The intestinal tract has many features that make it an attractive target for therapeutic gene transfer. Gardner, a professor of. Previous work with excised inside-out patches suggests that inositol 1,4,5-trisphosphate is the activating second messenger of the voltage-insensitive T-cell Ca2+-permeable channel. Rodriguez-Paris, J., Ballay, C., Inserra, M., Stidham, K., Colen, T., Roberson, J., Gardner, P., Schrijver, I. Schrijver, I., Ramalingam, S., Sankaran, R., Swanson, S., Dunlop, C. L., Keiles, S., Moss, R. B., Oehlert, J., Gardner, P., Wassman, E. R., Kammesheidt, A. A phase II, double-blind, randomized, placebo-controlled clinical trial of tgAAVCF using maxillary sinus delivery in patients with cystic fibrosis with antrostomies. Lifetime resident of Fullerton, passed away on 11/18/21 in her home. In patch-clamp experiments, ADO (1 mM) induced an outwardly-rectified whole-cell Cl- current (baseline, 2.5 +/- 0.8 pA pF-1, + ADO, 78.4 +/- 23.8 pA pF-1; P < 0.02), which was largely inhibited in cells internally perfused with a selective inhibitory peptide of the multifunctional Ca2+/calmodulin-dependent protein kinase, CaMK [273-302] (20 microM), as compared to a control peptide, CaMK [284-302]. A., McDonald, T. V., Gardner, P. STIMULATION OF CHLORIDE SECRETION BY P-1 PURINOCEPTOR AGONISTS IN CYSTIC-FIBROSIS PHENOTYPE AIRWAY EPITHELIAL-CELL LINE CFPEO-. Support Lucile Packard Children's Hospital Stanford and child and maternal health. This action was blocked by substituting Cs+ for K+ in the recording pipette and by the substance P antagonist. These data provide evidence for a novel in vitro mechanism of the antiproliferative action of this immunosuppressant. Various potentially confounding factors are discussed. Wagner, J. By means of path clamp recording and associated cell and molecular biological techniques, we have studied:1. The predominant effect of Bay K 8644 on these channels was to increase the probability of channel reopening, apparently without a major effect on mean channel open-time. While the function of nitric oxide as a direct cytotoxic effector molecule is well established, its function as a transducer molecule in immune cells is not. These results suggest that PGE1, acting through PKA, activates a Cl- current in Jurkat T cells. She is a Professor at Stanford University Medical Center. The mechanism of TCR-stimulated Ca2+ influx was studied in the Jurkat human T cell line using Ca2+ indicator dyes and whole-cell patch clamp. Phase I/II AAV-CFTR gene therapy trials.3. CF is an early target for in vivo gene therapy, since it is a monogenic autosomal recessive disease in which restoration of normal cAMP-regulated Cl- conductance can be achieved by complementation with a normal gene. She has served on the board of directors of several public and private companies, including Revance Therapeutics, Corium International, Inc. and CohBar, Inc. Dr. Gardner has also served as an advisor to Change Health Care, Inc.. View details for Web of Science ID A1991FH80200006. In this study, we tested the feasibility of utilizing DBHQ to improve Cl- secretion via the Ca(2+)-dependent pathway, in the cystic fibrosis (CF)-derived pancreatic epithelial cell line CFPAC-1. This pathway is defective in cystic fibrosis-derived human cloned T cells. View details for Web of Science ID A1996VQ33800028, View details for PubMedCentralID PMC2200601. She graduated from Harvard University / School Of Medicine in 1976. She and Rupert Brooke had, on her side at least, a passionate relationship. We show here that Ca2+ ionophore activates Cl- currents in cell-attached and whole-cell patch-clamp recordings of Jurkat T lymphocytes, but this activation is not direct. However, chronic respiratory inflammation and infection remain unexplained phenomena in disease pathogenesis. NFAT mediated gene transcription; modulations by kinases and phosphatases. The Ca-binding proteins found in T-cells include members of both the EF-hand and annexin families, as well as other types of Ca-binding proteins. The wider application of patch-clamp and microfluorimetry techniques to lymphocytes has helped to clarify some issues and raised many more. The identity of the amplified products was confirmed by hybridization to CFTR-specific probes and DNA sequencing. The transcription factor