Rakesh K Jain

Harvard University, Cambridge, Massachusetts, United States

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Publications (450)4675.71 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: To date, antiangiogenic therapy has failed to improve overall survival in cancer patients when used in the adjuvant setting (local-regional disease with no detectable systemic metastasis). The presence of lymph node metastases worsens prognosis, however their reliance on angiogenesis for growth has not been reported. Here, we introduce a novel chronic lymph node window (CLNW) model to facilitate new discoveries in the growth and spread of lymph node metastases. We use the CLNW in multiple models of spontaneous lymphatic metastases in mice to study the vasculature of metastatic lymph nodes (n = 9-12). We further test our results in patient samples (n = 20 colon cancer patients; n = 20 head and neck cancer patients). Finally, we test the ability of antiangiogenic therapy to inhibit metastatic growth in the CLNW. All statistical tests were two-sided. Using the CLNW, we reveal the surprising lack of sprouting angiogenesis during metastatic growth, despite the presence of hypoxia in some lesions. Treatment with two different antiangiogenic therapies showed no effect on the growth or vascular density of lymph node metastases (day 10: untreated mean = 1.2%, 95% confidence interval [CI] = 0.7% to 1.7%; control mean = 0.7%, 95% CI = 0.1% to 1.3%; DC101 mean = 0.4%, 95% CI = 0.0% to 3.3%; sunitinib mean = 0.5%, 95% CI = 0.0% to 1.0%, analysis of variance P = .34). We confirmed these findings in clinical specimens, including the lack of reduction in blood vessel density in lymph node metastases in patients treated with bevacizumab (no bevacizumab group mean = 257 vessels/mm(2), 95% CI = 149 to 365 vessels/mm(2); bevacizumab group mean = 327 vessels/mm(2), 95% CI = 140 to 514 vessels/mm(2), P = .78). We provide preclinical and clinical evidence that sprouting angiogenesis does not occur during the growth of lymph node metastases, and thus reveals a new mechanism of treatment resistance to antiangiogenic therapy in adjuvant settings. The targets of clinically approved angiogenesis inhibitors are not active during early cancer progression in the lymph node, suggesting that inhibitors of sprouting angiogenesis as a class will not be effective in treating lymph node metastases. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
    CancerSpectrum Knowledge Environment 09/2015; 107(9). DOI:10.1093/jnci/djv155 · 15.16 Impact Factor
  • Triantafyllos Stylianopoulos · Rakesh K Jain
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    ABSTRACT: Nanotherapeutics have improved the quality of life of cancer patients, primarily by reducing the adverse effects of chemotherapeutic agents, but improvements in overall survival are modest. This is in large part due to the fact that the Enhanced Permeability and Retention effect, which is the basis for the use of nanoparticles in cancer, can be also a barrier to the delivery of nanomedicines. A careful design of nanoparticle formulations can overcome barriers posed by the tumor microenvironment and result in better treatments. In this review, we first discuss strengths and limitations of clinically-approved nanoparticles. Then, we evaluate design parameters that can be modulated to optimize intratumoral delivery. The benefits of active tumor targeting and drug release rate on intratumoral delivery and treatment efficacy are also discussed. Finally, we suggest specific design strategies that should optimize delivery to most solid tumors and discuss under what conditions active targeting would be beneficial. Copyright © 2015. Published by Elsevier Inc.
    Nanomedicine: nanotechnology, biology, and medicine 08/2015; DOI:10.1016/j.nano.2015.07.015 · 5.98 Impact Factor
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    ABSTRACT: Pulmonary granulomas-the hallmark of Mycobacterium tuberculosis (MTB) infection-are dense cellular lesions that often feature regions of hypoxia and necrosis, partially due to limited transport of oxygen. Low oxygen in granulomas can impair the host immune response, while MTB are able to adapt and persist in hypoxic environments. Here, we used a physiologically based mathematical model of oxygen diffusion and consumption to calculate oxygen profiles within the granuloma, assuming Michaelis-Menten kinetics. An approximate analytical solution-using a priori and newly estimated parameters from experimental data in a rabbit model of tuberculosis-was able to predict the size of hypoxic and necrotic regions in agreement with experimental results from the animal model. Such quantitative understanding of transport limitations can inform future tuberculosis therapeutic strategies that may include adjunct host-directed therapies that facilitate oxygen and drug delivery for more effective treatment.
