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Papers by Robert Griffin

Research paper thumbnail of Pegylated IFN-α sensitizes melanoma cells to chemotherapy and causes premature senescence in endothelial cells by IRF-1 mediated signaling

Cell death & disease, 2010

Pegylated Interferon-α2b (pIFN-α) is an integral part of the drug regimen currently employed agai... more Pegylated Interferon-α2b (pIFN-α) is an integral part of the drug regimen currently employed against melanoma. Interferon Regulatory Factor-1 (IRF-1) plays an important role in the transcriptional regulation of the IFN response, cell cycle and apoptosis. We have studied pIFN-α induced responses when combined with the chemotherapy agent, vinblastine in tumor and endothelial cell lines and the connection to IRF-1 signaling. Levels of IRF-1/IRF-2 protein expression were found to be decreased in tumor versus normal tissues. pIFN-α induced IRF-1 signaling in human melanoma (M14) and endothelial (EA.hy926) cells and enhanced cell death when combined with vinblastine. Upon combined IFN-α and vinblastine treatment, p21 expression, PARP cleavage and activated Bak levels were increased in M14 cells. An increase in p21 and cyclin D1 expression occurred in EA.hy926 cells after 6 h of treatment with pIFN-α which dissipated by 24 h. This biphasic response, characteristic of cellular senescence, w...

Research paper thumbnail of SU-FF-J-160: Spatially Fractionated Radiation Therapy (GRID) On Implanted Tumors Using a Small Animal Conformal Radiation Therapy System

Medical Physics, 2009

ABSTRACT

Research paper thumbnail of Scheduling of Radiation with Angiogenesis Inhibitors Anginex and Avastin Improves Therapeutic Outcome via Vessel Normalization

Clinical Cancer Research, 2007

Purpose: To test whether a direct antiangiogenic peptide (anginex) and a vascular endothelial gro... more Purpose: To test whether a direct antiangiogenic peptide (anginex) and a vascular endothelial growth factor antibody (bevacizumab, Avastin) can transiently normalize vasculature within tumors to improve oxygen delivery, alleviate hypoxia, and increase the effect of radiation therapy. Experimental Design: Tumor oxygenation levels, microvessel density and pericyte coverage were monitored in three different solid tumor models (xenograft human ovarian carcinoma MA148, murine melanoma B16F10, and murine breast carcinoma SCK) in mice. Multiple treatment schedules were tested in these models to assess the influence on the effect of radiation therapy. Results: In all three tumor models, we found that tumor oxygenation levels, monitored daily in real time, were increased during the first 4 days of treatment with both anginex and bevacizumab. From treatment day 5 onward, tumor oxygenation in treated mice decreased significantly to below that in control mice. This “tumor oxygenation window” oc...

Research paper thumbnail of Vascular Disrupting Agent Arsenic Trioxide Enhances Thermoradiotherapy of Solid Tumors

Journal of Oncology, 2012

Our previous studies demonstrated arsenic trioxide- (ATO-) induced selective tumor vascular disru... more Our previous studies demonstrated arsenic trioxide- (ATO-) induced selective tumor vascular disruption and augmentation of thermal or radiotherapy effect against solid tumors. These results suggested that a trimodality approach of radiation, ATO, and local hyperthermia may have potent therapeutic efficacy against solid tumors. Here, we report the antitumor effect of hypofractionated radiation followed by ATO administration and local 42.5 °C hyperthermia and the effects of cisplatin and thermoradiotherapy. We found that the therapeutic efficacy of ATO-based thermoradiotherapy was equal or greater than that of cisplatin-based thermoradiotherapy, and marked evidence ofin vivoapoptosis and tumor necrosis were observed in ATO-treated tumors. We conclude that ATO-based thermoradiotherapy is a powerful means to control tumor growth by using vascular disruption to augment the effects of thermal and radiation therapy.

Research paper thumbnail of Molecular changes in bone marrow, tumor and serum after conductive ablation of murine 4T1 breast carcinoma

International Journal of Oncology, 2013

Research paper thumbnail of Experimental characterization of a SonoKnife applicator

Progress in Biomedical Optics and Imaging - Proceedings of SPIE, 2011

The SonoKnife is a scan-able high intensity line-focused ultrasound device for thermal ablation (... more The SonoKnife is a scan-able high intensity line-focused ultrasound device for thermal ablation (52 - 60°C) of superficially located advanced tumors or nodal disease in the head and neck. Based on preliminary simulation results, a prototype cylindrical section transducer operating at 3.5 MHz, with a 60 mm radius of curvature, an elevation of 30 mm and an aperture of 60

Research paper thumbnail of Dual thermal ablation modality of solid tumors in a mouse model

Progress in Biomedical Optics and Imaging - Proceedings of SPIE, 2011

Purpose: Develop a new combination therapy consisting of cryoablation and conductive high-tempera... more Purpose: Develop a new combination therapy consisting of cryoablation and conductive high-temperature ablation for enhanced thermal ablation of solid tumors. Methods: We have constructed an invasive probe that can be used for consecutive cryoablation and ...

