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PubMed2000

The impact of genomics on therapeutic drug development.

Genomics can be defined as a set of related technologies that are focused on the discovery of genes implicated in human disease. Although many of the estimated 100,000 genes in the human genome have been at least partially identified by nucleotide sequence, elucidation of biological function has been achieved for only a small percentage of these. An even smaller percentage of genes discovered by these methodologies have become valid drug targets. This review discusses the various genomics technologies and their likelihood of yielding therapeutic drugs. Emerging advances in microarray "chip" technology have allowed the parallel analysis of gene expression patterns for thousands of genes simultaneously. Sequence information derived from the genomes of many individuals is leading to the rapid discovery of single nucleotide polymorphisms or SNPs. Detection of these human polymorphisms will fuel the discipline of pharmacogenomics, resulting in an increase in the success of clinical trials, the rescue of drugs that have previously failed in clinical trials because of adverse reactions from patient subpopulations, and ultimately, in the development of more personalized drug therapies. The impending identification of all human genes will signal the end of the structural genomics phase and usher in the function genomics phase. Technologies have already begun to move toward high-throughput elucidation of gene relationships, interactions and, it is hoped, toward their functions.

Biotechnology↗

PubMed2006

Review article: The role of statins in reducing perioperative cardiac risk: Physiologic and clinical perspectives.

PURPOSE: To review the pathobiology and clinical implications of coronary vulnerable atherosclerotic plaques (VAPs), to discuss the role of statin therapy in VAP stabilization, and the potential benefits of perioperative statin therapy (PST) in reducing perioperative risk of acute coronary syndromes (ACSs). SOURCE: MEDLINE search using "perioperative", "cardiac morbidity", "atherosclerosis", "vulnerable plaque", "statins" and combinations of these terms as keywords. The reference lists of relevant articles were further reviewed to identify additional citations. PRINCIPAL FINDINGS: The nonstenotic, yet rupture-prone VAP causes most myocardial infarctions (MIs) and other ACSs, both in the nonsurgical and surgical patients. Large clinical trials in both primary and secondary prevention and in patients with ACSs have demonstrated that statin therapy will reduce cardiovascular morbidity and mortality across a broad spectrum of patient subgroups. These trials also suggest, and laboratory investigations establish, that statins possess favourable vascular effects independent of cholesterol reduction. Statins appear to interfere specifically with the pathophysiologic mechanisms implicated in atherothrombotic disease. Statins reduce vascular inflammation, improve endothelial function, stabilize VAPs, and reduce platelet aggregability and thrombus formation. Recent studies have shown that PST is associated with a reduced incidence of perioperative and long-term cardiovascular complications in high-risk patients. Combined therapy with statins and ss-blockers is a conceptually valid strategy targeting critical steps in the pathogenesis of an ACS. CONCLUSION: Emerging evidence for the efficacy and safety of PST is promising, especially when combined with ss-blocker therapy in patients at highest risk. Confirmation of this early evidence awaits the results of ongoing and future prospective randomized controlled trials.

Anticholesteremic Agents↗

PubMed2006

Psychosocial risk clustering in high school students.

BACKGROUND: This secondary analysis describes the frequency of self-reported psychosocial risk factors in a geographically defined population of adolescents and quantifies the extent of multiple risks. Cluster analysis is used to develop three empirically distinct psychosocial risk clusters. METHODS: High school students in grades 9-13 from all seven public and two catholic high schools in the study area completed a class-administered survey. The analysis is based on 3540 surveys reflecting approximately a 71% response. Cumulative risk was calculated by summing the number of times students exceeded a pre-defined threshold on a series of global rating scales. Risk clusters were created using a non-hierarchical cluster analysis technique for binary data. Clusters were partially validated by examining differences in socio-demographic and health utilization patterns. Reliability was assessed by examining two, three, and four-group solutions across gender and grade strata. RESULTS: Multiple symptoms of emotional distress were reported by 37% of the sample, multiple stressors by 62% of the sample, and poly-drug use by 33%. In addition, three empirically distinct clusters were derived. Normals, 21% of the sample, did not report excessive stress or distress, and did not use substances. The Stressed (45%) reported excessive stress and distress predominantly related to schoolwork, parents, and facing problems. Virtually none used drugs. Substance Users (34%) reported excessive stress, distress, and high levels of substance use: smoking, drinking, and use of illicit drugs. Clusters were significantly different with respect to most socio-demographic factors, self-reported general health, and most aspects of health service utilization suggesting that they have some validity for targeting programs. CONCLUSIONS: This study highlights the importance of focusing on multi-morbidities and illustrates the use of cluster analysis to identify risk profiles that may be amenable to school-based health promotion and prevention programs.

