Results for “Wisconsin” — Page 16

DOE OSTI2015

WE-G-303-02: Gold Nanoparticles as Radiosensitizers - What Does It Take To Go From the Bench to the Bedside?

Over the last decade, there has been a growing interest in applying nanotechnology to cancer detection, treatment, and treatment monitoring. Advances in nanotechnology have enabled the fabrication of nanoparticles from various materials with different shapes and sizes. Nanoparticles can be accumulated preferentially within tumors by either “passive targeting” through a phenomenon typically known as “enhanced permeability and retention” or “active targeting” in which nanoparticles are conjugated with antibodies or peptides directed against tumor and/or stromal markers. The tumor specificity of nanoparticles in conjunction with their unique physicochemical properties offers many novel strategies for cancer treatment and detection. For example, notable approaches in the radiation oncology setting include the use of gold nanoparticles for radiation response modulation of tumor or normal tissue and thermal ablation or hyperthermia treatment of tumors. Some of these approaches are currently being tested either on humans or on animals and, very likely, will become the clinical reality in the near future. Various computational and experimental techniques have also been applied to address unique research issues associated with nanoparticles and may become the standard tools for future investigations and clinical translations. Therefore, both clinicians and researchers may need to be properly educated about the basic principles as well as the promise of nanoparticle-based applications with regard to the future of cancer diagnostics and therapeutics. This symposium will familiarize the audience with the potential applications of nanoparticles in oncologic imaging and therapy using specific illustrative examples. The audience will be properly oriented by these illustrative examples to the multiple avenues for collaborative research amongst interdisciplinary teams of physicists, clinicians, engineers, chemists, and biologists in industry and academia. Learning Objectives: Understand the physical bases of gold nanoparticle applications for radiosensitization and x-ray fluorescence imaging Understand the parameters that define gold nanoparticle-mediated radiosensitization in biological systems Understand the potential of magnetic nanoparticle characterization of the microenvironment Understand the various strategies for radiolabeling of nanoparticles and their applications S.C. and S.K. acknowledge support from MD Anderson Cancer Center, NIH (R01CA155446 and P30CA16672) and DoD (W81XWH-12-1-0198); J.W. acknowledges support from NIH (U54CA151662-01); W.C. acknowledges support from the University of Wisconsin-Madison, NIH (R01CA169365, P30CA014520, and T32CA009206), DoD (W81XWH-11-1-0644 and W81XWH-11-1-0648), and ACS (125246-RSG-13-099-01-CCE)

60 APPLIED LIFE SCIENCES↗

DOE OSTI2015

WE-G-303-03: Advances in in Vivo Magnetic NanoparticleSensing

Over the last decade, there has been a growing interest in applying nanotechnology to cancer detection, treatment, and treatment monitoring. Advances in nanotechnology have enabled the fabrication of nanoparticles from various materials with different shapes and sizes. Nanoparticles can be accumulated preferentially within tumors by either “passive targeting” through a phenomenon typically known as “enhanced permeability and retention” or “active targeting” in which nanoparticles are conjugated with antibodies or peptides directed against tumor and/or stromal markers. The tumor specificity of nanoparticles in conjunction with their unique physicochemical properties offers many novel strategies for cancer treatment and detection. For example, notable approaches in the radiation oncology setting include the use of gold nanoparticles for radiation response modulation of tumor or normal tissue and thermal ablation or hyperthermia treatment of tumors. Some of these approaches are currently being tested either on humans or on animals and, very likely, will become the clinical reality in the near future. Various computational and experimental techniques have also been applied to address unique research issues associated with nanoparticles and may become the standard tools for future investigations and clinical translations. Therefore, both clinicians and researchers may need to be properly educated about the basic principles as well as the promise of nanoparticle-based applications with regard to the future of cancer diagnostics and therapeutics. This symposium will familiarize the audience with the potential applications of nanoparticles in oncologic imaging and therapy using specific illustrative examples. The audience will be properly oriented by these illustrative examples to the multiple avenues for collaborative research amongst interdisciplinary teams of physicists, clinicians, engineers, chemists, and biologists in industry and academia. Learning Objectives: Understand the physical bases of gold nanoparticle applications for radiosensitization and x-ray fluorescence imaging Understand the parameters that define gold nanoparticle-mediated radiosensitization in biological systems Understand the potential of magnetic nanoparticle characterization of the microenvironment Understand the various strategies for radiolabeling of nanoparticles and their applications S.C. and S.K. acknowledge support from MD Anderson Cancer Center, NIH (R01CA155446 and P30CA16672) and DoD (W81XWH-12-1-0198); J.W. acknowledges support from NIH (U54CA151662-01); W.C. acknowledges support from the University of Wisconsin-Madison, NIH (R01CA169365, P30CA014520, and T32CA009206), DoD (W81XWH-11-1-0644 and W81XWH-11-1-0648), and ACS (125246-RSG-13-099-01-CCE)

