Jean Zhao, PhD

Jean Zhao, PhD

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Jean Zhao, PhD

Jean Zhao received her PhD from Tufts University School of Medicine in 1999. She did her postdoctoral work in the laboratory of Dr. Thomas M. Roberts, became an Instructor in Medicine at Harvard Medical School in 2003, and joined the faculty of DFCI and Harvard Medical School in 2006.



Professor of Biological Chemistry and Molecular Pharmacology, Harvard Medical School


    Kinase signaling in cancer

    We are interested in how kinases in general, and phosphatidylinositol 3-kinases (PI3K) in particular, control malignant transformation. The work of our laboratory integrates molecular biology, tissue engineering and novel mouse models of human cancer to study oncogenic alterations in kinases that are involved in primary tumor formation and metastasis. In addition to our unique genetically engineered mouse models, we have developed a number of additional experimental systems, including, synthetic human tumors, and kinome-wide libraries of activated kinases to elucidate the mechanisms by which kinases function in cancer. We hope our studies will allow us to harness the potential of these molecules as specific targets for cancer therapies.

    Research Departments


      • Lysine vitcylation is a novel vitamin C-derived protein modification that enhances STAT1-mediated immune response. bioRxiv. 2023 Jun 27. View in: Pubmed

      • PI3Kß controls immune evasion in PTEN-deficient breast tumours. Nature. 2023 May; 617(7959):139-146. View in: Pubmed

      • Lactate regulates cell cycle by remodelling the anaphase promoting complex. Nature. 2023 Apr; 616(7958):790-797. View in: Pubmed

      • Targeting tumor-associated macrophages with STING agonism improves the antitumor efficacy of osimertinib in a mouse model of EGFR-mutant lung cancer. Front Immunol. 2023; 14:1077203. View in: Pubmed

      • PI(3,5)P 2 Controls the Signaling Activity of Class I PI3K. bioRxiv. 2023 Jan 25. View in: Pubmed

      • Preclinical and Clinical Efficacy of Trastuzumab Deruxtecan in Breast Cancer Brain Metastases. Clin Cancer Res. 2023 01 04; 29(1):174-182. View in: Pubmed

      • STING agonism overcomes STAT3-mediated immunosuppression and adaptive resistance to PARP inhibition in ovarian cancer. J Immunother Cancer. 2023 01; 11(1). View in: Pubmed

      • Targeting oncogenic KRAS with molecular brush-conjugated antisense oligonucleotides. Proc Natl Acad Sci U S A. 2022 07 19; 119(29):e2113180119. View in: Pubmed

      • STING agonism reprograms tumor-associated macrophages and overcomes resistance to PARP inhibition in BRCA1-deficient models of breast cancer. Nat Commun. 2022 05 31; 13(1):3022. View in: Pubmed

      • Maximizing TLR9 Activation in Cancer Immunotherapy with Dual-Adjuvanted Spherical Nucleic Acids. Nano Lett. 2022 05 25; 22(10):4058-4066. View in: Pubmed

      • Blocking PI3K p110ß Attenuates Development of PTEN-Deficient Castration-Resistant Prostate Cancer. Mol Cancer Res. 2022 05 04; 20(5):673-685. View in: Pubmed

      • p16INK4A-deficiency predicts response to combined HER2 and CDK4/6 inhibition in HER2+ breast cancer brain metastases. Nat Commun. 2022 03 18; 13(1):1473. View in: Pubmed

      • Targeting CDK4 and CDK6 in cancer. Nat Rev Cancer. 2022 06; 22(6):356-372. View in: Pubmed

      • Temporal and spatial topography of cell proliferation in cancer. Nat Cell Biol. 2022 03; 24(3):316-326. View in: Pubmed

      • Methylene-bridge tryptophan fatty acylation regulates PI3K-AKT signaling and glucose uptake. Cell Rep. 2022 03 15; 38(11):110509. View in: Pubmed

      • Sarm1 activation produces cADPR to increase intra-axonal Ca++ and promote axon degeneration in PIPN. J Cell Biol. 2022 02 07; 221(2). View in: Pubmed