Adolescent↗

PubMed2005

Role of tumour-associated N-glycolylated variant of GM3 ganglioside in cancer progression: effect over CD4 expression on T cells.

Gangliosides have diverse biological functions including modulation of immune system response. These molecules are differentially expressed on malignant cells compared with the corresponding normal ones and are involved in cancer progression affecting, in different ways, the host's anti-tumour specific immune responses. Although in humans the N-glycolylated variant of GM3 ganglioside is almost exclusively expressed in tumour tissues, the significance of this glycolipid for malignant cell biology remains obscure, while for NAcGM3 strong immune suppressive effects have been reported. The present work demonstrates, for the first time, the capacity of NGcGM3 ganglioside to down-modulate CD4 expression in murine and human T lymphocytes, especially in non-activated T cells. Thirty and tenfold reductions in CD4 expression were induced by purified NGcGM3 ganglioside in murine and human T lymphocytes, respectively. The CD4 complete recovery in these cells occurred after 48 h of ganglioside removal, due to neo-synthesis. Restored T cells kept similar sensitivity to ganglioside-induced CD4 down-modulation after a new challenge. In addition, a clear association between NGcGM3 insertion in lymphocyte plasma membranes and the CD4 down-modulation effect was documented. Notably, a possible role of this ganglioside in tumour progression, taking advantage of the X63 myeloma model, was also outlined. The relevance of these findings, characterizing NGcGM3 as a possible tumour immunesurveillance inhibitor and supporting the reason for its neo-expression in certain human cancers, is contributing to this unique heterophilic ganglioside validation as target for cancer immunotherapy.

Animals↗

PubMed2001

ST1571, a tyrosine kinase inhibitor for the treatment of chronic myelogenous leukemia: validating the promise of molecularly targeted therapy.

The deregulated tyrosine kinase activity of the Bcr-Abl fusion protein has been established as the causative molecular event in chronic myelogenous leukemia (CML). Thus the Bcr-Abl tyrosine kinase is an ideal target for pharmacologic inhibition. ST1571 (formerly CGP57148B), is an Abl-specific tyrosine kinase inhibitor that in preclinical studies selectively kills Bcr-Abl-containing cells in vitro and in vivo. The results of clinical studies have demonstrated the potential of molecularly targeted therapies, and ST1571 is emerging as a new therapeutic agent for CML.

Antineoplastic Agents↗

PubMed2006

Differential expression of genes encoding tight junction proteins in colorectal cancer: frequent dysregulation of claudin-1, -8 and -12.