NF-AT responds to Ca2+-calcineurin signals by translocating to the nucleus, where it participates in the activation of early immune response genes. A77 1726, the active metabolite of leflunomide, inhibits lymphocyte proliferation in vitro. The voltage-activated K+ channel is postulated to have a role in mitogenesis, based on studies that demonstrate an increase in K+ channel amplitude in the 24-48 hr following mitogen stimulation, and on studies that demonstrate that K+ channel blockers inhibit mitogenesis in a dose-dependent manner with the same potency sequence for ion channel block. Stanford professor Phyllis Gardner, MD, has been an outspoken skeptic of Elizabeth Holmes, and her now defunct company Theranos for years. Dr. Phyllis I. Gardner is an internist in Stanford, California. Chao, A. C., deSauvage, F. J., Dong, Y. J., Wagner, J. Cystic fibrosis (CF), a lethal disease common to Caucasians, is characterized by a defect in the CF transmembrane conductance regulator and the resulting defective cAMP-regulated Cl- secretion by epithelial cells. Michael Kovac // Getty Images Stanford professor Phyllis Gardner, MD, has been an outspoken skeptic of Elizabeth Holmes, and her now defunct company Theranos for years. This cost-effective array is based on a diversely applied platform technology and is suitable for both carrier screening and disease detection in Ashkenazi and Sephardic Jewish populations. Administration of an adenoviral vector encoding a secreted alkaline phosphatase to the lumen resulted in expression and secretion of this gene product into the circulation. View details for Web of Science ID A1994NM61500008. However, newer therapies directed at the specific underlying defects have emerged. A total of 183 mutations were identified, including 14 different amino acid-changing novel variants. Dr. Phyllis Gardner, a Stanford Medical School professor, was skeptical of the Theranos founder Elizabeth Holmes early on, having rejected Holmes' idea for a patch that could deploy. Gardner is played by actress Laurie Metcalf in the series premiere episode of 'The Dropout.' The role of calcium in the action of tumor necrosis factor (TNF) on human neutrophils is not clear. Dr. Phyllis Gardner, MD is an Internal Medicine Specialist in Stanford, CA and has over 47 years of experience in the medical field. In the present study, we investigated whether P1 agonist-induced Cl- secretion is preserved in cystic fibrosis airway epithelium and which signalling mechanism is involved. The arrayed primer extension array, based on a platform technology for disease detection with multiple applications, is a robust, cost-effective, and easily modifiable assay suitable for CF carrier screening and disease detection. The stimulant effect of CPCA (10 microM) was abolished by addition of the A2AR antagonist 3,7-dimethyl-1-propargylxanthine (DMPX) (100 microM; reported K(i) = 11 +/- 3 microM). Three channel types that may contribute to activation have also been described in B lymphocytes. Traditional therapeutic modalities address these problems with pancreatic enzyme replacement, vitamins and nutritional supplementation, antibiotics, and respiratory therapy. Lalonde, G., McDonald, T. V., Gardner, P., OHANLEY, P. D. A CAMP-REGULATED CHLORIDE CHANNEL IN LYMPHOCYTES THAT IS AFFECTED IN CYSTIC-FIBROSIS, TRIGGERING OF LYMPHOCYTES-T VIA EITHER T3-TI OR T11 SURFACE-STRUCTURES OPENS A VOLTAGE-INSENSITIVE PLASMA-MEMBRANE CALCIUM-PERMEABLE CHANNEL - REQUIREMENT FOR INTERLEUKIN-2 GENE-FUNCTION. Among the presbycusis group, these solely occurred within the GJB2 and SLC26A4 genes. View details for Web of Science ID 000083463500002. Thus, lymphocytes may be an accessible source of CF tissue for study of this defect, for cloning of the chloride channel complex, and for diagnosis of the disease. Dr. Gardner has spent more than 35 years in academia, medicine and industry. It is widely accepted that clinical testing using surrogate markers including pulmonary function will be useful in assessing clinical efficacy. Dr. Gardner brings to the CohBar Board over 35 years of experience in academia, medicine, pharmacology, drug delivery systems, and biotechnology investing and governance, and has received numerous national awards and honors. Sustained elevation of intracellular Ca2+ by cell surface receptors is often dependent on influx of Ca2+ across the plasma membrane through routes not involving voltage-gated Ca2+ channels. Wagner, J. In this review, we discuss agents that increase Cl- secretion via preserved Cl- secretory pathways, such as uridine triphosphate, or that enhance Na+ resorption, such as amiloride, thereby correcting altered airway secretions. These results suggest that CaM kinase mediates the Ca2+ pathway of Cl- channel activation. DBHQ (25 microM) caused a short-term rise in [Ca2+]i in the absence of ambient Ca2+, and a sustained elevation of [Ca2+]i in cell monolayers bathed in the efflux solution (1.2 mM Ca2+), which was largely attenuated by Ni2+ (5 mM). The Ca2+ signal can be separated into an early transient peak due to InsP3-released Ca2+ from intracellular stores, and a sustained plateau due to altered transmembrane Ca2+ flux. The involvement of CFTR suggests a possible cystic fibrosis heterozygote advantage against STa-induced diarrhea. @Stanford #PhyllisGardner was a skeptic of #ElizabethHolmes from the time she met Holmes . 1. A group of 257 self-identified Hispanics with clinical manifestations consistent with CF were studied by temporal temperature gradient electrophoresis and/or DNA sequencing. View details for Web of Science ID 000228736900018. tgAAVCF, an adeno-associated cystic fibrosis transmembrane conductance regulator (CFTR) viral vector/gene construct, was administered to 23 patients in a Phase II, double-blind, randomized, placebo-controlled clinical trial. This provider currently accepts 5 insurance plans. Since there is a significant increase in phosphoinositide turnover after stimulation via either the T3-Ti or T11 pathway, it is suggested that triggering of either structure opens a common set of channels through this mechanism. A., Gardner, P. RECOMBINANT HUMAN TUMOR-NECROSIS-FACTOR-ALPHA INDUCES CALCIUM OSCILLATION AND CALCIUM-ACTIVATED CHLORIDE CURRENT IN HUMAN NEUTROPHILS - THE ROLE OF CALCIUM CALMODULIN-DEPENDENT PROTEIN-KINASE. We demonstrate that intracellular release of inositol 1,4,5-trisphosphate (InsP3), either from stimulation of transfected human muscarinic receptors or from photolytic release of caged InsP3, activates whole cell Ca2+ current in the Jurkat T cell line. 0 (0 ratings) Leave a review. These include resting ionic homeostasis and the more complex signaling events involved in activation, proliferation, cytotoxic function, and volume regulation. Patch-clamp studies have identified a cAMP-dependent Cl- conductance in lymphocytes that is defectively regulated in cystic fibrosis. 3. Encina Hall West Suite 100 Stanford, CA 94305-6044 Phone: 650-723-1806 Campus Map When tested, persistence was observed in one patient for 41 days and in another for 10 weeks. (ABSTRACT TRUNCATED AT 400 WORDS), View details for Web of Science ID A1990DA09800009. Sinusitis recurred at a rate of 45% during one month of follow-up. Phyllis Gardner, Stanford University professor of medicine and health care venture capital firm partner, on her early suspicions about disgraced Theranos founder Elizabeth Holmes, whom she . 2. In conclusion, our results suggest that A2AR participates in regulation of airway C1 secretion via aCa2+-dependent signalling pathway, which involves CaMK and appears to be at least partially conserved in cystic fibrosis airway epithelial cells. Holmes wanted to build a patch that would scan the wearer for infections and release antibiotics. A., Messner, A. H., Moran, M. L., DAIFUKU, R., Kouyama, K., Desch, J. K., Manley, S., Norbash, A. M., Conrad, C. K., Friborg, S., Reynolds, T., Guggino, W. B., Moss, R. B., Carter, B. J., Wine, J. J., Flotte, T. R., Gardner, P. Maxillary sinusitis as a surrogate model for CF gene therapy clinical trials in patients with antrostomies. With fluorescent cytometry, using the visible wavelength calcium probe, fluo-3, and patch clamping, we investigated whether TNF induces cytosolic free Ca2+ changes and Ca(2+)-activated Cl- current, respectively. About Dr. Phyllis Gardner. The known potent A2 adenosine receptor (A2AR) agonist, 5'-(N-cyclopropyl) carboxamidoadenosine (CPCA, 2 microM) but not the A1 adenosine receptor agonist, N6-phenyl adenosine (N6-phenyl ADO, 10 microM) markedly increased 125I efflux rate (baseline, 5.9 +/- 