Gregg L Semenza

Johns Hopkins University, Baltimore, Maryland, United States

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Publications (398)3013.01 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Increased expression of CD47 has been reported to enable cancer cells to evade phagocytosis by macrophages and to promote the cancer stem cell phenotype, but the molecular mechanisms regulating CD47 expression have not been determined. Here we report that hypoxia-inducible factor 1 (HIF-1) directly activates transcription of the CD47 gene in hypoxic breast cancer cells. Knockdown of HIF activity or CD47 expression increased the phagocytosis of breast cancer cells by bone marrow-derived macrophages. CD47 expression was increased in mammosphere cultures, which are enriched for cancer stem cells, and CD47 deficiency led to cancer stem cell depletion. Analysis of datasets derived from thousands of patients with breast cancer revealed that CD47 expression was correlated with HIF target gene expression and with patient mortality. Thus, CD47 expression contributes to the lethal breast cancer phenotype that is mediated by HIF-1.
    Proceedings of the National Academy of Sciences 10/2015; DOI:10.1073/pnas.1520032112 · 9.67 Impact Factor
  • Maimon E Hubbi · Gregg L Semenza ·
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    ABSTRACT: Hypoxia is a physiological cue that impacts diverse physiological processes, including energy metabolism, autophagy, cell motility, angiogenesis, and erythropoiesis. One of the key cell-autonomous effects of hypoxia is as a modulator of cell proliferation. For most cell types, hypoxia induces decreased cell proliferation, since an increased number of cells, with a consequent increase in O2 demand, would only exacerbate hypoxic stress. However, certain cell populations can maintain cell proliferation in the face of hypoxia. This is a common pathological hallmark of cancers, but can also serve a physiological function, as in the maintenance of stem cell populations that reside in a hypoxic niche. This review will discuss major molecular mechanisms by which hypoxia regulates cell proliferation in different cell populations, with a particular focus on the role of hypoxia-inducible factors.
    AJP Cell Physiology 10/2015; DOI:10.1152/ajpcell.00279.2015 · 3.78 Impact Factor
  • Gregg L Semenza ·

    AJP Cell Physiology 09/2015; 309(6):C349. DOI:10.1152/ajpcell.zh0-7805-editorial.2015 · 3.78 Impact Factor
  • Nanduri R Prabhakar · Gregg L Semenza ·
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    ABSTRACT: The discovery of carotid bodies as sensory receptors for detecting arterial blood oxygen levels, and the identification and elucidation of the roles of hypoxia-inducible factors (HIFs) in oxygen homeostasis have propelled the field of oxygen biology. This review highlights the gas-messenger signaling mechanisms associated with oxygen sensing, as well as transcriptional and non-transcriptional mechanisms underlying the maintenance of oxygen homeostasis by HIFs and their relevance to physiology and pathology.
    Physiology 09/2015; 30(5):340-8. DOI:10.1152/physiol.00022.2015 · 4.86 Impact Factor
  • Nanduri R Prabhakar · Gregg L Semenza ·
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    ABSTRACT: Oxygen (O2) sensing by the carotid body and its chemosensory reflex is critical for homeostatic regulation of breathing and blood pressure. Carotid body responses to hypoxia are not uniform but instead exhibit remarkable inter-individual variations. The molecular mechanisms underlying variations in carotid body O2 sensing are not known. Hypoxia-inducible factor-1 (HIF-1) and HIF-2 mediate transcriptional responses to hypoxia. This article reviews the emerging evidence that proper expression of the HIF-α isoforms is a key molecular determinant for carotid body O2 sensing. HIF-1α deficiency leads to a blunted carotid body hypoxic response, which is due to increased abundance of HIF-2α, elevated anti-oxidant enzyme activity, and a reduced intracellular redox state. Conversely, HIF-2α deficiency results in augmented carotid body sensitivity to hypoxia, which is due to increased abundance of HIF-1α, elevated pro-oxidant enzyme activity, and an oxidized intracellular redox state. Double heterozygous mice with equally reduced HIF-1α and HIF-2α showed no abnormality in redox state or carotid body O2 sensing. Thus, mutual antagonism between HIF-α isoforms determines the redox state and thereby establishes the set point for hypoxic sensing by the carotid body.
