Publications by authors named "Robert J Griffin"

149 Publications

Bayesian variable selection for understanding mixtures in environmental exposures.

Stat Med 2021 Jun 15. Epub 2021 Jun 15.

Children's Environmental Health Initiative, University of Notre Dame, Notre Dame, Indiana, USA.

Social and environmental stressors are crucial factors in child development. However, there exists a multitude of measurable social and environmental factors-the effects of which may be cumulative, interactive, or null. Using a comprehensive cohort of children in North Carolina, we study the impact of social and environmental variables on 4th end-of-grade exam scores in reading and mathematics. To identify the essential factors that predict these educational outcomes, we design new tools for Bayesian linear variable selection using decision analysis. We extract a predictive optimal subset of explanatory variables by coupling a loss function with a novel model-based penalization scheme, which leads to coherent Bayesian decision analysis and empirically improves variable selection, estimation, and prediction on simulated data. The Bayesian linear model propagates uncertainty quantification to all predictive evaluations, which is important for interpretable and robust model comparisons. These predictive comparisons are conducted out-of-sample with a customized approximation algorithm that avoids computationally intensive model refitting. We apply our variable selection techniques to identify the joint collection of social and environmental stressors-and their interactions-that offer clear and quantifiable improvements in prediction of reading and mathematics exam scores.
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http://dx.doi.org/10.1002/sim.9099DOI Listing
June 2021

Exosome Traceability and Cell Source Dependence on Composition and Cell-Cell Cross Talk.

Int J Mol Sci 2021 May 19;22(10). Epub 2021 May 19.

Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.

Exosomes are small vesicles with an average diameter of 100 nm that are produced by many, if not all, cell types. Exosome cargo includes lipids, proteins, and nucleic acids arranged specifically in the endosomes of donor cells. Exosomes can transfer the donor cell components to target cells and can affect cell signaling, proliferation, and differentiation. Important new information about exosomes' remote communication with other cells is rapidly being accumulated. Recent data indicates that the results of this communication depend on the donor cell type and the environment of the host cell. In the field of cancer research, major questions remain, such as whether tumor cell exosomes are equally taken up by cancer cells and normal cells and whether exosomes secreted by normal cells are specifically taken up by other normal cells or also tumor cells. Furthermore, we do not know how exosome uptake is made selective, how we can trace exosome uptake selectivity, or what the most appropriate methods are to study exosome uptake and selectivity. This review will explain the effect of exosome source and the impact of the donor cell growth environment on tumor and normal cell interaction and communication. The review will also summarize the methods that have been used to label and trace exosomes to date.
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http://dx.doi.org/10.3390/ijms22105346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161017PMC
May 2021

Photothermal Response Induced by Nanocage-Coated Artificial Extracellular Matrix Promotes Neural Stem Cell Differentiation.

Nanomaterials (Basel) 2021 May 4;11(5). Epub 2021 May 4.

Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.

Strategies to increase the proportion of neural stem cells that differentiate into neurons are vital for therapy of neurodegenerative disorders. In vitro, the extracellular matrix composition and topography have been found to be important factors in stem cell differentiation. We have developed a novel artificial extracellular matrix (aECM) formed by attaching gold nanocages (AuNCs) to glass coverslips. After culturing rat neural stem cells (rNSCs) on these gold nanocage-coated surfaces (AuNC-aECMs), we observed that 44.6% of rNSCs differentiated into neurons compared to only 27.9% for cells grown on laminin-coated glass coverslips. We applied laser irradiation to the AuNC-aECMs to introduce precise amounts of photothermally induced heat shock in cells. Our results showed that laser-induced thermal stimulation of AuNC-aECMs further enhanced neuronal differentiation (56%) depending on the laser intensity used. Response to these photothermal effects increased the expression of heat shock protein 27, 70, and 90α in rNSCs. Analysis of dendritic complexity showed that this thermal stimulation promoted neuronal maturation by increasing dendrite length as thermal dose was increased. In addition, we found that cells growing on AuNC-aECMs post laser irradiation exhibited action potentials and increased the expression of voltage-gated Na+ channels compared to laminin-coated glass coverslips. These results indicate that the photothermal response induced in cells growing on AuNC-aECMs can be used to produce large quantities of functional neurons, with improved electrochemical properties, that can potentially be transplanted into a damaged central nervous system to provide replacement neurons and restore lost function.
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http://dx.doi.org/10.3390/nano11051216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147862PMC
May 2021

Cystic fibrosis improves COVID-19 survival and provides clues for treatment of SARS-CoV-2.

Purinergic Signal 2021 May 10. Epub 2021 May 10.

Bayer GU Oncology, St. Louis, MO, USA.

Systemic pools of ATP are elevated in individuals homozygous for cystic fibrosis (CF) as evidenced by elevated blood and plasma ATP levels. This elevated ATP level seems to provide benefit in the presence of advanced solid tumors (Abraham et al., Nature Medicine 2(5):593-596, 1996). We published in this journal a paper showing that IV ATP can elevate the depleted ATP pools of advanced cancer patients up to levels found in CF patients with subsequent clinical, biochemical, and quality of life (QOL) improvements (Rapaport et al., Purinergic Signalling 11(2): 251-262, 2015). We hypothesize that the elevated ATP levels seen in CF patients may be benefiting CF patients in another way: by improving their survival after contracting COVID-19. We discuss here the reasoning behind this hypothesis and suggest how these findings might be applied clinically in the general population.
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http://dx.doi.org/10.1007/s11302-021-09771-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107773PMC
May 2021

The Great Deceiver: miR-2392's Hidden Role in Driving SARS-CoV-2 Infection.

bioRxiv 2021 Apr 27. Epub 2021 Apr 27.

MicroRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional gene regulation that have a major impact on many diseases and provides an exciting avenue towards antiviral therapeutics. From patient transcriptomic data, we have discovered a circulating miRNA, miR-2392, that is directly involved with SARS-CoV-2 machinery during host infection. Specifically, we found that miR-2392 was key in driving downstream suppression of mitochondrial gene expression, increasing inflammation, glycolysis, and hypoxia as well as promoting many symptoms associated with COVID-19 infection. We demonstrate miR-2392 is present in the blood and urine of COVID-19 patients tested, but not detected in COVID-19 negative patients. These findings indicate the potential for developing a novel, minimally invasive, COVID-19 detection method. Lastly, using both human and hamster models, we have developed a novel miRNA-based antiviral therapeutic targeting miR-2392 that significantly reduces SARS-CoV-2 viability and may potentially inhibit a COVID-19 disease state in the host.
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http://dx.doi.org/10.1101/2021.04.23.441024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8095194PMC
April 2021

Mobocertinib (TAK-788): A Targeted Inhibitor of Exon 20 Insertion Mutants in Non-Small Cell Lung Cancer.

Cancer Discov 2021 Jul 25;11(7):1672-1687. Epub 2021 Feb 25.

ARIAD Pharmaceuticals, Inc., Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.

Most exon 20 insertion (ex20ins) driver mutations in non-small cell lung cancer (NSCLC) are insensitive to approved EGFR tyrosine kinase inhibitors (TKI). To address the limitations of existing therapies targeting -mutated NSCLC, mobocertinib (TAK-788), a novel irreversible EGFR TKI, was specifically designed to potently inhibit oncogenic variants containing activating ex20ins mutations with selectivity over wild-type EGFR. The and activity of mobocertinib was evaluated in engineered and patient-derived models harboring diverse ex20ins mutations. Mobocertinib inhibited viability of various EGFRex20ins-driven cell lines more potently than approved EGFR TKIs and demonstrated antitumor efficacy in patient-derived xenografts and murine orthotopic models. These findings support the ongoing clinical development of mobocertinib for the treatment of ex20ins-mutated NSCLC. SIGNIFICANCE: No oral EGFR-targeted therapies are approved for exon 20 insertion (ex20ins) mutation-driven NSCLC. Mobocertinib is a novel small-molecule EGFR inhibitor specifically designed to target EGFRex20ins mutants. Preclinical data reported here support the clinical development of mobocertinib in patients with NSCLC with exon 20 insertion mutations...
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http://dx.doi.org/10.1158/2159-8290.CD-20-1683DOI Listing
July 2021

Dysbiotic stress increases the sensitivity of the tumor vasculature to radiotherapy and c-Met inhibitors.

Angiogenesis 2021 Aug 24;24(3):597-611. Epub 2021 Feb 24.

Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.

Antibiotic-induced microbial imbalance, or dysbiosis, has systemic and long-lasting effects on the host and response to cancer therapies. However, the effects on tumor endothelial cells are largely unknown. Therefore, the goal of the current study was to generate matched B16-F10 melanoma associated endothelial cell lines isolated from mice with and without antibiotic-induced dysbiosis. After validating endothelial cell markers on a genomic and proteomic level, functional angiogenesis assays (i.e., migration and tube formation) also confirmed their vasculature origin. Subsequently, we found that tumor endothelial cells derived from dysbiotic mice (TEC-Dys) were more sensitive to ionizing radiotherapy in the range of clinically-relevant hypofractionated doses, as compared to tumor endothelial cells derived from orthobiotic mice (TEC-Ortho). In order to identify tumor vasculature-associated drug targets during dysbiosis, we used tandem mass tag mass spectroscopy and focused on the statistically significant cellular membrane proteins overexpressed in TEC-Dys. By these criteria c-Met was the most differentially expressed protein, which was validated histologically by comparing tumors with or without dysbiosis. Moreover, in vitro, c-Met inhibitors Foretinib, Crizotinib and Cabozantinib were significantly more effective against TEC-Dys than TEC-Ortho. In vivo, Foretinib inhibited tumor growth to a greater extent during dysbiosis as compared to orthobiotic conditions. Thus, we surmise that tumor response in dysbiotic patients may be greatly improved by targeting dysbiosis-induced pathways, such as c-Met, distinct from the many targets suppressed due to dysbiosis.
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http://dx.doi.org/10.1007/s10456-021-09771-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8295215PMC
August 2021

Simultaneous exposure to chronic irradiation and simulated microgravity differentially alters immune cell phenotype in mouse thymus and spleen.

Life Sci Space Res (Amst) 2021 Feb 29;28:66-73. Epub 2020 Sep 29.