      • How Compensatory Mechanisms and Adaptive Rewiring Have Shaped Our Understanding of Therapeutic Resistance in Cancer. Cancer Res. 2021 12 15; 81(24):6074-6077. View in: Pubmed

      • Disrupted PI3K subunit p110a signaling protects against pulmonary hypertension and reverses established disease in rodents. J Clin Invest. 2021 10 01; 131(19). View in: Pubmed

      • Lacrimal gland budding requires PI3K-dependent suppression of EGF signaling. Sci Adv. 2021 Jun; 7(27). View in: Pubmed

      • The role of the PIK3CA gene in the development and aging of the brain. Sci Rep. 2021 01 11; 11(1):291. View in: Pubmed

      • CDK4/6 inhibition reprograms the breast cancer enhancer landscape by stimulating AP-1 transcriptional activity. Nat Cancer. 2021 01; 2(1):34-48. View in: Pubmed

      • Divergent Roles of PI3K Isoforms in PTEN-Deficient Glioblastomas. Cell Rep. 2020 09 29; 32(13):108196. View in: Pubmed

      • PIK3CA C-terminal frameshift mutations are novel oncogenic events that sensitize tumors to PI3K-a inhibition. Proc Natl Acad Sci U S A. 2020 09 29; 117(39):24427-24433. View in: Pubmed

      • A sequential methodology for the rapid identification and characterization of breast cancer-associated functional SNPs. Nat Commun. 2020 07 03; 11(1):3340. View in: Pubmed

      • Integrating Immunotherapy and Targeted Therapy in Cancer Treatment: Mechanistic Insights and Clinical Implications. Clin Cancer Res. 2020 11 01; 26(21):5557-5566. View in: Pubmed

      • Limited Environmental Serine and Glycine Confer Brain Metastasis Sensitivity to PHGDH Inhibition. Cancer Discov. 2020 09; 10(9):1352-1373. View in: Pubmed

      • Increased lysosomal biomass is responsible for the resistance of triple-negative breast cancers to CDK4/6 inhibition. Sci Adv. 2020 06; 6(25):eabb2210. View in: Pubmed

      • High-throughput dynamic BH3 profiling may quickly and accurately predict effective therapies in solid tumors. Sci Signal. 2020 06 16; 13(636). View in: Pubmed

      • Inhibition of the transcriptional kinase CDK7 overcomes therapeutic resistance in HER2-positive breast cancers. Oncogene. 2020 01; 39(1):50-63. View in: Pubmed

      • PI3 kinase alpha and delta promote hematopoietic stem cell activation. JCI Insight. 2019 05 23; 5. View in: Pubmed

      • Buparlisib in Patients With Recurrent Glioblastoma Harboring Phosphatidylinositol 3-Kinase Pathway Activation: An Open-Label, Multicenter, Multi-Arm, Phase II Trial. J Clin Oncol. 2019 03 20; 37(9):741-750. View in: Pubmed

      • Improving orthotopic mouse models of patient-derived breast cancer brain metastases by a modified intracarotid injection method. Sci Rep. 2019 01 24; 9(1):622. View in: Pubmed

      • PARP Inhibition Elicits STING-Dependent Antitumor Immunity in Brca1-Deficient Ovarian Cancer. Cell Rep. 2018 12 11; 25(11):2972-2980.e5. View in: Pubmed

      • Targeted Profiling of RNA Translation. Curr Protoc Mol Biol. 2019 01; 125(1):e71. View in: Pubmed

      • A Conditional Dependency on MELK for the Proliferation of Triple-Negative Breast Cancer Cells. iScience. 2018 Nov 30; 9:149-160. View in: Pubmed

      • Structure-Based Drug Design and Identification of H2O-Soluble and Low Toxic Hexacyclic Camptothecin Derivatives with Improved Efficacy in Cancer and Lethal Inflammation Models in Vivo. J Med Chem. 2018 10 11; 61(19):8613-8624. View in: Pubmed

      • BRCA1-IRIS promotes human tumor progression through PTEN blockade and HIF-1a activation. Proc Natl Acad Sci U S A. 2018 10 09; 115(41):E9600-E9609. View in: Pubmed