    Annals of Biomedical Engineering 08/2015; DOI:10.1007/s10439-015-1415-3 · 3.23 Impact Factor
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    ABSTRACT: Subcutaneous xenografts have been used for decades to study hepatocellular carcinoma (HCC). These models do not reproduce the specific pathophysiological features of HCCs, which occur in cirrhotic livers that show pronounced necroinflammation, abnormal angiogenesis and extensive fibrosis. As these features are crucial for studying the role of the pathologic host microenvironment in tumor initiation, progression and treatment response, alternative HCC models are desirable. Here we describe a syngeneic orthotopic HCC model in immunocompetent mice with liver cirrhosis induced by carbon tetrachloride (CCl4) that recapitulates key features of human HCC. Induction of substantial hepatic fibrosis requires 12 weeks of CCl4 administration. Intrahepatic implantation of mouse HCC cell lines requires 30 min per mouse. Tumor growth varies by tumor cell line and mouse strain used. Alternatively, tumors can be induced in a genetically engineered mouse model. In this setting, CCl4 is administered for 12 weeks after tail-vein injection of Cre-expressing adenovirus (adeno-Cre) in Stk4(-/-)Stk3(F/-) (also known as Mst1(-/-)Mst2(F/-); F indicates a floxed allele) mice, and it results in the development of HCC tumors (hepatocarcinogenesis) concomitantly with liver cirrhosis.
    Nature Protocol 08/2015; 10(8):1264-1274. DOI:10.1038/nprot.2015.080 · 8.36 Impact Factor
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    ABSTRACT: We report the preclinical evaluation of PF-06463922, a potent and brain-penetrant ALK/ROS1 inhibitor. Compared with other clinically available ALK inhibitors, PF-06463922 displayed superior potency against all known clinically acquired ALK mutations, including the highly resistant G1202R mutant. Furthermore, PF-06463922 treatment led to regression of EML4-ALK-driven brain metastases, leading to prolonged mouse survival, in a superior manner. Finally, PF-06463922 demonstrated high selectivity and safety margins in a variety of preclinical studies. These results suggest that PF-06463922 will be highly effective for the treatment of patients with ALK-driven lung cancers, including those who relapsed on clinically available ALK inhibitors because of secondary ALK kinase domain mutations and/or brain metastases. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cancer Cell 07/2015; 27(7):1-12. DOI:10.1016/j.ccell.2015.05.010 · 23.89 Impact Factor
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    ABSTRACT: Micelles have been employed to encapsulate the supramolecular assembly of quantum dots with palladium(II) porphyrins for the quantification of O2 levels in aqueous media and in vivo. Förster resonance energy transfer (FRET) from the quantum dot to the palladium porphyrin provides a means for signal transduction under both one- and two-photon excitation. The palladium porphyrins are sensitive to O2 concentrations in the range of 0-160 torr. Since quantum dot (QD) emission is unaffected by the presence of oxygen, ratiometric sensing is established. The micelle-encapsulated QD-porphyrin assemblies have been employed for in vivo multiphoton imaging and lifetime-based oxygen measurements in mice with chronic dorsal skinfold chambers or cranial windows. Our results establish the utility of the QD-micelle approach for biological sensing applications.
    Journal of the American Chemical Society 07/2015; DOI:10.1021/jacs.5b04765 · 11.44 Impact Factor
  • Rakesh K Jain · Dai Fukumura · Dan G Duda
    The Cancer Journal 07/2015; 21(4):235-6. DOI:10.1097/PPO.0000000000000136 · 3.61 Impact Factor
  • Ana Batista · Lars Riedemann · Trupti Vardam · Rakesh K Jain
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    ABSTRACT: Strategies targeting the microenvironment of pediatric brain cancers have the potential to improve the efficacy of standard and genome-based molecular therapeutics. These strategies also have the potential of helping resolve many of the challenges associated with developing new drugs and running clinical trials for relatively small pediatric brain tumor population. Disrupting vital paracrine and physical interactions between cancer cells and surrounding stroma, targeting and normalizing the abnormal tumor vasculature, and/or inducing antitumor immunity represent some of the most promising approaches. A comprehensive characterization of the pediatric brain tumor microenvironment's composition and function and its modulation by chemoradiation and molecularly targeted therapies is warranted to develop and effectively implement these approaches.