BACKGROUND AND AIMS: As integral membrane proteins, claudins form tight junctions together with occludin. Several claudins were shown to be up-regulated in various cancer types. We performed an expression analysis of genes encoding tight junction proteins to display differential gene expression on RNA and protein level and to identify and validate potential targets for colorectal cancer (CRC) therapy. PATIENTS AND METHODS: Amplified and biotinylated cRNA from 30 microdissected CRC specimen and corresponding normal tissues was hybridized to Affymetrix U133set GeneChips. Quantification of differential protein expression of claudin-1, -8 and -12 between normal and corresponding tumour tissues was performed by Western blot analyses. Paraffin-embedded CRC tissue samples, colon cancer cell lines and normal tissue microarray were analysed for protein expression of claudin-1 by immunohistochemistry (IHC). RESULTS: Claudin-1 (CLDN1) and -12 (CLDN12) are frequently overexpressed in CRC, whereas claudin-8 (CLDN8) shows down-regulation in tumour tissue on RNA level. Quantification of proteins confirmed the overexpression of claudin-1 in tumour tissues, whereas changes of claudin-8 and -12 were not significantly detectable on protein level. IHC confirmed the markedly elevated expression level of claudin-1 in the majority of CRC, showing membranous and intracellular vesicular staining. CONCLUSIONS: Differential expression of genes encoding claudins in CRC suggests that these tight junction proteins may be associated to and involved in tumorigenesis. CLDN1 is frequently up-regulated in large proportion of CRC and may represent potential target molecule for blocking studies in CRC.

Aged↗

PubMed2006

Talking the talk on walking the walk: a 12-item generic walking scale suitable for neurological conditions?

BACKGROUND: The Multiple Sclerosis Walking Scale (MSWS-12) was developed to measure the impact of multiple sclerosis on walking. Many other disabling neurological conditions affect patients' ability to walk, and a generic measure of walking could provide valuable insights into patients' perceptions in clinical trials and epidemiological studies as well as routine clinical practice. OBJECTIVE: To evaluate the clinical usefulness and psychometric properties of the Walking Impact Scale (Walk-12), a modified version of the MSWS-12, in patients with neurological conditions. DESIGN: A prospective, observational study of 120 consecutive patients admitted for rehabilitation. The Walk-12 was used to measure the impact of neurological disability on walking. Traditional psychometric methods (data quality, scaling assumptions, targeting, reliability, validity and responsiveness) were used to assess the Walk-12. Transition questions were used on discharge to measure perception of change. Outcome was also measured using the timed walk test (TWT), Barthel Index (BI) and Functional Independence Measure (FIM). RESULTS: For the total group, missing data were few, scaling assumptions were satisfied, and internal consistency was 0.94. Correlations between the Walk-12 and TWT, BI and FIM motor score were moderate (r=-0.58, -0.26, -0.31). Responsiveness of the Walk-12 was high (effect size=1.12). Relationships between effect size and patients' and physiotherapists' opinion of change in walking demonstrated good concordance. Preliminary subgroup analyses indicate satisfactory psychometric properties across different neurological conditions; however, sample numbers in these analyses are small. CONCLUSIONS: In this sample of neurologically disabled patients the Walk-12 was clinically useful and satisfied standard psychometric criteria. This provides preliminary evidence that it may be suitable as a generic measure of walking ability.

Adolescent↗

PubMed1987

Simple measures of progress and outcome in the evaluation of mental health services.

There is a tautology regarding the use of progress and outcome measures. Such measures are easy to use in a reliable and valid fashion if the language of the measures is used as an integral part of (a) treatment planning and progress review, (b) clinical supervision, and (c) program management. The paper describes example guidelines and uses of measures in each of these functions. Also included are listings of scales with documented reliability and validity (by target population) and some sources for finding computer software for scoring some of the scales.

Evaluation Studies as Topic↗

PubMed1992

Hematotoxic effects of benzene analyzed by mathematical modeling.

The hematopoietic cell response to benzene intoxication in mice (during and after long-term inhalation) was analyzed by a mathematical model of murine hematopoiesis. Two complementary methods, Time-Curve and Steady-State Analysis, were developed to identify target cells for benzene toxicity and to quantify the extent of damage in different stages of development of these target cells. We found that (i) erythropoietic cells were the most sensitive; (ii) granulopoietic cells were about half as sensitive as erythropoietic and (iii) hematopoietic stem cells exhibited a sensitivity that ranged between that of erythropoietic and granulopoietic cells. A dose-response relationship between benzene levels and damage in target cells (valid from 1 to more than 900 ppm) was derived that was linear for doses up to 300 ppm and plateaued thereafter. This relationship indicated that benzene-induced hematotoxicity is subject to a saturable process. Recovery of hematopoiesis following chronic benzene intoxication was simulated for different doses and preceding exposure periods. The impaired recovery following exposure periods greater than 8 weeks could be explained by a severe reduction in the maximum self-maintenance of stem cells. This study indicates that the present mathematical model represents a useful approach to investigate alternate hypotheses for the action of hematotoxic agents.

