Support Lucile Packard Children's Hospital Stanford and child and maternal health. Lifetime resident of Fullerton, passed away on 11/18/21 in her home. Premack, B. Phospholipid bilayers composed of 1:1 w/w phosphotidylserine:phosphotidylethanolamine exposed to this toxin display discrete current flow events typical of transmembrane channels and consistent with the interpretation that this toxin acts by forming pores in phospholipid membranes. An alternative to pulmonary testing of new CF treatments is use of the maxillary sinuses as a surrogate model of CF lung disease. Little or no inflammatory or immune responses were observed.AAV-CFTR administration to the maxillary sinus results in successful, dose-dependent gene transfer to the maxillary sinus and alterations in sinus TEPD suggestive of a functional effect, with little or no cytopathic or host immune response. Pyrimidine and purine nucleosides were used to assess antagonism of the antiproliferative activity of A77 1726. 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. The wider application of patch-clamp and microfluorimetry techniques to lymphocytes has helped to clarify some issues and raised many more. In addition, voltage-gated K+ channels, which closely resemble the delayed rectifier K+ channel of nerve and muscle, can be classified into three subtypes, according to their voltage dependence of activation, inactivation kinetics, and pharmacological sensitivity. For each patient, a dose of 100,000 replication units of tgAAVCF was administered to one maxillary sinus, while the contralateral maxillary sinus received a placebo treatment, thereby establishing an inpatient control. The mutation spectrum in Hispanics, however, remains poorly defined. View details for Web of Science ID A1994PN23700032, View details for PubMedCentralID PMC1510420. 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. Clinical manifestations include both pancreatic and pulmonary insufficiency. Howard Rosen's Profile | Stanford Profiles The precise functional role of the voltage-activated K+ channel remains to be determined. Phyllis Gardner. 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. 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. 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. Wagner, J. 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. Exclusion criteria comprised known causes of hearing loss such as significant noise exposure, trauma, ototoxic medication, neoplasm, and congenital infection or syndrome, as well as congenital or pediatric onset. STANFORD, CA - MAY 24: Stanford University professor Phyllis Gardner poses for a portrait on May 24, 2019, in Stanford, Calif. Gardner's blunt criticism of Theranos and its disgraced founder . Significant transduction of the tissue was observed and histochemical staining was used to identify enterocytes as the primary targets of gene transfer. Schrijver, I., Oitmaa, E., Metspalu, A., Gardner, P. Diagnostic testing by CFTR gene mutation analysis in a large group of Hispanics novel mutations and assessment of a population-specific mutation spectrum. View details for Web of Science ID A1988Q219900001, Department: Medicine - Med/Clinical Pharmacology, Genetic Analysis of Presbycusis by Arrayed Primer Extension. 7. View details for Web of Science ID 000260722000005. Phyllis Gardner - Wikipedia CohBar Announces the Appointment of Dr. Phyllis Gardner to Voltage-insensitive Ca2+ channels, Ca2+-dependent K+ channels, other downstream Ca2+ dependent effector molecules; role in cellular activation and signal transduction.2. View details for Web of Science ID A1993KR82200022. The identity of the amplified products was confirmed by hybridization to CFTR-specific probes and DNA sequencing. Phyllis Gardner was a skeptic of Elizabeth Holmes dating back to when she met Holmes, nearly 20 years ago. 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. Bay K 8644 from 10(-9) to 10(-4) M caused a dose-dependent rise in the intracellular free Ca concentration, an effect that was not mimicked by the dihydropyridine Ca antagonist nifedipine. Season 15: "Theranos CEO on Trial"--Phyllis Gardner American Greed reveals fresh details about one of the most infamous alleged corporate fraud cases of the 21st century - Theranos, now back in. Phyllis Gardner (Professor) - explorecourses.stanford.edu 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. Future molecular diagnostic assays are expected to offer a greater variety of gene-specific tests, as well as combined mutation panels, which will aid in the management of the impressive genetic heterogeneity observed in hereditary hearing loss, especially in individuals with nonsyndromic forms. The effects of purinoceptor agonists on Cl- secretion were examined in a transformed cystic fibrosis airway phenotype epithelial cell line, CFPEo-. While STa and guanylin bind to the same receptor guanylyl cyclase and raise cell cGMP, the signaling mechanism distal to cGMP remains controversial. A77 1726, the active metabolite of leflunomide, inhibits lymphocyte proliferation in vitro. 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. SK&F 96365 has no effect on Ca2+ stores release or K+ channels. In contrast, the calcium-activated chloride current was not affected by antisense treatment. CFTR is required for the cAMP pathway but not for the calcium pathway. Schrijver, I., Kulm, M., Gardner, P. I., Pergament, E. P., Fiddler, M. B. She has previously served as Dean of Education. In summary, this Phase II trial confirms the safety of tgAAVCF but provides little support of its efficacy in the within-patient controlled sinus study. Dong, Y. J., Chen, G., Duran, G. E., Kouyama, K., Chao, A. C., Sikic, B. I., Gollapudi, S. V., Gupta, S., Gardner, P. INTERLEUKIN-2 TRANSCRIPTIONAL BLOCK BY MULTIFUNCTIONAL CA2+/CALMODULIN KINASE. Phyllis Gardner's Profile | Stanford Profiles MiMedx Announces Appointment of Phyllis Gardner, M.D. to These results suggest that there is no relationship between P-gp and the chloride channel activated by cell swelling. 