Division of Radiation Health, Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States. Electronic address:

Deep-space missions may alter immune cell phenotype in the primary (e.g., thymus) and secondary (e.g., spleen) lymphoid organs contributing to the progression of a variety of diseases. In deep space missions, astronauts will be exposed to chronic low doses of HZE radiation while being in microgravity. Ground-based models of long-term uninterrupted exposures to HZE radiation are not yet available. To obtain insight in the effects of concurrent exposure to microgravity and chronic irradiation (CIR), mice received a cumulative dose of chronic 0.5 Gy gamma rays over one month ± simulated microgravity (SMG). To obtain insight in a dose rate effect, additional mice were exposed to single acute irradiation (AIR) at 0.5 Gy gamma rays. We measured proportions of immune cells relative to total number of live cells in the thymus and spleen, stress level markers in plasma, and change in body weight, food consumption, and water intake. CIR affected thymic CD3+/CD335+ natural killer T (NK-T) cells, CD25+ regulatory T (Treg) cells, CD27+/CD335- natural killer (NK1) cells and CD11c+/CD11b- dendritic cells (DCs) differently in mice subjected to SMG than in mice with normal loading. No such effects of CIR on SMG as compared to normal loading were observed in cell types from the spleen. Differences between CIR and AIR groups (both under normal loading) were found in thymic Treg and DCs. Food consumption, water intake, and body weight were less after coexposure than singular or no exposure. Compared to sham, all treatment groups exhibited elevated plasma levels of the stress marker catecholamines. These data suggest that microgravity and chronic irradiation may interact with each other to alter immune cell phenotypes in an organ-specific manner and appropriate strategies are required to reduce the health risk of crewmembers.
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http://dx.doi.org/10.1016/j.lssr.2020.09.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900614PMC
February 2021

MSC exosome-mediated cardioprotection in ischemic mouse heart comparative proteomics of infarct and peri-infarct areas.

Mol Cell Biochem 2021 Apr 10;476(4):1691-1704. Epub 2021 Jan 10.

Department of Medicine, Cardiology Division, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA.

Mesenchymal stem cell (MSC) exosomes may limit cardiac injury, and even reverse cardiac damage in animal models of ischemia. To understand exosome-mediated improvement in cardiac function we examined the proteomic alternations in the MSC exosome-treated mice hearts subjected to left coronary artery (LCA) ligation, with particular emphasis on peri-infarct areas. At 7 days after LCA ligation, left ventricular end systolic thickness, infarct size and survival of mice were studied. Mass spectrometric analysis of infarct and peri-infarct areas was carried out. Expression of inflammatory markers (LOX-1 and NLRP3) and cell death markers (Bax, Bcl-2, Caspases 1 and 3 and GSDMD) were investigated by Western blots and immunofluorescence. Proteomic analysis of the infarct and peri-infarct areas in saline-treated hearts revealed differentially expressed proteins involved in inflammation and apoptotic cell death, while showing depletion of processes governing cell death. Exosome treatment significantly improved the proteomic profile in both infarct and peri-infarct areas, more so in the peri-infarct areas. The infarct size was smaller (9 ± 1%), and cardiac contractile function (fractional shortening) was preserved in the exosome-treated mice (28 ± 2%). Survival of exosome-treated mice was also better. White blood cell accumulation in and around the infarct area, expression of LOX-1 and NLRP3 inflammasome, and markers of cell death (cleaved Caspase-3, Caspase-1, GSDMD, Bcl-2 and Bax) were dramatically reduced by MSC exosome treatment (all p < 0.01). In cultured primary mouse cardiomyocytes, treatment with MSC exosomes essentially reversed inflammation-induced pro-apoptotic and inflammatory signals (p < 0.01). MSC exosomes exert their cardioprotective effects by suppressing inflammation and pro-apoptotic processes, particularly in the peri-infarct areas, resulting in preservation of cardiac function after LCA ligation.
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http://dx.doi.org/10.1007/s11010-020-04029-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8186026PMC
April 2021

Apportioned primary and secondary organic aerosol during pollution events of DISCOVER-AQ Houston.

Atmos Environ (1994) 2021 Jan;244

Department of Environmental Science, Baylor University, Waco, TX, USA.

Understanding the drivers for high ozone (O) and atmospheric particulate matter (PM) concentrations is a pressing issue in urban air quality, as this understanding informs decisions for control and mitigation of these key pollutants. The Houston, TX metropolitan area is an ideal location for studying the intersection between O and atmospheric secondary organic carbon (SOC) production due to the diversity of source types (urban, industrial, and biogenic) and the on- and off-shore cycling of air masses over Galveston Bay, TX. Detailed characterization of filter-based samples collected during Deriving Information on Surface Conditions from Column and VERtically Resolved Observations Relevant to Air Quality (DISCOVER-AQ) Houston field experiment in September 2013 were used to investigate sources and composition of organic carbon (OC) and potential relationships between daily maximum 8 h average O and PM. The current study employed a novel combination of chemical mass balance modeling defining primary (i.e. POC) versus secondary (i.e. SOC) organic carbon and radiocarbon (C) for apportionment of contemporary and fossil carbon. The apportioned sources include contemporary POC (biomass burning [BB], vegetative detritus), fossil POC (motor vehicle exhaust), biogenic SOC and fossil SOC. The filter-based results were then compared with real-time measurements by aerosol mass spectrometry. With these methods, a consistent urban background of contemporary carbon and motor vehicle exhaust was observed in the Houston metropolitan area. Real-time and filter-based characterization both showed that carbonaceous aerosols in Houston was highly impacted by SOC or oxidized OC, with much higher contributions from biogenic than fossil sources. However, fossil SOC concentration and fractional contribution had a stronger correlation with daily maximum 8 h average O, peaking during high PM and O events. The results indicate that point source emissions processed by on- and off-shore wind cycles likely contribute to peak events for both PM and O in the greater Houston metropolitan area.
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http://dx.doi.org/10.1016/j.atmosenv.2020.117954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784641PMC
January 2021

Photon GRID Radiation Therapy: A Physics and Dosimetry White Paper from the Radiosurgery Society (RSS) GRID/LATTICE, Microbeam and FLASH Radiotherapy Working Group.