2.0% min-1, + CPCA, 10.9 +/- 0.6% min-1; P < 0.01). Hearing loss has a genetic etiology in the majority of cases and is very common. Gardner was one of the first people to be publicly skeptical of Elizabeth Holmes, the founder of blood testing company Theranos, who was later found guilty of investor fraud. View details for Web of Science ID A1989AK17900033. View details for Web of Science ID A1989AX58900003. Dose-dependent changes in TEPD responses to pharmacologic intervention were observed following treatments. Schrijver, I., Kulm, M., Gardner, P. I., Pergament, E. P., Fiddler, M. B. This page may have moved, does not exist, or we may be experiencing a temporary issue. This finding demonstrates the potential of enterocytes to serve as heterotopic sites for the synthesis of heterologous gene products that would be secreted into the lumen of the intestinal tract or into the bloodstream. She has served on the board of directors of several public and private companies, including . These results suggest that there is no relationship between P-gp and the chloride channel activated by cell swelling. Ligation of the extracellular domains of the T-cell receptor activates receptor-associated tyrosine kinases that can phosphorylate the gamma-isoform of phospholipase C, increasing its catalytic activity. Site-directed mutagenesis of the predicted autoinhibitory domain yielded a mutant which was approximately 37% active in the absence of Ca2+/calmodulin, confirming the region as critical for autoregulation, and suggesting this mutant as a tool for studying the role of CaM kinase in nonneuronal tissues. Thus, DBHQ appears to enhance Cl- channel activity via a Ca(2+)-dependent mechanism involving CaMKII. By use of whole-cell patch clamp recordings, we show that nitric oxide activates cystic fibrosis transmembrane conductance regulator CI- currents in normal human cloned T cells by a cGMP-dependent mechanism. View details for Web of Science ID A1994NA28800008, View details for Web of Science ID A1994BB86U00010. The tgAAVCF administration was well tolerated, without adverse respiratory events, and there was no evidence of enhanced inflammation in sinus histopathology or alterations in serum-neutralizing antibody titer to adeno-associated virus (AAV) capsid protein after vector administration. View details for Web of Science ID A1989AU52300004. The current was similarly activated by 1 microM ionomycin, a Ca2+ ionophore. Raising intracellular free calcium concentration from 2 to 200 nM reversed the reduction, induced by substance P, in current peak amplitude and disclosed an apparent desensitization towards the neuropeptide action. Phyllis Gardner knew from the moment the 19-year-old student started talking about her "brilliant" idea that it wouldn't work. The Sunday Times' tech correspondent brings on Dr Phyllis Gardner, the Standord medical professor who came across Elizabeth Holmes before she started Theranos and then worked behind the scenes to expose her, to talk about her background at Stanford (4:00), and in industry (5:00), meeting a young Elizabeth Holmes (6:55), rejecting her first idea SK&F 96365 has no effect on Ca2+ stores release or K+ channels. It seems likely that rapid progress will be made in our understanding of these areas through a combination of immunological, biochemical, and electrophysiological approaches. With intracellular application of the Ca2+ chelator 1,2-bis (2-aminophenoxy)ethane-N,N,N',N'-tetraacetate (5 mM), the calmodulin antagonist (2 microM), CaM kinase II-(290-309), or the inhibitory peptide (10 microM), CaM kinase II-(273-302), the current was no longer activated by rhTNF alpha. Sense and misantisense oligomers served as controls. But that's not why people are recognizing Phyllis Gardner on the street and in airports these days. The Stanford Medicine Alumni Association presents Women in Medicine and Science, Phyllis Gardner - Like a Salmon Swimming Upstream Stanford Medicine Alumni Awards 2022: Marian Carlson 3. One of the best moments happens early in the series during a heated exchange between then-Stanford student Holmes and Stanford professor of medicine Phyllis Gardner (Laurie Metcalf,. In particular, the steady-state rise in interleukin-2 (T-cell growth factor) mRNA is dependent on the rise of [Ca2+]i resulting