H Baumann

Roswell Park Cancer Institute, Buffalo, New York, United States

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Publications (198)1066.3 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: We have previously shown that the (124)I-analog of methyl 3-(1'-m-iodobenzyloxy) ethyl-3-devinyl-pyropheophorbide-a derived as racemic mixture from chlorophyll-a can be used for PET (positron emission tomography)-imaging in animal tumor models. On the other hand, as a non-radioactive analog, it showed excellent fluorescence and photodynamic therapy (PDT) efficacy. Thus, a single agent in a mixture of radioactive ((124)I-) and non-radioactive ((127)I) material can be used for both dual-imaging and PDT of cancer. Before advancing to Phase I human clinical trials, we evaluated the activity of the individual isomers as well as the impact of a chiral center at position-3(1) in directing in vitro/in vivo cellular uptake, intracellular localization, epithelial tumor cell-specific retention, fluorescence/PET imaging, and photosensitizing ability. The results indicate that both isomers (racemates), either as methyl ester or carboxylic acid, were equally effective. However, the methyl ester analogs, due to subcellular deposition into vesicular structures, were preferentially retained. All derivatives containing carboxylic acid at the position-17(2) were noted to be substrate for the ABCG2 (a member of the ATP binding cassette transporters) protein explaining their low retention in lung tumor cells expressing this transporter. The compounds in which the chirality at position-3 has been substituted by a non-chiral functionality showed reduced cellular uptake, retention and lower PDT efficacy in mice bearing murine Colon26 tumors. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Bioorganic & medicinal chemistry 04/2015; 23(13). DOI:10.1016/j.bmc.2015.04.006 · 2.95 Impact Factor
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    ABSTRACT: We have applied continuous blood flow dynamics, quantified with diffuse correlation spectroscopy (DCS), in investigating photodynamic therapy (PDT) induced local photoreaction in a head and neck tumor model. Photoclor (0.47 µmol/kg) was intravenously administered 24 hour before PDT. Two types of fluence rates were implemented: Low fluence rate (14 mW/cm2) and high fluence rate (75 mW/cm2). The total delivered fluence was 100 J for both types. We observed that PDT induced substantial vascular shut down in both types. While the shutdown was persistent in tumors exposed to low fluence rate PDT, the shutdown was transient in tumors exposed to high fluence PDT. Loss of microvascular structures was confirmed by the microscopic analyses of tumor section following immunostaining for CD31. Blood flow dynamics related metrics were also strongly correlated with crosslinking of STAT3, a molecular marker of photoreaction. STAT3 analysis indicated that low fluence rate yields a substantially higher photoreaction, and, thus, a more effective PDT. Our results indicate that noninvasive blood flow measurements can monitor the efficacy of PDT in real-time and potentially provide a feedback for its optimization.
    Frontiers in Physics 03/2015; 3. DOI:10.3389/fphy.2015.00013
  • Jihnhee Yu · Albert Vexler · Alan D Hutson · Heinz Baumann
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    ABSTRACT: In many biomedical studies, a difference in upper quantiles is of specific interest since the upper quantile represents the upper range of biomarkers and/or is used as the cut-off value for a disease classification. In this article, we investigate two-group comparisons of an upper quantile based on the empirical likelihood methodology. Two approaches, the classical empirical likelihood and 'plug-in' empirical likelihood are used to construct the test statistics and their properties are theoretically investigated. Although the plug-in method is developed by the frame work of the empirical likelihood, the test statistic is not based on the maximization of the empirical likelihood, and is simplified by using indicator function in its construction, making it a unique test to investigate. Extensive simulation results demonstrate that the 'plug-in' empirical likelihood approach performs better to compare upper quantiles across various underlying distributions and sample sizes. For the actual application, we employ the developed methods to test the differences in upper quantiles in two different studies, the oral colonization of pneumonia pathogens for intensive care unit patients treated by two different oral treatments, and the biomarker expressions of normal and abnormal bronchial epithelial cells.
