Publications by authors named "Phuong T Dinh"

7 Publications

  • Page 1 of 1

Combined Proteomic and Genetic Interaction Mapping Reveals New RAS Effector Pathways and Susceptibilities.

Cancer Discov 2020 Dec 29;10(12):1950-1967. Epub 2020 Jul 29.

Baxter Laboratory, Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, California.

Activating mutations in RAS GTPases drive many cancers, but limited understanding of less-studied RAS interactors, and of the specific roles of different RAS interactor paralogs, continues to limit target discovery. We developed a multistage discovery and screening process to systematically identify genes conferring RAS-related susceptibilities in lung adenocarcinoma. Using affinity purification mass spectrometry, we generated a protein-protein interaction map of RAS interactors and pathway components containing hundreds of interactions. From this network, we constructed a CRISPR dual knockout library targeting 119 RAS-related genes that we screened for -dependent genetic interactions (GI). This approach identified new RAS effectors, including the adhesion controller RADIL and the endocytosis regulator RIN1, and >250 synthetic lethal GIs, including a potent -dependent interaction between and Many GIs link specific paralogs within and between gene families. These findings illustrate the power of multiomic approaches to uncover synthetic lethal combinations specific for hitherto untreatable cancer genotypes. SIGNIFICANCE: We establish a deep network of protein-protein and genetic interactions in the RAS pathway. Many interactions validated here demonstrate important specificities and redundancies among paralogous RAS regulators and effectors. By comparing synthetic lethal interactions across -dependent and -independent cell lines, we identify several new combination therapy targets for RAS-driven cancers..
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http://dx.doi.org/10.1158/2159-8290.CD-19-1274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710624PMC
December 2020

Hydra: A mixture modeling framework for subtyping pediatric cancer cohorts using multimodal gene expression signatures.

PLoS Comput Biol 2020 04 10;16(4):e1007753. Epub 2020 Apr 10.

Genomics Institute, University of California, Santa Cruz, Santa Cruz, California, United States of America.

Precision oncology has primarily relied on coding mutations as biomarkers of response to therapies. While transcriptome analysis can provide valuable information, incorporation into workflows has been difficult. For example, the relative rather than absolute gene expression level needs to be considered, requiring differential expression analysis across samples. However, expression programs related to the cell-of-origin and tumor microenvironment effects confound the search for cancer-specific expression changes. To address these challenges, we developed an unsupervised clustering approach for discovering differential pathway expression within cancer cohorts using gene expression measurements. The hydra approach uses a Dirichlet process mixture model to automatically detect multimodally distributed genes and expression signatures without the need for matched normal tissue. We demonstrate that the hydra approach is more sensitive than widely-used gene set enrichment approaches for detecting multimodal expression signatures. Application of the hydra analysis framework to small blue round cell tumors (including rhabdomyosarcoma, synovial sarcoma, neuroblastoma, Ewing sarcoma, and osteosarcoma) identified expression signatures associated with changes in the tumor microenvironment. The hydra approach also identified an association between ATRX deletions and elevated immune marker expression in high-risk neuroblastoma. Notably, hydra analysis of all small blue round cell tumors revealed similar subtypes, characterized by changes to infiltrating immune and stromal expression signatures.
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http://dx.doi.org/10.1371/journal.pcbi.1007753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176284PMC
April 2020

Low Potency of Indian Dust Mite Allergen Skin Prick Test Extracts Compared to FDA-Approved Extracts: A Double-Blinded Randomized Control Trial.

Allergy Rhinol (Providence) 2018 Jan-Dec;9:2152656718796746. Epub 2018 Sep 25.

Department of Healthcare Administration, University of Colorado, Denver, Colorado.

Background: Skin prick testing is the most important diagnostic tool to detect immunoglobulin E-mediated allergic diseases. With increase in the number of allergy tests performed in India, it is imperative to know the potency of indigenous extracts in comparison with U.S. Food and Drug Administration (USFDA)-approved extracts.

Methods: A randomized comparison trial of Indian manufactured and USFDA-approved extracts of (DP) and Dermatophagoides (DF) was done at Christian Medical College & Hospital, Vellore, India from April 2014 to June 2015, to compare the skin test reactivity of indigenous allergen extracts of dust mites against validated allergen. Study enrollment included 197 patients with allergic disorders that showed sensitivity to dust mite during routine allergy skin testing. Study participants were tested with varying dilutions of DP and DF indigenous extracts along with USFDA-approved allergens in a blinded fashion. Results were recorded, and statistical significance was calculated using the Friedman rank sum test.