    The Cancer Journal 07/2015; 21(4):307-13. DOI:10.1097/PPO.0000000000000125 · 3.61 Impact Factor
  • Proceedings of the National Academy of Sciences 06/2015; 112(27). DOI:10.1073/pnas.1507225112 · 9.81 Impact Factor
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    ABSTRACT: Background Despite being a highly vascularized tumor, glioblastoma response to anti-vascular endothelial growth factor (VEGF) therapy is transient, possibly because of tumor co-option of preexisting blood vessels and infiltration into surrounding brain. Integrins, which are upregulated after VEGF inhibition, may play a critical role in this resistance mechanism. We designed a study of cediranib, a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor, combined with cilengitide, an integrin inhibitor.
    Neuro-Oncology 05/2015; DOI:10.1093/neuonc/nov085 · 5.29 Impact Factor
  • Rakesh K Jain · Dai Fukumura · Dan G Duda
    The Cancer Journal 05/2015; 21(3):137. DOI:10.1097/PPO.0000000000000119 · 3.61 Impact Factor
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    ABSTRACT: Matrix metalloproteinase (MMP) 14 may mediate tumor progression through vascular and immune-modulatory effects. Orthotopic murine breast tumors (4T1 and E0771 with high and low MMP14 expression, respectively; n = 5-10 per group) were treated with an anti-MMP14 inhibitory antibody (DX-2400), IgG control, fractionated radiation therapy, or their combination. We assessed primary tumor growth, transforming growth factor β (TGFβ) and inducible nitric oxide synthase (iNOS) expression, macrophage phenotype, and vascular parameters. A linear mixed model with repeated observations, with Mann-Whitney or analysis of variance with Bonferroni post hoc adjustment, was used to determine statistical significance. All statistical tests were two-sided. DX-2400 inhibited tumor growth compared with IgG control treatment, increased macrophage numbers, and shifted the macrophage phenotype towards antitumor M1-like. These effects were associated with a reduction in active TGFβ and SMAD2/3 signaling. DX-2400 also transiently increased iNOS expression and tumor perfusion, reduced tissue hypoxia (median % area: control, 20.2%, interquartile range (IQR) = 6.4%-38.9%; DX-2400: 1.2%, IQR = 0.2%-3.2%, P = .044), and synergistically enhanced radiation therapy (days to grow to 800mm(3): control, 12 days, IQR = 9-13 days; DX-2400 plus radiation, 29 days, IQR = 26-30 days, P < .001) in the 4T1 model. The selective iNOS inhibitor, 1400W, abolished the effects of DX-2400 on vessel perfusion and radiotherapy. On the other hand, DX-2400 was not capable of inducing iNOS expression or synergizing with radiation in E0771 tumors. MMP14 blockade decreased immunosuppressive TGFβ, polarized macrophages to an antitumor phenotype, increased iNOS, and improved tumor perfusion, resulting in reduced primary tumor growth and enhanced response to radiation therapy, especially in high MMP14-expressing tumors. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
    JNCI Journal of the National Cancer Institute 04/2015; 107(4). DOI:10.1093/jnci/djv017 · 15.16 Impact Factor
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    ABSTRACT: Treatment of glioblastoma (GBM), the most common primary malignant brain tumor in adults, remains a significant unmet need in oncology. Historically, cytotoxic treatments provided little durable benefit, and tumors recurred within several months. This has spurred a substantial research effort to establish more effective therapies for both newly diagnosed and recurrent GBM. In this context, antiangiogenic therapy emerged as a promising treatment strategy because GBMs are highly vascular tumors. In particular, GBMs overexpress vascular endothelial growth factor (VEGF), a proangiogenic cytokine. Indeed, many studies have demonstrated promising radiographic response rates, delayed tumor progression, and a relatively safe profile for anti-VEGF agents. However, randomized phase III trials conducted to date have failed to show an overall survival benefit for antiangiogenic agents alone or in combination with chemoradiotherapy. These results indicate that antiangiogenic agents may not be beneficial in unselected populations of patients with GBM. Unfortunately, biomarker development has lagged behind in the process of drug development, and no validated biomarker exists for patient stratification. However, hypothesis-generating data from phase II trials that reveal an association between increased perfusion and/or oxygenation (ie, consequences of vascular normalization) and survival suggest that early imaging biomarkers could help identify the subset of patients who most likely will benefit from anti-VEGF agents. In this article, we discuss the lessons learned from the trials conducted to date and how we could potentially use recent advances in GBM biology and imaging to improve outcomes of patients with GBM who receive antiangiogenic therapy. © 2015 by American Society of Clinical Oncology.