Radiat Res 2020 12;194(6):665-677

Department of Radiation Oncology, University of Washington Medical Center, Seattle, Washington 98195.

The limits of radiation tolerance, which often deter the use of large doses, have been a major challenge to the treatment of bulky primary and metastatic cancers. A novel technique using spatial modulation of megavoltage therapy beams, commonly referred to as spatially fractionated radiation therapy (SFRT) (e.g., GRID radiation therapy), which purposefully maintains a high degree of dose heterogeneity across the treated tumor volume, has shown promise in clinical studies as a method to improve treatment response of advanced, bulky tumors. Compared to conventional uniform-dose radiotherapy, the complexities of megavoltage GRID therapy include its highly heterogeneous dose distribution, very high prescription doses, and the overall lack of experience among physicists and clinicians. Since only a few centers have used GRID radiation therapy in the clinic, wide and effective use of this technique has been hindered. To date, the mechanisms underlying the observed high tumor response and low toxicity are still not well understood. To advance SFRT technology and planning, the Physics Working Group of the Radiosurgery Society (RSS) GRID/Lattice, Microbeam and Flash Radiotherapy Working Groups, was established after an RSS-NCI Workshop. One of the goals of the Physics Working Group was to develop consensus recommendations to standardize dose prescription, treatment planning approach, response modeling and dose reporting in GRID therapy. The objective of this report is to present the results of the Physics Working Group's consensus that includes recommendations on GRID therapy as an SFRT technology, field dosimetric properties, techniques for generating GRID fields, the GRID therapy planning methods, documentation metrics and clinical practice recommendations. Such understanding is essential for clinical patient care, effective comparisons of outcome results, and for the design of rigorous clinical trials in the area of SFRT. The results of well-conducted GRID radiation therapy studies have the potential to advance the clinical management of bulky and advanced tumors by providing improved treatment response, and to further develop our current radiobiology models and parameters of radiation therapy design.
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http://dx.doi.org/10.1667/RADE-20-00047.1DOI Listing
December 2020

Evidence for Early Stage Anti-Tumor Immunity Elicited by Spatially Fractionated Radiotherapy-Immunotherapy Combinations.

Radiat Res 2020 12;194(6):688-697

Department of Radiation Oncology, University of Arkansas, Little Rock, Arkansas.

The combination of radiotherapy and immunotherapy may generate synergistic anti-tumor host immune responses and promote abscopal effects. Spatial fractionation of a radiation dose has been found to promote unique physiological responses of tumors, which might promote synergy with immunotherapy. To determine whether spatial fractionation may augment immune activity, whole-tumor or spatial fractionation grid radiation treatment (GRID) alone or in combination with antibodies against immune checkpoints PD1 and CTLA-4 were tested in an immunocompetent mouse model using a triple negative breast tumor (4T1). Tumor growth delay, immunohistochemistry and flow cytometry were used to characterize the effects of each treatment type. Whole-beam radiation with immune checkpoint inhibition significantly restrained tumor growth in the irradiated tumor, but not abscopal tumors, compared to either of these treatments alone. In mice that received spatially fractionated irradiation, evidence of abscopal immune responses were observed in contralateral tumors with markedly enhanced infiltration of both antigen-presenting cells and activated T cells, which were preceded by increased systemic IFNγ production and led to eventual tumor growth delay. These studies suggest that systemic immune activation may be triggered by employing GRID to a primary tumor lesion, promoting anti-tumor immune responses outside the treatment field. Interestingly, PD-L1 was found to be upregulated in abscopal tumors from GRID-treated mice. Combined radio-immunotherapy therapy is becoming a validated and novel approach in the treatment of cancer. With the potential increased benefit of GRID to augment both local and metastatic disease responses, further exploration of GRID treatment as a part of current standards of care is warranted.
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http://dx.doi.org/10.1667/RADE-20-00065.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008989PMC
December 2020

Spectroscopic investigation of radiation-induced reoxygenation in radiation-resistant tumors.

Neoplasia 2021 01 18;23(1):49-57. Epub 2020 Nov 18.

Department of Biomedical Engineering, University of Arkansas, Fayetteville, AR, USA. Electronic address:

Fractionated radiation therapy is believed to reoxygenate and subsequently radiosensitize surviving hypoxic cancer cells. Measuring tumor reoxygenation between radiation fractions could conceivably provide an early biomarker of treatment response. However, the relationship between tumor reoxygenation and local control is not well understood. We used noninvasive optical fiber-based diffuse reflectance spectroscopy to monitor radiation-induced changes in hemoglobin oxygen saturation (sO) in tumor xenografts grown from two head and neck squamous cell carcinoma cell lines - UM-SCC-22B and UM-SCC-47. Tumors were treated with 4 doses of 2 Gy over 2 consecutive weeks and diffuse reflectance spectra were acquired every day during the 2-week period. There was a statistically significant increase in sO in the treatment-responsive UM-SCC-22B tumors immediately following radiation. This reoxygenation trend was due to an increase in oxygenated hemoglobin (HbO) and disappeared over the next 48 h as sO returned to preradiation baseline values. Conversely, sO in the relatively radiation-resistant UM-SCC-47 tumors increased after every dose of radiation and was driven by a significant decrease in deoxygenated hemoglobin (dHb). Immunohistochemical analysis revealed significantly elevated expression of hypoxia-inducible factor (HIF-1) in the UM-SCC-47 tumors prior to radiation and up to 48 h postradiation compared with the UM-SCC-22B tumors. Our observation of a decrease in dHb, a corresponding increase in sO, as well as greater HIF-1α expression only in UM-SCC-47 tumors strongly suggests that the reoxygenation within these tumors is due to a decrease in oxygen consumption in the cancer cells, which could potentially play a role in promoting radiation resistance.
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http://dx.doi.org/10.1016/j.neo.2020.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683290PMC
January 2021