Research paper thumbnail of Multi-Angle Switched HIFU: A New Ultrasound Device for Controlled Non-Invasive Induction of Small Spherical Ablation Zones—Simulation and Ex-Vivo Results

Current HIFU devices produce elongated elliptical lesions (cigar shaped) in a single energy depos... more Current HIFU devices produce elongated elliptical lesions (cigar shaped) in a single energy deposition. This prohibits the effective use of HIFU in small animal research as well as in clinical treatment where small volumes of tissue surrounded by critical structures need to be destroyed. We developed an ultrasound ablation device that non-invasively creates spheroidal lesions of an arbitrary diameter of

Research paper thumbnail of SU-FF-T-336: Patient-Specific QA in MLC-Based GRID Therapy

Medical Physics, 2007

... W Gao, J Penagaricano, E Moros, P Corry, R Griffin, A Ivy, E Youssef, V Ratanatharathorn. ...... more ... W Gao, J Penagaricano, E Moros, P Corry, R Griffin, A Ivy, E Youssef, V Ratanatharathorn. ... The treatments were planned on the Pinnacle TPS using a step‐and‐shoot technique to generatechess‐board‐like patterns consisting of abutting opened‐and‐closed cells of 1cm×1cm. ...

Research paper thumbnail of TU-C-BRD-03: An Integrated Robotic-Based Irradiation System for Small Animal Research

Medical Physics, 2009

An integrated, image‐guided irradiation system for small animal research has been developed. The ... more An integrated, image‐guided irradiation system for small animal research has been developed. The system is capable of precise, accurate, reproducible and quantifiable 3D conformal delivery of radiationdose distributions to organs/tumors. The main hardware components are: (1) A Seifert Isovolt Titan 225 kV X‐ray tube with beam collimation provided by a custom‐made variable diameter “cone” or a set of motor‐driven symmetric “jaws”, thereby allowing field sizes from 0.5 mm in diameter to 7 cm square field at ∼33.5 cm SSD. (2) A six‐degrees‐of‐freedom (6DOF) robotic arm (Adept Viper s650) was integrated for precise animal positioning/motion (repeatability of ±0.020 mm in XYZ direction and angular precision of ±0.2°). The system is housed in a custom 6 × 6 × 6 ft3 shielded enclosure inside a laboratory. When the beam is aimed horizontally to (3) a flat panel amorphous silicon detector (XRD 0820 CN3, Perkin Elmer, Fremont, CA) a series of 2D‐radiographs can be recorded while the robot rotates the animal. Each image is composed of 1024 by 1024 pixels with a 200 μm pixel size at a frame rate of 7.5 Hz. An open source cone beam computed tomography(CBCT)reconstruction tool (OSCAR‐2, University of Toronto) using the Feldkamp‐Davis‐Kress (FDK) filtered back projection algorithm was implemented for CBCTimage reconstruction. Thus, targeting can be accomplished by the use of orthogonal radiographs and/or CBCT. A dose engine and CBCT‐based treatment planning are ongoing projects. Dosimetric measurements and preliminary animal experiments have demonstrated the basic capabilities of the system in terms of radiationdose,dose rate and precision targeting. The system has also been used successfully in experiments to detect the molecular signaling occurring after spatially fractionated radiation therapy (GRID) in vivo. A description of the system and a summary of experiments performed to date will be presented. Learning Objectives: 1. Appreciate the challenges of developing a high precision 3D conformal irradiator for small animals. 2. Learn about the main hardware components of the system and their integration. 3. Understand the advantages of using a 6DOF robot for imaging (motion) and beam delivery (positioning). 4. Learn about some of the potential research projects that such a system can make possible. This research was sponsored by the Arkansas Biosciences Institute and the Central Arkansas Radiation Therapy Institute.

Research paper thumbnail of SonoKnife: Feasibility of a line-focused ultrasound device for thermal ablation therapy

Medical Physics, 2011

To evaluate the feasibility of line-focused ultrasound for thermal ablation of superficially loca... more To evaluate the feasibility of line-focused ultrasound for thermal ablation of superficially located tumors. Methods: A SonoKnife is a cylindrical-section ultrasound transducer designed to radiate from its concave surface. This geometry generates a line-focus or acoustic edge. The motivation for this approach was the noninvasive thermal ablation of advanced head and neck tumors and positive neck nodes in reasonable treatment times. Line-focusing may offer advantages over the common point-focusing of spherically curved radiators such as faster coverage of a target volume by scanning of the acoustic edge. In this paper, The authors report studies using numerical models and phantom and ex vivo experiments using a SonoKnife prototype. Results: Acoustic edges were generated by cylindrical-section single-element ultrasound transducers numerically, and by the prototype experimentally. Numerically, simulations were performed to characterize the acoustic edge for basic design parameters: transducer dimensions, line-focus depth, frequency, and coupling thickness. The dimensions of the acoustic edge as a function of these parameters were determined. In addition, a step-scanning simulation produced a large thermal lesion in a reasonable treatment time. Experimentally, pressure distributions measured in degassed water agreed well with acoustic simulations, and sonication experiments in gel phantoms and ex vivo porcine liver samples produced lesions similar to those predicted with acoustic and thermal models. Conclusions: Results support the feasibility of noninvasive thermal ablation with a SonoKnife.

