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At least 73 records · Page 4Linked to original sources
PubMed2026

MT-RNR1 genotype testing for preventing aminoglycoside-mediated ototoxicity: A guideline developed by the UK Centre of Excellence in Regulatory Science and Innovation in Pharmacogenomics (CERSI-PGx).

Aminoglycosides are broad-spectrum antibiotics used in the management of severe infections. Aminoglycosides are associated with nephrotoxicity and ototoxicity. Although dosing strategies such as once-daily administration and therapeutic drug monitoring have reduced the incidence of nephrotoxicity, ototoxicity remains unpredictable and may occur at therapeutic concentrations. A strong association between specific mitochondrial DNA variants in MT-RNR1 (m.1555A > G, m.1494C > T and m.1095 T > C) and aminoglycoside-induced hearing loss exists. These variants (frequency ~1 in 330 individuals across populations) predispose to irreversible, sensorineural hearing loss following aminoglycoside exposure, sometimes after a single dose. Avoidance of aminoglycosides is recommended at any detectable variant level. In England, laboratory-based MT-RNR1 testing is nationally commissioned, whereas point-of-care testing in time-critical settings like neonatal sepsis is delivered in some centres. Approximately 20% of aminoglycoside use is predictable providing opportunities for pre-emptive pharmacogenetic testing. Where MT-RNR1 testing results are unavailable and clinical urgency is high, aminoglycoside treatment should not be delayed. Early health economic evidence suggests that point-of-care testing in neonates may be cost-saving by preventing lifelong hearing loss. Regulatory and Health Technology Assessment bodies support targeted implementation of testing alongside further evidence generation. Overall, integration of MT-RNR1 pharmacogenetic testing offers a feasible and proportionate strategy to reduce harm while preserving access to life-saving antibiotic therapy. This guideline is grounded in the latest evidence in this field but cannot account for all individual factors relevant to patient care. Therefore, prescribers must conduct a thorough assessment of each patient's risk-benefit profile, ensuring that therapy is optimized to maximize benefits while minimizing potential harms.

Humans↗
PubMed2005

Multicapillary electrophoresis of unlabeled DNA fragments with high-sensitive laser-induced fluorescence detection by counter-current migration of intercalation dye.

Analysis of PCR fragments for applications, such as screening of nucleotide polymorphisms, detection of somatic mutations, or quantification of reverse-transcription PCR products, becomes central in clinical research as well as preventive testing, diagnostic screening, and pharmacogenomic genotyping. A variety of CE techniques, utilizing great potential of multicapillary-array sequencers, is now commonly applied in prevention, diagnosis, and treatment of a wide range of genetic diseases (cancer, cardiovascular, and neurodegenerative diseases, etc.). Costs of fluorescently labeled primers is often a major factor in large-scale projects requiring mutation analysis in hundreds or thousands of samples. In the present paper we introduce a simple approach of detecting unlabeled DNA fragments through intercalation without a need for adding intercalator to the separation polymer matrix. The dye is only added to the anode reservoir, and mixing with the separated DNA fragments takes place upon its migration opposite to the direction of the CE separation. Using two common intercalating dyes (ethidium bromide and SYBR Green II) we present this method as a tool for routine PCR detection and quantification.

Coloring Agents↗
PubMed2000

The genomic revolution: is the real risk under-investment rather than bankrupt health care systems?

There is an element of 'scientific determinism' in much of the discussion of the genomic revolution. Recognition of the potential for improving health is more than matched by worries about both the ability of health care systems to cope and the potential for genetic testing to lead to discrimination. There are five main uses for genomics in the development of human diagnostics and therapeutics: pharmacogenomics, gene therapy, pharmacogenetics, genetic testing of symptomatic or at risk people, and population genotyping. Although there are potential health gains, several concerns exist: health gain may increase funding pressures on health care systems; providing cost-effectiveness thresholds may mean drugs for some patient groups may not be developed; random population genetic testing will meet economic and ethical obstacles; and private sector patenting risks a loss of data and access to data, which will inhibit the development of potentially cost-effective tests and therapies.