60 APPLIED LIFE SCIENCES↗

DOE OSTI2015

WE-G-303-04: Intrinsically Radiolabeled Nanoparticles: An Emerging Paradigm

Over the last decade, there has been a growing interest in applying nanotechnology to cancer detection, treatment, and treatment monitoring. Advances in nanotechnology have enabled the fabrication of nanoparticles from various materials with different shapes and sizes. Nanoparticles can be accumulated preferentially within tumors by either “passive targeting” through a phenomenon typically known as “enhanced permeability and retention” or “active targeting” in which nanoparticles are conjugated with antibodies or peptides directed against tumor and/or stromal markers. The tumor specificity of nanoparticles in conjunction with their unique physicochemical properties offers many novel strategies for cancer treatment and detection. For example, notable approaches in the radiation oncology setting include the use of gold nanoparticles for radiation response modulation of tumor or normal tissue and thermal ablation or hyperthermia treatment of tumors. Some of these approaches are currently being tested either on humans or on animals and, very likely, will become the clinical reality in the near future. Various computational and experimental techniques have also been applied to address unique research issues associated with nanoparticles and may become the standard tools for future investigations and clinical translations. Therefore, both clinicians and researchers may need to be properly educated about the basic principles as well as the promise of nanoparticle-based applications with regard to the future of cancer diagnostics and therapeutics. This symposium will familiarize the audience with the potential applications of nanoparticles in oncologic imaging and therapy using specific illustrative examples. The audience will be properly oriented by these illustrative examples to the multiple avenues for collaborative research amongst interdisciplinary teams of physicists, clinicians, engineers, chemists, and biologists in industry and academia. Learning Objectives: Understand the physical bases of gold nanoparticle applications for radiosensitization and x-ray fluorescence imaging Understand the parameters that define gold nanoparticle-mediated radiosensitization in biological systems Understand the potential of magnetic nanoparticle characterization of the microenvironment Understand the various strategies for radiolabeling of nanoparticles and their applications S.C. and S.K. acknowledge support from MD Anderson Cancer Center, NIH (R01CA155446 and P30CA16672) and DoD (W81XWH-12-1-0198); J.W. acknowledges support from NIH (U54CA151662-01); W.C. acknowledges support from the University of Wisconsin-Madison, NIH (R01CA169365, P30CA014520, and T32CA009206), DoD (W81XWH-11-1-0644 and W81XWH-11-1-0648), and ACS (125246-RSG-13-099-01-CCE)

60 APPLIED LIFE SCIENCES↗

DOE OSTI2015

Air-kerma strength determination of a new directional {sup 103}Pd source

Purpose: A new directional {sup 103}Pd planar source array called a CivaSheet™ has been developed by CivaTech Oncology, Inc., for potential use in low-dose-rate (LDR) brachytherapy treatments. The array consists of multiple individual polymer capsules called CivaDots, containing {sup 103}Pd and a gold shield that attenuates the radiation on one side, thus defining a hot and cold side. This novel source requires new methods to establish a source strength metric. The presence of gold material in such close proximity to the active {sup 103}Pd region causes the source spectrum to be significantly different than the energy spectra of seeds normally used in LDR brachytherapy treatments. In this investigation, the authors perform air-kerma strength (S{sub K}) measurements, develop new correction factors for these measurements based on an experimentally verified energy spectrum, and test the robustness of transferring S{sub K} to a well-type ionization chamber. Methods: S{sub K} measurements were performed with the variable-aperture free-air chamber (VAFAC) at the University of Wisconsin Medical Radiation Research Center. Subsequent measurements were then performed in a well-type ionization chamber. To realize the quantity S{sub K} from a directional source with gold material present, new methods and correction factors were considered. Updated correction factors were calculated using the MCNP 6 Monte Carlo code in order to determine S{sub K} with the presence of gold fluorescent energy lines. In addition to S{sub K} measurements, a low-energy high-purity germanium (HPGe) detector was used to experimentally verify the calculated spectrum, a sodium iodide (NaI) scintillating counter was used to verify the azimuthal and polar anisotropy, and a well-type ionization chamber was used to test the feasibility of disseminating S{sub K} values for a directional source within a cylindrically symmetric measurement volume. Results: The UW VAFAC was successfully used to measure the S{sub K} of four CivaDots with reproducibilities within 0.3%. Monte Carlo methods were used to calculate the UW VAFAC correction factors and the calculated spectrum emitted from a CivaDot was experimentally verified with HPGe detector measurements. The well-type ionization chamber showed minimal variation in response (<1.5%) as a function of source positioning angle, indicating that an American Association of Physicists in Medicine (AAPM) Accredited Dosimetry Calibration Laboratory calibrated well chamber would be a suitable device to transfer an S{sub K}-based calibration to a clinical user. S{sub K} per well-chamber ionization current ratios were consistent among the four dots measured. Additionally, the measurements and predictions of anisotropy show uniform emission within the solid angle of the VAFAC, which demonstrates the robustness of the S{sub K} measurement approach. Conclusions: This characterization of a new {sup 103}Pd directional brachytherapy source helps to establish calibration methods that could ultimately be used in the well-established AAPM Task Group 43 formalism. Monte Carlo methods accurately predict the changes in the energy spectrum caused by the fluorescent x-rays produced in the gold shield.