      • Targeted profiling of RNA translation reveals mTOR-4EBP1/2-independent translation regulation of mRNAs encoding ribosomal proteins. Proc Natl Acad Sci U S A. 2018 10 02; 115(40):E9325-E9332. View in: Pubmed

      • An alternative splicing switch in FLNB promotes the mesenchymal cell state in human breast cancer. Elife. 2018 07 30; 7. View in: Pubmed

      • CDK4/6 Inhibition in Cancer: Beyond Cell Cycle Arrest. Trends Cell Biol. 2018 11; 28(11):911-925. View in: Pubmed

      • Dual HDAC and PI3K Inhibition Abrogates NF?B- and FOXM1-Mediated DNA Damage Response to Radiosensitize Pediatric High-Grade Gliomas. Cancer Res. 2018 07 15; 78(14):4007-4021. View in: Pubmed

      • Correction: MELK is an oncogenic kinase essential for mitotic progression in basal-like breast cancer cells. Elife. 2018 03 12; 7. View in: Pubmed

      • Isoform-Selective Phosphatidylinositol 3-Kinase Inhibition in Cancer. J Clin Oncol. 2018 05 01; 36(13):1339-1342. View in: Pubmed

      • Oncogenic Kinase-Induced PKM2 Tyrosine 105 Phosphorylation Converts Nononcogenic PKM2 to a Tumor Promoter and Induces Cancer Stem-like Cells. Cancer Res. 2018 05 01; 78(9):2248-2261. View in: Pubmed

      • Allele-Specific Chromatin Recruitment and Therapeutic Vulnerabilities of ESR1 Activating Mutations. Cancer Cell. 2018 02 12; 33(2):173-186.e5. View in: Pubmed

      • Drug Resistance in HER2-Positive Breast Cancer Brain Metastases: Blame the Barrier or the Brain? Clin Cancer Res. 2018 04 15; 24(8):1795-1804. View in: Pubmed

      • Oridonin inhibits aberrant AKT activation in breast cancer. Oncotarget. 2018 May 08; 9(35):23878-23889. View in: Pubmed

      • Pik3ca is required for mouse uterine gland development and pregnancy. PLoS One. 2018; 13(1):e0191433. View in: Pubmed

      • PI3Ka inactivation in leptin receptor cells increases leptin sensitivity but disrupts growth and reproduction. JCI Insight. 2017 12 07; 2(23). View in: Pubmed

      • Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma. Nature. 2017 09 28; 549(7673):533-537. View in: Pubmed

      • MELK is not necessary for the proliferation of basal-like breast cancer cells. Elife. 2017 09 19; 6. View in: Pubmed

      • CDK4/6 inhibition triggers anti-tumour immunity. Nature. 2017 08 24; 548(7668):471-475. View in: Pubmed

      • CRKL Mediates p110ß-Dependent PI3K Signaling in PTEN-Deficient Cancer Cells. Cell Rep. 2017 07 18; 20(3):549-557. View in: Pubmed

      • PI3K-p110a mediates the oncogenic activity induced by loss of the novel tumor suppressor PI3K-p85a. Proc Natl Acad Sci U S A. 2017 07 03; 114(27):7095-7100. View in: Pubmed

      • Cell-Cycle-Targeting MicroRNAs as Therapeutic Tools against Refractory Cancers. Cancer Cell. 2017 04 10; 31(4):576-590.e8. View in: Pubmed

      • The emerging role of PI3K/AKT-mediated epigenetic regulation in cancer. Biochim Biophys Acta Rev Cancer. 2017 Aug; 1868(1):123-131. View in: Pubmed

      • Targeting of Ras-mediated FGF signaling suppresses Pten-deficient skin tumor. Proc Natl Acad Sci U S A. 2016 11 15; 113(46):13156-13161. View in: Pubmed

      • Rac1-mediated membrane raft localization of PI3K/p110ß is required for its activation by GPCRs or PTEN loss. Elife. 2016 10 04; 5. View in: Pubmed

      • NTRK2 activation cooperates with PTEN deficiency in T-ALL through activation of both the PI3K-AKT and JAK-STAT3 pathways. Cell Discov. 2016; 2:16030. View in: Pubmed

