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Open Access Publications from the University of California

Scholarly Works (54 results)

  • Article
  • Peer Reviewed
UC San Francisco Previously Published Works (2020)
    Cover page: Screening the general population for SARS CoV-2 virus and COVID-19 antibodies: a counter-argument
    • Article
    • Peer Reviewed
    UC San Francisco Previously Published Works (2011)
    Abstract Enzymes are critically important in the transportation, metabolism, and clearance of most therapeutic drugs used in clinical practice today. Many of these enzymes have significant genetic polymorphisms that affect the enzyme's rate kinetics. Regarding drug metabolism, specific polymorphisms to the cytochrome (CYP) P450 enzyme family are linked to phenotypes that describe reaction rates as "ultra", "intermediate", and "poor," as referenced to "extensive" metabolizers that are assigned to wildtype individuals. Activity scores is an alternate designation that provides more genotype-to-phenotype resolution. Understanding the relative change in enzyme activities or rate of clearance of specific drugs relative to an individual's genotypes is an important component in the interpretation of pharmacogenomic data for personalized medicine. Currently, the most relevant drug metabolizing enzymes are CYP 2D6, CYP 2C9, CYP 2C19, thiopurine methyltransferase (TPMT) and UDP-glucuronosyltransferase (UGT). Each of these enzymes is reactive to a host of different drug substrates. Pharmacogenomic tests that are in routine clinical practice include CYP 2C19 for clopidogrel, TPMT for thiopurine drugs, and UDP-1A1 for irinotecan. Other tests where there is considerable data but have not been widely implemented includes CYP 2C9 for warfarin, CYP 2D6 for tamoxifen and codeine, and CYP 2C19 for the proton pump inhibitors.
      Cover page: Drug metabolizing enzymes activities versus genetic variances for drug of clinical pharmacogenomic relevance
      • Article
      • Peer Reviewed
      UC San Francisco Previously Published Works (2012)
      B-type natriuretic peptide (BNP) and NT-proBNP are widely used plasma biomarkers for the diagnosis of acute decompensated heart failure and prognosis for future cardiac disease. The clinical performance of these tests for management of chronic heart failure is somewhat limited by the markers' high biological variation. Biomarkers such as galectin-3 and soluble ST2 that reflect ongoing remodeling via cardiac fibrosis of the heart may provide complementary information to the natriuretic peptides in the management of chronic heart failure with regards to risk stratification for future adverse cardiac events (death, myocardial infarction, and need for heart transplantation). However, implementation of these biomarkers into routine clinical practice requires documentation that these tests will enable therapeutic decisions that can be made to improve clinical outcomes, and the availability of commercial assays. This report will discuss the need for novel heart failure biomarkers, ideal characteristics of assays, and review and compare the clinical performance of assays for galectin-3 and sST2 for chronic heart failure disease management.
        Cover page: Biomarkers Beyond the Natriuretic Peptides for Chronic Heart Failure: Galectin-3 and Soluble ST2.
        • Article
        • Peer Reviewed
        UC San Francisco Previously Published Works (2013)

        Background

        We examined forensic serum toxicology and pharmacogenomics data from a woman on codeine shortly before she caused a motor vehicle accident.

        Methods

        A woman driving erratically collided with a parked car of a highway seriously injuring 2 men working to repair the parked vehicle. The woman tested positive for codeine, acetaminophen and barbital. She had been taking these medications for 20 years due to migraine headache. Serum toxicology and genotype analysis for cytochrome P450, UDP glucuronosyltransferase, and other metabolizing enzymes were measured.

        Results

        The woman was tried and convicted of driving under the influence resulting in bodily harm and was sentenced to 6 years. Toxicology results on peripheral blood showed a total and free codeine of 840 and 348 μg/L, respectively, and total morphine of 20 μg/L (17, 3, and 0 μg/L for morphine-3-glucuronide, morphine-6-glucuronide, and free morphine, respectively). She was heterozygous for CYP 2D6 *2/*4 (extensive/poor metabolism) and heterozygous for UGT 2B7 *1/*2 (extensive/ultra-rapid metabolism). The woman was also taking fluoxetine and bupropion which are strong inhibitors of CYP 2D6.