Research paper thumbnail of Efficacy and biodistribution of gold nanoparticles

Journal of Biomechanics, 2006

Research paper thumbnail of Dead or alive? Autofluorescence distinguishes heat-fixed from viable cells

International Journal of Hyperthermia, 2009

Purpose-A proof-of-concept study to evaluate a new autofluorescence method to differentiate necro... more Purpose-A proof-of-concept study to evaluate a new autofluorescence method to differentiate necrotic thermally fixed cells from viable tissue following thermal ablation. Methods-A conductive interstitial thermal therapy (CITT) device was used to ablate swine mammary tissue and rabbit VX-2 carcinomas in vivo. The ablated regions and 10-mm margins were resected 24 h following treatment, embedded in HistOmer ® and sectioned at 3 mm. The fresh sections were evaluated for gross viability with triphenyl tetrazolium chloride, 1 h post-resection. Representative non-viable and viable areas were then processed and embedded into paraffin, and sectioned at 5 μm. Standard H&E staining and proliferating cell nuclear antigen (PCNA) immunohistochemistry were compared against autofluorescence intensity, at 488-nm wavelength, for cellular viability. Results-Heat-fixed cells in non-viable regions exhibit increased autofluorescence intensity compared to viable tissue (area under receiver operating characteristics (ROC) curve =0.96; Mann-Whitney P <0.0001). An autofluorescence intensity-based classification rule achieved 92% sensitivity with 100% specificity for distinguishing non-viable from viable samples. In contrast, PCNA staining did not reliably distinguish heat-fixed, dead cells from viable cells. Conclusions-Examination of H&E-stained sections using autofluorescence intensity-based classification is a reliable and readily available method to accurately identify heat-fixed cells in ablated surgical margins.

Research paper thumbnail of Conductive interstitial thermal therapy (CITT) inhibits recurrence and metastasis in rabbit VX2 carcinoma model

International Journal of Hyperthermia, 2009

Purpose-To investigate the potential of conductive interstitial thermal therapy (CITT) to inhibit... more Purpose-To investigate the potential of conductive interstitial thermal therapy (CITT) to inhibit recurrence and metastasis in a partially resected tumour model. Method-Fifteen New Zealand white rabbits were implanted with VX2 tumour intramuscularly in the rear thigh. Once the tumour size reached 20-25 mm in diameter, three animals were randomly selected to serve as controls, while the remaining animals were designated as the study group and treated with CITT. In the CITT group, the partially resected tumour and margins were thermally ablated. In the control group the tumour was partially resected to simulate positive margins. The animals were monitored for up to 12 weeks. At the endpoint, the animals were sacrificed, and wholebody diagnostic necropsy was conducted immediately. Results-Recurrences and metastatic lesions were observed in iliac and popliteal lymph nodes and abdomens of all control animals. In contrast, the observed rate of recurrence and metastatic lesion was 0% among CITT-treated animals, significantly less than the ≥50% null-hypothesis rate expected upon treatment failure (exact binomial P = 0.0002). Complete histopatho-logical healing was obtained in 2 of 12 rabbits, and residual inflammation remained at the ablation site up to 12 weeks

Research paper thumbnail of Spatially Fractionated Radiation Induces Cytotoxicity and Changes in Gene Expression in Bystander and Radiation Adjacent Murine Carcinoma Cells

Radiation Research, 2012

Radiation-induced bystander effects have been extensively studied at low doses, since evidence of... more Radiation-induced bystander effects have been extensively studied at low doses, since evidence of bystander induced cell killing and other effects on unirradiated cells were found to be predominant at doses up to 0.5 Gy. Therefore, few studies have examined bystander effects induced by exposure to higher doses of radiation, such as spatially fractionated radiation (GRID) treatment. In the present study, we evaluate the ability of GRID treatment to induce changes in GRID adjacent (bystander) regions, in two different murine carcinoma cell lines following exposure to a single irradiation dose of 10 Gy. Murine SCK mammary carcinoma cells and SCCVII squamous carcinoma cells were irradiated using a brass collimator to create a GRID pattern of nine circular fields 12 mm in diameter with a center-to-center distance of 18 mm. Similar to the typical clinical implementation of GRID, this is approximately a 50:50 ratio of direct and bystander exposure. We also performed experiments by irradiating separate cultures and transferring the medium to unirradiated bystander cultures. Clonogenic survival was evaluated in both cell lines to determine the occurrence of radiation-induced bystander effects. For the purpose of our study, we have defined bystander cells as GRID adjacent cells that received approximately 1 Gy scatter dose or unirradiated cells receiving conditioned medium from irradiated cells. We observed significant bystander killing of cells adjacent to the GRID irradiated regions compared to sham treated controls. We also observed bystander killing of SCK and SCCVII cells cultured in conditioned medium obtained from cells irradiated with 10 Gy. Therefore, our results confirm the occurrence of bystander effects following exposure to a high-dose of radiation and suggest that cell-to-cell contact is not required for these effects. In addition, the gene expression profile for DNA damage and cellular stress response signaling in SCCVII cells after GRID exposure was studied. The occurrence of GRID-induced bystander gene expression changes in significant numbers of DNA damage and cellular stress response signaling genes, providing molecular evidence for possible mechanisms of bystander cell killing.