07 ISOTOPE AND RADIATION SOURCES↗

DOE OSTI2016

Technical Note: An investigation of polarity effects for wide-angle free-air chambers

Purpose: Wide-angle free-air chambers (WAFACs) are used as primary standard measurement devices for establishing the air-kerma strength of low-energy, low-dose rate brachytherapy seeds. The National Research Council of Canada (NRC) is commissioning a primary standard wide-angle free-air chamber (NRC WAFAC) to serve the calibration needs of Canadian clients. The University of Wisconsin has developed a similar variable-aperture free-air chamber (UW VAFAC) to be used as a research tool. As part of the NRC commissioning, measurements were carried out for both polarities of the applied bias voltage and the resulting effects were observed to be very large. Similar effects were identified with the UW VAFAC. The authors describe the measurements carried out to determine the underlying causes of the polarity effect and the approach used to eliminate it. Methods: The NRC WAFAC is based on the WAFAC design developed at the National Institute of Standards and Technology in the USA. Charge measurements for {sup 125}I and {sup 241}Am sources were carried out for both negative and positive polarities on the NRC WAFAC and UW VAFAC. Two aperture sizes were also investigated with the UW VAFAC. In addition, measurements on the NRC WAFAC were carried out with a small bias between the collecting electrode and the shield foil at the downstream end of the chamber. To mitigate all of the polarity effects, the downstream surface of the collecting electrode was covered with a thin layer of graphite on both the NRC and UW chambers. Results: Both chamber designs showed a difference of more than 30 % between the charge collected with positive and negative bias voltages for the smallest electrode separation. It was shown for the NRC WAFAC that charge could be collected in the small gap downstream of the collecting volume by applying a voltage between the shield foil and the collecting electrode, even though an insulating foil (Mylar or polyimide film) separated the conducting surface from the small gap region. The unwanted additional current was shown to be proportional to the size of the aperture for the UW VAFAC. The extra ionization produced in the small gap region was eliminated for both chambers by covering the insulating side of the collecting electrode with a grounded conducting layer. Conclusions: The small gap region downstream of the collecting electrode in the NRC WAFAC and UW VAFAC can serve as an unwanted source of ion current. It is concluded that a residual electric field in the small gap region may lead to ion transport and to charge being trapped on the surface of the foil. The foil then acts as a capacitor with an equal charge, but of opposite sign, being attracted to the conducting surface. Covering the back of the collecting electrode surface with a grounded conducting layer eliminated the polarity effect.

61 RADIATION PROTECTION AND DOSIMETRY↗

DOE OSTI2016

SU-C-BRC-01: A Monte Carlo Study of Out-Of-Field Doses From Cobalt-60 Teletherapy Units Intended for Historical Correlations of Dose to Normal Tissue

Purpose: Innovations in radiotherapy treatments, such as dynamic IMRT, VMAT, and SBRT/SRS, result in larger proportions of low-dose regions where normal tissues are exposed to low doses levels. Low doses of radiation have been linked to secondary cancers and cardiac toxicities. The AAPM TG Committee No.158 entitled, ‘Measurements and Calculations of Doses outside the Treatment Volume from External-Beam Radiation Therapy’, has been formed to review the dosimetry of non-target and out-of-field exposures using experimental and computational approaches. Studies on historical patients can provide comprehensive information about secondary effects from out-of-field doses when combined with long-term patient follow-up, thus providing significant insight into projecting future outcomes of patients undergoing modern-day treatments. Methods: We present a Monte Carlo model of a Theratron-1000 cobalt-60 teletherapy unit, which historically treated patients at the University of Florida, as a means of determining doses located outside the primary beam. Experimental data for a similar Theratron-1000 was obtained at the University of Wisconsin’s ADCL to benchmark the model for out-of-field dosimetry. An Exradin A12 ion chamber and TLD100 chips were used to measure doses in an extended water phantom to 60 cm outside the primary field at 5 and 10 cm depths. Results: Comparison between simulated and experimental measurements of PDDs and lateral profiles show good agreement for in-field and out-of-field doses. At 10 cm away from the edge of a 6×6, 10×10, and 20×20 cm2 field, relative out-of-field doses were measured in the range of 0.5% to 3% of the dose measured at 5 cm depth along the CAX. Conclusion: Out-of-field doses can be as high as 90 to 180 cGy assuming historical prescription doses of 30 to 60 Gy and should be considered when correlating late effects with normal tissue dose.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2016