    Pflügers Archiv - European Journal of Physiology 08/2015; DOI:10.1007/s00424-015-1719-z · 4.10 Impact Factor
  • Weibo Luo · Gregg L. Semenza ·

    Cancer Research 08/2015; 75(15 Supplement):525-525. DOI:10.1158/1538-7445.AM2015-525 · 9.33 Impact Factor
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    ABSTRACT: Triple negative breast cancer (TNBC) accounts for 10-15% of all breast cancer but is responsible for a disproportionate share of morbidity and mortality because of its aggressive characteristics and lack of targeted therapies. Chemotherapy induces enrichment of breast cancer stem cells (BCSCs), which are responsible for tumor recurrence and metastasis. Here, we demonstrate that chemotherapy induces the expression of the cystine transporter xCT and the regulatory subunit of glutamate-cysteine ligase (GCLM) in a hypoxia-inducible factor (HIF)-1-dependent manner, leading to increased intracellular glutathione levels, which inhibit mitogen-activated protein kinase kinase (MEK) activity through copper chelation. Loss of MEK-ERK signaling causes FoxO3 nuclear translocation and transcriptional activation of the gene encoding the pluripotency factor Nanog, which is required for enrichment of BCSCs. Inhibition of xCT, GCLM, FoxO3, or Nanog blocks chemotherapy-induced enrichment of BCSCs and impairs tumor initiation. These results suggest that, in combination with chemotherapy, targeting BCSCs by inhibiting HIF-1-regulated glutathione synthesis may improve outcome in TNBC.
    Proceedings of the National Academy of Sciences 07/2015; 112(33). DOI:10.1073/pnas.1513433112 · 9.67 Impact Factor
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    ABSTRACT: Aims Previously we demonstrated that both hypoxia inducible factor-1 (HIF-1) and bone morphogenetic protein-4 (BMP4) up-regulate transient receptor potential canonical (TRPC) 1 and TRPC6, resulting in increased basal intracellular Ca2+ concentration ([Ca2+]i) in pulmonary arterial smooth muscle cells (PASMCs), driving development of chronic hypoxia (CH)-induced pulmonary hypertension (CHPH). This study aims to determine whether HIF-1 regulates BMP4, and whether BMP4 mediates TRPC and basal [Ca2+]i increases in hypoxic PASMCs. Methods and results The level of BMP4 mature protein was increased for 183% in distal pulmonary arterial smooth muscle (PA) from CH (10% O2 for 21 days; CH) exposed rats, and 143% in PASMCs cultured under prolonged hypoxia (4% O2 for 60 h). In rat PASMCs, HIF-1α overexpression up-regulated, whereas HIF-1α knockdown under hypoxia decreased BMP4 expression; site-mutation identified two functional HIF-1-binding sites in Bmp4 gene promoter; noggin or BMP4 siRNA treatment blocked hypoxia-induced increases of TRPC1 and TRPC6 expression and basal [Ca2+]i. Likewise, in mice, exposure to CH increased BMP4 expression in distal PA for 80%, which was absent in HIF-1α heterozygous mutant mice. Comparing with wild-type littermates, BMP4 heterozygous mutant mice exposed to CH displayed lower BMP4 and TRPC levels in PA, decreased basal [Ca2+]i in PASMCs, and attenuated CHPH. In human PASMCs, HIF-1α knockdown attenuated hypoxia-induced BMP4 expression and knockdown of either HIF-1α or BMP4 abolished hypoxia-induced TRPC expression and basal [Ca2+]i. Conclusions BMP4 acts downstream of HIF-1 and mediates hypoxia-induced up-regulation of TRPC, leading to increased basal [Ca2+]i in PASMCs, promoting CHPH pathogenesis. © 2015 Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: [email protected] /* */
    Cardiovascular Research 07/2015; 107(1). DOI:10.1093/cvr/cvv122 · 5.94 Impact Factor
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    ABSTRACT: Kaposi's sarcoma (KS) is a vascular neoplasm caused by infection of endothelial or endothelial precursor cells with the Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8). Research efforts have focused on defining the molecular events explaining how KSHV promotes pathological angiogenesis and KS tumor formation. mTOR/HIF-1 is a fundamental pathway driving these processes through the upregulation of angiogenic and inflammatory proteins, including VEGF, ANGPTL4, and ANGPT2. Interestingly, HIF-1 has also been implicated in the upregulation of metabolic genes associated with aerobic glycolysis and the growth of solid tumors. However, whether HIF-1 plays a role in regulating cell metabolism in KS remains unexplored. Here, we show that the HIF-1 metabolic effector, pyruvate kinase 2 (PKM2), is upregulated upon KSHV infection of endothelial cells and is necessary to maintain aerobic glycolysis in infected cells. We further demonstrate that PKM2 regulates KS angiogenic phenotype by acting as a coactivator of HIF-1 and increasing the levels of HIF-1 angiogenic factors, including VEGF. Indeed, inhibition of PKM2 expression blocked endothelial cell migration and differentiation and the angiogenic potential of KSHV-infected cells. We also investigated whether PKM2 regulates the angiogenic dysregulation induced by the KSHV-encoded G protein-coupled receptor (vGPCR), a viral oncogene that promotes Kaposi's sarcomagenesis through the upregulation of HIF angiogenic factors. Interestingly, we found that PKM2 controls vGPCR-induced VEGF paracrine secretion and vGPCR oncogenesis. Our findings provide a molecular mechanism for how HIF-1 dysregulation fuels both angiogenesis and tumor metabolism in KS and support further investigations on therapeutic approaches targeting HIF-1 and PKM2 for KS treatment.
