34 results on '"Ana L. Romero-Weaver"'
Search Results
2. Complete mitogenome sequence of Aedes (Hulecoeteomyia) japonicus japonicus from Hawai’i Island
- Author
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Sangwoo Seok, Christopher M. Jacobsen, Ana L. Romero-Weaver, Xiaodi Wang, Valerie T. Nguyen, Travis C. Collier, Michael T. Riles, Omar S. Akbari, and Yoosook Lee
- Subjects
aedes japonicus japonicus ,arbovirus vector ,pacific island ,culicidae ,invasive species ,Genetics ,QH426-470 - Abstract
We report the first complete mitogenome (Mt) sequence of Aedes japonicus japonicus (Diptera: Culicidae). The sequence was extracted from one adult from the Big Island of Hawai’i Island. The length of the Ae. japonicus japonicus Mt was 16,528bp with 78.1% AT content. Its sequence is most similar to the Mt sequence of Aedes koreicus with 90.81% sequence identity. This is the first full Mt sequence available for this species and provides important genetic resource for studying population genetics and dynamics of this important invasive mosquito species.
- Published
- 2023
- Full Text
- View/download PDF
3. The L1014F Knockdown Resistance Mutation Is Not a Strong Correlate of Phenotypic Resistance to Pyrethroids in Florida Populations of Culex quinquefasciatus
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Alden S. Estep, Neil D. Sanscrainte, Jason Stuck, Isik Unlu, Agne Prasauskas, Stephanie J. Mundis, Nicholas Cotter, Ana L. Romero-Weaver, Troy J. Fedirko, Natalie L. Kendziorski, Kyle J. Kosinski, Daviela Ramirez, and Eva A. Buckner
- Subjects
Culex quinquefasciatus ,insecticide resistance ,knockdown resistance (kdr) ,CDC bottle bioassay ,Florida ,Science - Abstract
Culex quinquefasciatus is an important target for vector control because of its ability to transmit pathogens that cause disease. Most populations are resistant to pyrethroids and often to organophosphates, the two most common classes of active ingredients used by public health agencies. A knockdown resistance (kdr) mutation, resulting in an amino acid change from a leucine to phenylalanine in the voltage gated sodium channel, is one mechanism contributing to the pyrethroid resistant phenotype. Enzymatic resistance has also been shown to play a very important role. Recent studies have shown strong resistance in populations even when kdr is relatively low, which indicates that factors other than kdr may be larger contributors to resistance. In this study, we examined, on a statewide scale (over 70 populations), the strength of the correlation between resistance in the CDC bottle bioassay and the kdr genotypes and allele frequencies. Spearman correlation analysis showed only moderate (−0.51) or weak (−0.29) correlation between the kdr genotype and permethrin or deltamethrin resistance, respectively. The frequency of the kdr allele was an even weaker correlate than genotype. These results indicate that assessing kdr in populations of Culex quinquefasciatus is not a good surrogate for phenotypic resistance testing.
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- 2024
- Full Text
- View/download PDF
4. A concise guide on the bionomics and key morphological characteristics for identifying Aedes pertinax (Grabham, 1906) – a mosquito species from neotropics
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Ana L. Romero-Weaver, Michael T. Riles, Kristin Sloyer, Yoosook Lee, Lindsay P. Campbell, and Bryan V. Giordano
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Aedes pertinax ,mosquito ,Agriculture (General) ,S1-972 ,Plant culture ,SB1-1110 ,Biology (General) ,QH301-705.5 - Abstract
Aedes pertinax is a non-invasive mosquito first described in Jamaica by Grabham in 1906. It is currently classified in the Protoculex Group. It was first identified in the U.S. in 2015; its current distribution is unknown because it is so difficult to differentiate it from other mosquito species that are morphologically similar. It has not been reported in association with humans or animal diseases, but Ae. Atlanticus, another mosquito in the Protoculex Group, is a vector of the Keystone virus and the West Nile virus, which have the potential to cause encephalitis and death. Moreover, Ae. serratus, once classified as synonym of Ae. pertinax, was reported infected with yellow fever in Brazil in 2008. Because Ae. pertinax may be a vector and because it has expanded its geographical range, it should be monitored closely. This publication provides a description of the species so that it can be identified and monitored.