    Statistics in Biopharmaceutical Research 02/2014; 6(1):30-40. DOI:10.1080/19466315.2013.826597 · 0.70 Impact Factor
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    ABSTRACT: The primary objective was to evaluate safety of 3-(1'-hexyloxyethyl)pyropheophorbide-a (HPPH) photodynamic therapy (HPPH-PDT) for dysplasia and early squamous cell carcinoma of the head and neck (HNSCC). Secondary objectives were the assessment of treatment response and reporters for an effective PDT reaction. Patients with histologically proven oral dysplasia, carcinoma in situ (CiS ) or early stage HNSCC were enrolled in two sequentially conducted dose escalation studies with an expanded cohort at the highest dose level. These studies employed an HPPH dose of 4 mg/m2 and light doses from 50 to 140 J/cm2. Pathologic tumor responses were assessed at 3 months. Clinical follow up range was 5 to 40 months. PDT induced cross-linking of signal transducer and activator of transcription 3 (STAT3) were assessed as potential indicators of PDT effective reaction. Forty patients received HPPH-PDT. Common adverse events were pain and treatment site edema. Biopsy proven complete response rates were 46% for dysplasia and CiS, and 82% for SCCs lesions at 140 J/cm2. The responses in the CiS/dysplasia cohort are not durable. The PDT induced STAT3 cross-links is significantly higher (P=0.0033) in SCC than in CiS/dysplasia for all light-doses. HPPH-PDT is safe for the treatment of CiS/dysplasia and early stage cancer of the oral cavity. Early stage oral HNSCC appears to respond better to HPPH-PDT in comparison to premalignant lesions. The degree of STAT3 cross-linking is a significant reporter to evaluate HPPH-PDT mediated photoreaction.
    Clinical Cancer Research 10/2013; 19(23). DOI:10.1158/1078-0432.CCR-13-1735 · 8.19 Impact Factor
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    ABSTRACT: Signal transducer and activator of transcription (STAT) 3 inhibits dendritic cell (DC) differentiation and is constitutively activated in blasts of approximately half of AML patients. We investigated the correlation between STAT3 activity, DC maturation and the ability to stimulate T-cells in primary acute myeloid leukemia (AML)-derived DCs. STAT3 knock-down by shRNAmir increased the ability of AML-DCs to stimulate T-cells. Treatment of AML-DC with arsenic trioxide, but not AG490, JSI-124 or NSC-74859, led to a more mature phenotype and enhanced T-cell stimulation, while having minimal effect on normal DC. We conclude that AML-DCs have improved immunogenicity after reducing STAT3.
    Leukemia research 04/2013; 37(7). DOI:10.1016/j.leukres.2013.04.002 · 2.69 Impact Factor
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    ABSTRACT: Haptoglobin (Hp), an acute phase reactant and major hemoglobin-binding protein, has a unique role in host immunity. Previously, we demonstrated that Hp-deficient C57BL/6J mice exhibit stunted development of mature T- and B-cells resulting in markedly lower levels of antigen-specific IgG. The current study identified leukocyte-derived pro-Hp as a relevant mediator of an optimal immune response. Reconstitution of Hp(-/-) mice with Hp(+/+) bone marrow restored normal immune response to ovalbumin. Furthermore, transplanting a mixture of bone marrow-derived from B-cell-deficient and Hp-deficient mice into Rag1(-/-)/Hp(+/+) recipients resulted in mice with a defective immune response similar to Hp(-/-) mice. This suggests that Hp generated by the B-cell compartment, rather than by the liver, is functionally contributing to a normal immune response. Leukocytes isolated from the spleen express Hp and release a non-proteolytically processed pro-Hp that uniquely differed from liver-derived Hp by not binding to hemoglobin. While addition of purified plasma Hp to cultured B-cells did not alter responses, pro-Hp isolated from splenocytes enhanced cellular proliferation and production of IgG. Collectively, the comparison of wild-type and Hp-deficient mice suggests a novel regulatory activity for lymphocyte-derived Hp, including Hp produced by B-cells themselves, that supports in vivo survival and functional differentiation of the B-cells to ensure an optimal immune response.