DNA Fingerprinting↗
PubMed2006

Pharmacogenomics: challenges and opportunities.

The outcome of drug therapy is often unpredictable, ranging from beneficial effects to lack of efficacy to serious adverse effects. Variations in single genes are 1 well-recognized cause of such unpredictability, defining the field of pharmacogenetics (see Glossary). Such variations may involve genes controlling drug metabolism, drug transport, disease susceptibility, or drug targets. The sequencing of the human genome and the cataloguing of variants across human genomes are the enabling resources for the nascent field of pharmacogenomics (see Glossary), which tests the idea that genomic variability underlies variability in drug responses. However, there are many challenges that must be overcome to apply rapidly accumulating genomic information to understand variable drug responses, including defining candidate genes and pathways; relating disease genes to drug response genes; precisely defining drug response phenotypes; and addressing analytic, ethical, and technological issues involved in generation and management of large drug response data sets. Overcoming these challenges holds the promise of improving new drug development and ultimately individualizing the selection of appropriate drugs and dosages for individual patients.

Clinical Medicine↗
PubMed2006

Pharmacogenomic evaluation of the antidepressant citalopram in the mouse tail suspension test.

The identification of genetic variants regulating antidepressant response in human patients would allow for more individualized, rational, and successful drug treatments. We have previously identified the BALB/cJ inbred mouse strain as highly responsive to the selective serotonin reuptake inhibitor (SSRI) citalopram in the tail suspension test (TST), a widely used and well-established screening paradigm for detecting compounds with antidepressant activity. In contrast, A/J mice did not show a significant response to citalopram in this test despite exposure to equivalent plasma levels of the drug. To identify genetic determinants of this differential response, 506 F2 mice from an intercross between BALB/cJ and A/J mice were phenotyped. Composite interval mapping of 92 mice from the phenotypic extremes revealed three loci on chromosomes 7, 12, and 19 affecting citalopram response in the TST. The quantitative trait locus (QTL) at the telomeric end of chromosome 19 showed the greatest level of significance. Three candidate genes residing in this locus include those for vesicular monoamine transporter 2 (VMAT2, slc18a2), alpha 2A adrenergic receptor (adra2a), and beta 1 adrenergic receptor (adrb1). The protein coding regions of these three genes in BALB/cJ and A/J mice were sequenced and two polymorphisms were found in VMAT2 (Leu117Pro and Ser505Pro), while the transcribed regions of adra2a and adrb1 were of identical sequence between strains. Follow-up studies are needed to determine if the VMAT2 polymorphisms are functional and if they could explain the chromosome 19 QTL. The present quantitative trait study suggests possible candidate genes for human pharmacogenetic studies of therapeutic responses to SSRIs such as citalopram.

Animals↗
PubMed2000

Automated mass spectrometry: a revolutionary technology for clinical diagnostics.

For various diagnostic analyses and the studies of functional genomics, the use of an accurate and cost-effective analytic platform to analyze large numbers of samples is essential. An automated platform called MassArray (Sequenom, Inc, San Diego, CA), designed for high-throughput diagnostic analyses, has recently been validated. The platform combines miniaturized, two-dimensional chip arrays with proven high-fidelity enzymatic procedures and matrix-assisted laser-desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. Nanoliter dispensing of samples in high-density formats of 384 or greater results in improved throughput and reduced costs. Automation prevails from the initial assay design through sample processing and data analysis, for the most part eliminating the labor component of assay development and implementation. The MassArray platform is being used in the following areas: (1) molecular diagnosis of genetic disease and infectious agents, (2) pharmacogenomics, (3) paternity and/or identity testing, and (4) agriculture (e.g., marker-assisted breeding). MALDI-TOF mass spectrometry can also be used for analyzing proteins; therefore, genotype/phenotype testing can be performed on a single platform.

Adolescent↗
PubMed2026

Advanced and underlying therapeutic strategies in transformed small cell lung cancer.