SU-F-P-11: Long Term Dosimetric Stability of 6 TomoTherapy Systems

Purpose: The dosimetric stability of six TomoTherapy units was analyzed to investigate changes in performance over time and with system upgrades. Methods: Energy and output were tracked using monitor chamber signal, onboard MVCT detector signal and external ion chamber measurements. The systems (and monitoring periods) include 3 Hi-Art (67, 61 and 65 mos.), 2 HDA (29 and 25 mos.) and one research unit (7 mo.). Dose Control Stability system (DCS) was installed on 4 systems. Output stability is reported as deviation from reference monitor chamber signal for all systems, and from an external chamber for 4 systems. Energy stability was monitored using the relative (center versus off-axis) MVCT detector signal and/or the ratio of chamber measurements at 2 depths. The results from the clinical systems were used to benchmark the stability of the research unit, which has the same linear accelerator but runs at a higher dose rate. Results: The output based on monitor chamber data of all six systems is very stable. Non- DCS had a standard deviation of 1.7% and 1.8%. As expected, DCS systems had improved standard deviation: 0.003–0.05%. The energy was also very stable for all units. The standard deviation in exit detector flatness was 0.02–0.3%. Ion chamber output and 20/10 cm ratios supported these results. The stability for the research system, as monitored with a variety of metrics, is on par with the existing systems. Conclusion: The output and energy of six TomoTherapy units over a total of almost 10 years is quite stable. For each system, the results are consistent between the different measurement tools and techniques, proving not only the dosimetric stability, but that these quality parameters can be confirmed with various metrics. A research unit operating at a higher dose rate performed as well as the clinical treatment units. University of Wisconsin and Accuray Inc. (vendor of TomoTherapy systems) have a research agreement which supplies funds for research to the University. This project was partially supporting with these funds.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2016

SU-G-201-10: Experimental Determination of Modified TG-43 Dosimetry Parameters for the Xoft Axxent® Electronic Brachytherapy Source

Purpose: The establishment of an air kerma rate standard at NIST for the Xoft Axxent{sup ®} electronic brachytherapy source (Axxent{sup ®} source) motivated the establishment of a modified TG-43 dosimetry formalism. This work measures the modified dosimetry parameters for the Axxent{sup ®} source in the absence of a treatment applicator for implementation in Xoft’s treatment planning system. Methods: The dose-rate conversion coefficient (DRCC), radial dose function (RDF) values, and polar anisotropy (PA) were measured using TLD-100 microcubes with NIST-calibrated sources. The DRCC and RDF measurements were performed in liquid water using an annulus of Virtual Water™ designed to align the TLDs at the height of the anode at fixed radii from the source. The PA was measured at several distances from the source in a PMMA phantom. MCNP-determined absorbed dose energy dependence correction factors were used to convert from dose to TLD to dose to liquid water for the DRCC, RDF, and PA measurements. The intrinsic energy dependence correction factor from the work of Pike was used. The AKR was determined using a NIST-calibrated HDR1000 Plus well-type ionization chamber. Results: The DRCC was determined to be 8.6 (cGy/hr)/(µGy/min). The radial dose values were determined to be 1.00 (1cm), 0.60 (2cm), 0.42 (3cm), and 0.32 (4cm), with agreement ranging from (5.7% to 10.9%) from the work of Hiatt et al. 2015 and agreement from (2.8% to 6.8%) with internal MCNP simulations. Conclusion: This work presents a complete dataset of modified TG-43 dosimetry parameters for the Axxent{sup ®} source in the absence of an applicator. Prior to this study a DRCC had not been measured for the Axxent{sup ®} source. This data will be used for calculating dose distributions for patients receiving treatment with the Axxent{sup ®} source in Xoft’s breast balloon and vaginal applicators, and for intraoperative radiotherapy. Sources and partial funding for this work were provided by Xoft Inc. (a subsidiary of iCAD). This work was also supported by the Radiological Sciences T32 Training Grant through the University of Wisconsin-Madison Medical Physics department (5T32CA009206-37).

60 APPLIED LIFE SCIENCES↗

DOE OSTI2016

TU-H-206-02: Novel Linearly-Filled Derenzo PET Phantom Design

Purpose: To design a linearly-filled Derenzo positron emission tomography (PET) phantom, eliminating the extraneous radioisotope volumes in a conventional reservoir-type design. This activity reduction combined with the elimination of bubbles in smaller phantom channels would significantly reduce personnel dose, radioisotope cost, and would improve image quality by reducing out-of-slice activity scatter. Methods: A computer-aided design (CAD) was created of a modular Derenzo phantom consisting of three phantom layers with gaskets between the layers. The central piece contains the active pattern volume and channels connecting adjacent rods in a serpentine pattern. The two end-pieces contained an inlet and an outlet for filling purposes. Phantom prototypes were 3D printed on a Viper Si2 stereolithography machine. The two gaskets were fabricated from silicon sheets using a PLS 6.75 laser cutter. Phantoms were held together by pass-through glass-filled nylon bolts and nuts. Phantoms were filled with {sup 52}Mn, {sup 64}Cu, {sup 74}Br, and {sup 124}I for testing, and were imaged on a Siemens Inveon MicroPET scanner. Results: Four phantom prototypes were constructed using male Leur Lock fittings for inlet/outlet ports. 3D printed layers were sanded to ensure proper coupling to the silicon gaskets. The filling volume for each prototype was approximately 2.4 mL. The filling process was found to be rapid, leak-tight, and with minimal back-pressure. PET images were reconstructed by OSEM3D, and axial slices along the phantom pattern length were averaged to provide final images. Image distortion was isotope dependent with {sup 52}Mn and {sup 64}Cu having the least distortion and {sup 124}I having the most distortion. Conclusion: These results indicate that the linearlyfilled Derenzo design improves on conventional reservoir-type designs by eliminating potential bubbles in small channels and by reducing activity level, radioisotope volume, radioisotope cost, personnel dose, filling time, and out-of-slice activity scatter The method described in this abstract has been filed as a patent application to the US Patent and Trade Office by the Wisconsin Alumni Research Foundation (WARF).

