were recorded, 328 had previously received well specified types of chemotherapy; 254 presented one out of five characteristic balanced aberrations, whereas 168 cases presented different uncharacteristic balanced aberrations. In univariate analysis cases with translocations to 11q23 had most often received DNA topoisomerase II inhibitors, whereas patients with the uncharacteristic balanced rearrangements most often had received alkylating agents (p < 0.00000001). Inv(16), t(15;17), and t(9;22) were likewise significantly associated with previous therapy with DNA topoisomerase II inhibitors and to almost the same extent as translocations to 21q22. Patients with translocations to 11q23 were significantly younger as compared to all other groups of patients. Translocations to 11q23 predominated following therapy with epipodophyllotoxins, whereas patients with translocations to 21q22, inv(16), t(15;17), and t(9;22) most often had received anthracyclines. In a multivariate analysis taking age into consideration, however, these drug-specific associations were no longer significant. INTERPRETATION AND CONCLUSIONS: Specific balanced chromosome aberrations in t-MDS and t-AML involving chromosome bands 11q23 and 21q22, inv(16), t(15;17), and t(9;22) are all significantly associated with previous therapy with DNA topoisomerase II inhibitors, as compared to the uncharacteristic balanced aberrations most commonly observed after therapy with alkylating agents. Younger age and not a specific type of DNA topoisomerase II inhibitor seems to predispose specifically to development of t-MDS and t-AML with translocations to chromosome band 11q23.

Acute Disease↗
PubMed2001

Bone marrow stem cell protection from chemotherapy by low--molecular-weight compounds.

The stem cells of the bone marrow have the capacity for both self-renewal and derivation of all the blood cell lineages. Consequently, toxicity to these cells can result in neutropenia, agranulocytosis, thrombocytopenia, pancytopenia, or aplastic anemia. Many anticancer drugs adversely affect the bone marrow, and neutropenia is a common limiting factor in dose escalation. In this review, we discuss agents that appear to have potential as bone marrow sparing agents. Computerized catalogs of the National Library of Medicine and Medline were searched for reports on low-molecular-weight compounds that detailed effects on the hematopoietic progenitor cells. The most promising agents are the endogenous peptides p-glutamic acid-glutamic acid-aspartic acid-cysteine-lysine and acetyl-serine-aspartic acid-lysine-proline, and the exogenous compounds amifostine and ammonium trichloro[dioxoethylene-O,O']tellurate, but several others are also discussed. These compounds preserve stem cell function in the presence of antineoplastic drugs of diverse pharmacological classes, and they do so by various mechanisms of action. Their present status in clinical practice is also detailed. More needs to be learned about their mechanisms of action and therapeutic potential, but the results are encouraging for some of these compounds and more clinical trials should be expected.

Amifostine↗
PubMed2005

ChemDB: a public database of small molecules and related chemoinformatics resources.

MOTIVATION: The development of chemoinformatics has been hampered by the lack of large, publicly available, comprehensive repositories of molecules, in particular of small molecules. Small molecules play a fundamental role in organic chemistry and biology. They can be used as combinatorial building blocks for chemical synthesis, as molecular probes in chemical genomics and systems biology, and for the screening and discovery of new drugs and other useful compounds. RESULTS: We describe ChemDB, a public database of small molecules available on the Web. ChemDB is built using the digital catalogs of over a hundred vendors and other public sources and is annotated with information derived from these sources as well as from computational methods, such as predicted solubility and three-dimensional structure. It supports multiple molecular formats and is periodically updated, automatically whenever possible. The current version of the database contains approximately 4.1 million commercially available compounds and 8.2 million counting isomers. The database includes a user-friendly graphical interface, chemical reactions capabilities, as well as unique search capabilities. AVAILABILITY: Database and datasets are available on http://cdb.ics.uci.edu.

Access to Information↗
PubMedDate not supplied

Have structural adjustments led to health sector reform in Africa?

This paper explores the issue of whether and how structural adjustment in Sub-Saharan Africa has altered the level and nature of state involvement in the health care system. Stabilization and structural adjustment generally entail a reduction in aggregate demand, especially government spending, and a reduced role for the state in the provision of many goods and services. Consequently, there is an a priori concern that stabilization and adjustment in Africa may have resulted in lower health expenditures with deleterious effects on the health status of the population, particularly the poor. This paper concludes that structural adjustment programs in Africa did not reduce public health expenditures. In fact, many countries experienced higher real expenditures after adjustment. The fact that many indicators of health status deteriorated during the 1980s, however, presents somewhat of a paradox given the patterns of health expenditures. This paradox is resolved, by an investigation of the intrasectoral allocation of health expenditures which reveals that there are systematic biases in public expenditures towards tertiary and curative care, and a general weakness in the public sector's capacity to deliver adequate health care services even with higher real health sector budgets. In many countries, these biases have persisted despite government and donor intentions to promote health care reform. Finally, the paper reviews a set of policy and institutional issues which hinder the efficient use of budget resources, including overcentralization of health care administration, inappropriate drug and supply procurement practices, the lack of mechanisms for cost recovery, and poor organization, financial and personnel management. At each level of analysis, the paper catalogs those instances where progress is being made towards effective health care reform, including intrasectoral budget rationalization, administrative decentralization, the adoption of user fees for cost recovery, privatization in service delivery, particularly through non-governmental organizations, and organizational and management reform.