Enhanced response of radioresistant carcinoma cell line to heterogeneous dose distribution of grid; the role of high-dose bystander effect.

Int J Radiat Biol 2020 12 12;96(12):1585-1596. Epub 2020 Nov 12.

Radiation Oncology Research Center, Cancer institute, Tehran University of Medical Sciences, Tehran, Iran.

Purpose: The classical dogma that restricted the radiation effect to the directly irradiated cells has been challenged by the bystander effect. This off-target phenomenon which was manifested in adjacent cells via signaling of fully exposed cells might be involved in high-dose Grid therapy as well. Here, an in-vitro study was performed to examine the possible extent of carcinoma cells response to the inhomogeneous dose distribution of Grid irradiation in the context of the bystander effect.

Materials And Methods: Bystander effect was investigated in human carcinoma cell lines of HeLa and HN5 adjacent to those received high-dose Grid irradiation using 'medium transfer' and 'cell-to-cell contact' strategies. Based on the Grid peak-to-valley dose profile, medium transfer was exerted from 10 Gy uniformly exposed donors to 1.5 Gy uniformly irradiated recipients. Cell-contact bystander was evaluated after nonuniform dose distribution of 10 Gy Grid irradiation using cloning cylinders. GammaH2AX foci, micronucleus and clonogenic assays besides gene expression analysis were performed.

Results: Various parameters (ɑ/β, D37, D50) extracted from survival curve which fitted to the Linear Quadratic model, verified more radioresistance of HN5. Survival fraction at 2 Gy (SF2) indicated as 0.42 ± 0.06 in HeLa and 0.5 ± 0.03 in HN5. The level of survival decrease, DNA damages and micronucleus of cells located in the Grid shielded areas (1.5 Gy cell-to-cell contact bystander cells) were significantly more than the values obtained from cells which were irradiated by merely uniform dose of 1.5 Gy. The gH2AX foci and micronuclei frequencies were enhanced in cell-contact bystander approximately more than 1.8 times. Relative expression of DNA damage repair pathway genes ( and ) in bystander cells increased significantly. The most cell survival reduction (11.6 times) was revealed in the Grid bystander cells of radioresistant cell line (HN5). No statistically significant difference between 10 Gy uniform beam and Grid non-uniform beam was observed.

Conclusions: Various endpoints confirmed an augmented response of cells in the valley dose region of the Grid block significantly (compared with the cells irradiated by identical dose of uniform beam), suggesting the role of high-dose bystander effect which was more pronounced in resistant carcinoma cell lines. These findings could provide a partial explanation for the Grid beneficial response seen in a number of pre-clinical and clinical studies.
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http://dx.doi.org/10.1080/09553002.2020.1834163DOI Listing
December 2020

The Technical and Clinical Implementation of LATTICE Radiation Therapy (LRT).

Radiat Res 2020 Dec;194(6):737-746

Department of Radiation Oncology Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York.

The concept of spatially fractionated radiation therapy (SFRT) was conceived over 100 years ago, first in the form of GRID, which has been applied to clinical practice since its early inception and continued to the present even with markedly improved instrumentation in radiation therapy. LATTICE radiation therapy (LRT) was introduced in 2010 as a conceptual 3D extension of GRID therapy with several uniquely different features. Since 2014, when the first patient was treated, over 150 patients with bulky tumors worldwide have received LRT. Through a brief review of the basic principles and the analysis of the collective clinical experience, a set of technical recommendations and guidelines are proposed for the clinical implementation of LRT. It is to be recognized that the current clinical practice of SFRT (GRID or LRT) is still largely based on the heuristic principles. With advancements in basic biological research and the anticipated clinical trials to systemically assess the efficacy and risk, progressively robust optimizations of the technical parameters are essential for the broader application of SFRT in clinical practice.
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http://dx.doi.org/10.1667/RADE-20-00066.1DOI Listing
December 2020

Indirect cell death and the LQ model in SBRT and SRS.

J Radiosurg SBRT 2020 ;7(1):1-4

Department of Radiation Oncology, University of Minnesota Medical School, Minneapolis, MN, USA.

High-dose hypofractionated SBRT and SRS indirectly kills substantial fractions of tumor cells via causing vascular damage. The LQ formula may work well for certain clinical cases of SBRT and SRS when the indirect/additional tumor cell death secondary to vascular damage is small. However, when the indirect cell death is extensive, the LQ model will underestimate the clinical outcome of SBRT and SRS.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406346PMC
January 2020

History and current perspectives on the biological effects of high-dose spatial fractionation and high dose-rate approaches: GRID, Microbeam & FLASH radiotherapy.