60 APPLIED LIFE SCIENCES↗

DOE OSTI2016

WE-A-201-00: Anne and Donald Herbert Distinguished Lectureship On Modern Statistical Modeling

Chris Marshall: Memorial Introduction Donald Edmonds Herbert Jr., or Don to his colleagues and friends, exemplified the “big tent” vision of medical physics, specializing in Applied Statistics and Dynamical Systems theory. He saw, more clearly than most, that “Making models is the difference between doing science and just fooling around [ref Woodworth, 2004]”. Don developed an interest in chemistry at school by “reading a book” - a recurring theme in his story. He was awarded a Westinghouse Science scholarship and attended the Carnegie Institute of Technology (later Carnegie Mellon University) where his interest turned to physics and led to a BS in Physics after transfer to Northwestern University. After (voluntary) service in the Navy he earned his MS in Physics from the University of Oklahoma, which led him to Johns Hopkins University in Baltimore to pursue a PhD. The early death of his wife led him to take a salaried position in the Physics Department of Colorado College in Colorado Springs so as to better care for their young daughter. There, a chance invitation from Dr. Juan del Regato to teach physics to residents at the Penrose Cancer Hospital introduced him to Medical Physics, and he decided to enter the field. He received his PhD from the University of London (UK) under Prof. Joseph Rotblat, where I first met him, and where he taught himself statistics. He returned to Penrose as a clinical medical physicist, also largely self-taught. In 1975 he formalized an evolving interest in statistical analysis as Professor of Radiology and Head of the Division of Physics and Statistics at the College of Medicine of the University of South Alabama in Mobile, AL where he remained for the rest of his career. He also served as the first Director of their Bio-Statistics and Epidemiology Core Unit working in part on a sickle-cell disease. After retirement he remained active as Professor Emeritus. Don served for several years as a consultant to the Nuclear Regulatory Commission and may be remembered for his critique of the National Academy of Sciences BEIR III report (stating that their methodology “imposes a Delphic quality to the .. risk estimates”.) This led to his appointment as a member of the BEIR V committee. Don presented refresher courses at the AAPM, ASTRO and RSNA meetings and was active in the AAPM as a member or chair of several committees. He was the principal author of AAPM Report 43, which is essentially a critique of established clinical studies prior to 1992. He was co-editor of the Proceedings of many symposia on Time, Dose and Fractionation held in Madison, Wisconsin. He received the AAPM lifetime Achievement award in 2004. Don’s second wife of 46 years, Ann, predeceased him and he is survived by daughters Hillary and Emily, son John and two grandsons. Don was a true gentleman with a unique and erudite writing style illuminated by pithy quotations. If he had a fault it was, perhaps, that he did not realize how much smarter he was than the rest of us. This presentation draws heavily on a biography and video interview in the History and Heritage section of the AAPM website. The quote is his own. Andrzej Niemierko: Statistical modeling plays an essential role in modern medicine for quantitative evaluation of the effect of treatment. This session will feature an overview of statistical modeling techniques used for analyzing the many types of research data and an exploration of recent advances in new statistical modeling methodologies. Learning Objectives: To learn basics of statistical modeling methodology. To discuss statistical models that are frequently used in radiation oncology To discuss advanced modern statistical modeling methods and applications.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2016