    Molecular Immunology 03/2013; 55(3). DOI:10.1016/j.molimm.2013.03.008 · 3.00 Impact Factor
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    ABSTRACT: Photodynamic therapy (PDT) has recently emerged as a potential treatment alternative for head and neck cancer. There is strong evidence that imprecise PDT dosimetry results in variations in clinical responses. Quantitative tools are likely to play an essential role in bringing PDT to a full realization of its potential benefits. They can provide standardization of site-specific individualized protocols that are used to monitor both light and photosensitizer (HPPH) dose, as well as the tissue response for individual patients. To accomplish this, we used a custom instrument and a hand-held probe that allowed quantification of blood flow, blood volume, blood oxygen saturation and drug concentration.
    Conference on Optical Methods for Tumor Treatment and Detection -; 03/2013
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    E C Tracy · M J Bowman · B W Henderson · H Baumann
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    ABSTRACT: Background: Photodynamic therapy (PDT) causes tissue damage that initiates a local inflammatory response. Post-PDT reactions are considered to assist in mobilising the immune system thereby affecting tumour recurrence. The initiating process of the PDT-dependent tissue reaction remains to be determined. Methods: Primary cultures of human lung cells were established. The photoreaction mediated by pyropheophorbide-a, at specific subcellular sites and levels resulting in the release of alarmins by epithelial cells (Eps), was defined by immunoblot analyses and expression profiling. The activity of Ep-derived factors to stimulate expression of proinflammatory mediators, including IL-6, and to enhance neutrophil binding by fibroblasts (Fbs) was determined by functional bioassays. Results: Epithelial cells release IL-1β as the primary Fb-stimulatory activity under basal conditions. Intracellular IL-1α, externalised following photoreaction, accounts for most of the PDT-mediated Fb activation. Expression of IL-1 is subject to increase or loss during oncogenic transformation resulting in altered alarmin functions mobilisable by PDT. Photoreaction by a cell surface-bound photosensitiser (PS) is 10-fold more effective than PSs localised to mitochondria or lysosomes. High-dose intracellular, but not cell surface, photoreaction inactivates IL-1 and reduces Fb stimulation. Conclusion: These in vitro data suggest that the subcellular site and intensity of photoreaction influence the magnitude of the stromal cell response to the local damage and, in part, support the relationship of PDT dose and level of post-PDT inflammatory response observed in vivo.
    British Journal of Cancer 09/2012; 107(9):1534-46. DOI:10.1038/bjc.2012.429 · 4.82 Impact Factor
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    ABSTRACT: Photodynamic therapy (PDT) efficacy depends on the local dose deposited in the lesion as well as oxygen availability in the lesion. We report significant interlesion differences between two patients with oral lesions treated with the same drug dose and similar light dose of 2-1[hexyloxyethyl]-2-devinylpyropheophorbide-a (HPPH)-mediated photodynamic therapy (PDT). Pre-PDT and PDT-induced changes in hemodynamic parameters and HPPH photosensitizer content, quantified by diffuse optical methods, demonstrated substantial differences between the two lesions. The differences in PDT action determined by the oxidative cross-linking of signal transducer and activator of transcription 3 (STAT3), a molecular measure of accumulated local PDT photoreaction, also showed >100-fold difference between the lesions, greatly exceeding what would be expected from the slight difference in light dose. Our results suggest diffuse optical spectroscopies can provide in vivo metrics that are indicative of local PDT dose in oral lesions.