      • Mitotic MELK-eIF4B signaling controls protein synthesis and tumor cell survival. Proc Natl Acad Sci U S A. 2016 08 30; 113(35):9810-5. View in: Pubmed

      • CDK4/6 inhibition: the late harvest cycle begins. Oncotarget. 2016 08 02; 7(31):48854-48856. View in: Pubmed

      • Discovery of a Series of 5,11-Dihydro-6H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6-ones as Selective PI3K-d/? Inhibitors. ACS Med Chem Lett. 2016 Oct 13; 7(10):908-912. View in: Pubmed

      • Combined inhibition of PI3K and PARP is effective in the treatment of ovarian cancer cells with wild-type PIK3CA genes. Gynecol Oncol. 2016 09; 142(3):548-56. View in: Pubmed

      • Tyrosine receptor kinase B is a drug target in astrocytomas. Neuro Oncol. 2017 01; 19(1):22-30. View in: Pubmed

      • PI3K/AKT Signaling Regulates H3K4 Methylation in Breast Cancer. Cell Rep. 2016 06 21; 15(12):2692-704. View in: Pubmed

      • Combination inhibition of PI3K and mTORC1 yields durable remissions in mice bearing orthotopic patient-derived xenografts of HER2-positive breast cancer brain metastases. Nat Med. 2016 07; 22(7):723-6. View in: Pubmed

      • A cell-based quantitative high-throughput image screening identified novel autophagy modulators. Pharmacol Res. 2016 08; 110:35-49. View in: Pubmed

      • PI3K in the ventromedial hypothalamic nucleus mediates estrogenic actions on energy expenditure in female mice. Sci Rep. 2016 Mar 18; 6:23459. View in: Pubmed

      • Effective use of PI3K inhibitor BKM120 and PARP inhibitor Olaparib to treat PIK3CA mutant ovarian cancer. Oncotarget. 2016 Mar 15; 7(11):13153-66. View in: Pubmed

      • Overcoming Therapeutic Resistance in HER2-Positive Breast Cancers with CDK4/6 Inhibitors. Cancer Cell. 2016 Mar 14; 29(3):255-269. View in: Pubmed

      • Corrigendum: Essential roles of PI(3)K-p110ß in cell growth, metabolism and tumorigenesis. Nature. 2016 05 12; 533(7602):278. View in: Pubmed

      • Mouse models of human PIK3CA-related brain overgrowth have acutely treatable epilepsy. Elife. 2015 Dec 03; 4. View in: Pubmed

      • Modeling human PIK3CA-related congenital brain overgrowth and epilepsy in mice. Int J Dev Neurosci. 2015 Dec; 47(Pt A):46. View in: Pubmed

      • A PI3K p110ß-Rac signalling loop mediates Pten-loss-induced perturbation of haematopoiesis and leukaemogenesis. Nat Commun. 2015 Oct 07; 6:8501. View in: Pubmed

      • CDK7-dependent transcriptional addiction in triple-negative breast cancer. Cell. 2015 Sep 24; 163(1):174-86. View in: Pubmed

      • The ERa-PI3K Cascade in Proopiomelanocortin Progenitor Neurons Regulates Feeding and Glucose Balance in Female Mice. Endocrinology. 2015 Dec; 156(12):4474-91. View in: Pubmed

      • Bioprinting for cancer research. Trends Biotechnol. 2015 Sep; 33(9):504-13. View in: Pubmed

      • Light-triggered, self-immolative nucleic Acid-drug nanostructures. J Am Chem Soc. 2015 May 20; 137(19):6112-5. View in: Pubmed

      • Class IA Phosphatidylinositol 3-Kinase Isoform p110a Mediates Vascular Remodeling. Arterioscler Thromb Vasc Biol. 2015 Jun; 35(6):1434-44. View in: Pubmed

      • Chemopreventive effects of aspirin at a glance. Biochim Biophys Acta. 2015 Apr; 1855(2):254-63. View in: Pubmed

      • Role of phosphoinositide 3-OH kinase p110ß in skeletal myogenesis. Mol Cell Biol. 2015 Apr; 35(7):1182-96. View in: Pubmed

      • PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting. Nat Rev Cancer. 2015 Jan; 15(1):7-24. View in: Pubmed