Research paper thumbnail of Enhancement of tumor thermal therapy using gold nanoparticle–assisted tumor necrosis factor-α delivery

Molecular Cancer Therapeutics, 2006

Research paper thumbnail of Advanced Small Animal Conformal Radiation Therapy Device

Technology in cancer research & treatment, Feb 20, 2016

We have developed a small animal conformal radiation therapy device that provides a degree of geo... more We have developed a small animal conformal radiation therapy device that provides a degree of geometrical/anatomical targeting comparable to what is achievable in a commercial animal irradiator. small animal conformal radiation therapy device is capable of producing precise and accurate conformal delivery of radiation to target as well as for imaging small animals. The small animal conformal radiation therapy device uses an X-ray tube, a robotic animal position system, and a digital imager. The system is in a steel enclosure with adequate lead shielding following National Council on Radiation Protection and Measurements 49 guidelines and verified with Geiger-Mueller survey meter. The X-ray source is calibrated following AAPM TG-61 specifications and mounted at 101.6 cm from the floor, which is a primary barrier. The X-ray tube is mounted on a custom-made "gantry" and has a special collimating assembly system that allows field size between 0.5 mm and 20 cm at isocenter. Thr...

Research paper thumbnail of Nanotherapeutics for enhancing thermal therapy of cancer

International Journal of Hyperthermia, 2007

The current work describes the synergistic enhancement of hyperthermic cancer therapy by selectiv... more The current work describes the synergistic enhancement of hyperthermic cancer therapy by selective thermal sensitization and induction of vascular injury at the tumor site. The specificity of this response was mediated by CYT-6091: a pegylated colloidal gold-based nanotherapeutic designed to selectively deliver an inflammatory cytokine, tumor necrosis factor alpha (TNF), to solid tumors. FSaII murine fibrosarcoma-bearing C3H mice received an intravenous injection of either soluble TNF or CYT-6091 (50-250 microg/kg TNF). Four hours later the tumors were exposed to localized heating (42.5 or 43.5 degrees C, 60 min). Tumor responses were assessed by growth delay and/or perfusion. Both soluble TNF and CYT-6091 reduced tumor perfusion by 80% of control (no treatment), 4 hours post administration. However, soluble TNF was toxic to the tumor burdened mice and resulted in 40% mortality alone and 100% mortality when combined with hyperthermia. Conversely, no toxicities were noted with CYT-6091 alone or when combined with hyperthermia. Additionally, CYT-6091 combined with heat yielded significant tumor regression in vivo as compared to heat or CYT-6091 alone as demonstrated by tumor growth delay. Pretreatment with soluble TNF or CYT-6091 followed by heating reduced in vitro tumor and endothelial cell survival by 40-50% (TNF) and 70-75% (CYT-6091) of the control cell (i.e. tumor and endothelial) values, respectively. CYT-6091, by selectively delivering TNF to solid tumors, improves the safety of TNF treatment. In addition, the targeted delivery of TNF augments cancer thermal therapy efficacy possibly by inducing a tumor-localized inflammatory response.

Research paper thumbnail of Microbeam Radiation Therapy Alters Vascular Architecture and Tumor Oxygenation and is Enhanced by a Galectin-1 Targeted Anti-Angiogenic Peptide

Research paper thumbnail of Galectins as Molecular Targets for Therapeutic Intervention

International journal of molecular sciences, Jan 19, 2018

Galectins are a family of small, highly conserved, molecular effectors that mediate various biolo... more Galectins are a family of small, highly conserved, molecular effectors that mediate various biological processes, including chemotaxis and angiogenesis, and that function by interacting with various cell surface glycoconjugates, usually targeting β-galactoside epitopes. Because of their significant involvement in various biological functions and pathologies, galectins have become a focus of therapeutic discovery for clinical intervention against cancer, among other pathological disorders. In this review, we focus on understanding galectin structure-function relationships, their mechanisms of action on the molecular level, and targeting them for therapeutic intervention against cancer.