    Angiogenesis 06/2015; 18(4). DOI:10.1007/s10456-015-9475-4 · 4.88 Impact Factor
  • Gregg L. Semenza ·
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    ABSTRACT: Intratumoral hypoxia is a common finding in breast cancer and is associated with a significantly increased risk of metastasis and patient mortality. Hypoxia-inducible factors activate the transcription of a large battery of genes encoding proteins that promote primary tumor vascularization and growth, stromal cell recruitment, extracellular matrix remodeling, premetastatic niche formation, cell motility, local tissue invasion, extravasation at sites of metastasis, and maintenance of the cancer stem cell phenotype that is required to generate secondary tumors. Recent preclinical studies suggest that the combination of cytotoxic chemotherapy with drugs that inhibit hypoxia-inducible factors may improve outcome for women with triple-negative breast cancer. Copyright © 2015 Elsevier B.V. All rights reserved.
    Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 06/2015; DOI:10.1016/j.bbamcr.2015.05.036 · 5.02 Impact Factor
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    ABSTRACT: Diabetic eye disease is the most common cause of severe vision loss in the working-age population in the developed world, and proliferative diabetic retinopathy (PDR) is its most vision-threatening sequela. In PDR, retinal ischemia leads to the up-regulation of angiogenic factors that promote neovascularization. Therapies targeting vascular endothelial growth factor (VEGF) delay the development of neovascularization in some, but not all, diabetic patients, implicating additional factor(s) in PDR pathogenesis. Here we demonstrate that the angiogenic potential of aqueous fluid from PDR patients is independent of VEGF concentration, providing an opportunity to evaluate the contribution of other angiogenic factor(s) to PDR development. We identify angiopoietin-like 4 (ANGPTL4) as a potent angiogenic factor whose expression is up-regulated in hypoxic retinal Müller cells in vitro and the ischemic retina in vivo. Expression of ANGPTL4 was increased in the aqueous and vitreous of PDR patients, independent of VEGF levels, correlated with the presence of diabetic eye disease, and localized to areas of retinal neovascularization. Inhibition of ANGPTL4 expression reduced the angiogenic potential of hypoxic Müller cells; this effect was additive with inhibition of VEGF expression. An ANGPTL4 neutralizing antibody inhibited the angiogenic effect of aqueous fluid from PDR patients, including samples from patients with low VEGF levels or receiving anti-VEGF therapy. Collectively, our results suggest that targeting both ANGPTL4 and VEGF may be necessary for effective treatment or prevention of PDR and provide the foundation for studies evaluating aqueous ANGPTL4 as a biomarker to help guide individualized therapy for diabetic eye disease.
    Proceedings of the National Academy of Sciences 05/2015; 112(23). DOI:10.1073/pnas.1423765112 · 9.67 Impact Factor
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    ABSTRACT: Hypoxia-inducible factor 1α (HIF-1α) expression is a hallmark of intratumoral hypoxia that is associated with breast cancer metastasis and patient mortality. Previously, we demonstrated that HIF-1 stimulates the expression and activity of TAZ, which is a transcriptional effector of the Hippo signaling pathway, by increasing TAZ synthesis and nuclear localization. Here, we report that direct protein-protein interaction between HIF-1α and TAZ has reciprocal effects: HIF-1α stimulates transactivation mediated by TAZ and TAZ stimulates transactivation mediated by HIF-1α. Inhibition of TAZ expression impairs the hypoxic induction of HIF-1 target genes, such as PDK1, LDHA, BNIP3 and P4HA2 in response to hypoxia, whereas inhibition of HIF-1α expression impairs TAZ-mediated transactivation of the CTGF promoter. Taken together, these results complement our previous findings and establish bidirectional crosstalk between HIF-1α and TAZ that increases their transcriptional activities in hypoxic cells.