        Conclusions

        Based on her genotype and phenotype and reports by the arresting officer, we suggest that the subject in question was not intoxicated by opiates at the time of her motor vehicle accident and may have been falsely incarcerated.
          Cover page: Lack of impairment due to confirmed codeine use prior to a motor vehicle accident: role of pharmacogenomics.
          • Article
          • Peer Reviewed
          UC San Francisco Previously Published Works (2019)
            Cover page: Analytical and clinical concordance of free light chain assay
            • Thesis
            • Peer Reviewed
            UC San Francisco Electronic Theses and Dissertations (2013)

            Tamoxifen is a selective estrogen receptor modulator (SERM) that is used for the treatment of estrogen receptor positive (ER+) breast cancer, most commonly as an adjuvant for the prevention of disease recurrence. Several retrospective studies suggest that functional CYP2D6 polymorphisms are associated with the clinical outcome of tamoxifen adjuvant therapy; variants that confer reduced enzymatic activity are associated with poorer outcomes. The biological basis for this association is that tamoxifen is a pro-drug and CYP2D6 metabolism is important for the formation of the potent anti-estrogenic metabolite, endoxifen. The general goal of this work was to investigate the effect of CYP2D6 polymorphisms and other variables on tamoxifen and tamoxifen metabolite exposure in order to clarify the best use of clinical tamoxfien pharmacogenetic test data.

            An LC-MS/MS assay was developed and validated for the quantitation of tamoxifen, N-desmethyltamoxifen, and endoxifen in human serum. The assay was found to be robust for the measurement of these analytes at physiologically relevant concentrations. In collaboration with the Women's Healthy Eating and Living (WHEL) study group, serum endoxifen concentrations were shown to be associated with the clinical outcome of tamoxifen adjuvant therapy, and a sub-therapeutic endoxifen risk group was defined. Extensive CYP2D6 genotypes were determined for WHEL study subjects using the Roche P450 AmpliChip, and an analysis was performed to determine the extent to which genotype cutoffs define the sub-therapeutic endoxifen risk group among Caucasian subjects. Of subjects who carried two null CYP2D6 alleles, approximately 72% fell into the sub-therapeutic endoxifen risk group, but this accounted for less than a quarter of all subjects within the risk group. Poor metabolizer phenocopies were present in all genotype groups. In addition, inter-ethnic differences in serum tamoxifen and tamoxifen metabolites were determined between Caucasian, Asian, Hispanic, and African American subjects within the WHEL cohort, with Asians and Hispanics exhibiting higher median endoxifen concentrations. Finally, an association study was performed in order to determine if variants in candidate genes (UGT2B7, ABCC2, CYP2C19) influence serum endoxifen concentrations in Caucasian subjects. Statistically significant associations were determined, but are unlikely to be clinically relevant due to small effect.

              Cover page: Tamoxifen Pharmacogenetics: CYP2D6 and Other Variables Influencing Tamoxifen and Tamoxifen Metabolite Exposure
              • Article
              • Peer Reviewed
              UC San Francisco Previously Published Works (2022)

              Objective

              Determine the COVID-19 seroconversion rate for patients with multiple myeloma receiving a COVID-19 vaccine.

              Materials and methods

              After 45 patients received their second COVID-19 vaccine dose, their serum IgG antibodies were measured: 22 with monoclonal gammopathy (MG) of unknown significance, 3 with smoldering myeloma, 2 with light chain amyloidosis, and 18 with MG (9 in remission, 6 out of remission, and 3 with free light-chain gammopathy alone). A second serum specimen was retained for 16 patients with MG. Their antibody levels were compared to those of 78 uninfected healthy vaccinated control patients.

              Results

              Three patients with MG had low antibody levels on blood collected 98, 100, and 113 days after the initial vaccine dose (2 with MG of unknown significance and 1 with hypogammaglobulemia). The other 40 patients with MG (seroconversion rate 93%) and both patients with amyloidosis produced antibodies. Relative to days after vaccination, patients with MG had lower antibody levels than control patients.