Research paper thumbnail of Pegylated IFN-α sensitizes melanoma cells to chemotherapy and causes premature senescence in endothelial cells by IRF-1 mediated signaling

Cell death & disease, 2010

Pegylated Interferon-α2b (pIFN-α) is an integral part of the drug regimen currently employed agai... more Pegylated Interferon-α2b (pIFN-α) is an integral part of the drug regimen currently employed against melanoma. Interferon Regulatory Factor-1 (IRF-1) plays an important role in the transcriptional regulation of the IFN response, cell cycle and apoptosis. We have studied pIFN-α induced responses when combined with the chemotherapy agent, vinblastine in tumor and endothelial cell lines and the connection to IRF-1 signaling. Levels of IRF-1/IRF-2 protein expression were found to be decreased in tumor versus normal tissues. pIFN-α induced IRF-1 signaling in human melanoma (M14) and endothelial (EA.hy926) cells and enhanced cell death when combined with vinblastine. Upon combined IFN-α and vinblastine treatment, p21 expression, PARP cleavage and activated Bak levels were increased in M14 cells. An increase in p21 and cyclin D1 expression occurred in EA.hy926 cells after 6 h of treatment with pIFN-α which dissipated by 24 h. This biphasic response, characteristic of cellular senescence, w...

Research paper thumbnail of SU-FF-J-160: Spatially Fractionated Radiation Therapy (GRID) On Implanted Tumors Using a Small Animal Conformal Radiation Therapy System

Medical Physics, 2009

ABSTRACT

Research paper thumbnail of Scheduling of Radiation with Angiogenesis Inhibitors Anginex and Avastin Improves Therapeutic Outcome via Vessel Normalization

Clinical Cancer Research, 2007

Purpose: To test whether a direct antiangiogenic peptide (anginex) and a vascular endothelial gro... more Purpose: To test whether a direct antiangiogenic peptide (anginex) and a vascular endothelial growth factor antibody (bevacizumab, Avastin) can transiently normalize vasculature within tumors to improve oxygen delivery, alleviate hypoxia, and increase the effect of radiation therapy. Experimental Design: Tumor oxygenation levels, microvessel density and pericyte coverage were monitored in three different solid tumor models (xenograft human ovarian carcinoma MA148, murine melanoma B16F10, and murine breast carcinoma SCK) in mice. Multiple treatment schedules were tested in these models to assess the influence on the effect of radiation therapy. Results: In all three tumor models, we found that tumor oxygenation levels, monitored daily in real time, were increased during the first 4 days of treatment with both anginex and bevacizumab. From treatment day 5 onward, tumor oxygenation in treated mice decreased significantly to below that in control mice. This “tumor oxygenation window” oc...

Research paper thumbnail of Vascular Disrupting Agent Arsenic Trioxide Enhances Thermoradiotherapy of Solid Tumors

Journal of Oncology, 2012

Our previous studies demonstrated arsenic trioxide- (ATO-) induced selective tumor vascular disru... more Our previous studies demonstrated arsenic trioxide- (ATO-) induced selective tumor vascular disruption and augmentation of thermal or radiotherapy effect against solid tumors. These results suggested that a trimodality approach of radiation, ATO, and local hyperthermia may have potent therapeutic efficacy against solid tumors. Here, we report the antitumor effect of hypofractionated radiation followed by ATO administration and local 42.5 °C hyperthermia and the effects of cisplatin and thermoradiotherapy. We found that the therapeutic efficacy of ATO-based thermoradiotherapy was equal or greater than that of cisplatin-based thermoradiotherapy, and marked evidence ofin vivoapoptosis and tumor necrosis were observed in ATO-treated tumors. We conclude that ATO-based thermoradiotherapy is a powerful means to control tumor growth by using vascular disruption to augment the effects of thermal and radiation therapy.

Research paper thumbnail of Molecular changes in bone marrow, tumor and serum after conductive ablation of murine 4T1 breast carcinoma

International Journal of Oncology, 2013

Research paper thumbnail of Experimental characterization of a SonoKnife applicator

Progress in Biomedical Optics and Imaging - Proceedings of SPIE, 2011

The SonoKnife is a scan-able high intensity line-focused ultrasound device for thermal ablation (... more The SonoKnife is a scan-able high intensity line-focused ultrasound device for thermal ablation (52 - 60°C) of superficially located advanced tumors or nodal disease in the head and neck. Based on preliminary simulation results, a prototype cylindrical section transducer operating at 3.5 MHz, with a 60 mm radius of curvature, an elevation of 30 mm and an aperture of 60

Research paper thumbnail of Dual thermal ablation modality of solid tumors in a mouse model

Progress in Biomedical Optics and Imaging - Proceedings of SPIE, 2011

Purpose: Develop a new combination therapy consisting of cryoablation and conductive high-tempera... more Purpose: Develop a new combination therapy consisting of cryoablation and conductive high-temperature ablation for enhanced thermal ablation of solid tumors. Methods: We have constructed an invasive probe that can be used for consecutive cryoablation and ...

