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Expansion of cytotoxic T lymphocytes (CTLs) is a crucial step in almost all cancer immunotherapeutic methods. Current techniques for expansion of tumor-reactive CTLs present major limitations. This study introduces a novel method to effectively produce and expand tumor-activated CTLs using high-voltage pulsed electric fields. We hypothesize that utilizing high-voltage pulsed electric fields may be an ideal method to activate and expand CTLs due to their non-thermal cell death mechanism. Tumor cells were subjected to high-frequency irreversible electroporation (HFIRE) with various electric field magnitudes (1250, 2500 V/cm) and pulse widths (1, 5, and 10 µs), or irreversible electroporation (IRE) at 1250 V/cm. The treated tumor cells were subsequently cocultured with CD4+ and CD8+ T cells along with antigen-presenting cells. We show that tumor-activated CTLs can be produced and expanded when exposed to treated tumor cells. Our results suggest that CTLs are more effectively expanded when pulsed with HFIRE conditions that induce significant cell death (longer pulse widths and higher voltages). Activated CD8+ T cells demonstrate cytotoxicity to untreated tumor cells suggesting effector function of the activated CTLs. The activated CTLs produced with our technique could be used for clinical applications with the goal of targeting and eliminating the tumor.
Nastaran Alinezhadbalalami; Philip M. Graybill; Khan Mohammad Imran; Scott S. Verbridge; Irving C. Allen; Rafael V. Davalos. Generation of Tumor-activated T cells Using Electroporation. Bioelectrochemistry 2021, 142, 107886 .
AMA StyleNastaran Alinezhadbalalami, Philip M. Graybill, Khan Mohammad Imran, Scott S. Verbridge, Irving C. Allen, Rafael V. Davalos. Generation of Tumor-activated T cells Using Electroporation. Bioelectrochemistry. 2021; 142 ():107886.
Chicago/Turabian StyleNastaran Alinezhadbalalami; Philip M. Graybill; Khan Mohammad Imran; Scott S. Verbridge; Irving C. Allen; Rafael V. Davalos. 2021. "Generation of Tumor-activated T cells Using Electroporation." Bioelectrochemistry 142, no. : 107886.
We describe the isolation and characterization of a novel insect-specific flavivirus (ISFV), tentatively named Aripo virus (ARPV), that was isolated from Psorophora albipes mosquitoes collected in Trinidad. The ARPV genome was determined and phylogenetic analyses showed that it is a dual host associated ISFV, and clusters with the main mosquito-borne flaviviruses. ARPV antigen was significantly cross-reactive with Japanese encephalitis virus serogroup antisera, with significant cross-reactivity to Ilheus and West Nile virus (WNV). Results suggest that ARPV replication is limited to mosquitoes, as it did not replicate in the sandfly, culicoides or vertebrate cell lines tested. We also demonstrated that ARPV is endocytosed into vertebrate cells and is highly immunomodulatory, producing a robust innate immune response despite its inability to replicate in vertebrate systems. We show that prior infection or coinfection with ARPV limits WNV-induced disease in mouse models, likely the result of a robust ARPV-induced type I interferon response.
Albert J. Auguste; Rose M. Langsjoen; Danielle L. Porier; Jesse H. Erasmus; Nicholas A. Bergren; Bethany G. Bolling; Huanle Luo; Ankita Singh; Hilda Guzman; Vsevolod L. Popov; Amelia P.A. Travassos da Rosa; Tian Wang; Lin Kang; Irving C. Allen; Christine V.F. Carrington; Robert B. Tesh; Scott C. Weaver. Isolation of a novel insect-specific flavivirus with immunomodulatory effects in vertebrate systems. Virology 2021, 562, 50 -62.
AMA StyleAlbert J. Auguste, Rose M. Langsjoen, Danielle L. Porier, Jesse H. Erasmus, Nicholas A. Bergren, Bethany G. Bolling, Huanle Luo, Ankita Singh, Hilda Guzman, Vsevolod L. Popov, Amelia P.A. Travassos da Rosa, Tian Wang, Lin Kang, Irving C. Allen, Christine V.F. Carrington, Robert B. Tesh, Scott C. Weaver. Isolation of a novel insect-specific flavivirus with immunomodulatory effects in vertebrate systems. Virology. 2021; 562 ():50-62.
Chicago/Turabian StyleAlbert J. Auguste; Rose M. Langsjoen; Danielle L. Porier; Jesse H. Erasmus; Nicholas A. Bergren; Bethany G. Bolling; Huanle Luo; Ankita Singh; Hilda Guzman; Vsevolod L. Popov; Amelia P.A. Travassos da Rosa; Tian Wang; Lin Kang; Irving C. Allen; Christine V.F. Carrington; Robert B. Tesh; Scott C. Weaver. 2021. "Isolation of a novel insect-specific flavivirus with immunomodulatory effects in vertebrate systems." Virology 562, no. : 50-62.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible RNA virus that is the causative agent of the Coronavirus disease 2019 (COVID-19) pandemic. Patients with severe COVID-19 may develop acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) and require mechanical ventilation. Key features of SARS-CoV-2 induced pulmonary complications include an overexpression of pro-inflammatory chemokines and cytokines that contribute to a ‘cytokine storm.’ In the current study an inflammatory state in Calu-3 human lung epithelial cells was characterized in which significantly elevated transcripts of the immunostimulatory chemokines CXCL9, CXCL10, and CXCL11 were present. Additionally, an increase in gene expression of the cytokines IL-6, TNFα, and IFN-γ was observed. The transcription of CXCL9, CXCL10, IL-6, and IFN-γ was also induced in the lungs of human transgenic angiotensin converting enzyme 2 (ACE2) mice infected with SARS-CoV-2. To elucidate cell signaling pathways responsible for chemokine upregulation in SARS-CoV-2 infected cells, small molecule inhibitors targeting key signaling kinases were used. The induction of CXCL9, CXCL10, and CXCL11 gene expression in response to SARS-CoV-2 infection was markedly reduced by treatment with the AKT inhibitor GSK690693. Samples from COVID-19 positive individuals also displayed marked increases in CXCL9, CXCL10, and CXCL11 transcripts as well as transcripts in the AKT pathway. The current study elucidates potential pathway specific targets for reducing the induction of chemokines that may be contributing to SARS-CoV-2 pathogenesis via hyperinflammation.