      • Measurement of PIP3 levels reveals an unexpected role for p110ß in early adaptive responses to p110a-specific inhibitors in luminal breast cancer. Cancer Cell. 2015 Jan 12; 27(1):97-108. View in: Pubmed

      • Cyclin C is a haploinsufficient tumour suppressor. Nat Cell Biol. 2014 Nov; 16(11):1080-91. View in: Pubmed

      • MELK is an oncogenic kinase essential for mitotic progression in basal-like breast cancer cells. Elife. 2014 May 20; 3:e01763. View in: Pubmed

      • PI3K isoform dependence of PTEN-deficient tumors can be altered by the genetic context. Proc Natl Acad Sci U S A. 2014 Apr 29; 111(17):6395-400. View in: Pubmed

      • Hematopoiesis and RAS-driven myeloid leukemia differentially require PI3K isoform p110a. J Clin Invest. 2014 Apr; 124(4):1794-809. View in: Pubmed

      • A genetic mouse model of invasive endometrial cancer driven by concurrent loss of Pten and Lkb1 Is highly responsive to mTOR inhibition. Cancer Res. 2014 Jan 01; 74(1):15-23. View in: Pubmed

      • The gene dosage of class Ia PI3K dictates the development of PTEN hamartoma tumor syndrome. Cell Cycle. 2013 Dec 01; 12(23):3589-93. View in: Pubmed

      • Coordinate activation of Shh and PI3K signaling in PTEN-deficient glioblastoma: new therapeutic opportunities. Nat Med. 2013 Nov; 19(11):1518-23. View in: Pubmed

      • Mutant PIK3CA accelerates HER2-driven transgenic mammary tumors and induces resistance to combinations of anti-HER2 therapies. Proc Natl Acad Sci U S A. 2013 Aug 27; 110(35):14372-7. View in: Pubmed

      • Spatially distinct roles of class Ia PI3K isoforms in the development and maintenance of PTEN hamartoma tumor syndrome. Genes Dev. 2013 Jul 15; 27(14):1568-80. View in: Pubmed

      • Central GLP-2 enhances hepatic insulin sensitivity via activating PI3K signaling in POMC neurons. Cell Metab. 2013 Jul 02; 18(1):86-98. View in: Pubmed

      • Conditional loss of ErbB3 delays mammary gland hyperplasia induced by mutant PIK3CA without affecting mammary tumor latency, gene expression, or signaling. Cancer Res. 2013 Jul 01; 73(13):4075-85. View in: Pubmed

      • Opposing effects of androgen deprivation and targeted therapy on prostate cancer prevention. Cancer Discov. 2013 Jan; 3(1):44-51. View in: Pubmed

      • The p110a and p110ß isoforms of PI3K play divergent roles in mammary gland development and tumorigenesis. Genes Dev. 2012 Jul 15; 26(14):1573-86. View in: Pubmed

      • Functional characterization of an isoform-selective inhibitor of PI3K-p110ß as a potential anticancer agent. Cancer Discov. 2012 May; 2(5):425-33. View in: Pubmed

      • Kinome-wide selectivity profiling of ATP-competitive mammalian target of rapamycin (mTOR) inhibitors and characterization of their binding kinetics. J Biol Chem. 2012 Mar 23; 287(13):9742-9752. View in: Pubmed

      • Lysosomal transmembrane protein LAPTM4B promotes autophagy and tolerance to metabolic stress in cancer cells. Cancer Res. 2011 Dec 15; 71(24):7481-9. View in: Pubmed

      • The acute effects of leptin require PI3K signaling in the hypothalamic ventral premammillary nucleus. J Neurosci. 2011 Sep 14; 31(37):13147-56. View in: Pubmed

      • Oncogenic PIK3CA-driven mammary tumors frequently recur via PI3K pathway-dependent and PI3K pathway-independent mechanisms. Nat Med. 2011 Aug 07; 17(9):1116-20. View in: Pubmed

      • Therapeutic implications of GIPC1 silencing in cancer. PLoS One. 2010 Dec 30; 5(12):e15581. View in: Pubmed

      • COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature. 2010 Dec 16; 468(7326):968-72. View in: Pubmed