from ion movement across this channel. Dr. Phyllis Gardner Despite Holmes' ability to charm older white businessman, assembling an impressive all-male board of directors at Theranos, there was one person who told her what she was. A., Reynolds, T., Moran, M. L., Moss, R. B., Wine, J. J., Flotte, T. R., Gardner, P. A phase I/II study of tgAAV-CF for the treatment of chronic sinusitis in patients with cystic fibrosis. Nghiem, P., OLLICK, T., Gardner, P., Schulman, H. ACTIVATION OF CA2+ CURRENT IN JURKAT T-CELLS FOLLOWING THE DEPLETION OF CA2+ STORES BY MICROSOMAL CA2+-ATPASE INHIBITORS. The effects of purinoceptor agonists on Cl- secretion were examined in a transformed cystic fibrosis airway phenotype epithelial cell line, CFPEo-. The Stanford professor was one of the first people to doubt Holmes' credentials and products, dismissing Holmes' patch idea when she was a 19-year-old student at the university. Bacterial cultures and increased sinus leukocytes corroborated recurrent sinusitis. Phyllis Gardner Professor of Medicine (Clinical Pharmacology) Medicine - Clinical Pharmacology Bio ACADEMIC APPOINTMENTS Professor, Medicine - Clinical Pharmacology Research & Scholarship CURRENT RESEARCH AND SCHOLARLY INTERESTS View details for Web of Science ID 000231054600008. The advent of universal newborn hearing screening in the United States and other countries, together with the identification of genes involved in the process of hearing, have led to an increase in both the need and opportunity for accurate molecular diagnosis of patients with hearing loss. An alternative to pulmonary testing of new CF treatments is use of the maxillary sinuses as a surrogate model of CF lung disease. Dr. Phyllis Gardner, MD is a board certified internist in Stanford, California. The Ca2+ current was reversibly blocked by > 90% with 0.3 mM Cd2+, whereas the same concentration of Ni2+ or Co2+ blocked only 50 to 60% of the current. A luciferase assay quantitated interleukin-2 gene promoter activity in stimulated cells transfected with an interleukin-2 promoter-luciferase gene construct. Bath-application of DBHQ induced an outwardly-rectifying whole-cell Cl- current, which was abolished by pipette addition of BAPTA (5 mM) or CaMK [273-302] (20 microM), an inhibitory peptide of multifunctional Ca2+/calmodulin-dependent protein kinase (CaMKII). Neither the primary efficacy endpoint, defined as the rate of relapse of clinically defined, endoscopically diagnosed recurrent sinusitis, nor several secondary endpoints (sinus transepithelial potential difference [TEPD], histopathology, sinus fluid interleukin [IL]-8 measurements) achieved statistical significance when comparing treated to control sinuses within patients. The results suggest that the dihydropyridine Ca agonist Bay K 8644 interacts with both voltage-gated and receptor-operated Ca channels and also suggest potential strategies for development of a new class of immunomodulatory drugs. Hereditary sensorineural hearing loss: advances in molecular genetics and mutation analysis, Genotyping microarray for the detection of more than 200 CFTR mutations in ethnically diverse populations. @stanford: Currently teaching. Phyllis I. Gardner (born July 7, 1950) is a Professor of Medicine at the Stanford University School of Medicine. It is unclear whether or not this type of Ca2+ channel is present in straight B-cell lines. When she told her professor Dr Phyllis Gardner about her idea, Gardner told her it was ambitious . The P1 agonists tested (at 0.01 and 0.1 mM) revealed a rank order of potency of 5'-N-ethylcarboxamine adenosine (NECA) > 2-chloro-adenosine (2-Cl-ADO) > R-phenylisopropyl adenosine (R-PIA). Deafness and hearing impairment have a genetic cause in at least half the cases. We conclude that CFTR mRNA is expressed in lymphocytes, consistent with the cAMP regulation of chloride transport present in normal lymphocytes but defective in CF-derived lymphocytes. She has served on the board of directors of several public and private companies, including . View details for Web of Science ID A1993KR82200022. . [1] [2] [3] You may use our global navigation in the heading bar or return to our home page using the buttons below. View details for DOI 10.2353/jmoldx.2007.060100, View details for Web of Science ID 000245427600013, View