    Biomedical Optics Express 09/2012; 3(9):2142-53. DOI:10.1364/BOE.3.002142 · 3.50 Impact Factor
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    ABSTRACT: BACKGROUND:Constitutive activation of signal transducer and activator of transcription-3 (STAT3) was detected in blasts from approximately 50% of patients with acute myeloid leukemia (AML) and was correlated with an adverse outcome. In vitro treatment of AML blasts with arsenic trioxide (ATO) down-regulated STAT3 activity within 6 hours associated with a reduced viability within 48 hours.METHODS:A phase 1 clinical trial to evaluate the biologically effective dose and/or the maximally tolerated dose (MTD) of ATO in vivo in conjunction with high-dose cytarabine (Hidac) and idarubicin (Ida) in patients with AML aged <60 years was conducted. Data were compared with 117 historic AML patients who had received treatment with Hidac/Ida.RESULTS:In total, 61 patients were enrolled onto 11 different dose levels (from 0.01 to 0.65 mg/kg ideal body weight). The MTD was 0.5 mg/kg. Compared with historic controls, patients who received ATO/Hidac/Ida, although they had similar pretreatment characteristics, had better overall survival (P = .039).CONCLUSIONS:ATO priming may have improved the outcome of patients aged <60 years with AML who received Hidac/Ida. The current data suggested that ATO may enhance the effect of chemotherapy. The authors concluded that further studies of this novel combination are warranted. Cancer 2011;. © 2011 American Cancer Society.
    Cancer 11/2011; 117(21):4831 - 4868. DOI:10.1002/cncr.26097 · 4.90 Impact Factor
  • 53rd ASH Annual Meeting; 11/2011
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    ABSTRACT: Immune cells are key regulators of neoplastic progression, which is often mediated through their release of cytokines. Inflammatory cytokines such as IL-6 exert tumor-promoting activities by driving growth and survival of neoplastic cells. However, whether these cytokines also have a role in recruiting mediators of adaptive anticancer immunity has not been investigated. Here, we report that homeostatic trafficking of tumor-reactive CD8+ T cells across microvascular checkpoints is limited in tumors despite the presence of inflammatory cytokines. Intravital imaging in tumor-bearing mice revealed that systemic thermal therapy (core temperature elevated to 39.5°C ± 0.5°C for 6 hours) activated an IL-6 trans-signaling program in the tumor blood vessels that modified the vasculature such that it could support enhanced trafficking of CD8+ effector/memory T cells (Tems) into tumors. A concomitant decrease in tumor infiltration by Tregs during systemic thermal therapy resulted in substantial enhancement of Tem/Treg ratios. Mechanistically, IL-6 produced by nonhematopoietic stromal cells acted cooperatively with soluble IL-6 receptor-α and thermally induced gp130 to promote E/P-selectin- and ICAM-1-dependent extravasation of cytotoxic T cells in tumors. Parallel increases in vascular adhesion were induced by IL-6/soluble IL-6 receptor-α fusion protein in mouse tumors and patient tumor explants. Finally, a causal link was established between IL-6-dependent licensing of tumor vessels for Tem trafficking and apoptosis of tumor targets. These findings suggest that the unique IL-6-rich tumor microenvironment can be exploited to create a therapeutic window to boost T cell-mediated antitumor immunity and immunotherapy.
    The Journal of clinical investigation 09/2011; 121(10):3846-59. DOI:10.1172/JCI44952 · 13.77 Impact Factor
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    ABSTRACT: The ATP-dependent transporter ABCG2 exports certain photosensitizers (PS) from cells, implying that the enhanced expression of ABCG2 by cancer cells may confer resistance to photodynamic therapy (PDT) mediated by those PS. In 35 patient-derived primary cultures of lung epithelial and stromal cells, PS with different subcellular localization and affinity for ABCG2 displayed cell-type specific retention both independent and dependent on ABCG2. In the majority of cases, the ABCG2 substrate 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH) was lost from fibroblastic cells more rapidly than from their epithelial counterparts, even in the absence of detectable ABCG2 expression, facilitating selective eradication by PDT of epithelial over fibroblastic cells in tumor/stroma co-cultures. Pairwise comparison of normal and transformed epithelial cells also identified tumor cells with elevated or reduced retention of HPPH, depending on ABCG2. Enhanced ABCG2 expression led to the selective PDT survival of tumor cells in tumor/stroma co-cultures. This survival pattern was reversible through HPPH derivatives that are not ABCG2 substrates or the ABCG2 inhibitor imatinib mesylate. PS retention, not differences in subcellular distribution or cell signaling responses, was determining cell type selective death by PDT. These data suggest that up-front knowledge of tumor characteristics, specifically ABCG2 status, could be helpful in individualized PDT treatment design.