Transformed small-cell lung cancer (T-SCLC) is a clinically important form of histologic transformation and a mechanism of acquired resistance in non-small-cell lung cancer (NSCLC). It is associated with poor prognosis, with a median overall survival of only about 9-13 months. This review summarizes recent advances in the mechanisms, diagnosis, monitoring, and treatment of T-SCLC. Repeat biopsy remains the gold standard for confirming histologic transformation, whereas molecular profiling and liquid biopsy may facilitate early detection and longitudinal disease monitoring. Platinum-etoposide remains the most commonly used clinical standard after transformation, but its benefit is typically transient and durable disease control remains uncommon. Continuation of EGFR tyrosine kinase inhibitors combined with chemotherapy may prolong progression-free survival in selected patients but has not consistently improved overall survival. Anti-angiogenic therapy, particularly anlotinib, and chemo-immunotherapy have shown encouraging activity in selected patients, while emerging strategies targeting DLL3, MYC, SOX2, and epigenetic regulators may broaden the therapeutic landscape. Prospective studies integrating repeat tissue sampling, comprehensive genomic profiling, biomarker-guided patient stratification, pharmacogenomics, functional drug-sensitivity testing where feasible, and integrated multi-omics approaches are needed to advance molecularly guided and individualized treatment for T-SCLC.

advanced therapy↗
PubMed1999

[Expanding scope and impact of services provided by clinical laboratory practice through molecular diagnostics].

Recent progress in molecular biology and biotechnology has facilitated assays for DNA or RNA sequences to diagnose infectious, neoplastic and genetic diseases. Many of the assays have been used clinically, and are now an essential part of patient care under advanced medicine. A clinical laboratory needs to ensure services for clinical needs such as provision of tests with required turnaround time and high quality as well as consulting practice for individual requests. For quality assurance of assays, it is particularly important to monitor clinical validation of the results by correlating them with the patient's status to prove clinically relevant. Staff need to be trained to become familiar with both molecular pathogenesis and technology so that they can provide informative tests with high quality. Along with advances in pharmacogenomics, the findings of the human genome project have raised the prospect of developing tests for individualized medicine based on genetic information such as those predicting individual susceptibility to diseases to facilitate prevention and indicate responsiveness to drugs for choice of treatment. Molecular diagnostic tests will contribute to an efficient process of decision making on patient care and result in cost savings through earlier and more accurate diagnosis. The scope and impact of services provided by clinical laboratory practice through molecular diagnostics will continue to expand in its integration into clinical practice.

Biotechnology↗
PubMed2006

Reproducibility of gene expression signature-based predictions in replicate experiments.

PURPOSE: The goals of this analysis were to (a) determine concordance of gene expression results from replicate experiments, (b) examine prediction agreement of multigene predictors on replicate data, and (c) assess the robustness of prediction results in the face of noise. PATIENTS AND METHODS: Affymetrix U133A gene chips were used for gene expression profiling of 97 fine-needle aspiration biopsies from breast cancer. Thirty-five cases were profiled in replicates: 17 within the same laboratory, 11 in two different laboratories, and 15 to assess manual and robotic labeling. We used data from 62 cases to develop 111 distinct pharmacogenomic predictors of response to therapy. These were tested on cases profiled in duplicates to determine prediction agreement and accuracy. To evaluate the robustness of the pharmacogenomic predictors, we also introduced random noise into the informative genes in one half of the replicates. RESULTS: The average concordance correlation coefficient was 0.978 (range, 0.96-0.99) for intralaboratory replicates, 0.962 (range, 0.94-0.98) for between-laboratory replicates, and 0.971 (range, 0.93-0.99) for manual versus robotic labeling. The mean % prediction agreement on replicate data was 97% (95% CI, 0.96-0.98; SD, 0.006), 92% (95% CI, 0.90-0.93; SD, 0.009), and 94% (95% CI, 0.92-0.95; SD, 0.008) for support vector machines, diagonal linear discriminant analysis, and k-nearest neighbor prediction methods, respectively. Mean accuracy in the test set was 77% (95% CI, 0.74-0.79; SD, 0.014), 66% (95% CI, 0.63-0.73; SD, 0.015), and 64% (95% CI, 0.60-0.67; SD, 0.016), respectively. CONCLUSION: Gene expression results obtained with Affymetrix U133A chips are highly reproducible within and across two high-volume laboratories. Pharmacogenomic predictions yielded >90% agreement in replicate data.