    Oncotarget 05/2015; 6(14):11768-78. DOI:10.18632/oncotarget.4190 · 6.36 Impact Factor
  • Gregg L Semenza ·
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    ABSTRACT: When tissue perfusion is impaired, the resulting reduction in O2 availability activates hypoxia-inducible factor 1 (HIF-1), which mediates increased transcription of genes encoding multiple angiogenic factors including vascular endothelial growth factor, stromal-derived factor 1, placental growth factor, and angiopoietins, leading to the mobilization of bone marrow-derived angiogenic cells, increased angiogenesis, and arterial remodeling. These HIF-1-dependent responses are impaired by aging or loss of function mutations at the locus encoding the HIF-1α subunit. In mouse models of limb ischemia and lung transplant rejection, the augmentation of HIF-1 activity by gene therapy or chemical inducers was associated with maintenance of tissue perfusion that prevented limb amputation and allograft rejection, respectively. Thus, targeting HIF-1 may be of therapeutic benefit in these clinical contexts and others in which impaired tissue perfusion plays a role in disease pathogenesis.
    Journal of Investigative Medicine 05/2015; DOI:10.1097/JIM.0000000000000206 · 1.69 Impact Factor
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    Gregg L Semenza · Nanduri R Prabhakar ·
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    ABSTRACT: Obstructive sleep apnea (OSA) is one of the most common causes of hypertension in western societies. OSA causes chronic intermittent hypoxia (CIH) in specialized O2-sensing glomus cells of the carotid body. CIH generates increased reactive oxygen species (ROS) that trigger a feed-forward mechanism in which increased intracellular calcium levels ([Ca(2+)]i) trigger increased HIF-1α synthesis and increased HIF-2α degradation. As a result, the normal homeostatic balance between HIF-1α-dependent pro-oxidant and HIF-2α-dependent anti-oxidant enzymes is disrupted, leading to further increases in ROS. Carotid body sensory nerves project to the nucleus tractus solitarius, from which the information is relayed via interneurons to the rostral ventrolateral medulla in the brainstem, which sends sympathetic neurons to the adrenal medulla to stimulate the release of epinephrine and norepinephrine, catecholamines that increase blood pressure. At each synapse, neurotransmitters trigger increased [(Ca2+)]i, HIF-1α:HIF-2α and Nox2:Sod2 activity that generates increased ROS levels. These responses are not observed in other regions of the brainstem that do not receive input from the carotid body or signal to the sympathetic nervous system. Thus, sympathetic nervous system homeostasis is dependent on a balance between HIF-1α and HIF-2α, disruption of which results in hypertension in OSA patients. Copyright © 2015, Journal of Applied Physiology.
    Journal of Applied Physiology 05/2015; DOI:10.1152/japplphysiol.00162.2015 · 3.06 Impact Factor
  • Maimon E Hubbi · Gregg L Semenza ·
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    ABSTRACT: Hypoxia has long been known to serve as a stimulus for cell cycle arrest. Hypoxia-mediated cell cycle arrest is mediated through the actions of HIF1A (hypoxia inducible factor 1, alpha subunit [basic helix-loop-helix transcription factor]), which has a nontranscriptional role as an inhibitor of MCM (minichromosome maintenance complex component) helicase activity. We identified chaperone-mediated autophagy as a pathway for selective degradation of HIF1A through lysosomes prior to the onset of DNA replication. CDK2 (cyclin-dependent kinase 2) mediates degradation of HIF1A at the G1/S transition, whereas CDK1 (cyclin-dependent kinase 1) increases HIF1A levels and transcriptional activity prior to the onset of G1 phase. Lysosomal inhibitors induce cell cycle arrest, which is recovered by knockdown of HIF1A and EPAS1/HIF2A. These findings establish lysosomes as essential regulators of cell cycle progression through the degradation of HIF1A.