      • PI3K signaling in the ventromedial hypothalamic nucleus is required for normal energy homeostasis. Cell Metab. 2010 Jul 07; 12(1):88-95. View in: Pubmed

      • Specific roles of the p110alpha isoform of phosphatidylinsositol 3-kinase in hepatic insulin signaling and metabolic regulation. Cell Metab. 2010 Mar 03; 11(3):220-30. View in: Pubmed

      • Estrogen receptor-negative breast cancer: new insights into subclassification and targeting. Clin Cancer Res. 2009 Oct 15; 15(20):6309-10. View in: Pubmed

      • Phosphatidyl inositol 3-kinase signaling in hypothalamic proopiomelanocortin neurons contributes to the regulation of glucose homeostasis. Endocrinology. 2009 Nov; 150(11):4874-82. View in: Pubmed

      • Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 2009 Aug; 8(8):627-44. View in: Pubmed

      • SIK1 couples LKB1 to p53-dependent anoikis and suppresses metastasis. Sci Signal. 2009 Jul 21; 2(80):ra35. View in: Pubmed

      • 3-Phosphoinositide-dependent kinase 1 potentiates upstream lesions on the phosphatidylinositol 3-kinase pathway in breast carcinoma. Cancer Res. 2009 Aug 01; 69(15):6299-306. View in: Pubmed

      • Should individual PI3 kinase isoforms be targeted in cancer? Curr Opin Cell Biol. 2009 Apr; 21(2):199-208. View in: Pubmed

      • Essential roles of PI(3)K-p110beta in cell growth, metabolism and tumorigenesis. Nature. 2008 Aug 07; 454(7205):776-9. View in: Pubmed

      • Integrative genomic approaches identify IKBKE as a breast cancer oncogene. Cell. 2007 Jun 15; 129(6):1065-79. View in: Pubmed

      • Surveillance mechanism linking Bub1 loss to the p53 pathway. Proc Natl Acad Sci U S A. 2007 May 15; 104(20):8334-9. View in: Pubmed

      • The p110alpha isoform of phosphatidylinositol 3-kinase is essential for polyomavirus middle T antigen-mediated transformation. J Virol. 2007 Jul; 81(13):7069-76. View in: Pubmed

      • PI3 kinases in cancer: from oncogene artifact to leading cancer target. Sci STKE. 2006 Dec 12; 2006(365):pe52. View in: Pubmed

      • The p110alpha isoform of PI3K is essential for proper growth factor signaling and oncogenic transformation. Proc Natl Acad Sci U S A. 2006 Oct 31; 103(44):16296-300. View in: Pubmed

      • The oncogenic properties of mutant p110alpha and p110beta phosphatidylinositol 3-kinases in human mammary epithelial cells. Proc Natl Acad Sci U S A. 2005 Dec 20; 102(51):18443-8. View in: Pubmed

      • A genetic screen for candidate tumor suppressors identifies REST. Cell. 2005 Jun 17; 121(6):837-48. View in: Pubmed

      • Androgen-induced differentiation and tumorigenicity of human prostate epithelial cells. Cancer Res. 2004 Dec 15; 64(24):8867-75. View in: Pubmed

      • Functional genetics and experimental models of human cancer. Trends Mol Med. 2004 Jul; 10(7):344-50. View in: Pubmed

      • Simian virus 40 large T antigen targets the spindle assembly checkpoint protein Bub1. Proc Natl Acad Sci U S A. 2004 Jan 27; 101(4):947-52. View in: Pubmed

      • A chemical genetic screen identifies inhibitors of regulated nuclear export of a Forkhead transcription factor in PTEN-deficient tumor cells. Cancer Cell. 2003 Dec; 4(6):463-76. View in: Pubmed

      • Human mammary epithelial cell transformation through the activation of phosphatidylinositol 3-kinase. Cancer Cell. 2003 May; 3(5):483-95. View in: Pubmed


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      Dana-Farber Cancer Institute

      450 Brookline Avenue Smith 936B Boston, MA 02215
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      Dana-Farber Cancer Institute

      Location Avtar

      Dana-Farber Cancer Institute

      450 Brookline Avenue Smith 936B Boston, MA 02215
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      42.3374, -71.1082