Br J Radiol 2020 Sep 30;93(1113):20200217. Epub 2020 Jul 30.

Patrick G Johnston Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK.

The effects of various forms of ionising radiation are known to be mediated by interactions with cellular and molecular targets in irradiated and in some cases non-targeted tissue volumes. Despite major advances in advanced conformal delivery techniques, the probability of normal tissue complication (NTCP) remains the major dose-limiting factor in escalating total dose delivered during treatment. Potential strategies that have shown promise as novel delivery methods in achieving effective tumour control whilst sparing organs at risk involve the modulation of critical dose delivery parameters. This has led to the development of techniques using high dose spatial fractionation (GRID) and ultra-high dose rate (FLASH) which have translated to the clinic. The current review discusses the historical development and biological basis of GRID, microbeam and FLASH radiotherapy as advanced delivery modalities that have major potential for widespread implementation in the clinic in future years.
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http://dx.doi.org/10.1259/bjr.20200217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465857PMC
September 2020

Glioma-derived exosomes drive the differentiation of neural stem cells to astrocytes.

PLoS One 2020 10;15(7):e0234614. Epub 2020 Jul 10.

Department of Basic Sciences, New York Institute of Technology College of Osteopathic Medicine at Arkansas State University, Jonesboro, Arkansas, United States of America.

Exosomes appear to be effective inter-cellular communicators delivering several types of molecules, such as proteins and RNAs, suggesting that they could influence neural stem cell (NSC) differentiation. Our RNA sequencing studies demonstrated that the RNAs related to cell proliferation and astrocyte differentiation were upregulated in human mesenchymal stem cells (hMSC) when co-cultured with exosomes obtained from the culture medium of human glioma cells (U87). Metallothionein 3 and elastin genes, which are related to cell proliferation, increased 10 and 7.2 fold, respectively. Expression of genes for astrocyte differentiation, such as tumor growth factor alpha, induced protein 3 of the NOTCH1 family, colony stimulating factor and interleukin 6 of the STAT3 family and Hes family bHLH transcription factor 1 also increased by 2.3, 10, 4.7 and 2.9 fold, respectively. We further examined the effects of these exosomes on rat fetal neural stem cell (rNSC) differentiation using the secreted exosomes from U87 glioma cells or exosomes from U87 cells that were stimulated with interleukin 1β (IL-1β). The rNSCs, extracted from rat brains at embryonic day 14 (E14), underwent a culture protocol that normally leads to predominant (~90%) differentiation to ODCs. However, in the presence of the exosomes from untreated or IL-1β-treated U87 cells, significantly more cells differentiated into astrocytes, especially in the presence of exosomes obtained from the IL-1β-challenged glioma cells. Moreover, glioma-derived exosomes appeared to inhibit rNSC differentiation into ODCs or astrocytes as indicated by a significantly increased population of unlabeled cells. A portion of the resulting astrocytes co-expressed both CD133 and glial fibrillary acidic protein (GFAP) suggesting that exosomes from U87 cells could promote astrocytic differentiation of NSCs with features expected from a transformed cell. Our data clearly demonstrated that exosomes secreted by human glioma cells provide a strong driving force for rat neural stem cells to differentiate into astrocytes, uncovering potential pathways and therapeutic targets that might control this aggressive tumor type.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0234614PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351166PMC
September 2020

A Radiation Mitigator as a Potential Treatment for COVID-19.

Radiat Res 2020 06;193(6):505

Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205.

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http://dx.doi.org/10.1667/RADE-20-000PCDOI Listing
June 2020

Understanding High-Dose, Ultra-High Dose Rate, and Spatially Fractionated Radiation Therapy.

Int J Radiat Oncol Biol Phys 2020 07 13;107(4):766-778. Epub 2020 Apr 13.

Division of Cancer Treatment and Diagnosis, Rockville, Maryland.

The National Cancer Institute's Radiation Research Program, in collaboration with the Radiosurgery Society, hosted a workshop called Understanding High-Dose, Ultra-High Dose Rate and Spatially Fractionated Radiotherapy on August 20 and 21, 2018 to bring together experts in experimental and clinical experience in these and related fields. Critically, the overall aims were to understand the biological underpinning of these emerging techniques and the technical/physical parameters that must be further defined to drive clinical practice through innovative biologically based clinical trials.
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http://dx.doi.org/10.1016/j.ijrobp.2020.03.028DOI Listing
July 2020

3D cultures for modeling nanomaterial-based photothermal therapy.

Nanoscale Horiz 2020 03 29;5(3):400-430. Epub 2019 Nov 29.

Center for Integrative Nanotechnology Sciences, University of Arkansas at Little Rock, 2801 S University Avenue, Little Rock, AR 72204, USA.

Photothermal therapy (PTT) is one of the most promising techniques for cancer tumor ablation. Nanoparticles are increasingly being investigated for use with PTT and can serve as theranostic agents. Based on the ability of near-infrared nano-photo-absorbers to generate heat under laser irradiation, PTT could prove advantageous in certain situations over more classical cancer therapies. To analyze the efficacy of nanoparticle-based PTT, preclinical in vitro studies typically use 2D cultures, but this method cannot completely mimic the complex tumor organization, bioactivity, and physiology that all control the complex penetration depth, biodistribution, and tissue diffusion parameters of nanomaterials in vivo. To fill this knowledge gap, 3D culture systems have been explored for PTT analysis. These models provide more realistic microenvironments that allow spatiotemporal oxygen gradients and cancer cell adaptations to be considered. This review highlights the work that has been done to advance 3D models for cancer microenvironment modeling, specifically in the context of advanced, functionalized nanoparticle-directed PTT.
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http://dx.doi.org/10.1039/c9nh00628aDOI Listing
March 2020

Characterizing Elevated Urban Air Pollutant Spatial Patterns with Mobile Monitoring in Houston, Texas.