Biopsy, Needle↗
PubMed2005

Asthma pharmacogenomics.

It is expected that future treatments will be preceded by genetic tests to prescribe the most effect asthma medication while lowering the risk of adverse side effects. However, it will not be necessary to describe all the genetic determinants affecting drug response to apply pharmacogenomics to asthma therapy. Whether pharmacogenomics becomes common practice may not depend on the availability of tests, but on factors such as affordability, ease of application, and ease of interpreting the results.

Asthma↗
PubMed2000

The future of antiplatelet therapy: optimizing management in patients with acute coronary syndrome.

In the past few years, the antiplatelet armamentarium has been markedly enriched. With the intravenous platelet glycoprotein IIb/IIIa inhibitors and the new thienopyridine clopidogrel, the options for acute and chronic antiplatelet therapy have expanded. Future therapies will optimize the application of these agents. For example, in percutaneous coronary intervention, it appears that patients may benefit by loading with an adenosine diphosphate receptor blocker before the procedure and may well benefit indefinitely from continuation of this therapy. Patients with aspirin resistance or the P1A2 single nucleotide polymorphism that is common in the population may derive particular benefit from dual antiplatelet therapy. Similarly, patients who present with unstable angina while receiving chronic aspirin therapy and those with involvement of more than one atherosclerotic bed deserve consideration for dual antiplatelet therapy. New applications will be facilitated by point-of-care testing for platelet biology and genotyping, pharmacogenomics, and protection from inflammation in patients with serologic evidence of elevated markers, such as C-reactive protein. Indeed, even with the recent explosion of relevant data and enriched therapeutic choices, we are just beginning to understand the optimal application of these therapies to the appropriate clinical indications and patient groups.

Angina, Unstable↗
PubMed2003

Impact of molecular medicine on pathophysiology, medical practice, and medical education.

This article brings an overview of the influence of molecular medicine on pathophysiology, medical practice, and medical education. Various aspects of the growing impact of molecular medicine on clinical practice are discussed: diagnostic and predictive testing, gene and targeted therapy, and pharmacogenomics. Insufficient data from appropriate clinical studies and evidence-based medicine presently limit the applications of molecular medicine in clinical practice. Incorporation of conceptual and clinical aspects of molecular medicine in undergraduate and postgraduate curricula and a continuing education of medical professionals is an urgent imperative for the demands of medical care quality to be met in near future. The emphasis should be put on bedside-orientated molecular medicine. The prerequisite is translational research aimed to translate basic information into the improvement of healthcare of individual patients and the population as a whole.

Education, Medical↗
PubMed2000

The DNA Rx. Advances in genetics give physicians ability to tailor drugs to patients' unique makeup.

Thanks to the recently completed first draft of the human genome map, the potential for advances in medical science seems endless. That's especially true in pharmacogenomics, with futuristic-sounding drugs and screening tests already available. William Evans (left), chairman of pharmaceutical science at St. Jude Children's Research Hospital, Memphis, Tenn., developed one of only a few pharmacogenomic applications available so far.

Cost Savings↗
PubMed2005

Pharmacodiagnostic testing in breast cancer: focus on HER2 and trastuzumab therapy.