Research paper thumbnail of Multi-Angle Switched HIFU: A New Ultrasound Device for Controlled Non-Invasive Induction of Small Spherical Ablation Zones—Simulation and Ex-Vivo Results

Current HIFU devices produce elongated elliptical lesions (cigar shaped) in a single energy depos... more Current HIFU devices produce elongated elliptical lesions (cigar shaped) in a single energy deposition. This prohibits the effective use of HIFU in small animal research as well as in clinical treatment where small volumes of tissue surrounded by critical structures need to be destroyed. We developed an ultrasound ablation device that non-invasively creates spheroidal lesions of an arbitrary diameter of

Research paper thumbnail of SU-FF-T-336: Patient-Specific QA in MLC-Based GRID Therapy

Medical Physics, 2007

... W Gao, J Penagaricano, E Moros, P Corry, R Griffin, A Ivy, E Youssef, V Ratanatharathorn. ...... more ... W Gao, J Penagaricano, E Moros, P Corry, R Griffin, A Ivy, E Youssef, V Ratanatharathorn. ... The treatments were planned on the Pinnacle TPS using a step‐and‐shoot technique to generatechess‐board‐like patterns consisting of abutting opened‐and‐closed cells of 1cm×1cm. ...

Research paper thumbnail of TU-C-BRD-03: An Integrated Robotic-Based Irradiation System for Small Animal Research

Medical Physics, 2009

An integrated, image‐guided irradiation system for small animal research has been developed. The ... more An integrated, image‐guided irradiation system for small animal research has been developed. The system is capable of precise, accurate, reproducible and quantifiable 3D conformal delivery of radiationdose distributions to organs/tumors. The main hardware components are: (1) A Seifert Isovolt Titan 225 kV X‐ray tube with beam collimation provided by a custom‐made variable diameter “cone” or a set of motor‐driven symmetric “jaws”, thereby allowing field sizes from 0.5 mm in diameter to 7 cm square field at ∼33.5 cm SSD. (2) A six‐degrees‐of‐freedom (6DOF) robotic arm (Adept Viper s650) was integrated for precise animal positioning/motion (repeatability of ±0.020 mm in XYZ direction and angular precision of ±0.2°). The system is housed in a custom 6 × 6 × 6 ft3 shielded enclosure inside a laboratory. When the beam is aimed horizontally to (3) a flat panel amorphous silicon detector (XRD 0820 CN3, Perkin Elmer, Fremont, CA) a series of 2D‐radiographs can be recorded while the robot rotates the animal. Each image is composed of 1024 by 1024 pixels with a 200 μm pixel size at a frame rate of 7.5 Hz. An open source cone beam computed tomography(CBCT)reconstruction tool (OSCAR‐2, University of Toronto) using the Feldkamp‐Davis‐Kress (FDK) filtered back projection algorithm was implemented for CBCTimage reconstruction. Thus, targeting can be accomplished by the use of orthogonal radiographs and/or CBCT. A dose engine and CBCT‐based treatment planning are ongoing projects. Dosimetric measurements and preliminary animal experiments have demonstrated the basic capabilities of the system in terms of radiationdose,dose rate and precision targeting. The system has also been used successfully in experiments to detect the molecular signaling occurring after spatially fractionated radiation therapy (GRID) in vivo. A description of the system and a summary of experiments performed to date will be presented. Learning Objectives: 1. Appreciate the challenges of developing a high precision 3D conformal irradiator for small animals. 2. Learn about the main hardware components of the system and their integration. 3. Understand the advantages of using a 6DOF robot for imaging (motion) and beam delivery (positioning). 4. Learn about some of the potential research projects that such a system can make possible. This research was sponsored by the Arkansas Biosciences Institute and the Central Arkansas Radiation Therapy Institute.

Research paper thumbnail of SonoKnife: Feasibility of a line-focused ultrasound device for thermal ablation therapy

Medical Physics, 2011

To evaluate the feasibility of line-focused ultrasound for thermal ablation of superficially loca... more To evaluate the feasibility of line-focused ultrasound for thermal ablation of superficially located tumors. Methods: A SonoKnife is a cylindrical-section ultrasound transducer designed to radiate from its concave surface. This geometry generates a line-focus or acoustic edge. The motivation for this approach was the noninvasive thermal ablation of advanced head and neck tumors and positive neck nodes in reasonable treatment times. Line-focusing may offer advantages over the common point-focusing of spherically curved radiators such as faster coverage of a target volume by scanning of the acoustic edge. In this paper, The authors report studies using numerical models and phantom and ex vivo experiments using a SonoKnife prototype. Results: Acoustic edges were generated by cylindrical-section single-element ultrasound transducers numerically, and by the prototype experimentally. Numerically, simulations were performed to characterize the acoustic edge for basic design parameters: transducer dimensions, line-focus depth, frequency, and coupling thickness. The dimensions of the acoustic edge as a function of these parameters were determined. In addition, a step-scanning simulation produced a large thermal lesion in a reasonable treatment time. Experimentally, pressure distributions measured in degassed water agreed well with acoustic simulations, and sonication experiments in gel phantoms and ex vivo porcine liver samples produced lesions similar to those predicted with acoustic and thermal models. Conclusions: Results support the feasibility of noninvasive thermal ablation with a SonoKnife.