    Journal of Clinical Oncology 02/2015; 33(10). DOI:10.1200/JCO.2014.55.9575 · 18.43 Impact Factor
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    ABSTRACT: Conventional drug delivery systems for solid tumors are composed of a nano-carrier that releases its therapeutic load. These two-stage nanoparticles utilize the enhanced permeability and retention (EPR) effect to enable preferential delivery to tumor tissue. However, the size-dependency of the EPR, the limited penetration of nanoparticles into the tumor as well as the rapid binding of the particles or the released cytotoxic agents to cancer cells and stromal components inhibit the uniform distribution of the drug and the efficacy of the treatment. Here, we employ mathematical modeling to study the effect of particle size, drug release rate and binding affinity on the distribution and efficacy of nanoparticles to derive optimal design rules. Furthermore, we introduce a new multi-stage delivery system. The system consists of a 20-nm primary nanoparticle, which releases 5-nm secondary particles, which in turn release the chemotherapeutic drug. We found that tuning the drug release kinetics and binding affinities leads to improved delivery of the drug. Our results also indicate that multi-stage nanoparticles are superior over two-stage nano-carriers provided they have a faster drug release rate and for high binding affinity drugs. Furthermore, our results suggest that smaller nanoparticles achieve better treatment outcome.
    Annals of Biomedical Engineering 02/2015; 43(9). DOI:10.1007/s10439-015-1276-9 · 3.23 Impact Factor
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    ABSTRACT: Brain metastasis is an end stage in breast cancer progression. Traditional treatment options have minimal efficacy, and overall survival is on the order of months. The incidence of brain metastatic disease is increasing with the improved management of systemic disease and prolongation of survival. Unfortunately, the targeted therapies that control systemic disease have diminished efficacy against brain lesions. There are reasons to be optimistic, however, as emerging therapies have shown promise in preclinical and early clinical settings. This review discusses recent advances in breast cancer brain metastasis therapy and potential approaches for successful treatment. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cancer Cell 02/2015; 27(2):163-175. DOI:10.1016/j.ccell.2015.01.001 · 23.89 Impact Factor
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    ABSTRACT: Addition of anti-VEGF antibody therapy to standard chemotherapies has improved survival and is an accepted standard of care for advanced non-small cell lung cancer (NSCLC). However, the mechanisms by which anti-VEGF therapy increases survival remain unclear. We evaluated dynamic CT-based vascular parameters and plasma cytokines after bevacizumab alone and after bevacizumab plus chemotherapy with carboplatin and nab-paclitaxel in advanced NSCLC patients to explore potential biomarkers of treatment response and resistance to this regimen. Thirty-six patients were enrolled in this study. The primary end point was 6-mo progression-free survival rate, which was 74% (95% CI: 57, 97). This regimen has a promising overall response rate of 36% and median time to progression of 8.5 (6.0, 38.7) mo and overall survival of 12.2 (9.6, 44.1) mo. We found that anti-VEGF therapy led to a sustained increase in plasma PlGF, a potential pharmacodynamic marker. We also found that higher levels of soluble VEGFR1 measured before starting bevacizumab with chemotherapy were associated with worse survival, supporting its potential role as biomarker of treatment resistance. Our imaging biomarker studies indicate that bevacizumab-based treatment-while reducing blood flow, volume, and permeability in the overall population-may be associated with improved survival in patients with improved tumor vasculature and blood perfusion after treatment. This hypothesis-generating study supports the notion that excessively decreasing vascular permeability and pruning/rarefaction after bevacizumab therapy may negatively impact the outcome of combination therapy in NSCLC patients. This hypothesis warrants further dose-titration studies of bevacizumab to examine the dose effect on tumor vasculature and treatment efficacy.
