Schrijver, I., Kulm, M., Gardner, P. I., Pergament, E. P., Fiddler, M. B. The molecular genetic basis for the majority of these patients remains obscure, however, because of the absence of associated clinical features in approximately 70% (ie, nonsyndromic hearing loss) of patients, genetic heterogeneity, and the lack of molecular genetic tests that can evaluate a large number of mutations across multiple genes.We report on the development of a diagnostic panel with 198 mutations underlying sensorineural (mostly nonsyndromic) hearing loss. Various potentially confounding factors are discussed. 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. Whole-cell recordings from JurkaT E6-1 human T-lymphocytes revealed two components of substance P action on the outward K+ current: (i) dose- and time-dependent reduction of current peak amplitude; and (ii) acceleration of the current inactivation rate. 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]. These findings suggest that two Ca2+/calmodulin-responsive enzymes, multifunctional CaM kinase and calcineurin, could mediate the divergent effects of Ca2+ signals in T-lymphocyte regulation. These results favour the involvement of A2AR. 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. Phosphorylation of the cystic fibrosis transmembrane conductance regulator (CFTR) by cAMP-dependent protein kinase leads to chloride flux in epithelial cells. Deafness and hearing impairment have a genetic cause in at least half the cases. 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 Phyllis Gardner Professor of Medicine (Clinical Pharmacology) Medicine - Clinical Pharmacology Bio ACADEMIC APPOINTMENTS Professor, Medicine - Clinical Pharmacology Research & Scholarship CURRENT RESEARCH AND SCHOLARLY INTERESTS Homozygous and compound heterozygous pathogenic mutations were exclusively seen in affected individuals. Cystic fibrosis (CF) is the most common lethal genetic disease among Caucasians, primarily affecting epithelial tissues of the lung and gut. Dr. Gardner has spent more than 35 years in academia, medicine and industry. The current was similarly activated by 1 microM ionomycin, a Ca2+ ionophore. A., Moran, M. L., Messner, A. H., DAIFUKU, R., Conrad, C. K., Reynolds, T., Guggino, W. B., Moss, R. B., Carter, B. J., Wine, J. J., Flotte, T. R., Gardner, P. Nuclear export of NF-ATc enhanced by glycogen synthase kinase-3. View details for Web of Science ID A1994NA28800008, View details for Web of Science ID A1994BB86U00010. Significant transduction of the tissue was observed and histochemical staining was used to identify enterocytes as the primary targets of gene transfer. In addition, the current was blocked by 10 microM 5-nitro-2(3-phenylpropylamino) benzoic acid (NPPB), a potent Cl- channel blocker. The wider application of patch-clamp and microfluorimetry techniques to lymphocytes has helped to clarify some issues and raised many more. Their conflicting politics, and his conflicted feelings, led the . Who Is Phyllis Gardner? View details for Web of Science ID A1991GP26900012. The role of calcium in the action of tumor necrosis factor (TNF) on human neutrophils is not clear. We are interested in the general process of signal transduction, focusing on the role that ion channels play in this process. 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. 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. We show the cDNA structure of two variants of this human CaM kinase, gamma B and gamma C, which are predicted to translate to 518 and 495 amino acids, respectively. 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. About Dr. Phyllis Gardner. Holmes forged ahead anyway. View details for Web of Science ID A1994NH08400029. T-cell receptor signalling activates multifunctional CaM kinase. A prospective, randomized, double-blind, placebo-controlled, within-subjects, phase II clinical trial of the effect AAV-CFTR on clinical recurrence of sinusitis will determine the clinical efficacy of AAV gene therapy for CF. 2) via calcineurin. 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). Transduction of these cells could have application in DNA-mediated oral vaccination. The involvement of CFTR suggests a possible cystic fibrosis heterozygote advantage against STa-induced diarrhea. View details for Web of Science ID A1991GF80400001. T cell clones (TCC) from controls and CF patients displayed equivalent Ca(2+)-mediated Cl- current; however, TCC from patients with CF but not controls displayed defective cAMP-mediated Cl-current. 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. Foreman, P. K., Wainwright, M. J., Alicke, B., Kovesdi, I., Wickham, T. J., Smith, J. G., Meier-Davis, S., Fix, J. These results suggest that CaM kinase mediates the Ca2+ pathway of Cl- channel activation. 