Environ Sci Technol 2020 02 29;54(4):2133-2142. Epub 2020 Jan 29.

Environmental Defense Fund , 257 Park Avenue South , New York , New York 10010 , United States.

Diverse urban air pollution sources contribute to spatially variable atmospheric concentrations, with important public health implications. Mobile monitoring shows promise for understanding spatial pollutant patterns, yet it is unclear whether uncertainties associated with temporally sparse sampling and instrument performance limit our ability to identify locations of elevated pollution. To address this question, we analyze 9 months of repeated weekday daytime on-road mobile measurements of black carbon (BC), particle number (PN), and nitrogen oxide (NO, NO) concentrations within 24 census tracts across Houston, Texas. We quantify persistently elevated, intermittent, and extreme concentration behaviors at 50 m road segments on surface streets and 90 m segments on highways relative to median statistics across the entire sampling domain. We find elevated concentrations above uncertainty levels (±40%) within portions of every census tract, with median concentration increases ranging from 2 to 3× for NO, and >9× for NO. In contrast, PN exhibits elevated concentrations of 1.5-2× the domain-wide median and distinct spatial patterns relative to other pollutants. Co-located elevated concentrations of primary combustion tracers (BC and NO) near 30% of metal recycling and concrete batch plant facilities within our sampled census tracts are comparable to those measured within 200 m of highways. Our results demonstrate how extensive mobile monitoring across multiple census tracts can quantitatively characterize urban air pollution source patterns and are applicable to developing effective source mitigation policies.
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http://dx.doi.org/10.1021/acs.est.9b05523DOI Listing
February 2020

Molecular events in MSC exosome mediated cytoprotection in cardiomyocytes.

Sci Rep 2019 12 17;9(1):19276. Epub 2019 Dec 17.

Department of Medicine, Cardiology Division, University of Arkansas for Medical Sciences, Little Rock, AR and the Central Arkansas Veterans Healthcare system, Little Rock, AR, 72205, USA.

A host of hormonal-metabolic alterations take place following exposure of cardiomyocytes to hypoxia and other noxious stimuli. Here, we demonstrate that exposure of cultured rat cardiomyocytes to lipopolysaccharide (LPS) resulted in upregulation (~1.5 fold) of oxidized low-density lipoprotein receptor-1 (LOX-1). There was also a marked increase in apoptosis 12 hrs after LPS treatment with caspase-3 levels being significantly elevated (~1.3 fold) and a significant increase in LDH release at 24 hrs. Interestingly, there was a ~1.4-fold upregulation of LC-3 expression post-LPS treatment indicating development of autophagy, which probably is a compensatory response to combat cellular injury induced by LPS. Treatment with LPS also reduced the size and morphology of cardiomyocyte spheroids. In an attempt to limit LPS-induced injury, cardiomyocytes were treated with exosomes derived from mesenchymal stromal cells (MSCs). We noted a significant suppression of LOX-1 expression that in turn suppressed apoptosis as well as autophagic response and restored spheroid morphology. Mass spectrophotometric analysis of MSC exosomes revealed a cargo rich in proteins which are involved in pathways negatively modulating cell death and apoptosis while promoting cell survival. This is first report to our knowledge on the initial molecular events in MSC exosome mediated cytoprotection of stressed cardiomyocytes.
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http://dx.doi.org/10.1038/s41598-019-55694-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917778PMC
December 2019

Gastrointestinal Tract Dysbiosis Enhances Distal Tumor Progression through Suppression of Leukocyte Trafficking.

Cancer Res 2019 12 7;79(23):5999-6009. Epub 2019 Oct 7.

Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas.

The overall use of antibiotics has increased significantly in recent years. Besides fighting infections, antibiotics also alter the gut microbiota. Commensal bacteria in the gastrointestinal tract are crucial to maintain immune homeostasis, and microbial imbalance or dysbiosis affects disease susceptibility and progression. We hypothesized that antibiotic-induced dysbiosis of the gut microbiota would suppress cytokine profiles in the host, thereby leading to changes in the tumor microenvironment. The induced dysbiosis was characterized by alterations in bacterial abundance, composition, and diversity in our animal models. On the host side, antibiotic-induced dysbiosis caused elongated small intestines and ceca, and B16-F10 melanoma and Lewis lung carcinoma progressed more quickly than in control mice. Mechanistic studies revealed that this progression was mediated by suppressed TNFα levels, both locally and systemically, resulting in reduced expression of tumor endothelial adhesion molecules, particularly intercellular adhesion molecule-1 (ICAM-1) and a subsequent decrease in the number of activated and effector CD8 T cells in the tumor. However, suppression of ICAM-1 or its binding site, the alpha subunit of lymphocyte function-associated antigen-1, was not seen in the spleen or thymus during dysbiosis. TNFα supplementation in dysbiotic mice was able to increase ICAM-1 expression and leukocyte trafficking into the tumor. Overall, these results demonstrate the importance of commensal bacteria in supporting anticancer immune surveillance, define an important role of tumor endothelial cells within this process, and suggest adverse consequences of antibiotics on cancer control. SIGNIFICANCE: Antibiotic-induced dysbiosis enhances distal tumor progression by altering host cytokine levels, resulting in suppression of tumor endothelial adhesion molecules and activated and effector CD8 T cells in the tumor.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-4108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6891208PMC
December 2019

Plasmonic Nanofactors as Switchable Devices to Promote or Inhibit Neuronal Activity and Function.