WE-A-201-01: Memorial Introduction

Chris Marshall: Memorial Introduction Donald Edmonds Herbert Jr., or Don to his colleagues and friends, exemplified the “big tent” vision of medical physics, specializing in Applied Statistics and Dynamical Systems theory. He saw, more clearly than most, that “Making models is the difference between doing science and just fooling around [ref Woodworth, 2004]”. Don developed an interest in chemistry at school by “reading a book” - a recurring theme in his story. He was awarded a Westinghouse Science scholarship and attended the Carnegie Institute of Technology (later Carnegie Mellon University) where his interest turned to physics and led to a BS in Physics after transfer to Northwestern University. After (voluntary) service in the Navy he earned his MS in Physics from the University of Oklahoma, which led him to Johns Hopkins University in Baltimore to pursue a PhD. The early death of his wife led him to take a salaried position in the Physics Department of Colorado College in Colorado Springs so as to better care for their young daughter. There, a chance invitation from Dr. Juan del Regato to teach physics to residents at the Penrose Cancer Hospital introduced him to Medical Physics, and he decided to enter the field. He received his PhD from the University of London (UK) under Prof. Joseph Rotblat, where I first met him, and where he taught himself statistics. He returned to Penrose as a clinical medical physicist, also largely self-taught. In 1975 he formalized an evolving interest in statistical analysis as Professor of Radiology and Head of the Division of Physics and Statistics at the College of Medicine of the University of South Alabama in Mobile, AL where he remained for the rest of his career. He also served as the first Director of their Bio-Statistics and Epidemiology Core Unit working in part on a sickle-cell disease. After retirement he remained active as Professor Emeritus. Don served for several years as a consultant to the Nuclear Regulatory Commission and may be remembered for his critique of the National Academy of Sciences BEIR III report (stating that their methodology “imposes a Delphic quality to the .. risk estimates”.) This led to his appointment as a member of the BEIR V committee. Don presented refresher courses at the AAPM, ASTRO and RSNA meetings and was active in the AAPM as a member or chair of several committees. He was the principal author of AAPM Report 43, which is essentially a critique of established clinical studies prior to 1992. He was co-editor of the Proceedings of many symposia on Time, Dose and Fractionation held in Madison, Wisconsin. He received the AAPM lifetime Achievement award in 2004. Don’s second wife of 46 years, Ann, predeceased him and he is survived by daughters Hillary and Emily, son John and two grandsons. Don was a true gentleman with a unique and erudite writing style illuminated by pithy quotations. If he had a fault it was, perhaps, that he did not realize how much smarter he was than the rest of us. This presentation draws heavily on a biography and video interview in the History and Heritage section of the AAPM website. The quote is his own. Andrzej Niemierko: Statistical modeling plays an essential role in modern medicine for quantitative evaluation of the effect of treatment. This session will feature an overview of statistical modeling techniques used for analyzing the many types of research data and an exploration of recent advances in new statistical modeling methodologies. Learning Objectives: To learn basics of statistical modeling methodology. To discuss statistical models that are frequently used in radiation oncology To discuss advanced modern statistical modeling methods and applications.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2016

WE-A-201-02: Modern Statistical Modeling

Chris Marshall: Memorial Introduction Donald Edmonds Herbert Jr., or Don to his colleagues and friends, exemplified the “big tent” vision of medical physics, specializing in Applied Statistics and Dynamical Systems theory. He saw, more clearly than most, that “Making models is the difference between doing science and just fooling around [ref Woodworth, 2004]”. Don developed an interest in chemistry at school by “reading a book” - a recurring theme in his story. He was awarded a Westinghouse Science scholarship and attended the Carnegie Institute of Technology (later Carnegie Mellon University) where his interest turned to physics and led to a BS in Physics after transfer to Northwestern University. After (voluntary) service in the Navy he earned his MS in Physics from the University of Oklahoma, which led him to Johns Hopkins University in Baltimore to pursue a PhD. The early death of his wife led him to take a salaried position in the Physics Department of Colorado College in Colorado Springs so as to better care for their young daughter. There, a chance invitation from Dr. Juan del Regato to teach physics to residents at the Penrose Cancer Hospital introduced him to Medical Physics, and he decided to enter the field. He received his PhD from the University of London (UK) under Prof. Joseph Rotblat, where I first met him, and where he taught himself statistics. He returned to Penrose as a clinical medical physicist, also largely self-taught. In 1975 he formalized an evolving interest in statistical analysis as Professor of Radiology and Head of the Division of Physics and Statistics at the College of Medicine of the University of South Alabama in Mobile, AL where he remained for the rest of his career. He also served as the first Director of their Bio-Statistics and Epidemiology Core Unit working in part on a sickle-cell disease. After retirement he remained active as Professor Emeritus. Don served for several years as a consultant to the Nuclear Regulatory Commission and may be remembered for his critique of the National Academy of Sciences BEIR III report (stating that their methodology “imposes a Delphic quality to the .. risk estimates”.) This led to his appointment as a member of the BEIR V committee. Don presented refresher courses at the AAPM, ASTRO and RSNA meetings and was active in the AAPM as a member or chair of several committees. He was the principal author of AAPM Report 43, which is essentially a critique of established clinical studies prior to 1992. He was co-editor of the Proceedings of many symposia on Time, Dose and Fractionation held in Madison, Wisconsin. He received the AAPM lifetime Achievement award in 2004. Don’s second wife of 46 years, Ann, predeceased him and he is survived by daughters Hillary and Emily, son John and two grandsons. Don was a true gentleman with a unique and erudite writing style illuminated by pithy quotations. If he had a fault it was, perhaps, that he did not realize how much smarter he was than the rest of us. This presentation draws heavily on a biography and video interview in the History and Heritage section of the AAPM website. The quote is his own. Andrzej Niemierko: Statistical modeling plays an essential role in modern medicine for quantitative evaluation of the effect of treatment. This session will feature an overview of statistical modeling techniques used for analyzing the many types of research data and an exploration of recent advances in new statistical modeling methodologies. Learning Objectives: To learn basics of statistical modeling methodology. To discuss statistical models that are frequently used in radiation oncology To discuss advanced modern statistical modeling methods and applications.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2016