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. 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. Stanford Hospital and Clinics. Young, W., Chen, J., Jung, F., Gardner, P. Freeman Spogli Institute for International Studies, Institute for Computational and Mathematical Engineering (ICME), Institute for Human-Centered Artificial Intelligence (HAI), Institute for Stem Cell Biology and Regenerative Medicine, Stanford Institute for Economic Policy Research (SIEPR), Stanford Woods Institute for the Environment, Office of VP for University Human Resources, Office of Vice President for Business Affairs and Chief Financial Officer. This review addresses the genetics of hearing loss, discusses the most commonly offered genetic assays for nonsyndromic hearing loss, with advantages and limitations, proposes a practical testing algorithm, and highlights current developments. It seems likely that rapid progress will be made in our understanding of these areas through a combination of immunological, biochemical, and electrophysiological approaches. Patch clamp studies have identified an InsP3-activated, Ca2+ permeable channel in the plasma membrane of T lymphocytes that may be responsible for the sustained elevation of [Ca2+]i during continuous TCR/CD3 occupancy. 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. A phase II, double-blind, randomized, placebo-controlled clinical trial of tgAAVCF using maxillary sinus delivery in patients with cystic fibrosis with antrostomies. 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. We conclude that expression of mutant CFTR in human TCC is accompanied by ion channel dysfunction characteristic of the CF phenotype, and is accompanied by a reduction in IL-10 secretion after polyclonal activation. 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 include resting ionic homeostasis and the more complex signaling events involved in activation, proliferation, cytotoxic function, and volume regulation. She is currently licensed to practice medicine in California. However, the absence of voltage-dependent activation, relative conductance sequence for divalent cations (Ca2+ > Ba2+ approximately Sr2+ > Mn2+), and lack of inhibition by nifedipine, D600, diltiazem, delta-conotoxin, or aga-IVa were unlike that of voltage-gated Ca2+ channels. After surgically accessing the intestine, an E1-, E3-deleted adenoviral vector encoding beta-galactosidase (beta-Gal) was directly injected into various regions of the small and large intestine of rats and rabbits. In the Peyer's patches, a high level of expression was localized to epithelial cells, potentially M cells, overlying the lymphoid follicle domes. To characterize the CaM kinase present in these tissues we have cloned an isoform of this kinase from human T lymphocytes. View details for Web of Science ID A1991GF80400001. View details for Web of Science ID A1991EZ66600057, In both T- and B-lymphocyte activation, antigen receptor or mitogen stimulation results in phosphoinositide turnover, generation of InsP3 and diacylglycerol, and a sustained rise in intracellular Ca2+, from both intracellular Ca2+ stores release and enhanced transmembrane Ca2+ influx. View details for Web of Science ID A1994NH08400029. Thus, DBHQ appears to enhance Cl- channel activity via a Ca(2+)-dependent mechanism involving CaMKII. 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. When the vector was directly administered to segments of the distal ileum containing a Peyer's patch, transgene expression was approximately 10-fold higher than in segments lacking a Peyer's patch. This leads to production of inositol 1,4,5-trisphosphate, release of stored intracellular Ca, and activation of Ca-permeable plasma membrane channels. T-cell receptor signalling activates multifunctional CaM kinase. Phyllis I. Gardner (born July 7, 1950) is a Professor of Medicine at the Stanford University School of Medicine. The expression of the three K+ channel subtypes varies with the cell's developmental state and functional class. 5. Gardner and. The current was similarly activated by 1 microM ionomycin, a Ca2+ ionophore. If you see your name among the Troy High School graduates, someone is looking for you! Cystic fibrosis is associated with defective regulation of apical membrane chloride channels in airway epithelial cells. These results suggest that CaM kinase mediates the Ca2+ pathway of Cl- channel activation. 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. Amino acid differences between these isoforms and the rat brain gamma isoform (which we refer to as gamma A) are localized to the variable domain. View details for Web of Science ID 000231054600008. Jan 18, 2022 Updated Mar 17, 2022, 5:09pm PDT Years before Theranos founder Elizabeth Holmes was prosecuted for fraud, Dr. Phyllis Gardner saw right through her. View details for Web of Science ID A1994NM61500008. Dr. Phyllis Gardner, MD, is an Internal Medicine specialist practicing in Stanford, CA with 47 years of experience. Chao, A. C., ZIFFERBLATT, J. Cystic fibrosis (CF) is a common genetic disorder characterized by defective epithelial chloride transport and progressive lung disease. Their conflicting politics, and his conflicted feelings, led the . Addition of BAPTA (10 mM), a Ca2+ chelator, to the perfusion pipette also abolished the ADO-elicited Cl- current. She has served on the board of directors of several public and private companies, including . 