              Conclusion

              After receiving a COVID-19 vaccine, most patients with MG produce anti-SARS-CoV-2 antibodies comparable to levels in uninfected vaccinated healthy control patients.
                Cover page: Adequate Antibody Response to COVID-19 Vaccine in Patients with Monoclonal Gammopathies and Light Chain Amyloidosis
                • Article
                • Peer Reviewed
                UC San Francisco Previously Published Works (2022)

                Introduction

                Viral infections have been implicated in the initiation of the autoimmune diseases. Recent reports suggest that a proportion of patients with COVID-19 develop severe disease with multiple organ injuries. We evaluated the relationship between COVID-19 severity, prevalence and persistence of antinuclear and other systemic and organ specific autoantibodies as well as SARS-CoV-2 infection specific anti-nucleocapsid (N) IgG antibodies and protective neutralizing antibody (Nab) levels.

                Methods

                Samples from 119 COVID-19 patients categorized based on their level of care and 284 healthy subjects were tested for the presence and persistence of antinuclear and other systemic and organ specific autoantibodies as well as SARS-CoV-2 and neutralizing antibody levels.

                Results

                The data shows significantly increased levels of anti RNP-A, anti-nucleocapsid and neutralizing antibody among patients receiving ICU care compared to non-ICU care. Furthermore, subjects receiving ICU care demonstrated significantly higher nucleocapsid IgG levels among the RNP-A positive cohort compared to RNP-A negative cohort. Notably, the expression of anti RNP-A antibodies is transient that reverts to non-reactive status between 20 and 60 days post symptom onset.

                Conclusions

                COVID-19 patients in ICU care exhibit significantly higher levels of transient RNP-A autoantibodies, anti-nucleocapsid, and SARS-CoV-2 neutralizing antibodies compared to patients in non-ICU care.
                  Cover page: Transient expression of antinuclear RNP-A antibodies in patients with acute COVID-19 infection
                  • Article
                  • Peer Reviewed
                  UC San Francisco Previously Published Works (2016)
                  Statin responsiveness is an area of great research interest given the success of the drug class in the treatment of hypercholesterolemia and in primary and secondary prevention of cardiovascular disease. Interrogation of the patient's genome for gene variants will eventually guide anti-hyperlipidemic intervention. In this review, we discuss methodological approaches to discover genetic markers predictive of class-wide and drug-specific statin efficacy and safety. Notable pharmacogenetic findings are summarized from hypothesis-free genome wide and hypothesis-led candidate gene association studies. Physiogenomic models and clinical decision support systems will be required for DNA-guided statin therapy to reach practical use in medicine.
                    Cover page: Laboratory Medicine in the Clinical Decision Support for Treatment of Hypercholesterolemia Pharmacogenetics of Statins
                    • Article
                    • Peer Reviewed
                    UC San Francisco Previously Published Works (2022)

                    Background

                    The levels of circulating troponin are principally required in addition to electrocardiograms for the effective diagnosis of acute coronary syndrome. Current standard-of-care troponin assays provide a snapshot or momentary view of the levels due to the requirement of a blood draw. This modality further restricts the number of measurements given the clinical context of the patient. In this communication, we present the development and early validation of non-invasive transdermal monitoring of cardiac troponin-I to detect its elevated state.

                    Methods

                    Our device relies on infrared spectroscopic detection of troponin-I through the dermis and is tested in stepwise laboratory, benchtop, and clinical studies. Patients were recruited with suspected acute coronary syndrome.

                    Results

                    We demonstrate a significant correlation (r = 0.7774, P < 0.001, n = 52 biologically independent samples) between optically-derived data and blood-based immunoassay measurements with and an area under receiver operator characteristics of 0.895, sensitivity of 96.3%, and specificity of 60% for predicting a clinically meaningful threshold for defining elevated Troponin I.

                    Conclusion

                    This preliminary work introduces the potential of a bloodless transdermal measurement of troponin-I based on molecular spectroscopy. Further, potential pitfalls associated with infrared spectroscopic mode of inquiry are outlined including requisite steps needed for improving the precision and overall diagnostic value of the device in future studies.
                      Cover page: Development and preliminary validation of infrared spectroscopic device for transdermal assessment of elevated cardiac troponin
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