Results: Using the Friedman rank sum test with a Tukey adjustment for multiple comparisons, we found that the extracts in each dilution were significantly different ( < .0001). The full strength indigenous extracts, B-DF (DF allergen standard extract from Bioproducts and Diagnostics, India) and C-DF (DF allergen extract from Creative Diagnostics, India) extracts, had mean wheal sizes of 7.69 (standard deviation [SD] 9.91) and 31.01(SD 51.04), respectively. The full strength S-DF (DF allergen extract from Jubilant Hollister Stier, Spokane, WA, USA) had a mean wheal size of 109.97 (SD 162.73), which was significantly higher ( < .0001) than both the indigenous extracts. For each of the dilutions, the S-DF mean wheal size was significantly greater than that of the corresponding B-DF and C-DF wheal sizes. The full strength indigenous C-DP (DP allergen extract from Creative Diagnostics, India) had mean wheal size of 39.37 (SD 51.74). The full strength standard S-DP (DP allergen extract from Jubilant Hollister Stier, Spokane, WA, USA) extract had a mean wheal size of 167.66 (SD 270.80), which was significantly higher ( < .0001) than the indigenous C-DP extract. Similar differences were seen across all dilutions.

Conclusion: The indigenous extracts have significantly lower potency compared to USFDA-approved extracts; hence, there is an urgent need for policy makers to institute stringent criteria for standardization of antigens in India.
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http://dx.doi.org/10.1177/2152656718796746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156211PMC
September 2018

Phosphate availability regulates ethylene biosynthesis gene expression and protein accumulation in white clover (Trifolium repens L.) roots.

Biosci Rep 2016 12 17;36(6). Epub 2016 Nov 17.

Institute of Fundamental Sciences, Massey University, Private Bag 11222, Palmerston North 4474, New Zealand.

The expression and accumulation of members of the 1-aminocyclopropane-1-carboxylate (ACC) synthase (ACS) and ACC oxidase (ACO) gene families was examined in white clover roots grown in either P (phosphate) sufficient or P-deprived defined media. The accumulation of one ACO isoform, TR-ACO1, was positively influenced after only 1 h of exposure to low P, and this was maintained over a 7-day time-course. Up-regulation of TR-ACS1, TR-ACS2 and TR-ACS3 transcript abundance was also observed within 1 h of exposure to low P in different tissue regions of the roots, followed by a second increase in abundance of TR-ACS2 after 5-7 days of exposure. An increase in transcript abundance of TR-ACO1 and TR-ACO3, but not TR-ACO2, was observed after 1 h of exposure to low P, with a second increase in TR-ACO1 transcripts occurring after 2-5 days. These initial increases of the TR-ACS and TR-ACO transcript abundance occurred before the induction of Trifolium repens PHOSPHATE TRANSPORTER 1 (TR-PT1), and the addition of sodium phosphite did not up-regulate TR-ACS1 expression over 24 h. In situ hybridization revealed some overlap of TR-ACO mRNA accumulation, with TR-ACO1 and TR-ACO2 in the root tip regions, and TR-ACO1 and TR-ACO3 mRNA predominantly in the lateral root primordia. TR-ACO1p-driven GFP expression showed that activation of the TR-ACO1 promoter was initiated within 24 h of exposure to low P (as determined by GFP protein accumulation). These results suggest that the regulation of ethylene biosynthesis in white clover roots is biphasic in response to low P supply.
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http://dx.doi.org/10.1042/BSR20160148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5293567PMC
December 2016

Broad Meloidogyne Resistance in Potato Based on RNA Interference of Effector Gene 16D10.

J Nematol 2015 Mar;47(1):71-8

Department of Plant Pathology, Washington State University, Pullman, WA 99164.