    Photochemistry and Photobiology 08/2011; 87(6):1405-18. DOI:10.1111/j.1751-1097.2011.00992.x · 2.68 Impact Factor
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    ABSTRACT: Among the photosensitizers investigated, both ring-D and ring-B reduced chlorins containing the m-iodobenzyloxyethyl group at position-3 and a carboxylic acid functionality at position-17(2) showed the highest uptake by tumor cells and light-dependent photoreaction that correlated with maximal tumor-imaging [positron emission tomography (PET) and fluorescence] and long-term photodynamic therapy (PDT) efficacy in BALB/c mice bearing Colon26 tumors. However, among the ring-D reduced compounds, the isomer containing the 1'-m-iobenzyloxyethyl group at position-3 was more effective than the corresponding 8-(1'-m-iodobenzyloxyethyl) derivative. All photosensitizers showed maximum uptake by tumor tissue 24 h after injection, and the tumors exposed with light at low fluence and fluence rates (128 J/cm(2), 14 mW/cm(2)) produced significantly enhanced tumor eradication than those exposed at higher fluence and fluence rate (135 J/cm(2), 75 mW/cm(2)). Interestingly, dose-dependent cellular uptake of the compounds and light-dependent STAT3 dimerization have emerged as sensitive rapid indicators for PDT efficacy in vitro and in vivo and could be used as in vitro/in vivo biomarkers for evaluating and optimizing the in vivo treatment parameters of the existing and new PDT candidates.
    Journal of Medicinal Chemistry 08/2011; 54(19):6859-73. DOI:10.1021/jm200805y · 5.48 Impact Factor
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    ABSTRACT: A variety of cytokines play a role in the response to an inflammatory stimulus. The interleukin-6 (IL-6)-type cytokines are released in response to tissue injury or an inflammatory stimulus. They act locally and systemically to generate a variety of physiologic responses, principal among them is the acute phase response. The IL-6 type cytokines demonstrate pleiotropy and redundancy of actions. This is made possible by the distinctive characteristics of the IL-6 receptor complex, which contains an ubiquitous subunit that is shared by most IL-6-type cytokines, as well as a cytokine-specific subunit.
    Journal of Intensive Care Medicine 01/2011; 26(1):3-12. DOI:10.1177/0885066610395678 · 7.21 Impact Factor
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    ABSTRACT: A variety of cytokines play a role in the inflammatory response. Interleukin 6 (IL-6) type cytokines are released in response to tissue injury or an inflammatory stimulus, and act locally and systemically to generate a variety of physiologic responses. Interleukin 6 concentrations are elevated after surgery, trauma, and critical illness. The magnitude of IL-6 elevation correlates with the extent of tissue trauma/injury severity. Furthermore, there is an association between IL-6 elevations and adverse outcome. Interleukin 6 concentrations can be used to stratify patients for therapeutic intervention.