    Proceedings of the National Academy of Sciences 02/2015; 112(5):1547-1552. DOI:10.1073/pnas.1424024112 · 9.81 Impact Factor
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    ABSTRACT: Tuberculosis (TB) causes almost 2 million deaths annually, and an increasing number of patients are resistant to existing therapies. Patients who have TB require lengthy chemotherapy, possibly because of poor penetration of antibiotics into granulomas where the bacilli reside. Granulomas are morphologically similar to solid cancerous tumors in that they contain hypoxic microenvironments and can be highly fibrotic. Here, we show that TB-infected rabbits have impaired small molecule distribution into these disease sites due to a functionally abnormal vasculature, with a low-molecular-weight tracer accumulating only in peripheral regions of granulomatous lesions. Granuloma-associated vessels are morphologically and spatially heterogeneous, with poor vessel pericyte coverage in both human and experimental rabbit TB granulomas. Moreover, we found enhanced VEGF expression in both species. In tumors, antiangiogenic, specifically anti-VEGF, treatments can "normalize" their vasculature, reducing hypoxia and creating a window of opportunity for concurrent chemotherapy; thus, we investigated vessel normalization in rabbit TB granulomas. Treatment of TB-infected rabbits with the anti-VEGF antibody bevacizumab significantly decreased the total number of vessels while normalizing those vessels that remained. As a result, hypoxic fractions of these granulomas were reduced and small molecule tracer delivery was increased. These findings demonstrate that bevacizumab treatment promotes vascular normalization, improves small molecule delivery, and decreases hypoxia in TB granulomas, thereby providing a potential avenue to improve delivery and efficacy of current treatment regimens.
    Proceedings of the National Academy of Sciences 01/2015; 112(6). DOI:10.1073/pnas.1424563112 · 9.81 Impact Factor
  • Kamila Naxerova · Rakesh K Jain
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    ABSTRACT: In cancer, much uncertainty remains regarding the origins of metastatic disease. Models of metastatic progression offer competing views on when dissemination occurs (at an early or late stage of tumour development), whether metastases at different sites arise independently and directly from the primary tumour or give rise to each other, and whether dynamic cell exchange occurs between synchronously growing lesions. Although it is probable that many routes can lead to the establishment of systemic disease, clinical observations suggest that distinct modes of metastasis might prevail in different tumour types. Gaining a more-comprehensive understanding of the evolutionary processes that underlie metastasis is not only relevant from a basic biological perspective, but also has profound clinical implications. The 'tree of life' of metastatic cancer contains answers to many outstanding questions about the development of systemic disease, but has only been reconstructed in a limited number of patients. Here we review available data on the phylogenetic relationships between primary solid tumours and their metastases, and examine to what degree they support different models of metastatic progression. We provide a description of experimental methods for lineage tracing in human cancer, ranging from broad DNA-sequencing approaches to more-targeted techniques, and discuss their respective benefits and caveats. Finally, we propose future research questions in the area of cancer phylogenetics.