Victoria Callahan; Seth Hawks; Matthew Crawford; Caitlin Lehman; Holly Morrison; Hannah Ivester; Ivan Akhrymuk; Niloufar Boghdeh; Rafaela Flor; Carla Finkielstein; Irving Allen; James Weger-Lucarelli; Nisha Duggal; Molly Hughes; Kylene Kehn-Hall. The Pro-Inflammatory Chemokines CXCL9, CXCL10 and CXCL11 Are Upregulated Following SARS-CoV-2 Infection in an AKT-Dependent Manner. Viruses 2021, 13, 1062 .
AMA StyleVictoria Callahan, Seth Hawks, Matthew Crawford, Caitlin Lehman, Holly Morrison, Hannah Ivester, Ivan Akhrymuk, Niloufar Boghdeh, Rafaela Flor, Carla Finkielstein, Irving Allen, James Weger-Lucarelli, Nisha Duggal, Molly Hughes, Kylene Kehn-Hall. The Pro-Inflammatory Chemokines CXCL9, CXCL10 and CXCL11 Are Upregulated Following SARS-CoV-2 Infection in an AKT-Dependent Manner. Viruses. 2021; 13 (6):1062.
Chicago/Turabian StyleVictoria Callahan; Seth Hawks; Matthew Crawford; Caitlin Lehman; Holly Morrison; Hannah Ivester; Ivan Akhrymuk; Niloufar Boghdeh; Rafaela Flor; Carla Finkielstein; Irving Allen; James Weger-Lucarelli; Nisha Duggal; Molly Hughes; Kylene Kehn-Hall. 2021. "The Pro-Inflammatory Chemokines CXCL9, CXCL10 and CXCL11 Are Upregulated Following SARS-CoV-2 Infection in an AKT-Dependent Manner." Viruses 13, no. 6: 1062.
Cancer is the second leading cause of death worldwide despite major advancements in diagnosis and therapy over the past century. One of the most debilitating aspects of cancer is the burden brought on by metastatic disease. Therefore, an ideal treatment protocol would address not only debulking larger primary tumors but also circulating tumor cells and distant metastases. To address this need, the use of immune modulating therapies has become a pillar in the oncology armamentarium. A therapeutic option that has recently emerged is the use of focal ablation therapies that can destroy a tumor through various physical or mechanical mechanisms and release a cellular lysate with the potential to stimulate an immune response. Histotripsy is a non-invasive, non-ionizing, non-thermal, ultrasound guided ablation technology that has shown promise over the past decade as a debulking therapy. As histotripsy therapies have developed, the full picture of the accompanying immune response has revealed a wide range of immunogenic mechanisms that include DAMP and anti-tumor mediator release, changes in local cellular immune populations, development of a systemic immune response, and therapeutic synergism with the inclusion of checkpoint inhibitor therapies. These studies also suggest that there is an immune effect from histotripsy therapies across multiple murine tumor types that may be reproducible. Overall, the effects of histotripsy on tumors show a positive effect on immunomodulation.
Alissa Hendricks-Wenger; Ruby Hutchison; Eli Vlaisavljevich; Irving Coy Allen. Immunological Effects of Histotripsy for Cancer Therapy. Frontiers in Oncology 2021, 11, 1 .
AMA StyleAlissa Hendricks-Wenger, Ruby Hutchison, Eli Vlaisavljevich, Irving Coy Allen. Immunological Effects of Histotripsy for Cancer Therapy. Frontiers in Oncology. 2021; 11 ():1.
Chicago/Turabian StyleAlissa Hendricks-Wenger; Ruby Hutchison; Eli Vlaisavljevich; Irving Coy Allen. 2021. "Immunological Effects of Histotripsy for Cancer Therapy." Frontiers in Oncology 11, no. : 1.
New therapies to treat pancreatic cancer are direly needed. However, efficacious interventions lack a strong preclinical model that can recapitulate patients’ anatomy and physiology. Likewise, the availability of human primary malignant tissue for ex vivo studies is limited. These are significant limitations in the biomedical device field. We have developed RAG2/IL2RG deficient pigs using CRISPR/Cas9 as a large animal model with the novel application of cancer xenograft studies of human pancreatic adenocarcinoma. In this proof-of-concept study, these pigs were successfully generated using on-demand genetic modifications in embryos, circumventing the need for breeding and husbandry. Human Panc01 cells injected subcutaneously into the ears of RAG2/IL2RG deficient pigs demonstrated 100% engraftment with growth rates similar to those typically observed in mouse models. Histopathology revealed no immune cell infiltration and tumor morphology was highly consistent with the mouse models. The electrical properties and response to irreversible electroporation of the tumor tissue were found to be similar to excised human pancreatic cancer tumors. The ample tumor tissue produced enabled improved accuracy and modeling of the electrical properties of tumor tissue. Together, this suggests that this model will be useful and capable of bridging the gap of translating therapies from the bench to clinical application.
Alissa Hendricks-Wenger; Kenneth N. Aycock; Margaret A. Nagai-Singer; Sheryl Coutermarsh-Ott; Melvin F. Lorenzo; Jessica Gannon; Kyungjun Uh; Kayla Farrell; Natalie Beitel-White; Rebecca M. Brock; Alexander Simon; Holly A. Morrison; Joanne Tuohy; Sherrie Clark-Deener; Eli Vlaisavljevich; Rafael V. Davalos; Kiho Lee; Irving C. Allen. Establishing an immunocompromised porcine model of human cancer for novel therapy development with pancreatic adenocarcinoma and irreversible electroporation. Scientific Reports 2021, 11, 1 -14.
AMA StyleAlissa Hendricks-Wenger, Kenneth N. Aycock, Margaret A. Nagai-Singer, Sheryl Coutermarsh-Ott, Melvin F. Lorenzo, Jessica Gannon, Kyungjun Uh, Kayla Farrell, Natalie Beitel-White, Rebecca M. Brock, Alexander Simon, Holly A. Morrison, Joanne Tuohy, Sherrie Clark-Deener, Eli Vlaisavljevich, Rafael V. Davalos, Kiho Lee, Irving C. Allen. Establishing an immunocompromised porcine model of human cancer for novel therapy development with pancreatic adenocarcinoma and irreversible electroporation. Scientific Reports. 2021; 11 (1):1-14.
Chicago/Turabian StyleAlissa Hendricks-Wenger; Kenneth N. Aycock; Margaret A. Nagai-Singer; Sheryl Coutermarsh-Ott; Melvin F. Lorenzo; Jessica Gannon; Kyungjun Uh; Kayla Farrell; Natalie Beitel-White; Rebecca M. Brock; Alexander Simon; Holly A. Morrison; Joanne Tuohy; Sherrie Clark-Deener; Eli Vlaisavljevich; Rafael V. Davalos; Kiho Lee; Irving C. Allen. 2021. "Establishing an immunocompromised porcine model of human cancer for novel therapy development with pancreatic adenocarcinoma and irreversible electroporation." Scientific Reports 11, no. 1: 1-14.