Animals↗

PubMed2004

The discovery, biology, and drug development of sialyl Lea and sialyl Lex.

The discoveries of sialylated, fucosylated lacto-, and neolacto-type carbohydrate structures were accomplished with the aid of analytical methods and monoclonal antibodies such as the immunostaining of thin layer chromatograms. Based on the use of such antibodies, these structures, notably sialyl Le(a) and sialyl Le(x), were demonstrated to be highly expressed in many malignant cancers. A diagnostic assay using one of these antibodies (CA19-9) is now established as one of the more commonly used assays for pancreatic and gastrointestinal cancers worldwide. Upon further study, several laboratories have demonstrated that the level of expression of these carbohydrate tumor markers is also positively correlated with patient survival and is a prognostic indicator of metastatic disease. Concurrent with this finding, both sialyl Le(a) and sialyl Le(x) were shown to bind to a family of carbohydrate-binding proteins involved in the extravasation of cells from the bloodstream, called the selectins. Thus, sialyl Le(a) and sialyl Le(x) expressed on cell surfaces play functional roles in medical conditions that require extravasation of cells from the bloodstream which include a wide range of inflammatory diseases and cancer metastasis. Many studies have confirmed the function of sialyl Le(a) and sialyl Le(x) in animal models of these diseases and the inhibition of binding of sialyl Le(a) and sialyl Le(x) to the selectins is a validated drug target in the pharmaceutical industry. Thus, a new class of drugs, arising from the field of glycobiology, is based on the rational design of small molecule drugs that mimic the structures sialyl Le(a) and sialyl Le(x) and can potently inhibit their functional binding to the selectins.

Animals↗

PubMed2005

Adults with dyslexia demonstrate space-based and object-based covert attention deficits: shifting attention to the periphery and shifting attention between objects in the left visual field.

Performance on a covert visual attention task is compared between a group of adults with developmental dyslexia (specifically phonological difficulties) and a group of age and IQ matched controls. The group with dyslexia were generally slower to detect validly-cued targets. Costs of shifting attention toward the periphery when the target was invalidly cued were significantly higher for the group with dyslexia, while costs associated with shifts toward the fovea tended to be lower. Higher costs were also shown by the group with dyslexia for up-down shifts of attention in the periphery. A visual field processing difference was found, in that the group with dyslexia showed higher costs associated with shifting attention between objects in they LVF. These findings indicate that these adults with dyslexia have difficulty in both the space-based and the object-based components of covert visual attention, and more specifically to stimuli located in the periphery.

Adult↗

PubMed2006

Pharmacogenomics of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors.

The EGFR is a validated anticancer target whose successful exploitation has added novel agents to our current treatment protocols. Subsets of patients have shown to benefit the most from these therapies, and though these differential responses have yet to be completely defined, they are mostly of genetic nature. Egfr amplifications have shown to increase sensitivity to both small molecule inhibitors and specific monoclonal antibodies targeting the EGFR. A somatic/germline egfr intron 1 CA repeat sequence polymorphism has shown to have an important role in the control of EGFR protein expression, and has been linked to an increased risk of familial breast cancer, a worse outcome in patients with colorectal cancer, and anti-EGFR treatment efficacy in preclinical models. Egfr activating mutations have been recently described in lung cancer linking a cluster of genotypes with sensitivity to EGFR tyrosine kinase pharmacological inhibition. Despite the initial excitement that this discovery elicited, follow-up reports have not unequivocally confirmed this finding, and these drugs have been solidly efficacious both in individual patients and in diseases generally lacking egfr mutations such as pancreas cancer. We are witnessing exciting developments in the field of the pharmacogenomics of cancer, and this has particularly evolved in the area pertaining EGFR tyrosine kinase inhibitors. This review will discuss the background and currently available preclinical and clinical data.