details for PubMedCentralID PMC1867437. These results show that Ca2+ changes are associated with the effects of rhTNF alpha and that CaM kinase plays a role in the mechanism underlying rhTNF alpha-induced activation of Ca(2+)-activated Cl- current in human neutrophils. Specific attenuation of interleukin-2 transcriptional induction occurs in Jurkat T cells following pretreatment with a Ca2+ ionophore. By use of whole cell patch-clamp and Indo-1 fluorescence studies of the Jurkat T leukaemic cell line, we show that the new organic antagonist of receptor-mediated Ca2+ entry, SK&F 96365, inhibits the T cell Ca2+ current in a dose-dependent fashion, with an IC50 of 12 microM. Many of the critical T-cell signal transducing enzymes such as phospholipase C and protein kinase C contain intrinsic Ca-binding domains, but for the most part the rise in cytoplasmic Ca is transduced by specialized Ca-binding proteins that lack catalytic domains. A similar order of potency was seen in transformed cystic fibrosis nasal polyp cells, CFNPEo- (ADO > ATP > AMP > ADP). Dong, Y. J., Chao, A. C., Kouyama, K., Hsu, Y. P., BOCIAN, R. C., Moss, R. B., Gardner, P. MOLECULAR STRATEGIES FOR THERAPY OF CYSTIC-FIBROSIS, INHIBITION BY SK-AND-F-96365 OF CA2+ CURRENT, IL-2 PRODUCTION AND ACTIVATION IN T-LYMPHOCYTES. These assays suggest a pore diameter in the order of 2 nm. The treatment, however, did not reverse substance P-induced acceleration of the rate of current decay. Addition of adenosine (ADO; 0.1-1 mM) markedly increased 125I efflux rate. Individuals who carry two mild mutations in the GJB2 gene possibly have an increased risk of developing early presbycusis. Here we show that STa, guanylin and cGMP each activate intestinal Cl- secretion, and that this is abolished by inhibitors of cAMP-dependent protein kinase (PKA), suggesting that PKA is a major mediator of this effect. This panel, developed on a microarray, is capable of simultaneous evaluation of multiple mutations in 8 genes (GJB2, GJB6, GJB3, GJA1, SLC26A4, SLC26A5 and the mitochondrial genes encoding 12S rRNA and tRNA-Ser[UCN]).The arrayed primer extension array for sensorineural hearing loss is based on a versatile platform technology and is a robust, cost-effective, and easily modifiable assay. We used antisense oligodeoxynucleotides to CFTR to reduce the expression of CFTR in colonic and tracheal epithelial cells. A defect in regulation of a chloride channel appears to be the molecular basis for cystic fibrosis (CF), a common lethal genetic disease. One secondary endpoint, measurements of the anti-inflammatory cytokine IL-10 in sinus fluid, was significantly (p < 0.03) increased in the tgAAVCF-treated sinus relative to the placebo-treated sinus at day 90 after vector instillation. Using CF sinusitis as a surrogate model for testing clinical efficacy of new treatments is attractive because CF upper respiratory disease is similar to the lower respiratory disease with respect to electrophysiology and microbiology.Sinusitis recurrence in untreated sinuses was analyzed during a prospective, randomized, unblinded, dose-escalation, within-subjects, phase I clinical trial of the adeno-associated virus mediated cystic fibrosis transmembrane conductance regulator (AAV-CFTR) gene transfer.Clinical symptoms combined with sinus endoscopy proved useful in the diagnosis of unilateral and bilateral sinusitis recurrence. Sinus CT scans were also useful in diagnosing recurrent sinusitis in this surrogate model of CF infectious exacerbations.CF sinusitis as a surrogate for lung disease is particularly well-suited for phase II clinical trials of gene transfer agents, with the potential for measuring clinical efficacy in relatively small numbers of patients over relatively short periods of time. 61 comments Phyllis Gardner (pictured), a professor of medicine at Stanford, criticized Elizabeth Holmes' blood testing company long before fraud charges were brought against her. Spectrofluorescence of Indo/AM dye measured intracellular Ca2+ mobilization. Recent national guidelines suggest that all couples contemplating pregnancy should be informed of molecular screening for CF carrier status for purposes of genetic counseling. Support teaching, research, and patient care.
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