Research paper thumbnail of Efficacy and biodistribution of gold nanoparticles

Journal of Biomechanics, 2006

Research paper thumbnail of Dead or alive? Autofluorescence distinguishes heat-fixed from viable cells

International Journal of Hyperthermia, 2009

Purpose-A proof-of-concept study to evaluate a new autofluorescence method to differentiate necro... more Purpose-A proof-of-concept study to evaluate a new autofluorescence method to differentiate necrotic thermally fixed cells from viable tissue following thermal ablation. Methods-A conductive interstitial thermal therapy (CITT) device was used to ablate swine mammary tissue and rabbit VX-2 carcinomas in vivo. The ablated regions and 10-mm margins were resected 24 h following treatment, embedded in HistOmer ® and sectioned at 3 mm. The fresh sections were evaluated for gross viability with triphenyl tetrazolium chloride, 1 h post-resection. Representative non-viable and viable areas were then processed and embedded into paraffin, and sectioned at 5 μm. Standard H&E staining and proliferating cell nuclear antigen (PCNA) immunohistochemistry were compared against autofluorescence intensity, at 488-nm wavelength, for cellular viability. Results-Heat-fixed cells in non-viable regions exhibit increased autofluorescence intensity compared to viable tissue (area under receiver operating characteristics (ROC) curve =0.96; Mann-Whitney P <0.0001). An autofluorescence intensity-based classification rule achieved 92% sensitivity with 100% specificity for distinguishing non-viable from viable samples. In contrast, PCNA staining did not reliably distinguish heat-fixed, dead cells from viable cells. Conclusions-Examination of H&E-stained sections using autofluorescence intensity-based classification is a reliable and readily available method to accurately identify heat-fixed cells in ablated surgical margins.

Research paper thumbnail of Conductive interstitial thermal therapy (CITT) inhibits recurrence and metastasis in rabbit VX2 carcinoma model

International Journal of Hyperthermia, 2009

Purpose-To investigate the potential of conductive interstitial thermal therapy (CITT) to inhibit... more Purpose-To investigate the potential of conductive interstitial thermal therapy (CITT) to inhibit recurrence and metastasis in a partially resected tumour model. Method-Fifteen New Zealand white rabbits were implanted with VX2 tumour intramuscularly in the rear thigh. Once the tumour size reached 20-25 mm in diameter, three animals were randomly selected to serve as controls, while the remaining animals were designated as the study group and treated with CITT. In the CITT group, the partially resected tumour and margins were thermally ablated. In the control group the tumour was partially resected to simulate positive margins. The animals were monitored for up to 12 weeks. At the endpoint, the animals were sacrificed, and wholebody diagnostic necropsy was conducted immediately. Results-Recurrences and metastatic lesions were observed in iliac and popliteal lymph nodes and abdomens of all control animals. In contrast, the observed rate of recurrence and metastatic lesion was 0% among CITT-treated animals, significantly less than the ≥50% null-hypothesis rate expected upon treatment failure (exact binomial P = 0.0002). Complete histopatho-logical healing was obtained in 2 of 12 rabbits, and residual inflammation remained at the ablation site up to 12 weeks

Research paper thumbnail of Spatially Fractionated Radiation Induces Cytotoxicity and Changes in Gene Expression in Bystander and Radiation Adjacent Murine Carcinoma Cells

Radiation Research, 2012

Radiation-induced bystander effects have been extensively studied at low doses, since evidence of... more Radiation-induced bystander effects have been extensively studied at low doses, since evidence of bystander induced cell killing and other effects on unirradiated cells were found to be predominant at doses up to 0.5 Gy. Therefore, few studies have examined bystander effects induced by exposure to higher doses of radiation, such as spatially fractionated radiation (GRID) treatment. In the present study, we evaluate the ability of GRID treatment to induce changes in GRID adjacent (bystander) regions, in two different murine carcinoma cell lines following exposure to a single irradiation dose of 10 Gy. Murine SCK mammary carcinoma cells and SCCVII squamous carcinoma cells were irradiated using a brass collimator to create a GRID pattern of nine circular fields 12 mm in diameter with a center-to-center distance of 18 mm. Similar to the typical clinical implementation of GRID, this is approximately a 50:50 ratio of direct and bystander exposure. We also performed experiments by irradiating separate cultures and transferring the medium to unirradiated bystander cultures. Clonogenic survival was evaluated in both cell lines to determine the occurrence of radiation-induced bystander effects. For the purpose of our study, we have defined bystander cells as GRID adjacent cells that received approximately 1 Gy scatter dose or unirradiated cells receiving conditioned medium from irradiated cells. We observed significant bystander killing of cells adjacent to the GRID irradiated regions compared to sham treated controls. We also observed bystander killing of SCK and SCCVII cells cultured in conditioned medium obtained from cells irradiated with 10 Gy. Therefore, our results confirm the occurrence of bystander effects following exposure to a high-dose of radiation and suggest that cell-to-cell contact is not required for these effects. In addition, the gene expression profile for DNA damage and cellular stress response signaling in SCCVII cells after GRID exposure was studied. The occurrence of GRID-induced bystander gene expression changes in significant numbers of DNA damage and cellular stress response signaling genes, providing molecular evidence for possible mechanisms of bystander cell killing.