    Nature Reviews Clinical Oncology 01/2015; 12(5). DOI:10.1038/nrclinonc.2014.238 · 15.70 Impact Factor
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    ABSTRACT: Sorafenib—a broad tyrosine kinase inhibitor—is the only approved systemic therapy for advanced hepatocellular carcinoma (HCC), but provides limited survival benefits. Recently, immunotherapy has emerged as a promising treatment strategy, but its role remains unclear in HCCs, which are associated with decreased cytotoxic CD8+ T-lymphocyte infiltration in both murine and human tumors. Moreover, we have shown in mouse models that after sorafenib treatment, intratumoral hypoxia is increased and may fuel evasive resistance. Using orthotopic HCC models, we now show that increased hypoxia after sorafenib treatment promotes immunosuppression, characterized by increased intratumoral expression of the immune checkpoint inhibitor programmed death-ligand 1 (PD-L1) and accumulation of T-regulatory cells and M2-type macrophages. We also show that the recruitment of the immunosuppressive cells is mediated in part by hypoxia-induced upregulation of stromal cell-derived 1 alpha (SDF1α). Inhibition of the SDF1α receptor (C-X-C receptor type 4 or CXCR4) using AMD3100 prevented the polarization toward an immunosuppressive microenvironment after sorafenib treatment, inhibited tumor growth, reduced lung metastasis, and improved survival. However, combination of AMD3100 and sorafenib did not significantly change cytotoxic CD8+ T-lymphocyte infiltration into HCC tumors and did not modify their activation status. In separate experiments, antibody blockade of the PD-L1 receptor PD-1 showed anti-tumor effects in treatment-naïve tumors in orthotopic (grafted and genetically engineered) models of HCC. However, anti-PD-1 antibody treatment had additional anti-tumor activity only when combined with sorafenib and AMD3100, and not when combined with sorafenib alone. Conclusion: Anti-PD-1 treatment can boost anti-tumor immune responses in HCC models. When used in combination with sorafenib, this immunotherapy approach shows efficacy only with concomitant targeting of the hypoxic and immunosuppressive microenvironment with agents such as CXCR4 inhibitors. This article is protected by copyright. All rights reserved.
    Hepatology 12/2014; 61(5). DOI:10.1002/hep.27665 · 11.19 Impact Factor
  • Nitric Oxide 11/2014; 42C:115. DOI:10.1016/j.niox.2014.09.051 · 3.18 Impact Factor

Publication Stats

51k Citations
4,675.71 Total Impact Points

Institutions

  • 1995–2015
    • Harvard University
      Cambridge, Massachusetts, United States
  • 1994–2015
    • Massachusetts General Hospital
      • • Edwin L. Steele Laboratory for Tumor Biology
      • • Department of Radiation Oncology
      • • Department of Neurology
      Boston, Massachusetts, United States
  • 1992–2015
    • Harvard Medical School
      • Department of Radiation Oncology
      Boston, Massachusetts, United States
  • 2012
    • Boston Children's Hospital
      Boston, Massachusetts, United States
  • 2011
    • Vesalius Research Center
      Louvain, Flanders, Belgium
  • 2010
    • University of California, Irvine
      Irvine, California, United States
    • Dana-Farber Cancer Institute
      • Center for Neuro-Oncology
      Boston, Massachusetts, United States
  • 2007–2010
    • Duke University Medical Center
      • Department of Radiation Oncology
      Durham, NC, United States
    • University Hospital Essen
      Essen, North Rhine-Westphalia, Germany
    • Boston College, USA
      Boston, Massachusetts, United States
  • 2009
    • Beth Israel Deaconess Medical Center
      Boston, Massachusetts, United States
  • 2004–2009
    • Duke University
      • Department of Surgery
      Durham, North Carolina, United States
    • University of Tsukuba
      • Institute of Clinical Medicine
      Tsukuba, Ibaraki-ken, Japan
  • 2002–2009
    • Massachusetts Institute of Technology
      • • Division of Health Sciences and Technology
      • • Department of Biological Engineering
      Cambridge, Massachusetts, United States
  • 2006
    • University Hospital of Lausanne
      Lausanne, Vaud, Switzerland
    • Mayo Clinic - Rochester
      Рочестер, Minnesota, United States
  • 1979–2006
    • Carnegie Mellon University
      • • Department of Chemical Engineering
      • • Department of Biomedical Engineering
      Pittsburgh, PA, United States
  • 2005
    • Rensselaer Polytechnic Institute
      • Department of Electrical, Computer, and Systems Engineering
      Троя, New York, United States
  • 2001
    • Norwegian University of Science and Technology
      • Department of Physics
      Trondheim, Sor-Trondelag Fylke, Norway
  • 2000
    • Vlaams Instituut voor Biotechnologie
      Gand, Flanders, Belgium
  • 1998
    • Bucknell University
      • Department of Mechanical Engineering
      Lewisburg, Pennsylvania, United States
  • 1979–1980
    • Columbia University
      • Department of Chemical Engineering
      New York, New York, United States
  • 1974–1976
    • University of Delaware
      Delaware, United States