Africa South of the Sahara↗
PubMed1998

Medication errors analysis is an opportunity to improve practice.

The United States Pharmacopeia (USP) Medication Errors Reporting (MER) Program collected and cataloged 2,213 reports between October 1991 and November 1996. Medication errors occur in all health care facilities, involve health care practitioners from all disciplines, and involve drugs from all categories, including neuromuscular blocking agents (38 out of 2,213). This class of drugs is discussed as an example of the program, and we trust will serve the reader as an educational guide about medication errors that occur with drugs in any class. When used inappropriately, they represent a higher morbidity and mortality than many other drug classes analyzed. Reports indicate various causes for the errors, such as similar-appearing products, and include suggestions by practitioners to prevent recurrence of the error. The USP Advisory Panel on Medication Errors has developed recommendations for facilities that are intended to prevent errors with neuromuscular blocking agents (NMB). The USP Medication Errors Reporting Program is presented in cooperation with the Institute for Safe Medication Practices (ISMP).

Adverse Drug Reaction Reporting Systems↗
PubMed2005

Kinetic mechanism for p38 MAP kinase alpha. A partial rapid-equilibrium random-order ternary-complex mechanism for the phosphorylation of a protein substrate.

p38 Mitogen-activated protein kinase alpha (p38 MAPKalpha) is a member of the MAPK family. It is activated by cellular stresses and has a number of cellular substrates whose coordinated regulation mediates inflammatory responses. In addition, it is a useful anti-inflammatory drug target that has a high specificity for Ser-Pro or Thr-Pro motifs in proteins and contains a number of transcription factors as well as protein kinases in its catalog of known substrates. Fundamental to signal transduction research is the understanding of the kinetic mechanisms of protein kinases and other protein modifying enzymes. To achieve this end, because peptides often make only a subset of the full range of interactions made by proteins, protein substrates must be utilized to fully elucidate kinetic mechanisms. We show using an untagged highly active form of p38 MAPKalpha, expressed and purified from Escherichia coli[Szafranska AE, Luo X & Dalby KN (2005) Anal Biochem336, 1-10) that at pH 7.5, 10 mm Mg2+ and 27 degrees C p38 MAPKalpha phosphorylates ATF2Delta115 through a partial rapid-equilibrium random-order ternary-complex mechanism. This mechanism is supported by a combination of steady-state substrate and inhibition kinetics, as well as microcalorimetry and published structural studies. The steady-state kinetic experiments suggest that magnesium adenosine triphosphate (MgATP), adenylyl (beta,gamma-methylene) diphosphonic acid (MgAMP-PCP) and magnesium adenosine diphosphate (MgADP) bind p38 MAPKalpha with dissociation constants of KA = 360 microm, KI = 240 microm, and KI > 2000 microm, respectively. Calorimetry experiments suggest that MgAMP-PCP and MgADP bind the p38 MAPKalpha-ATF2Delta115 binary complex slightly more tightly than they do the free enzyme, with a dissociation constant of Kd approximately 70 microm. Interestingly, MgAMP-PCP exhibits a mixed inhibition pattern with respect to ATF2Delta115, whereas MgADP exhibits an uncompetitive-like pattern. This discrepancy occurs because MgADP, unlike MgAMP-PCP, binds the free enzyme weakly. Intriguingly, no inhibition by 2 mm adenine or 2 mm MgAMP was detected, suggesting that the presence of a beta-phosphate is essential for significant binding of an ATP analog to the enzyme. Surprisingly, we found that inhibition by the well-known p38 MAPKalpha inhibitor SB 203580 does not follow classical linear inhibition kinetics at concentrations > 100 nm, as previously suggested, demonstrating that caution must be used when interpreting kinetic experiments using this inhibitor.

Activating Transcription Factor 2↗
PubMed2002

Clinical proteomics for cancer biomarker discovery and therapeutic targeting.

As we emerge into the post-genome era, proteomics finds itself as the driving force field as we translate the nucleic acid information archive into understanding how the cell actually works and how disease processes operate. Even so, the traditionally held view of proteomics as simply cataloging and developing lists of the cellular protein repertoire of a cell are now changing, especially in the sub-discipline of clinical proteomics. The most relevant information archive to clinical applications and drug development involves the elucidation of the information flow of the cell; the "software" of protein pathway networks and circuitry. The deranged circuitry of the cell as the drug target itself as well as the effect of the drug on not just the target, but also the entire network, is what we now are striving towards. Clinical proteomics, as a new and most exciting sub-discipline of proteomics, involves the bench-to-bedside clinical application of proteomic tools. Unlike the genome, there are potentially thousands of proteomes: each cell type has its own unique proteome. Moreover, each cell type can alter its proteome depending on the unique tissue microenvironment in which it resides, giving rise to multiple permutations of a single proteome. Since there is no polymerase chain reaction equivalent to proteomics- identifying and discovering the "wiring diagram" of a human diseased cell in a biopsy specimen remains a daunting challenge. New micro-proteomic technologies are being and still need to be developed to drill down into the proteomes of clinically relevant material. Cancer, as a model disease, provides a fertile environment to study the application of proteomics at the bedside. The promise of clinical proteomics and the new technologies that are developed is that we will detect cancer earlier through discovery of biomarkers, we will discover the next generation of targets and imaging biomarkers, and we can then apply this knowledge to patient-tailored therapy.

Algorithms↗