Infants are prone to enteric infections due to an underdeveloped immune system. The maternal microbiota, through shaping the neonatal microbiota, helps establish a strong immune system in infants. We and others have observed the phenomenon of enhanced early neonatal immunoglobulin A (IgA) production in preweaning immunocompetent mice nursed by immunodeficient dams. Here, we show that this enhancement of IgA in neonates results from maternally derived microbiota. In addition, we have found that the neonatal IgA production can be induced by Lactobacillus reuteri, which is enriched in the milk of immunodeficient dams. Moreover, we show that while the production of neonatal IgA is dependent on neonatal T cells, the immunodeficient maternal microbiota-mediated enhancement of neonatal IgA has a T cell–independent component. Indeed, this enhancement may be dependent on type 3 innate lymphoid cells in the neonatal small intestinal lamina propria. Interestingly, maternal microbiota-induced neonatal IgA does not cross-react with common enteric pathogens. Future investigations will determine the functional consequences of having this extra IgA.
Qinghui Mu; Brianna K. Swartwout; Michael Edwards; Jing Zhu; Grace Lee; Kristin Eden; Xavier Cabana-Puig; Dylan K. McDaniel; Jiangdi Mao; Leila Abdelhamid; Rebecca M. Brock; Irving Coy Allen; Christopher M. Reilly; Xin M. Luo. Regulation of neonatal IgA production by the maternal microbiota. Proceedings of the National Academy of Sciences 2021, 118, 1 .
AMA StyleQinghui Mu, Brianna K. Swartwout, Michael Edwards, Jing Zhu, Grace Lee, Kristin Eden, Xavier Cabana-Puig, Dylan K. McDaniel, Jiangdi Mao, Leila Abdelhamid, Rebecca M. Brock, Irving Coy Allen, Christopher M. Reilly, Xin M. Luo. Regulation of neonatal IgA production by the maternal microbiota. Proceedings of the National Academy of Sciences. 2021; 118 (9):1.
Chicago/Turabian StyleQinghui Mu; Brianna K. Swartwout; Michael Edwards; Jing Zhu; Grace Lee; Kristin Eden; Xavier Cabana-Puig; Dylan K. McDaniel; Jiangdi Mao; Leila Abdelhamid; Rebecca M. Brock; Irving Coy Allen; Christopher M. Reilly; Xin M. Luo. 2021. "Regulation of neonatal IgA production by the maternal microbiota." Proceedings of the National Academy of Sciences 118, no. 9: 1.
Persulfides (R−SSH) have been hypothesized as potent redox modulators and signaling compounds. Reported herein is the synthesis, characterization, and in vivo evaluation of a persulfide donor that releases N‐acetyl cysteine persulfide (NAC‐SSH) in response to the prokaryote‐specific enzyme nitroreductase. The donor, termed NDP‐NAC, decomposed in response to E. coli nitroreductase, resulting in release of NAC‐SSH. NDP‐NAC elicited gastroprotective effects in mice that were not observed in animals treated with control compounds incapable of persulfide release or in animals treated with Na2S. NDP‐NAC induced these effects by the upregulation of beneficial small‐ and medium‐chain fatty acids and through increasing growth of Turicibacter sanguinis, a beneficial gut bacterium. It also decreased the populations of Synergistales bacteria, opportunistic pathogens implicated in gastrointestinal infections. This study reveals the possibility of maintaining gut health or treating microbiome‐related diseases by the targeted delivery of reactive sulfur species.
Kearsley M. Dillon; Holly A. Morrison; Chadwick R. Powell; Ryan J. Carrazzone; Veronica M. Ringel‐Scaia; Ethan W. Winckler; R. McAlister Council‐Troche; Irving C. Allen; John B. Matson. Targeted Delivery of Persulfides to the Gut: Effects on the Microbiome. Angewandte Chemie 2021, 133, 6126 -6132.
AMA StyleKearsley M. Dillon, Holly A. Morrison, Chadwick R. Powell, Ryan J. Carrazzone, Veronica M. Ringel‐Scaia, Ethan W. Winckler, R. McAlister Council‐Troche, Irving C. Allen, John B. Matson. Targeted Delivery of Persulfides to the Gut: Effects on the Microbiome. Angewandte Chemie. 2021; 133 (11):6126-6132.
Chicago/Turabian StyleKearsley M. Dillon; Holly A. Morrison; Chadwick R. Powell; Ryan J. Carrazzone; Veronica M. Ringel‐Scaia; Ethan W. Winckler; R. McAlister Council‐Troche; Irving C. Allen; John B. Matson. 2021. "Targeted Delivery of Persulfides to the Gut: Effects on the Microbiome." Angewandte Chemie 133, no. 11: 6126-6132.
Persulfides (R−SSH) have been hypothesized as potent redox modulators and signaling compounds. Reported herein is the synthesis, characterization, and in vivo evaluation of a persulfide donor that releases N‐acetyl cysteine persulfide (NAC‐SSH) in response to the prokaryote‐specific enzyme nitroreductase. The donor, termed NDP‐NAC, decomposed in response to E. coli nitroreductase, resulting in release of NAC‐SSH. NDP‐NAC elicited gastroprotective effects in mice that were not observed in animals treated with control compounds incapable of persulfide release or in animals treated with Na2S. NDP‐NAC induced these effects by the upregulation of beneficial small‐ and medium‐chain fatty acids and through increasing growth of Turicibacter sanguinis, a beneficial gut bacterium. It also decreased the populations of Synergistales bacteria, opportunistic pathogens implicated in gastrointestinal infections. This study reveals the possibility of maintaining gut health or treating microbiome‐related diseases by the targeted delivery of reactive sulfur species.
Kearsley M. Dillon; Holly A. Morrison; Chadwick R. Powell; Ryan J. Carrazzone; Veronica M. Ringel‐Scaia; Ethan W. Winckler; R. McAlister Council‐Troche; Irving C. Allen; John B. Matson. Targeted Delivery of Persulfides to the Gut: Effects on the Microbiome. Angewandte Chemie International Edition 2021, 60, 6061 -6067.
AMA StyleKearsley M. Dillon, Holly A. Morrison, Chadwick R. Powell, Ryan J. Carrazzone, Veronica M. Ringel‐Scaia, Ethan W. Winckler, R. McAlister Council‐Troche, Irving C. Allen, John B. Matson. Targeted Delivery of Persulfides to the Gut: Effects on the Microbiome. Angewandte Chemie International Edition. 2021; 60 (11):6061-6067.