    Autophagy 05/2015; 11(5). DOI:10.1080/15548627.2015.1037063 · 11.75 Impact Factor
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    ABSTRACT: Reflexes initiated by the carotid body, the principal O2-sensing organ, are critical for maintaining cardiorespiratory homeostasis during hypoxia. O2 sensing by the carotid body requires carbon monoxide (CO) generation by heme oxygenase-2 (HO-2) and hydrogen sulfide (H2S) synthesis by cystathionine-γ-lyase (CSE). We report that O2 stimulated the generation of CO, but not that of H2S, and required two cysteine residues in the heme regulatory motif (Cys(265) and Cys(282)) of HO-2. CO stimulated protein kinase G (PKG)-dependent phosphorylation of Ser(377) of CSE, inhibiting the production of H2S. Hypoxia decreased the inhibition of CSE by reducing CO generation resulting in increased H2S, which stimulated carotid body neural activity. In carotid bodies from mice lacking HO-2, compensatory increased abundance of nNOS (neuronal nitric oxide synthase) mediated O2 sensing through PKG-dependent regulation of H2S by nitric oxide. These results provide a mechanism for how three gases work in concert in the carotid body to regulate breathing. Copyright © 2015, American Association for the Advancement of Science.
    Science Signaling 04/2015; 8(373):ra37. DOI:10.1126/scisignal.2005846 · 6.28 Impact Factor
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    ABSTRACT: Hypoxia-inducible factor 1 (HIF-1) mediates many of the systemic and cellular responses to intermittent hypoxia (IH), which is an experimental model that simulates O2 saturation profiles occurring with recurrent apnea. IH-evoked HIF-1α synthesis and stability are due to increased reactive oxygen species (ROS) generated by NADPH oxidases, especially Nox2. However, the mechanisms by which IH activates Nox2 are not known. We recently reported that IH activates xanthine oxidase (XO) and the resulting increase in ROS elevates intracellular calcium levels. Since Nox2 activation requires increased intracellular calcium levels, we hypothesized XO-mediated calcium signaling contributes to Nox activation by IH. We tested this possibility in rat pheochromocytoma PC12 cells subjected to IH consisting alternating cycles of hypoxia (1.5% O2 for 30 sec) and normoxia (21% O2 for 5 min). Kinetic analysis revealed that IH-induced XO preceded Nox activation. Inhibition of XO activity either by allopurinol or by siRNA prevented IH-induced Nox activation, translocation of the cytosolic subunits p47phox and p67phox to the plasma membrane and their interaction with gp91phox. ROS generated by XO also contribute to IH-evoked Nox activation via calcium-dependent protein kinase C stimulation. More importantly, silencing XO blocked IH-induced upregulation of HIF-1α demonstrating that HIF-1α activation by IH requires Nox2 activation by XO.
    PLoS ONE 03/2015; 10(3):e0119762. DOI:10.1371/journal.pone.0119762 · 3.23 Impact Factor
  • Zhao-Ji Liu · Gregg L Semenza · Hua-Feng Zhang ·
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    ABSTRACT: Accumulating evidence has shown that the hypoxic microenvironment, which is critical during cancer development, plays a key role in regulating breast cancer progression and metastasis. The effects of hypoxia-inducible factor 1 (HIF-1), a master regulator of the hypoxic response, have been extensively studied during these processes. In this review, we focus on the roles of HIF-1 in regulating breast cancer cell metastasis, specifically its effects on multiple key steps of metastasis, such as epithelial-mesenchymal transition (EMT), invasion, extravasation, and metastatic niche formation. We also discuss the roles of HIF-1-regulated non-coding RNAs in breast cancer metastasis, and therapeutic opportunities for breast cancer through targeting the HIF-1 pathway. 概要 肿瘤, 特别是实体瘤, 其内部微环境处于一种低氧或缺氧的状态, 肿瘤的这种低氧微环境将诱导活化低氧诱导因子(HIF-1)信号通路。 HIF-1信号通路在乳腺癌的转移中发挥着重要的作用。 乳腺癌的转移涉及肿瘤细胞的浸润、 进入血管、 通过血液循环迁移、 到达远端毛细血管内壁、 穿透血管壁进入新的器官以及在新的部位形成转移灶等步骤, 过程非常复杂。 本文重点围绕HIF-1在转移各个步骤中的作用进行综述。
    Journal of Zhejiang University SCIENCE B 01/2015; 16(1):32-43. DOI:10.1631/jzus.B1400221 · 1.28 Impact Factor
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    ABSTRACT: Intratumoral hypoxia, which is associated with breast cancer metastasis and patient mortality, increases the percentage of breast cancer stem cells (BCSCs) but the underlying molecular mechanisms have not been delineated. Here we report that hypoxia-inducible factor 1 (HIF-1) triggers the expression and activity of TAZ, a transcriptional co-activator that is required for BCSC maintenance, through two discrete mechanisms. First, HIF-1 binds directly to the WWTR1 gene and activates transcription of TAZ mRNA. Second, HIF-1 activates transcription of the SIAH1 gene, which encodes a ubiquitin protein ligase that is required for the hypoxia-induced ubiquitination and proteasome-dependent degradation of LATS2, a kinase that inhibits the nuclear localization of TAZ. Inhibition of HIF-1α, TAZ, or SIAH1 expression by short hairpin RNA blocked the enrichment of BCSCs in response to hypoxia. Human breast cancer database analysis revealed that increased expression (greater than the median) of both TAZ and HIF-1 target genes, but neither one alone, is associated with significantly increased patient mortality. Taken together, these results establish a molecular mechanism for induction of the BCSC phenotype in response to hypoxia.