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. About Phyllis Gardner, M.D. It is possible that disruption of IL-10-mediated anti-inflammatory homeostasis may contribute to early onset sustained inflammation in CF airways. View details for Web of Science ID A1994PH77400001. Stimulation of T cells by externally applied PGE1 stimulated 125I efflux and activated a slowly developing membrane current. The patients were between ages 20 and 65 yr, with adult-onset sensorineural hearing loss of unknown etiology, and carried a clinical diagnosis of early presbycusis. SCHUMANN, M. A., Gardner, P., Raffin, T. A. 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. Chao, A. C., Kouyama, K., Heist, E. K., Dong, Y. J., Gardner, P. ACTIVATION OF CFTR CHLORIDE CURRENT BY NITRIC-OXIDE IN HUMAN T-LYMPHOCYTES. 2. Cao, W. W., Kao, P. N., Chao, A. C., Gardner, P., Ng, J., Morris, R. E. CALCIUM-DEPENDENT AND CAMKII-DEPENDENT CHLORIDE SECRETION INDUCED BY THE MICROSOMAL CA2+-ATPASE INHIBITOR 2,5-DI-(TERT-BUTYL)-1,4-HYDROQUINONE IN CYSTIC-FIBROSIS PANCREATIC EPITHELIAL-CELLS. @Stanford #PhyllisGardner was a skeptic of #ElizabethHolmes from the time she met Holmes . NFAT mediated gene transcription; modulations by kinases and phosphatases. There is also an associated K+ efflux and membrane hyperpolarization. CFTR involvement in cAMP regulation of Cl- conductance in lymphocytes is further supported by our demonstration of the presence of appropriately spliced CFTR mRNA segments in human B and T lymphocytes as detected by an optimized reverse-transcription and polymerase chain reaction approach. Lecturer in Management, Gradaute School of Business (2011 - Present) Lecturer, Department of Chemical Engineering (2009 - Present) Lecturer, Department of Chemical Engineering (2000 - 2003) Honors & Awards Fellow, American Institute of Medical and Biological Engineers (AIMBE) (2014 - Present) Member, National Academy of Engineering (2005 - Present) Multifunctional CaM kinase also attenuated interleukin-2 activation by calcineurin plus phorbol ester. 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. Gardner, a professor of. View details for Web of Science ID A1995QV29100011. Dr. Phyllis I. Gardner is an internist in Stanford, California. Bacterial cultures and increased sinus leukocytes corroborated recurrent sinusitis. View details for Web of Science ID A1997WQ51300045. Finally, a Ca2(+)-activated K+ channel in T cells has recently been described. 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). Rodriguez-Paris, J., Ballay, C., Inserra, M., Stidham, K., Colen, T., Roberson, J., Gardner, P., Schrijver, I. View details for Web of Science ID A1991FH80200006. Stimulation of human T-lymphocytes via either the surface T3-Ti antigen-major histocompatibility complex receptor complex or the T11 molecule results in clonal proliferation through a calcium-dependent mechanism. These results are consistent with the activation of Cl- secretion via a P1 purinoceptor. Beals, C. R., Sheridan, C. M., Turck, C. W., Gardner, P., Crabtree, G. R. Reduced IL-10 secretion by CD4(+) T lymphocytes expressing mutant cystic fibrosis transmembrane conductance regulator (CFTR). Hearing loss has a genetic etiology in the majority of cases and is very common. 4. These include resting ionic homeostasis and the more complex signaling events involved in activation, proliferation, cytotoxic function, and volume regulation. 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. Addition of rhTNF alpha activated Cl- current in 80% of tested cells; the activated current was blocked by 10 microM 5-nitro-2-3-phenylpropylamino)benzoic acid, a Cl- channel blocker. Three types of T-cell channels are described in this review. The linear relationship of current amplitude to holding potential when examined over the -60 to +60 mV range indicates that this pore has a constant mean single channel conductance level of 350-400 pS. 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. 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. Wagner, J. A chloride ion transport defect has been described in human CF-derived lymphocytes; however, it has not been possible to detect CFTR mRNA in lymphocytes. She is currently a tenured professor at the School of Medicine at Stanford University . View details for Web of Science ID 000078432500017. View details for Web of Science ID 000074207900007, View details for Web of Science ID 000074088900015, View details for Web of Science ID 000073201700014.
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