Chicago/Turabian StyleKearsley M. Dillon; Holly A. Morrison; Chadwick R. Powell; Ryan J. Carrazzone; Veronica M. Ringel‐Scaia; Ethan W. Winckler; R. McAlister Council‐Troche; Irving C. Allen; John B. Matson. 2021. "Targeted Delivery of Persulfides to the Gut: Effects on the Microbiome." Angewandte Chemie International Edition 60, no. 11: 6061-6067.
Brucella abortus is a zoonotic pathogen that causes brucellosis. Because of Brucella’s unique LPS layer and intracellular localization predominately within macrophages, it can often evade immune detection. However, pattern recognition receptors are capable of sensing Brucella pathogen-associated molecular patterns (PAMPS). For example, NOD-like receptors (NLRs) can form a multi-protein inflammasome complex to attenuate Brucella pathogenesis. The inflammasome activates IL-1β and IL-18 to drive immune cell recruitment. Alternatively, inflammasome activation also initiates inflammatory cell death, termed pyroptosis, which augments bacteria clearance. In this report, we assess canonical and non-canonical inflammasome activation following B. abortus infection. We conducted in vivo studies using Asc-/- mice and observed decreased mouse survival, immune cell recruitment, and increased bacteria load. We also conducted studies with Caspase-11-/- mice and did not observe any significant impact on B. abortus pathogenesis. Through mechanistic studies using Asc-/- macrophages, our data suggests that the protective role of ASC may result from the induction of pyroptosis through a gasdermin D-dependent mechanism in macrophages. Additionally, we show that the recognition of Brucella is facilitated by sensing the PAMP gDNA rather than the less immunogenic LPS. Together, these results refine our understanding of the role that inflammasome activation and pyroptosis plays during brucellosis.
Juselyn D. Tupik; Sheryl L. Coutermarsh-Ott; Angela H. Benton; Kellie A. King; Hanna D. Kiryluk; Clayton C. Caswell; Irving C. Allen. ASC-Mediated Inflammation and Pyroptosis Attenuates Brucella abortus Pathogenesis Following the Recognition of gDNA. Pathogens 2020, 9, 1008 .
AMA StyleJuselyn D. Tupik, Sheryl L. Coutermarsh-Ott, Angela H. Benton, Kellie A. King, Hanna D. Kiryluk, Clayton C. Caswell, Irving C. Allen. ASC-Mediated Inflammation and Pyroptosis Attenuates Brucella abortus Pathogenesis Following the Recognition of gDNA. Pathogens. 2020; 9 (12):1008.
Chicago/Turabian StyleJuselyn D. Tupik; Sheryl L. Coutermarsh-Ott; Angela H. Benton; Kellie A. King; Hanna D. Kiryluk; Clayton C. Caswell; Irving C. Allen. 2020. "ASC-Mediated Inflammation and Pyroptosis Attenuates Brucella abortus Pathogenesis Following the Recognition of gDNA." Pathogens 9, no. 12: 1008.
Breast cancer is a devastating malignancy, accounting for 40,000 female deaths and 30% of new female cancer diagnoses in the United States in 2019 alone. The leading cause of breast cancer related deaths is the metastatic burden. Therefore, preclinical models for breast cancer need to analyze metastatic burden to be clinically relevant. The 4T1 breast cancer model provides a spontaneously-metastasizing, quantifiable mouse model for stage IV human breast cancer. However, most 4T1 protocols quantify the metastatic burden by manually counting stained colonies on tissue culture plates. While this is sufficient for tissues with lower metastatic burden, human error in manual counting causes inconsistent and variable results when plates are confluent and difficult to count. This method offers a computer-based solution to human counting error. Here, we evaluate the protocol using the lung, a highly metastatic tissue in the 4T1 model. Images of methylene blue-stained plates are acquired and uploaded for analysis in Fiji-ImageJ. Fiji-ImageJ then determines the percentage of the selected area of the image that is blue, representing the percentage of the plate with metastatic burden. This computer-based approach offers more consistent and expeditious results than manual counting or histopathological evaluation for highly metastatic tissues. The consistency of Fiji-ImageJ results depends on the quality of the image. Slight variations in results between images can occur, thus it is recommended that multiple images are taken and results averaged. Despite its minimal limitations, this method is an improvement to quantifying metastatic burden in the lung by offering consistent and rapid results.
Margaret A. Nagai-Singer; Alissa Hendricks-Wenger; Rebecca M. Brock; Holly A. Morrison; Juselyn D. Tupik; Sheryl Coutermarsh-Ott; Irving C. Allen. Using Computer-based Image Analysis to Improve Quantification of Lung Metastasis in the 4T1 Breast Cancer Model. Journal of Visualized Experiments 2020, e61805 .
AMA StyleMargaret A. Nagai-Singer, Alissa Hendricks-Wenger, Rebecca M. Brock, Holly A. Morrison, Juselyn D. Tupik, Sheryl Coutermarsh-Ott, Irving C. Allen. Using Computer-based Image Analysis to Improve Quantification of Lung Metastasis in the 4T1 Breast Cancer Model. Journal of Visualized Experiments. 2020; (164):e61805.
Chicago/Turabian StyleMargaret A. Nagai-Singer; Alissa Hendricks-Wenger; Rebecca M. Brock; Holly A. Morrison; Juselyn D. Tupik; Sheryl Coutermarsh-Ott; Irving C. Allen. 2020. "Using Computer-based Image Analysis to Improve Quantification of Lung Metastasis in the 4T1 Breast Cancer Model." Journal of Visualized Experiments , no. 164: e61805.
Objective: Tissue electroporation is achieved by applying a series of electric pulses to destabilize cell membranes within the target tissue. The treatment volume is dictated by the electric field distribution, which depends on the pulse parameters and tissue type and can be readily predicted using numerical methods. These models require the relevant tissue properties to be known beforehand. This study aims to quantify electrical and thermal properties for three different tissue types relevant to current clinical electroporation. Methods: Pancreatic, brain, and liver tissue were harvested from pigs, then treated with IRE pulses in a parallel-plate configuration. Resulting current and temperature readings were used to calculate the conductivity and its temperature dependence for each tissue type. Finally, a computational model was constructed to examine the impact of differences between tissue types. Results: Baseline conductivity values (mean 0.11, 0.14, and 0.12 S/m) and temperature coefficients of conductivity (mean 2.0, 2.3, and 1.2 % per degree Celsius) were calculated for pancreas, brain, and liver, respectively. The accompanying computational models suggest field distribution and thermal damage volumes are dependent on tissue type. Conclusion: The three tissue types show similar electrical and thermal responses to IRE, though brain tissue exhibits the greatest differences. The results also show that tissue type plays a role in the expected ablation and thermal damage volumes. Significance: The conductivity and its changes due to heating are expected to have a marked impact on the ablation volume. Incorporating these tissue properties aids in the prediction and optimization of electroporation-based therapies.