Research paper thumbnail of Enhancement of tumor thermal therapy using gold nanoparticle–assisted tumor necrosis factor-α delivery

Molecular Cancer Therapeutics, 2006

Research paper thumbnail of Advanced Small Animal Conformal Radiation Therapy Device

Technology in cancer research & treatment, Feb 20, 2016

We have developed a small animal conformal radiation therapy device that provides a degree of geo... more We have developed a small animal conformal radiation therapy device that provides a degree of geometrical/anatomical targeting comparable to what is achievable in a commercial animal irradiator. small animal conformal radiation therapy device is capable of producing precise and accurate conformal delivery of radiation to target as well as for imaging small animals. The small animal conformal radiation therapy device uses an X-ray tube, a robotic animal position system, and a digital imager. The system is in a steel enclosure with adequate lead shielding following National Council on Radiation Protection and Measurements 49 guidelines and verified with Geiger-Mueller survey meter. The X-ray source is calibrated following AAPM TG-61 specifications and mounted at 101.6 cm from the floor, which is a primary barrier. The X-ray tube is mounted on a custom-made "gantry" and has a special collimating assembly system that allows field size between 0.5 mm and 20 cm at isocenter. Thr...

Research paper thumbnail of Nanotherapeutics for enhancing thermal therapy of cancer

International Journal of Hyperthermia, 2007

The current work describes the synergistic enhancement of hyperthermic cancer therapy by selectiv... more The current work describes the synergistic enhancement of hyperthermic cancer therapy by selective thermal sensitization and induction of vascular injury at the tumor site. The specificity of this response was mediated by CYT-6091: a pegylated colloidal gold-based nanotherapeutic designed to selectively deliver an inflammatory cytokine, tumor necrosis factor alpha (TNF), to solid tumors. FSaII murine fibrosarcoma-bearing C3H mice received an intravenous injection of either soluble TNF or CYT-6091 (50-250 microg/kg TNF). Four hours later the tumors were exposed to localized heating (42.5 or 43.5 degrees C, 60 min). Tumor responses were assessed by growth delay and/or perfusion. Both soluble TNF and CYT-6091 reduced tumor perfusion by 80% of control (no treatment), 4 hours post administration. However, soluble TNF was toxic to the tumor burdened mice and resulted in 40% mortality alone and 100% mortality when combined with hyperthermia. Conversely, no toxicities were noted with CYT-6091 alone or when combined with hyperthermia. Additionally, CYT-6091 combined with heat yielded significant tumor regression in vivo as compared to heat or CYT-6091 alone as demonstrated by tumor growth delay. Pretreatment with soluble TNF or CYT-6091 followed by heating reduced in vitro tumor and endothelial cell survival by 40-50% (TNF) and 70-75% (CYT-6091) of the control cell (i.e. tumor and endothelial) values, respectively. CYT-6091, by selectively delivering TNF to solid tumors, improves the safety of TNF treatment. In addition, the targeted delivery of TNF augments cancer thermal therapy efficacy possibly by inducing a tumor-localized inflammatory response.

Research paper thumbnail of Microbeam Radiation Therapy Alters Vascular Architecture and Tumor Oxygenation and is Enhanced by a Galectin-1 Targeted Anti-Angiogenic Peptide

Research paper thumbnail of Galectins as Molecular Targets for Therapeutic Intervention

International journal of molecular sciences, Jan 19, 2018

Galectins are a family of small, highly conserved, molecular effectors that mediate various biolo... more Galectins are a family of small, highly conserved, molecular effectors that mediate various biological processes, including chemotaxis and angiogenesis, and that function by interacting with various cell surface glycoconjugates, usually targeting β-galactoside epitopes. Because of their significant involvement in various biological functions and pathologies, galectins have become a focus of therapeutic discovery for clinical intervention against cancer, among other pathological disorders. In this review, we focus on understanding galectin structure-function relationships, their mechanisms of action on the molecular level, and targeting them for therapeutic intervention against cancer.