Antineoplastic Agents↗

PubMed2006

Biophysical characterization of an indolinone inhibitor in the ATP-binding site of DNA gyrase.

Fighting bacterial resistance is a challenging task in the field of medicinal chemistry. DNA gyrase represents a validated antibacterial target and has drawn much interest in recent years. By a structure-based approach we have previously discovered compound 1, an indolinone derivative, possessing inhibitory activity against DNA gyrase. In the present paper, a detailed biophysical characterization of this inhibitor is described. Using mass spectrometry, NMR spectroscopy, and fluorescence experiments we have demonstrated that compound 1 binds reversibly to the ATP-binding site of the 24 kDa N-terminal fragment of DNA gyrase B from Escherichia coli (GyrB24) with low micromolar affinity. Based on these data, a plausible molecular model of compound 1 in the active site of GyrB24 was constructed. The predicted binding mode explains the competitive inhibitory mechanism with respect to ATP and forms a useful basis for further development of potent DNA gyrase inhibitors.

Adenosine Triphosphate↗

PubMed2006

Memantine, an uncompetitive low affinity NMDA open-channel antagonist improves clinical rating scores in a multiple infarct embolic stroke model in rabbits.

The blockade of NMDA receptors has been pursued as a strategy to reduce the consequences of acute ischemic stroke (AIS) and NMDA receptors remain a valid therapeutic target to treat AIS. Because the pharmacological and toxicity profile of memantine in Alzheimer's disease patients appears to be good, we determined whether memantine would be effective at improving behavioral performance following embolic strokes in rabbits. For these studies, we used a rabbit multiple infarct ischemia model with a well-defined behavioral endpoint. In this study, memantine dissolved in PBS was given intravenously either as a bolus injection (over 1 min) or infused over 60 min. The P(50) of the control groups measured 24 h after embolization were 1.12 +/- 0.18 mg and 1.08 +/- 0.23 mg for the bolus injected and infused groups, respectively. Bolus injections of memantine at 1 mg/kg and 10 mg/kg were not effective at altering the P(50) value and memantine at a dose of 25 mg/kg was lethal. However, slowly infused memantine (25 mg/kg) significantly increased the P(50) value to 2.31 +/- 0.48 mg and 3.13 +/- 1.13 mg when given 5 and 60 min following embolization, respectively. Memantine administered 180 min following embolization also increased the P(50) value to 2.69 +/- 2.21 mg, but the response was variable. These results suggest that uncompetitive NMDA antagonists, more specifically open channel blockers, which may be alternatives to high affinity NMDA antagonists, may have substantial therapeutic benefit for the treatment of AIS and memantine or new dual activity analogs of memantine should be further pursued as a useful therapy to treat the behavioral deficits associated with multiple-infarct ischemia.

Animals↗

PubMed2005

Endothelins in breast tumour cell invasion.

Endothelins are a family of small, structurally related, vasoactive peptides that have a great number of physiological roles in many tissues. The 'endothelin axis' consists of three 21 amino acid peptides (ET-1, ET-2 and ET-3), two G-protein-coupled receptors (ET-RA and ET-RB), and two activating peptidases or endothelin-converting enzymes (ECE-1 and ECE-2). There is increased expression of the endothelin axis in invasive breast cancer compared to the normal breast or non-invasive neoplastic tissue. Endothelin expression is associated with invading regions of tumours in patient biopsies and is more common in tumours with high histological grade and lymphovascular invasion, and there is increased systemic endothelin in patients with lymph node metastases compared to those without lymph node involvement. Stimulation of breast tumour cell lines with endothelins leads to an invasive phenotype in vitro. Over-expression of the endothelins and their receptors is insufficient to induce an invasive phenotype in benign cells, yet expression by tumour cells leads to markedly increased invasive ability indicating that endothelins act in concert with other factors--both autocrine and paracrine--including cytokines, matrix metalloproteinases and the activation of tumour-associated macrophages. The association between endothelins, poor prognosis and invasion may mean that the endothelin axis is a valid therapeutic target for the treatment of invasive breast cancer. This review summarises our current knowledge of endothelins in breast cancer invasion and discusses the potential further directions of such research as well as the possibility of anti-endothelin-based therapy of breast cancer.