Natalie Beitel-White; Melvin F. Lorenzo; Yajun Zhao; Rebecca M. Brock; Sheryl Coutermarsh-Ott; Irving C. Allen; Navid Manuchehrabadi; Rafael V. Davalos. Multi-Tissue Analysis on the Impact of Electroporation on Electrical and Thermal Properties. IEEE Transactions on Biomedical Engineering 2020, 68, 771 -782.
AMA StyleNatalie Beitel-White, Melvin F. Lorenzo, Yajun Zhao, Rebecca M. Brock, Sheryl Coutermarsh-Ott, Irving C. Allen, Navid Manuchehrabadi, Rafael V. Davalos. Multi-Tissue Analysis on the Impact of Electroporation on Electrical and Thermal Properties. IEEE Transactions on Biomedical Engineering. 2020; 68 (3):771-782.
Chicago/Turabian StyleNatalie Beitel-White; Melvin F. Lorenzo; Yajun Zhao; Rebecca M. Brock; Sheryl Coutermarsh-Ott; Irving C. Allen; Navid Manuchehrabadi; Rafael V. Davalos. 2020. "Multi-Tissue Analysis on the Impact of Electroporation on Electrical and Thermal Properties." IEEE Transactions on Biomedical Engineering 68, no. 3: 771-782.
New therapeutic strategies and paradigms are direly needed for the treatment of cancer. While the surgical removal of tumors is favored in most cancer treatment plans, resection options are often limited based on tumor localization. Over the last two decades, multiple tumor ablation strategies have emerged as promising stand-alone or combination therapeutic options for patients. These strategies are often employed to treat tumors in areas where surgical resection is not possible or where chemotherapeutics have proven ineffective. The type of cell death induced by the ablation modality is a critical aspect of therapeutic success that can impact the efficacy of the treatment and systemic anti-tumor immune system responses. Electroporation-based ablation technologies include electrochemotherapy, irreversible electroporation, and other modalities that rely on pulsed electric fields to create pores in cell membranes. These pores can either be reversible or irreversible depending on the electric field parameters and can induce cell death either alone or in combination with a therapeutic agent. However, there have been many controversial findings among these technologies as to the cell death type initiated, from apoptosis to pyroptosis. As cell death mechanisms can impact treatment side effects and efficacy, we review the main types of cell death induced by electroporation-based treatments and summarize the impact of these mechanisms on treatment response. We also discuss potential reasons behind the variability of findings such as the similarities between cell death pathways, differences between cell-types, and the variation in electric field strength across the treatment area.
Rebecca M. Brock; Natalie Beitel-White; Rafael V. Davalos; Irving C. Allen. Starting a Fire Without Flame: The Induction of Cell Death and Inflammation in Electroporation-Based Tumor Ablation Strategies. Frontiers in Oncology 2020, 10, 1235 .
AMA StyleRebecca M. Brock, Natalie Beitel-White, Rafael V. Davalos, Irving C. Allen. Starting a Fire Without Flame: The Induction of Cell Death and Inflammation in Electroporation-Based Tumor Ablation Strategies. Frontiers in Oncology. 2020; 10 ():1235.
Chicago/Turabian StyleRebecca M. Brock; Natalie Beitel-White; Rafael V. Davalos; Irving C. Allen. 2020. "Starting a Fire Without Flame: The Induction of Cell Death and Inflammation in Electroporation-Based Tumor Ablation Strategies." Frontiers in Oncology 10, no. : 1235.
New methods of tumor ablation have shown exciting efficacy in pre-clinical models but often demonstrate limited success in the clinic. Due to a lack of quality or quantity in primary malignant tissue specimens, therapeutic development and optimization studies are typically conducted on healthy tissue or cell-line derived rodent tumors that don't allow for high resolution modeling of mechanical, chemical, and biological properties. These surrogates do not accurately recapitulate many critical components of the tumor microenvironment that can impact in situ treatment success. Here, we propose utilizing patient-derived xenograft (PDX) models to propagate clinically relevant tumor specimens for the optimization and development of novel tumor ablation modalities. Specimens from three individual pancreatic ductal adenocarcinoma (PDAC) patients were utilized to generate PDX models. This process generated 15–18 tumors that were allowed to expand to 1.5 cm in diameter over the course of 50–70 days. The PDX tumors were morphologically and pathologically identical to primary tumor tissue. Likewise, the PDX tumors were also found to be physiologically superior to other in vitro and ex vivo models based on immortalized cell lines. We utilized the PDX tumors to refine and optimize irreversible electroporation (IRE) treatment parameters. IRE, a novel, non-thermal tumor ablation modality, is being evaluated in a diverse range of cancer clinical trials including pancreatic cancer. The PDX tumors were compared against either Pan02 mouse derived tumors or resected tissue from human PDAC patients. The PDX tumors demonstrated similar changes in electrical conductivity and Joule heating following IRE treatment. Computational modeling revealed a high similarity in the predicted ablation size of the PDX tumors that closely correlate with the data generated with the primary human pancreatic tumor tissue. Gene expression analysis revealed that IRE treatment resulted in an increase in biological pathway signaling associated with interferon gamma signaling, necrosis and mitochondria dysfunction, suggesting potential co-therapy targets. Together, these findings highlight the utility of the PDX system in tumor ablation modeling for IRE and increasing clinical application efficacy. It is also feasible that the use of PDX models will significantly benefit other ablation modality testing beyond IRE.
Rebecca M. Brock; Natalie Beitel-White; Sheryl Coutermarsh-Ott; Douglas J. Grider; Melvin F. Lorenzo; Veronica M. Ringel-Scaia; Navid Manuchehrabadi; Robert C. G. Martin; Rafael V. Davalos; Irving C. Allen. Patient Derived Xenografts Expand Human Primary Pancreatic Tumor Tissue Availability for ex vivo Irreversible Electroporation Testing. Frontiers in Oncology 2020, 10, 1 .