WE-FG-BRA-08: Potential Role of the Glycolytic Oscillator in Acute Hypoxia in Tumors

Purpose: Oscillatory dynamics in acute hypoxia have been observed, but poorly understood. They have mostly been attributed to vascular perturbations, but no link has yet been made to metabolic causes. We set out to determine the fundamental frequencies and test for coherence in tumor oxygen dynamics and spatial properties. Methods: Severe combined immunodeficient (SCID) mice were inoculated onto bilateral flanks with human derived head and neck carcinoma (UW-SCC22) cell line xenografts. Oxygen dynamics were monitored in the tumor every minute for an hour using three modalities: blood oxygen level dependent - magnetic resonance imaging (BOLD-MRI), hemoglobin oxygen saturation photoacoustic, and locally manufactured optical probes for spectral fitting. A statistical test was used to separate fluctuating from non-fluctuating voxels and pixels in BOLD-MRI and photoacoustic data respectively. The power spectrum density (PSD) and the autocorrelation functions were calculated for the time series of each voxel, pixel and region, of the BOLD-MRI, photoacoustic or fiber optic data respectively. Results: Using all three techniques, intermittent oxygen dynamics with both coherent and incoherent signatures was observed in the tumors. Upon averaging the PSDs of fluctuating voxels and pixels, it was found that these oscillations occurred with periods of minutes to tens of minutes from all three approaches. Observations from the BOLD-MRI and photoacoustic data showed that clusters of voxels oscillated in a synchronized manner. Conclusion: We were able to use three different modalities to show that fluctuation in tumor oxygen is both coherent and incoherent, with periods of minutes to tens of minutes. These periods are very similar to those from the well-established metabolic, non-linear biomechanical phenomenon called the glycolytic oscillator. This may provide an additional explanation to the cause of cyclic hypoxia. Such dynamics could have profound implications in hypofractionated radiotherapy regiments and could help guide treatment and make it more patient specific. The authors would like to thank the University of Wisconsin Carbone Cancer Center (UWCCC) for the funds to complete this project. This work is also supported in part by NIH/NCI P30 CA014520- UW Comprehensive Cancer Center Support”.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2025

Cryptic cycling by electroactive bacterioplankton in Trout Bog Lake

The potential for extracellular electron transfer (EET) is a prevailing genomic feature of humic lake bacterioplankton. However, there has been little evidence for the substantial ecological contribution predicted by genetics. We hypothesized that anoxygenic phototrophic electrotrophs and accompanying heterotrophic electrogens cycle dissolved organic matter (DOM) between oxidized and reduced states. We predicted that such bacterioplankton would exhibit diel-scale oscillations due to the light dependency of photosynthesis. Using Trout Bog Lake in Wisconsin, USA, as our model ecosystem, we profiled the water column with depth-discrete metagenomic, physiochemical, and electrochemical analyses. We observed variation in oxidation reduction potential (ORP) in response to sunlight, initiating at depths populated by anoxygenic phototrophs with EET genes. We developed an automated buoy to measure electric current flow between many pairs of electrodes simultaneously, observing correlation in electron consumption to sunlight. Our results, combined with published metatranscriptomic analysis, indicate the occurrence of electron cycling between phototrophic oxidation (electrotrophic metabolism) by Chlorobium and anaerobic respiration (electrogenic metabolism) by Geothrix, involving DOM. We also repeatedly observed gradual seasonal increases in hypolimnion ORP throughout summer. These diel and seasonal patterns imply that electroactive DOM mediates the ecology of electroactive bacteria in lakes, controlling humic lake methane emissions.IMPORTANCEWe investigated the physical, chemical, and redox characteristics of a bog lake and electrodes hung therein to test the hypothesis that dissolved organic matter is being cycled between oxidized and reduced states by electroactive bacterioplankton powered by phototrophy. To do so, we performed field-based analyses on multiple timescales using both established and novel instrumentation. We paired these analyses with recently developed bioinformatics pipelines for metagenomics data to investigate genes that enable electroactive metabolism and accompanying metabolisms. Our results are consistent with our hypothesis and yet upend some of our other expectations. Our findings have implications for understanding greenhouse gas emissions from lakes, including electroactivity as an integral part of lake metabolism throughout more of the anoxic parts of lakes and for a longer portion of the summer than expected. Our results also give a sense of what electroactivity occurs at given depths and provide a strong basis for future studies.

carbon emissions↗

DOE OSTI2022

Soil Origin and Plant Genotype Modulate Switchgrass Aboveground Productivity and Root Microbiome Assembly