Nanomaterials (Basel) 2019 Jul 18;9(7). Epub 2019 Jul 18.

Center for Integrative Nanotechnology Sciences, University of Arkansas at Little Rock, Little Rock, AR 72204, USA.

Gold nanosystems have been investigated extensively for a variety of applications, from specific cancer cell targeting to tissue regeneration. Specifically, a recent and exciting focus has been the gold nanosystems' interface with neuronal biology. Researchers are investigating the ability to use these systems neuronal applications ranging from the enhancement of stem cell differentiation and therapy to stimulation or inhibition of neuronal activity. Most of these new areas of research are based on the integration of the plasmonic properties of such nanosystems into complex synthetic extracellular matrices (ECM) that can interact and affect positively the activity of neuronal cells. Therefore, the ability to integrate the plasmonic properties of these nanoparticles into multidimensional and morphological structures to support cellular proliferation and activity is potentially of great interest, particularly to address medical conditions that are currently not fully treatable. This review discusses some of the promising developments and unique capabilities offered by the integration of plasmonic nanosystems into morphologically complex ECM devices, designed to control and study the activity of neuronal cells.
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http://dx.doi.org/10.3390/nano9071029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669654PMC
July 2019

Reoxygenation and Repopulation of Tumor Cells after Ablative Hypofractionated Radiotherapy (SBRT and SRS) in Murine Tumors.

Radiat Res 2019 08 12;192(2):159-168. Epub 2019 Jun 12.

a Department of Radiation Oncology, University of Minnesota Medical School, Minneapolis, Minnesota.

In this work, we investigated the change in tumor microenvironment caused by semi-ablative high-dose irradiation and its implication on tumor cell survival, reoxygenation of hypoxic cells and repopulation in FSaII tumors grown subcutaneously in the hind legs of C3H mice. Tumors were exposed to 10-30 Gy of X-ray radiation in a single exposure, and the vascularity and blood perfusion were assessed based on the levels of CD31 expression and Hoechst 33342 perfusion, respectively. The tumor hypoxia was assessed by staining for pimonidazole adduct formation and the expression of hypoxia-inducible factor-1α (HIF-1α) and carbonic anhydrase 9 (CA9). Tumor cell survival was determined using excision assay method. The proportion of hypoxic cells in the tumor was determined from the surviving cell fraction in tumors exposed to a test dose under aerobic and hypoxic conditions. Radiation expsoure markedly reduced the functional vascularity and blood perfusion, and profoundly increased the expression of HIF-1α and CA9 pointing to an increase in tumor hypoxia. The overall clonogenic cell survival progressively decreased during 2-5 days postirradiation, most likely due to the radiation-induced vascular dysfunction. In turn, the proportion of surviving hypoxic cells decreased over several days postirradiation, presumably due to reoxygenation of hypoxic cells. The oxygen supplied through small fractions of blood vessels that survived the high-dose exposure, together with a reduction of oxygen consumption due to massive cell death, appeared to be the cause of the reoxygenation of hypoxic cells. The surviving tumor cells then subsequently repopulated. The findings from this study using a murine tumor model suggest that the efficacy of stereotactic body radiotherapy (SBRT) and stereotactic radiosurgery (SRS) may be significantly improved by allowing an inter-fraction time for reoxygenation while avoiding repopulation.
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http://dx.doi.org/10.1667/RR15346.1DOI Listing
August 2019

Enhanced Photothermal Treatment Efficacy and Normal Tissue Protection via Vascular Targeted Gold Nanocages.

Nanotheranostics 2019 22;3(2):145-155. Epub 2019 Mar 22.

Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, AR.

A major challenge in photothermal treatment is generating sufficient heat to eradicate diseased tissue while sparing normal tissue. Au nanomaterials have shown promise as a means to achieve highly localized photothermal treatment. Toward that end, the synthetic peptide anginex was conjugated to Au nanocages. Anginex binds to galectin-1, which is highly expressed in dividing endothelial cells found primarily in the tumor vasculature. The skin surface temperature during a 10 min laser exposure of subcutaneous murine breast tumors did not exceed 43°C and no normal tissue damage was observed, yet a significant anti-tumor effect was observed when laser was applied 24 h post-injection of targeted nanocages. Untargeted particles showed little effect in immunocompetent, tumor-bearing mice under these conditions. Photoacoustic, photothermal, and ICP-MS mapping of harvested tissue showed distribution of particles near the vasculature throughout the tumor. This uptake pattern within the tumor combined with a minimal overall temperature rise were nonetheless sufficient to induce marked photothermal efficacy and evidence of tumor control. Importantly, this evidence suggests that bulk tumor temperature during treatment does not correlate with treatment outcome, which implies that targeted nanomedicine can be highly effective when closely bound/distributed in and around the tumor endothelium and extensive amounts of direct tumor cell binding may not be a prerequisite of effective photothermal approaches.
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http://dx.doi.org/10.7150/ntno.32395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6470343PMC
June 2020