AMA StyleRebecca M. Brock, Natalie Beitel-White, Sheryl Coutermarsh-Ott, Douglas J. Grider, Melvin F. Lorenzo, Veronica M. Ringel-Scaia, Navid Manuchehrabadi, Robert C. G. Martin, Rafael V. Davalos, Irving C. Allen. Patient Derived Xenografts Expand Human Primary Pancreatic Tumor Tissue Availability for ex vivo Irreversible Electroporation Testing. Frontiers in Oncology. 2020; 10 ():1.
Chicago/Turabian StyleRebecca M. Brock; Natalie Beitel-White; Sheryl Coutermarsh-Ott; Douglas J. Grider; Melvin F. Lorenzo; Veronica M. Ringel-Scaia; Navid Manuchehrabadi; Robert C. G. Martin; Rafael V. Davalos; Irving C. Allen. 2020. "Patient Derived Xenografts Expand Human Primary Pancreatic Tumor Tissue Availability for ex vivo Irreversible Electroporation Testing." Frontiers in Oncology 10, no. : 1.
NLRP1 is an inflammasome forming pattern recognition receptor (PRR). When activated by pathogen- and damage- associated molecular patterns (PAMPS/DAMPS), NLRP1 inflammasome formation leads to inflammation through the production of proinflammatory cytokines IL-18 and IL-1β. As with other inflammasome forming NLR family members, NLRP1 also regulates cell death processes, termed pyroptosis. The domain structure of NLRP1 differs between mice and humans, making it possible for the function of the inflammasome to differ between species and adds complexity to the study of this NLR family member. In humans, mutations in both coding and non-coding regions of the NLRP1 gene are linked to a variety of diseases. Likewise, interruption of NLRP1 inhibitors or changes in the prevalence of NLRP1 activators can also impact disease pathobiology. Adding to its complexity, the NLRP1 inflammasome plays a dichotomous role in human diseases, functioning to either attenuate or augment miscellaneous biological processes in a tissue specific manner. For example, NLRP1 plays a protective role in the gastrointestinal tract by modulating the microbiome composition; however, it augments neurological disorders, cardio-pulmonary diseases, and cancer through promoting inflammation. Thus, it is critical that the role of NLRP1 in each of these disease processes be robustly defined. In this review, we summarize the current research landscape to provide a better understanding of the mechanisms associated with NLRP1 function and dysfunction in human disease pathobiology. We propose that a better understanding of these mechanisms will ultimately result in improved insight into immune system dysfunction and therapeutic strategies targeting inflammasome function in multiple human diseases.
Juselyn D. Tupik; Margaret A. Nagai-Singer; Irving C. Allen. To protect or adversely affect? The dichotomous role of the NLRP1 inflammasome in human disease. Molecular Aspects of Medicine 2020, 76, 100858 .
AMA StyleJuselyn D. Tupik, Margaret A. Nagai-Singer, Irving C. Allen. To protect or adversely affect? The dichotomous role of the NLRP1 inflammasome in human disease. Molecular Aspects of Medicine. 2020; 76 ():100858.
Chicago/Turabian StyleJuselyn D. Tupik; Margaret A. Nagai-Singer; Irving C. Allen. 2020. "To protect or adversely affect? The dichotomous role of the NLRP1 inflammasome in human disease." Molecular Aspects of Medicine 76, no. : 100858.
Background The clustered regularly interspaced short palindromic repeats (CRISPR) and Cas9 protein system is a revolutionary tool for gene therapy. Despite promising reports of the utility of CRISPR–Cas9 for in vivo gene editing, a principal problem in implementing this new process is delivery of high molecular weight DNA into cells. Results Using poly(lactic-co-glycolic acid) (PLGA), a nanoparticle carrier was designed to deliver a model CRISPR–Cas9 plasmid into primary bone marrow derived macrophages. The engineered PLGA-based carriers were approximately 160 nm and fluorescently labeled by encapsulation of the fluorophore 6,13-bis(triisopropylsilylethynyl) pentacene (TIPS pentacene). An amine-end capped PLGA encapsulated 1.6 wt% DNA, with an encapsulation efficiency of 80%. Release studies revealed that most of the DNA was released within the first 24 h and corresponded to ~ 2–3 plasmid copies released per nanoparticle. In vitro experiments conducted with murine bone marrow derived macrophages demonstrated that after 24 h of treatment with the PLGA-encapsulated CRISPR plasmids, the majority of cells were positive for TIPS pentacene and the protein Cas9 was detectable within the cells. Conclusions In this work, plasmids for the CRISPR–Cas9 system were encapsulated in nanoparticles comprised of PLGA and were shown to induce expression of bacterial Cas9 in murine bone marrow derived macrophages in vitro. These results suggest that this nanoparticle-based plasmid delivery method can be effective for future in vivo applications of the CRISPR–Cas9 system.
Ami Jo; Veronica M. Ringel-Scaia; Dylan K. McDaniel; Cassidy A. Thomas; Rui Zhang; Judy S. Riffle; Irving C. Allen; Richey M. Davis. Fabrication and characterization of PLGA nanoparticles encapsulating large CRISPR–Cas9 plasmid. Journal of Nanobiotechnology 2020, 18, 1 -14.
AMA StyleAmi Jo, Veronica M. Ringel-Scaia, Dylan K. McDaniel, Cassidy A. Thomas, Rui Zhang, Judy S. Riffle, Irving C. Allen, Richey M. Davis. Fabrication and characterization of PLGA nanoparticles encapsulating large CRISPR–Cas9 plasmid. Journal of Nanobiotechnology. 2020; 18 (1):1-14.
Chicago/Turabian StyleAmi Jo; Veronica M. Ringel-Scaia; Dylan K. McDaniel; Cassidy A. Thomas; Rui Zhang; Judy S. Riffle; Irving C. Allen; Richey M. Davis. 2020. "Fabrication and characterization of PLGA nanoparticles encapsulating large CRISPR–Cas9 plasmid." Journal of Nanobiotechnology 18, no. 1: 1-14.