Root-knot nematodes (Meloidogyne spp.) are a significant problem in potato (Solanum tuberosum) production. There is no potato cultivar with Meloidogyne resistance, even though resistance genes have been identified in wild potato species and were introgressed into breeding lines. The objectives of this study were to generate stable transgenic potato lines in a cv. Russet Burbank background that carry an RNA interference (RNAi) transgene capable of silencing the 16D10 Meloidogyne effector gene, and test for resistance against some of the most important root-knot nematode species affecting potato, i.e., M. arenaria, M. chitwoodi, M. hapla, M. incognita, and M. javanica. At 35 days after inoculation (DAI), the number of egg masses per plant was significantly reduced by 65% to 97% (P < 0.05) in the RNAi line compared to wild type and empty vector controls. The largest reduction was observed in M. hapla, whereas the smallest reduction occurred in M. javanica. Likewise, the number of eggs per plant was significantly reduced by 66% to 87% in M. arenaria and M. hapla, respectively, compared to wild type and empty vector controls (P < 0.05). Plant-mediated RNAi silencing of the 16D10 effector gene resulted in significant resistance against all of the root-knot nematode species tested, whereas R Mc1(blb) , the only known Meloidogyne resistance gene in potato, did not have a broad resistance effect. Silencing of 16D10 did not interfere with the attraction of M. incognita second-stage juveniles to roots, nor did it reduce root invasion.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4388582PMC
March 2015

RNA Interference of Effector Gene Mc16D10L Confers Resistance Against Meloidogyne chitwoodi in Arabidopsis and Potato.

Phytopathology 2014 Oct;104(10):1098-106

Meloidogyne chitwoodi, a quarantine pathogen, is a significant problem in potato-producing areas worldwide. In spite of considerable genetic diversity in wild potato species, no commercial potato cultivars with resistance to M. chitwoodi are available. Nematode effector genes are essential for the molecular interactions between root-knot nematodes and their hosts. Stable transgenic lines of Arabidopsis and potato (Solanum tuberosum) with resistance against M. chitwoodi were developed. RNA interference (RNAi) construct pART27(16D10i-2) was introduced into Arabidopsis thaliana and potato to express double-stranded RNA complementary to the putative M. chitwoodi effector gene Mc16D10L. Plant-mediated RNAi led to a significant level of resistance against M. chitwoodi in Arabidopsis and potato. In transgenic Arabidopsis lines, the number of M. chitwoodi egg masses and eggs was reduced by up to 57 and 67% compared with empty vector controls, respectively. Similarly, in stable transgenic lines of potato, the number of M. chitwoodi egg masses and eggs was reduced by up to 71 and 63% compared with empty vector controls, respectively. The relative transcript level of Mc16D10L was reduced by up to 76% in M. chitwoodi eggs and infective second-stage juveniles that developed on transgenic pART27(16D10i-2) potato, suggesting that the RNAi effect is systemic and heritable in M. chitwoodi.
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http://dx.doi.org/10.1094/PHYTO-03-14-0063-RDOI Listing
October 2014

Nondestructive imaging of plant-parasitic nematode development and host response to nematode pathogenesis.

Phytopathology 2014 May;104(5):497-506

The secluded lifestyle of endoparasitic plant nematodes hampers progress toward a comprehensive understanding of plant-nematode interactions. A novel technique that enables nondestructive, long-term observations of a wide range of live nematodes in planta is presented here. As proof of principle, Pratylenchus penetrans, Heterodera schachtii, and Meloidogyne chitwoodi were labeled fluorescently with PKH26 and used to infect Arabidopsis thaliana grown in microscopy rhizosphere chambers. Nematode behavior, development, and morphology were observed for the full duration of each parasite's life cycle by confocal microscopy for up to 27 days after inoculation. PKH26 accumulated in intestinal lipid droplets and had no negative effect on nematode infectivity. This technique enabled visualization of Meloidogyne gall formation, nematode oogenesis, and nematode morphological features, such as the metacorpus, vulva, spicules, and cuticle. Additionally, microscopy rhizosphere chambers were used to characterize plant organelle dynamics during M. chitwoodi infection. Peroxisome abundance strongly increased in early giant cells but showed a marked decrease at later stages of feeding site development, which suggests a modulation of plant peroxisomes by root-knot nematodes during the infection process. Taken together, this technique facilitates studies aimed at deciphering plant-nematode interactions at the cellular and subcellular level and enables unprecedented insights into nematode behavior in planta.
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http://dx.doi.org/10.1094/PHYTO-08-13-0240-RDOI Listing
May 2014