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. Phyllis I Gardner | Departments | Stanford Directory 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,. View details for DOI 10.2353/jmoldx.2007.060100, View details for Web of Science ID 000245427600013, View details for PubMedCentralID PMC1867437. Phyllis Gardner Professor of Medicine (Clinical Pharmacology) Medicine - Clinical Pharmacology Bio ACADEMIC APPOINTMENTS Professor, Medicine - Clinical Pharmacology Research & Scholarship CURRENT RESEARCH AND SCHOLARLY INTERESTS ADO (0.1-mM) and CPCA (2 microM) both induced a marked increase in intracellular [Ca2+] ([Ca2+]i); the effect of the latter was again abolished by pretreatment of the cells with DMPX. New patients are welcome. Holmes wanted to build a patch that would scan the wearer for infections and release antibiotics. The same Ca2+ influx pathway could be activated by IP3-dependent or IP3-independent means, and therefore appeared to be regulated by the fullness of the microsomal Ca2+ stores rather than by the direct action of IP3. The intestinal tract has many features that make it an attractive target for therapeutic gene transfer. 6. Who is Elizabeth Holmes? Theranos founder delays 11-year prison - MSN These data provide evidence for a novel in vitro mechanism of the antiproliferative action of this immunosuppressant. 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. These channels in normal cells are activated by cyclic AMP-dependent protein kinase and protein kinase C. In cystic fibrosis these kinases fail to activate otherwise normal Cl- channels. She attended the Slade School of Fine Art and was a suffragette when they met. The effect of Ca2+ ionophore on whole-cell Cl- currents is inhibited by a specific peptide inhibitor of multifunctional Ca2+/calmodulin-dependent protein kinase (CaM kinase). Chao, A. C., deSauvage, F. J., Dong, Y. J., Wagner, J. Several mutations in the selected disorders that are not prevalent per se in the Ashkenazi Jewish populations, as well pseudodeficiency alleles, are also included in the array. We report here that normal human B-lymphoblasts display whole cell Cl- conductances induced by calcium-mediated pathways, volume regulation, and cAMP which are equivalent to currents described in epithelial cells. SK&F 96365 also inhibits [3H]-thymidine incorporation and interleukin-2 (IL-2) synthesis in peripheral blood lymphocytes. @stanford: Currently teaching. Ca2+/calmodulin activation of Cl- channels presents a pathway with therapeutic potential for circumventing defective regulation of Cl- channels in cystic fibrosis. Purification of the NF-AT kinase revealed that it is composed of a priming kinase activity and glycogen synthase kinase-3 (GSK-3). Depletion of stored Ca2+ by either receptor stimulation or microsomal Ca(2+)-ATPase inhibition activated a low conductance, Ca(2+)-selective, non-voltage-activated membrane current. Phyllis Gardner, an American biologist, was born on July 7, 1950, and is well known for being one of the first to question and challenge Elizabeth Holmes' beliefs. These results suggest that PGE1, acting through PKA, activates a Cl- current in Jurkat T cells. 2. Dr. Phyllis Gardner, MD is an Internal Medicine Specialist in Stanford, CA and has over 47 years of experience in the medical field. The Ca2+ signal can be further resolved at the level of the single cell into a series of repetitive oscillations between peak and trough levels with a period of 16-20 s. The oscillations may be part of a frequency-encoded signaling system. The involvement of CFTR suggests a possible cystic fibrosis heterozygote advantage against STa-induced diarrhea. She is a Professor at Stanford University Medical Center. 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. B., Shah, N., Messner, A. H., Moran, M. L., Norbash, A. M., Moss, R. B., Wine, J. J., Gardner, P. Adenovirus-mediated transduction of intestinal cells in vivo. A > 90% block of inducible interleukin-2 reporter gene activity was initiated by transfection of a constitutively active mutant of multifunctional Ca2+/calmodulin-dependent protein kinase (CaM kinase or CaM kinase II), but not by constitutive mutants of CaM kinase IV, calcineurin or protein kinase C. The block was complete six hours after kinase transfection and showed specificity for interleukin-2; there was no change in beta-actin transcription or in c-fos transcription induced by phorbol myristyl acetate, and a Rous sarcoma virus promoter was stimulated threefold. Furthermore, the 3'-end of the gene was found in a T cell cDNA library. 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. 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. View details for Web of Science ID 000078432500017. 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 . 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. This is supported by a comparison with other large CFTR studies. Stimulation of T-lymphocytes via either structure results in opening of an identical set of voltage-insensitive plasma membrane Ca2+-permeable channels through the action of a diffusible second messenger. After more than a decade in conceptualisation and experimentation, four systems that have commercial potential are discussed: i) implantable microchips with on-demand microdosage for one or more therapeutic agents under internal control or external control using a wireless link; ii) nanopore pumps, implantable titanium pumps, consisting of a drug reservoir with a nanopore-release membrane, capable of delivering potent small or macromolecules at constant serum levels for sustained periods of time; iii) nanocages, microfabricated nanopore immunoisolation chambers for cellular implants, capable of natural feedback-controlled delivery of proteins and peptides; and iv) nanobuckets, micromachined silicon porous particles with drug-loading capacity and targeting ligands for localised delivery.