Coal is one of the most abundant and economic sources for global energy production. However, the burning of coal is widely recognized as a significant contributor to atmospheric particulate matter linked to deleterious respiratory impacts. Recently, we have discovered that burning coal generates large quantities of otherwise rare Magnéli phase titanium suboxides from TiO2 minerals naturally present in coal. These nanoscale Magnéli phases are biologically active without photostimulation and toxic to airway epithelial cells in vitro and to zebrafish in vivo. Here, we sought to determine the clinical and physiological impact of pulmonary exposure to Magnéli phases using mice as mammalian model organisms. Mice were exposed to the most frequently found Magnéli phases, Ti6O11, at 100 parts per million (ppm) via intratracheal administration. Local and systemic titanium concentrations, lung pathology, and changes in airway mechanics were assessed. Additional mechanistic studies were conducted with primary bone marrow derived macrophages. Our results indicate that macrophages are the cell type most impacted by exposure to these nanoscale particles. Following phagocytosis, macrophages fail to properly eliminate Magnéli phases, resulting in increased oxidative stress, mitochondrial dysfunction, and ultimately apoptosis. In the lungs, these nanoparticles become concentrated in macrophages, resulting in a feedback loop of reactive oxygen species production, cell death, and the initiation of gene expression profiles consistent with lung injury within 6 weeks of exposure. Chronic exposure and accumulation of Magnéli phases ultimately results in significantly reduced lung function impacting airway resistance, compliance, and elastance. Together, these studies demonstrate that Magnéli phases are toxic in the mammalian airway and are likely a significant nanoscale environmental pollutant, especially in geographic regions where coal combustion is a major contributor to atmospheric particulate matter.
Dylan K. McDaniel; Veronica M. Ringel-Scaia; Holly A. Morrison; Sheryl Coutermarsh-Ott; McAlister Council-Troche; Jonathan W. Angle; Justin B. Perry; Grace Davis; Weinan Leng; Valerie Minarchick; Yi Yang; Bo Chen; Sky W. Reece; David A. Brown; Thomas E. Cecere; Jared M. Brown; Kymberly M. Gowdy; Michael F. Jr. Hochella; Irving C. Allen. Pulmonary Exposure to Magnéli Phase Titanium Suboxides Results in Significant Macrophage Abnormalities and Decreased Lung Function. Frontiers in Immunology 2019, 10, 2714 .
AMA StyleDylan K. McDaniel, Veronica M. Ringel-Scaia, Holly A. Morrison, Sheryl Coutermarsh-Ott, McAlister Council-Troche, Jonathan W. Angle, Justin B. Perry, Grace Davis, Weinan Leng, Valerie Minarchick, Yi Yang, Bo Chen, Sky W. Reece, David A. Brown, Thomas E. Cecere, Jared M. Brown, Kymberly M. Gowdy, Michael F. Jr. Hochella, Irving C. Allen. Pulmonary Exposure to Magnéli Phase Titanium Suboxides Results in Significant Macrophage Abnormalities and Decreased Lung Function. Frontiers in Immunology. 2019; 10 ():2714.
Chicago/Turabian StyleDylan K. McDaniel; Veronica M. Ringel-Scaia; Holly A. Morrison; Sheryl Coutermarsh-Ott; McAlister Council-Troche; Jonathan W. Angle; Justin B. Perry; Grace Davis; Weinan Leng; Valerie Minarchick; Yi Yang; Bo Chen; Sky W. Reece; David A. Brown; Thomas E. Cecere; Jared M. Brown; Kymberly M. Gowdy; Michael F. Jr. Hochella; Irving C. Allen. 2019. "Pulmonary Exposure to Magnéli Phase Titanium Suboxides Results in Significant Macrophage Abnormalities and Decreased Lung Function." Frontiers in Immunology 10, no. : 2714.
Over the last decade, significant progress has been achieved in defining mechanisms underlying NLR regulation of immune system function. However, several NLR family members continue to defy our best attempts at characterization and routinely exhibit confounding data. This is particularly true for NLR family members that regulate signaling associated with the activation of other pattern recognition receptors. NLRX1 is a member of this NLR sub-group and acts as an enigmatic regulator of immune system function. NLRX1 has been shown to negatively regulate type-I interferon, attenuate pro-inflammatory NF-κB signaling, promote reactive oxygen species production, and modulate autophagy, cell death, and proliferation. However, the mechanism/s associated with NLRX1 modulation of these pathways is not fully understood and there are inconsistencies within the field. Likewise, it is highly likely that the full repertoire of biological functions impacted by NLRX1 are yet to be defined. Recent mouse studies have shown that NLRX1 significantly impacts a multitude of diseases, including cancer, virus infection, osteoarthritis, traumatic brain injury, and inflammatory bowel disease. Thus, it is essential that the underlying mechanism associated with NLRX1 function in each of these diseases be robustly defined. Here, we summarize the current progress in understanding mechanisms associated with NLRX1 function. We also offer insight into both unique and overlapping mechanisms regulated by NLRX1 that likely contribute to disease pathobiology. Ultimately, we believe that an improved understanding of NLRX1 will result in better defined mechanisms associated with immune system attenuation and the resolution of inflammation in a myriad of diseases.
Margaret A. Nagai-Singer; Holly A. Morrison; Irving C. Allen. NLRX1 Is a Multifaceted and Enigmatic Regulator of Immune System Function. Frontiers in Immunology 2019, 10, 2419 .
AMA StyleMargaret A. Nagai-Singer, Holly A. Morrison, Irving C. Allen. NLRX1 Is a Multifaceted and Enigmatic Regulator of Immune System Function. Frontiers in Immunology. 2019; 10 ():2419.
Chicago/Turabian StyleMargaret A. Nagai-Singer; Holly A. Morrison; Irving C. Allen. 2019. "NLRX1 Is a Multifaceted and Enigmatic Regulator of Immune System Function." Frontiers in Immunology 10, no. : 2419.
High-frequency irreversible electroporation (H-FIRE) is an emerging electroporation-based therapy used to ablate cancerous tissue. Treatment consists of delivering short, bipolar pulses (1–10 μs) in a series of 80–100 bursts (1 burst/s, 100 μs on-time). Reducing pulse duration leads to reduced treatment volumes compared to traditional IRE, therefore larger voltages must be applied to generate ablations comparable in size. We show that adjuvant calcium enhances ablation area in vitro for H-FIRE treatments of several pulse durations (1, 2, 5, 10 μs). Furthermore, H-FIRE treatment using 10 μs pulses delivered with 1 mM CaCl2 results in cell death thresholds (771 ± 129 V/cm) comparable to IRE thresholds without calcium (698 ± 103 V/cm). Quantifying the reversible electroporation threshold revealed that CaCl2 enhances the permeabilization of cells compared to a NaCl control. Gene expression analysis determined that CaCl2 upregulates expression of eIFB5 and 60S ribosomal subunit genes while downregulating NOX1/4, leading to increased signaling in pathways that may cause necroptosis. The opposite was found for control treatment without CaCl2 suggesting cells experience an increase in pro survival signaling. Our study is the first to identify key genes and signaling pathways responsible for differences in cell response to H-FIRE treatment with and without calcium.
Elisa M. Wasson; Nastaran Alinezhadbalalami; Rebecca Brock; Irving C. Allen; Scott S. Verbridge; Rafael V. Davalos. Understanding the role of calcium-mediated cell death in high-frequency irreversible electroporation. Bioelectrochemistry 2019, 131, 107369 .