    Journal of Intensive Care Medicine 11/2010; 26(2). DOI:10.1177/0885066610384188 · 7.21 Impact Factor
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    ABSTRACT: We present initial results obtained during the course of a Phase I clinical trial of 2-1[hexyloxyethyl]-2-devinylpyropheophorbide-a (HPPH)-mediated photo-dynamic therapy (PDT) in a head and neck cancer patient. We quantified blood flow, oxygenation and HPPH drug photobleaching before and after therapeutic light treatment by utilizing fast, non-invasive diffuse optical methods. Our results showed that HPPH-PDT induced significant drug photobleaching, and reduction in blood flow and oxygenation suggesting significant vascular and cellular reaction. These changes were accompanied by cross-linking of the signal transducer and activator of transcription 3 (STAT3), a molecular measure for the oxidative photoreaction. These preliminary results suggest diffuse optical spectroscopies permit non-invasive monitoring of PDT in clinical settings of head and neck cancer patients.
    Optics Express 07/2010; 18(14):14969-78. DOI:10.1364/OE.18.014969 · 3.49 Impact Factor
  • Cancer Research 04/2010; 70(8 Supplement):2262-2262. DOI:10.1158/1538-7445.AM10-2262 · 9.28 Impact Factor
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    ABSTRACT: A variety of cytokines play a role in the inflammatory response. Interleukin-6 (IL-6)-type cytokines are released in response to tissue injury or an inflammatory stimulus, and act locally and systemically to generate a variety of physiologic responses. Interleukin-6 concentrations are elevated after surgery, trauma, and critical illness. The magnitude of IL-6 elevation correlates with the extent of tissue trauma/injury severity. Furthermore, there is an association between IL-6 elevation and adverse outcome. Interleukin-6 levels can also be used to stratify patients for therapeutic intervention.
    Journal of Intensive Care Medicine 04/2010; 26(2):73-87. DOI:10.1177/0885066610395679 · 7.21 Impact Factor
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    Mustafa Benekli · Heinz Baumann · Meir Wetzler
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    ABSTRACT: Signal transducer and activator of transcription (STAT) proteins comprise a seven-member family of latent cytoplasmic transcription factors that are activated through tyrosine phosphorylation by a variety of cytokines and growth factors. Aberrant activation of STATs accompanies malignant cellular transformation with resultant leukemogenesis. Constitutive activation of STATs has been demonstrated in various leukemias. A better understanding of the mechanisms of dysregulation of the STAT pathway and understanding of the cause and effect relationship in leukemogenesis may serve as a basis for designing novel therapeutic strategies directed against STATs. Mechanisms of STAT activation, the potential role of STAT signaling in leukemogenesis, and recent advances in drug discovery targeting the STAT pathway are the focus of this review.
    Journal of Clinical Oncology 09/2009; 27(26):4422-32. DOI:10.1200/JCO.2008.21.3264 · 18.43 Impact Factor

Publication Stats

10k Citations
1,066.30 Total Impact Points

Institutions

  • 1978–2015
    • Roswell Park Cancer Institute
      • • Department of Molecular and Cellular Biology
      • • Department of Surgery
      • • Department of Dermatology
      Buffalo, New York, United States
  • 1987–2002
    • University of South Carolina
      • Department of Biological Sciences
      Columbia, SC, United States
  • 1996
    • Centre for Cellular and Molecular Biology
      Bhaganagar, Andhra Pradesh, India
    • The Children's Hospital of Buffalo
      New York, New York, United States
  • 1995
    • Poznan University of Medical Sciences
      • Department of Cancer Immunology
      Posen, Greater Poland Voivodeship, Poland
  • 1991–1994
    • Jagiellonian University
      • Department of Cell Biochemistry
      Cracovia, Lesser Poland Voivodeship, Poland
  • 1993
    • Greater Poland Cancer Centre
      Posen, Greater Poland Voivodeship, Poland
  • 1991–1992
    • McMaster University
      • Department of Pathology and Molecular Medicine
      Hamilton, Ontario, Canada
  • 1990
    • Seattle Institute for Biomedical and Clinical Research
      Seattle, Washington, United States
    • The Scripps Research Institute
      لا هویا, California, United States
  • 1989
    • Molecular and Cellular Biology Program
      Seattle, Washington, United States