Breast Neoplasms↗

PubMed2004

Covert orienting within peripersonal and extrapersonal space: young adults.

Covert orienting within peripersonal (near) and extrapersonal (far) space was investigated in a large sample of young adults. The participants made speeded responses to targets in a simple, go/no-go detection task. Stimuli, equated for eccentricity and size, were presented at two distinct distances from the observer, representing peripersonal space and extrapersonal space. Within each distance condition cues and targets were presented at the four corners of an imaginary square allowing assessment of the influence of attention upon targets presented in the upper and lower as well as left and right visual fields. In the neutral condition lower field targets had a small advantage over upper field targets. This effect was also observed under cued conditions. When presented in peripersonal space, near targets benefited more from valid cuing than did targets in the other conditions. This pattern is discussed in terms of Previc's [Behav. Brain Sci. 13 (1990) 519] model of visual field specialization.

Adolescent↗

PubMed2006

Oncostatin M induces cell detachment and enhances the metastatic capacity of T-47D human breast carcinoma cells.

Oncostatin M (OSM), an IL-6 family cytokine, has previously been shown to increase migration of several breast cancer cell lines in vitro. Our studies report additional effects of OSM treatment on the human breast carcinoma cell line T-47D. OSM treatment alters T-47D cell morphology from a normal epithelial phenotype to a mesenchymal-like phenotype that is associated with cell detachment from substratum. These effects are also seen with H3922 human breast cancer cells. OSM treatment of T-47D cells for 5-8 days leads to a three-fold increase in cell detachment. OSM-induced detachment of T-47D cells is blocked by the protein kinase inhibitors UO126 and bisindolylmaleimide, indicating a role for MAP kinases and protein kinase C in OSM signaling events that regulate cell detachment. T-47D cells induced to detach by OSM have a reduced capacity to re-adhere to laminin in comparison to other extracellular matrix components. Detached multi-cell aggregates of T-47D cells are viable, whereas detached single cells appear apoptotic. In addition, OSM treatment induces the secretion of the lysosomal proteases cathepsins D and L from T-47D cells, which have been implicated in invasion and metastasis. Importantly, OSM-treated T-47D cells show a 250% increase in invasive capacity as measured by the Matrigel invasion chamber assay. Collectively, these data demonstrate that OSM induces a motile/invasive phenotype in T-47D cells in vitro, and suggest that OSM may enhance metastasis in vivo. Our results suggest that OSM itself may be a valid therapeutic target.

Antineoplastic Agents↗

PubMed2005

Novel actions of IGFBP-3 on intracellular signaling pathways of insulin-secreting cells.

Understanding mechanisms underlying apoptotic destruction of insulin-secreting cells is critical to validate therapeutic targets for type 1 diabetes mellitus. We recently reported insulin-like growth factor binding protein-3 (IGFBP-3) as a novel mediator of apoptosis in insulin-secreting cells. In light of emerging IGF-independent roles for IGFBP-3, we investigated the mechanisms underlying actions of the novel, recombinant human mutant G(56)G(80)G(81)-IGFBP-3, which lacks intrinsic IGF binding affinity. Using the rat insulinoma RINm5F cell line, we report the first studies in insulin-secreting cells that IGFBP-3 selectively suppresses multiple, key intracellular phosphorelays. By immunoblot, we demonstrate that G(56)G(80)G(81)-IGFBP-3 suppresses phosphorylation of c-raf-MEK-ERK pathway and p38 kinase in time-dependent and dose-dependent manners. SAPK/JNK signaling was unaffected. These data delineate several novel intracellular sites of action for IGFBP-3 in insulin-secreting cells.

Animals↗