    Oncotarget 12/2014; 5(24):12509-27. DOI:10.18632/oncotarget.2997 · 6.36 Impact Factor
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    ABSTRACT: Triple negative breast cancers (TNBCs) are defined by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 expression, and are treated with cytotoxic chemotherapy such as paclitaxel or gemcitabine, with a durable response rate of less than 20%. TNBCs are enriched for the basal subtype gene expression profile and the presence of breast cancer stem cells, which are endowed with self-renewing and tumor-initiating properties and resistance to chemotherapy. Hypoxia-inducible factors (HIFs) and their target gene products are highly active in TNBCs. Here, we demonstrate that HIF expression and transcriptional activity are induced by treatment of MDA-MB-231, SUM-149, and SUM-159, which are human TNBC cell lines, as well as MCF-7, which is an ER(+)/PR(+) breast cancer line, with paclitaxel or gemcitabine. Chemotherapy-induced HIF activity enriched the breast cancer stem cell population through interleukin-6 and interleukin-8 signaling and increased expression of multidrug resistance 1. Coadministration of HIF inhibitors overcame the resistance of breast cancer stem cells to paclitaxel or gemcitabine, both in vitro and in vivo, leading to tumor eradication. Increased expression of HIF-1α or HIF target genes in breast cancer biopsies was associated with decreased overall survival, particularly in patients with basal subtype tumors and those treated with chemotherapy alone. Based on these results, clinical trials are warranted to test whether treatment of patients with TNBC with a combination of cytotoxic chemotherapy and HIF inhibitors will improve patient survival.
    Proceedings of the National Academy of Sciences 12/2014; 111(50). DOI:10.1073/pnas.1421438111 · 9.67 Impact Factor

Publication Stats

67k Citations
3,013.01 Total Impact Points


  • 1988-2015
    • Johns Hopkins University
      • • Department of Biological Chemistry
      • • McKusick-Nathans Institute of Genetic Medicine
      • • Division of Pulmonary and Critical Care Medicine
      • • Department of Pediatrics
      • • Department of Medicine
      Baltimore, Maryland, United States
  • 1999-2012
    • Johns Hopkins Medicine
      • • Department of Medicine
      • • Department of Pediatrics
      • • Wilmer Eye Institute
      Baltimore, Maryland, United States
    • Beth Israel Deaconess Medical Center
      • Department of Neurology
      Boston, MA, United States
  • 2011
    • VA Palo Alto Health Care System
      Palo Alto, California, United States
  • 2010
    • University of Utah
      • School of Medicine
      Salt Lake City, Utah, United States
  • 2008
    • Harvard Medical School
      Boston, Massachusetts, United States
    • Tazuke Kofukai Medical Research Institute, Kitano Hospital
      Ōsaka, Ōsaka, Japan
  • 2007
    • University of Chicago
      • Department of Medicine
      Chicago, IL, United States
  • 2000
    • University of Cincinnati
      • Department of Neurology
      Cincinnati, Ohio, United States
  • 1996
    • Otsuka America Pharmaceutical
      Princeton, New Jersey, United States
  • 1995
    • University of Alabama at Birmingham
      • Division of Hematology / Oncology
      Birmingham, Alabama, United States
  • 1991
    • Vanderbilt University
      • Division of Hematology and Oncology
      Nashville, MI, United States