AMA StyleElisa M. Wasson, Nastaran Alinezhadbalalami, Rebecca Brock, Irving C. Allen, Scott S. Verbridge, Rafael V. Davalos. Understanding the role of calcium-mediated cell death in high-frequency irreversible electroporation. Bioelectrochemistry. 2019; 131 ():107369.
Chicago/Turabian StyleElisa M. Wasson; Nastaran Alinezhadbalalami; Rebecca Brock; Irving C. Allen; Scott S. Verbridge; Rafael V. Davalos. 2019. "Understanding the role of calcium-mediated cell death in high-frequency irreversible electroporation." Bioelectrochemistry 131, no. : 107369.
Background Despite promising treatments for breast cancer, mortality rates remain high and treatments for metastatic disease are limited. High-frequency irreversible electroporation (H-FIRE) is a novel tumor ablation technique that utilizes high-frequency bipolar electric pulses to destabilize cancer cell membranes and induce cell death. However, there is currently a paucity of data pertaining to immune system activation following H-FIRE and other electroporation based tumor ablation techniques. Methods Here, we utilized the mouse 4T1 mammary tumor model to evaluate H-FIRE treatment parameters on cancer progression and immune system activation in vitro and in vivo. Findings H-FIRE effectively ablates the primary tumor and induces a pro-inflammatory shift in the tumor microenvironment. We further show that local treatment with H-FIRE significantly reduces 4T1 metastases. H-FIRE kills 4T1 cells through non-thermal mechanisms associated with necrosis and pyroptosis resulting in damage associated molecular pattern signaling in vitro and in vivo. Our data indicate that the level of tumor ablation correlates with increased activation of cellular immunity. Likewise, we show that the decrease in metastatic lesions is dependent on the intact immune system and H-FIRE generates 4T1 neoantigens that engage the adaptive immune system to significantly attenuate tumor progression. Interpretation Cell death and tumor ablation following H-FIRE treatment activates the local innate immune system, which shifts the tumor microenvironment from an anti-inflammatory state to a pro-inflammatory state. The non-thermal damage to the cancer cells and increased innate immune system stimulation improves antigen presentation, resulting in the engagement of the adaptive immune system and improved systemic anti-tumor immunity.
Veronica M. Ringel-Scaia; Natalie Beitel-White; Melvin F. Lorenzo; Rebecca Brock; Kathleen E. Huie; Sheryl Coutermarsh-Ott; Kristin Eden; Dylan McDaniel; Scott S. Verbridge; John H. Rossmeisl; Kenneth J. Oestreich; Rafael V. Davalos; Irving C. Allen. High-frequency irreversible electroporation is an effective tumor ablation strategy that induces immunologic cell death and promotes systemic anti-tumor immunity. EBioMedicine 2019, 44, 112 -125.
AMA StyleVeronica M. Ringel-Scaia, Natalie Beitel-White, Melvin F. Lorenzo, Rebecca Brock, Kathleen E. Huie, Sheryl Coutermarsh-Ott, Kristin Eden, Dylan McDaniel, Scott S. Verbridge, John H. Rossmeisl, Kenneth J. Oestreich, Rafael V. Davalos, Irving C. Allen. High-frequency irreversible electroporation is an effective tumor ablation strategy that induces immunologic cell death and promotes systemic anti-tumor immunity. EBioMedicine. 2019; 44 ():112-125.
Chicago/Turabian StyleVeronica M. Ringel-Scaia; Natalie Beitel-White; Melvin F. Lorenzo; Rebecca Brock; Kathleen E. Huie; Sheryl Coutermarsh-Ott; Kristin Eden; Dylan McDaniel; Scott S. Verbridge; John H. Rossmeisl; Kenneth J. Oestreich; Rafael V. Davalos; Irving C. Allen. 2019. "High-frequency irreversible electroporation is an effective tumor ablation strategy that induces immunologic cell death and promotes systemic anti-tumor immunity." EBioMedicine 44, no. : 112-125.
Nanomaterials are critical components in the Earth system’s past, present, and future characteristics and behavior. They have been present since Earth’s origin in great abundance. Life, from the earliest cells to modern humans, has evolved in intimate association with naturally occurring nanomaterials. This synergy began to shift considerably with human industrialization. Particularly since the Industrial Revolution some two-and-a-half centuries ago, incidental nanomaterials (produced unintentionally by human activity) have been continuously produced and distributed worldwide. In some areas, they now rival the amount of naturally occurring nanomaterials. In the past half-century, engineered nanomaterials have been produced in very small amounts relative to the other two types of nanomaterials, but still in large enough quantities to make them a consequential component of the planet. All nanomaterials, regardless of their origin, have distinct chemical and physical properties throughout their size range, clearly setting them apart from their macroscopic equivalents and necessitating careful study. Following major advances in experimental, computational, analytical, and field approaches, it is becoming possible to better assess and understand all types and origins of nanomaterials in the Earth system. It is also now possible to frame their immediate and long-term impact on environmental and human health at local, regional, and global scales.
Michael F. Hochella Jr.; David W. Mogk; James Ranville; Irving C. Allen; George W. Luther; Linsey C. Marr; B. Peter McGrail; Mitsu Murayama; Nikolla P. Qafoku; Kevin M. Rosso; Nita Sahai; Paul A. Schroeder; Peter Vikesland; Paul Westerhoff; Yi Yang. Natural, incidental, and engineered nanomaterials and their impacts on the Earth system. Science 2019, 363, eaau8299 .
AMA StyleMichael F. Hochella Jr., David W. Mogk, James Ranville, Irving C. Allen, George W. Luther, Linsey C. Marr, B. Peter McGrail, Mitsu Murayama, Nikolla P. Qafoku, Kevin M. Rosso, Nita Sahai, Paul A. Schroeder, Peter Vikesland, Paul Westerhoff, Yi Yang. Natural, incidental, and engineered nanomaterials and their impacts on the Earth system. Science. 2019; 363 (6434):eaau8299.
Chicago/Turabian StyleMichael F. Hochella Jr.; David W. Mogk; James Ranville; Irving C. Allen; George W. Luther; Linsey C. Marr; B. Peter McGrail; Mitsu Murayama; Nikolla P. Qafoku; Kevin M. Rosso; Nita Sahai; Paul A. Schroeder; Peter Vikesland; Paul Westerhoff; Yi Yang. 2019. "Natural, incidental, and engineered nanomaterials and their impacts on the Earth system." Science 363, no. 6434: eaau8299.