Switchgrass (Panicum virgatum) is a model perennial grass for bioenergy production that can be productive in agricultural lands that are not suitable for food production. There is growing interest in whether its associated microbiome may be adaptive in low- or no-input cultivation systems. However, the relative impact of plant genotype and soil factors on plant microbiome and biomass are a challenge to decouple. To address this, a common garden greenhouse experiment was carried out using six common switchgrass genotypes, which were each grown in four different marginal soils collected from long-term bioenergy research sites in Michigan and Wisconsin. We characterized the fungal and bacterial root communities with high-throughput amplicon sequencing of the ITS and 16S rDNA markers, and collected phenological plant traits during plant growth, as well as soil chemical traits. At harvest, we measured the total plant aerial dry biomass. Significant differences in richness and Shannon diversity across soils but not between plant genotypes were found. Generalized linear models showed an interaction between soil and genotype for fungal richness but not for bacterial richness. Community structure was also strongly shaped by soil origin and soil origin × plant genotype interactions. Overall, plant genotype effects were significant but low. Random Forest models indicate that important factors impacting switchgrass biomass included NO 3 – , Ca 2+ , PO 4 3– , and microbial biodiversity. We identified 54 fungal and 52 bacterial predictors of plant aerial biomass, which included several operational taxonomic units belonging to Glomeraceae and Rhizobiaceae, fungal and bacterial lineages that are involved in provisioning nutrients to plants.

plant biomass↗

DOE OSTI2019

Wide Distribution of Phage That Infect Freshwater SAR11 Bacteria

Fonsibacter (LD12 subclade) is among the most abundant bacterioplankton in freshwater ecosystems. These bacteria belong to the order Pelagibacterales (SAR11) and are related to Pelagibacter (marine SAR11), which dominates many marine habitats. Although a few Pelagibacter phage (Pelagiphage) have been described, no phage that infect Fonsibacter have been reported. In this study, we describe two groups of Podoviridae phage that infect Fonsibacter. A complete Fonsibacter genome containing a prophage was reconstructed from metagenomic data. A circularized and complete genome related to the prophage, referred to as uv-Fonsiphage-EPL (lysogenic strategy), shows high similarity to marine Pelagiphage HTVC025P. Additionally, we reconstructed three complete genomes and one draft genome of phage related to marine Pelagiphage HTVC010P and predicted a lytic strategy. The similarity in codon usage and cooccurrence patterns of HTVC010P-related phage and Fonsibacter suggested that these phage infect Fonsibacter. Similar phage were detected in Lake Mendota, Wisconsin, where Fonsibacter is also present. A search of related phage revealed the worldwide distribution of some genotypes in freshwater ecosystems, suggesting their substantial role in shaping indigenous microbial assemblages and influence on biogeochemical cycling. However, the uv-Fonsiphage-EPL and one group of HTVC010P-related phage have a more limited distribution in freshwater ecosystems. Overall, the findings provide insights into the genomic features of phage that infect Fonsibacter and expand understanding of the ecology and evolution of these important bacteria. Fonsibacter represents a significant microbial group of freshwater ecosystems. Although the genomic and metabolic features of these bacteria have been well studied, no phage infecting them has been reported. In this study, we reconstructed complete genomes of Fonsibacter and infecting phage and revealed their close relatedness to the phage infecting marine SAR11 members. Also, we illustrated that phage that infect Fonsibacter are widely distributed in freshwater habitats. In summary, the results contribute new insights into the ecology and evolution of Fonsibacter and phage.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2019

The role of permafrost on the morphology of an MIS 3 moraine from the southern Laurentide Ice Sheet

The Laurentide Ice Sheet (LIS) represents the single largest contributor to global sea level during the late Pleistocene glacial-interglacial cycle. Fluctuations of global sea level prior to the Last Glacial Maximum (LGM; 26–19 ka) are well documented, but the terrestrial extent of the LIS prior to the LGM is uncertain. In central Wisconsin, United States, three north-south–trending end moraines of the LIS are preserved. The two eastward moraines are constrained to the LGM through radiocarbon and surface exposure dating methods, while the westward moraine is constrained only by relative dating techniques and is estimated to be up to >125 ka. Here, we report surface exposure ages from this westward moraine (the Arnott moraine) and demonstrate that the LIS reached an equivalent extent to its LGM position at ca. 35 ka, during Marine Isotope Stage (MIS) 3. These new age constraints for the Arnott moraine are significantly younger than prior estimates, which were based on sediment weathering and low-relief moraine morphology. To address this dichotomy between the relatively young exposure dates and the low relief, we applied a landscape diffusion model to the Arnott moraine and found that during permafrost conditions, intense erosion can act to efficiently and quickly smooth the moraine surface. Here, this study connects the LIS as a potential source for sea-level lowering during MIS 3 while simultaneously demonstrating the inherent uncertainty associated with relative dating techniques if nonlinear erosional conditions are not accounted for in periglacial terrains.

58 GEOSCIENCES↗

DOE OSTI2013

Callpath Library

The "Callpath Library" is a software abstraction layer over a number of stack tracing utilities. It allows tool develoopers to conveniently represent and mNipulate call paths gathered fro U. Wisconsin's Stackwalker API and GNU Backtrace.

Gamblin, T.↗