Pharmacogenomics is defined as research into inherited genetic variations that determine an individual's response to therapeutic agents. In oncology, pharmacogenomics based on somatic molecular alterations inherited by subsequent cancer cell generations forms the basis of molecular targeting of novel therapeutic agents. What has emerged from clinical experience with such agents is the need for appropriate pharmacodiagnostic approaches to ensure the drugs are correctly targeted. Given the broad range of pharmacogenomic agents currently under evaluation for cancer therapy, it appears that a rapid extension of pharmacodiagnostic profiling will be required in the next 5-10 years, if not sooner. If this is to be successfully achieved, lessons learned in the past, particularly during the development of HER2 (ERBB2) testing for directing trastuzumab therapy in breast cancer, may provide a valuable framework for the development of future pharmacodiagnostic assays system. This article reviews the biological and clinical rationale for targeting breast cancer with trastuzumab and the steps taken to validate and improve pharmacodiagnostic procedures for testing tumor HER2 protein expression and HER2 gene amplification. Attention is given to quality assurance and reproducibility of testing approaches and the optimal selection of patients for response to trastuzumab. This approach serves as a paradigm for the future development of pharmacodiagnostic tests in oncology.

Antibodies, Monoclonal↗
PubMed2006

Gene Express Inc.

Gene Express, Inc. is a technology-licensing company and provider of Standardized Reverse Transcription Polymerase Chain Reaction (StaRT-PCR) services. Designed by and for clinical researchers involved in pharmaceutical, biomarker and molecular diagnostic product development, StaRT-PCR is a unique quantitative and standardized multigene expression measurement platform. StaRT-PCR meets all of the performance characteristics defined by the US FDA as required to support regulatory submissions [101,102] , and by the Clinical Laboratory Improvement Act of 1988 (CLIA) as necessary to support diagnostic testing [1] . A standardized mixture of internal standards (SMIS), manufactured in bulk, provides integrated quality control wherein each native template target gene is measured relative to a competitive template internal standard. Bulk production enables the compilation of a comprehensive standardized database from across multiple experiments, across collaborating laboratories and across the entire clinical development lifecycle of a given compound or diagnostic product. For the first time, all these data are able to be directly compared. Access to such a database can dramatically shorten the time from investigational new drug (IND) to new drug application (NDA), or save time and money by hastening a substantiated 'no-go' decision. High-throughput StaRT-PCR is conducted at the company's automated Standardized Expression Measurement (SEM) Center. Currently optimized for detection on a microcapillary electrophoretic platform, StaRT-PCR products also may be analyzed on microarray, high-performance liquid chromatography (HPLC), or matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) platforms. SEM Center services deliver standardized genomic data--data that will accelerate the application of pharmacogenomic technology to new drug and diagnostic test development and facilitate personalized medicine.

Gene Expression Profiling↗
PubMed2004

Predictive genetic test decisions for Huntington's disease: context, appraisal and new moral imperatives.

Predictive testing is one of the new genetic technologies which, in conjunction with developing fields such as pharmacogenomics, promises many benefits for preventive and population health. Understanding how individuals appraise and make genetic test decisions is increasingly relevant as the technology expands. "Lay" understandings of genetic risk and test decision-making, located within holistic life frameworks including family or kin relationships, may vary considerably from clinical representations of these phenomena. The predictive test for Huntington's disease (HD), whilst specific to a single-gene, serious, mature-onset but currently untreatable disorder, is regarded as a model in this context. This paper reports upon a qualitative Australian study which investigated predictive test decision-making by individuals at risk for HD, the contexts of their decisions and the appraisals which underpinned them. In-depth interviews were conducted in Australia with 16 individuals at 50% risk for HD, with variation across testing decisions, gender, age and selected characteristics. Findings suggested predictive testing was regarded as a significant life decision with important implications for self and others, while the right "not to know" genetic status was staunchly and unanimously defended. Multiple contexts of reference were identified within which test decisions were located, including intra- and inter-personal frameworks, family history and experience of HD, and temporality. Participants used two main criteria in appraising test options: perceived value of, or need for the test information, for self and/or significant others, and degree to which such information could be tolerated and managed, short and long-term, by self and/or others. Selected moral and ethical considerations involved in decision-making are examined, as well as the clinical and socio-political contexts in which predictive testing is located. The paper argues that psychosocial vulnerabilities generated by the availability of testing technologies and exacerbated by policy imperatives towards individual responsibility and self-governance should be addressed at broader societal levels.

Adult↗