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- 2023
5. A Concise Guide to the Bionomics and Key Morphological Characteristics for Identifying Culex coronator (Dyar & Knab, 1906) – an Invasive Mosquito Species from the Neotropics
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Ana L. Romero-Weaver, Lawrence E. Reeves, Michael T. Riles, Yoosook Lee, and Bryan V. Giordano
- Subjects
Culex ,Invasive ,mosquito ,bionomics ,Agriculture (General) ,S1-972 ,Plant culture ,SB1-1110 ,Biology (General) ,QH301-705.5 - Abstract
Culex coronator Dyar and Knab is a highly invasive Neotropical species, first described at the beginning of the 20th century in Trinidad and Tobago (Dyar and Knab 1906). This is an important invasive species in Florida, which needs to be carefully surveilled by mosquito control experts. This article is structured similar to those from Walter Reed Biosystematics Unit (WRBU) so that readers would obtain the similar level of details offered through WRBU species pages, which is widely used by anyone interested in mosquito biology, research, and education.
- Published
- 2023
6. Mosquito Control Priorities in Florida—Survey Results from Florida Mosquito Control Districts
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Rishi Kondapaneni, Ashley N. Malcolm, Brian M. Vazquez, Eric Zeng, Tse-Yu Chen, Kyle J. Kosinski, Ana L. Romero-Weaver, Bryan V. Giordano, Benjamin Allen, Michael T. Riles, Daniel Killingsworth, Lindsay P. Campbell, Eric P. Caragata, and Yoosook Lee
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mosquito control ,vectors ,Florida ,survey ,vector control ,control priority ,Medicine - Abstract
Florida lies within a subtropical region where the climate allows diverse mosquito species including invasive species to thrive year-round. As of 2021, there are currently 66 state-approved Florida Mosquito Control Districts, which are major stakeholders for Florida public universities engaged in mosquito research. Florida is one of the few states with extensive organized mosquito control programs. The Florida State Government and Florida Mosquito Control Districts have long histories of collaboration with research institutions. During fall 2020, we carried out a survey to collect baseline data on the current control priorities from Florida Mosquito Control Districts relating to (1) priority control species, (2) common adult and larval control methods, and (3) major research questions to address that will improve their control and surveillance programs. The survey data showed that a total of 17 distinct mosquito species were considered to be priority control targets, with many of these species being understudied. The most common control approaches included truck-mounted ultra-low-volume adulticiding and biopesticide-based larviciding. The districts held interest in diverse research questions, with many prioritizing studies on basic science questions to help develop evidence-based control strategies. Our data highlight the fact that mosquito control approaches and priorities differ greatly between districts and provide an important point of comparison for other regions investing in mosquito control, particularly those with similar ecological settings, and great diversity of potential mosquito vectors, such as in Florida. Our findings highlight a need for greater alignment of research priorities between mosquito control and mosquito research. In particular, we note a need to prioritize filling knowledge gaps relating to understudied mosquito species that have been implicated in arbovirus transmission.
- Published
- 2021
- Full Text
- View/download PDF
7. Data from Pharmacologic Suppression of JAK1/2 by JAK1/2 Inhibitor AZD1480 Potently Inhibits IL-6–Induced Experimental Prostate Cancer Metastases Formation
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Marja T. Nevalainen, Dennis Huszar, Michael Zinda, Kalle Alanen, Tuomas Mirtti, David T. Hoang, Benjamin Leiby, Zhiyong Liao, Junaid Abdulghani, Ana L. Romero-Weaver, Paraskevi Vogiatzi, Pooja Talati, and Lei Gu
- Abstract
Metastatic prostate cancer is lethal and lacks effective strategies for prevention or treatment, requiring novel therapeutic approaches. Interleukin-6 (IL-6) is a cytokine that has been linked with prostate cancer pathogenesis by multiple studies. However, the direct functional roles of IL-6 in prostate cancer growth and progression have been unclear. In the present study, we show that IL-6 is produced in distant metastases of clinical prostate cancers. IL-6–activated signaling pathways in prostate cancer cells induced a robust 7-fold increase in metastases formation in nude mice. We further show that IL-6 promoted migratory prostate cancer cell phenotype, including increased prostate cancer cell migration, microtubule reorganization, and heterotypic adhesion of prostate cancer cells to endothelial cells. IL-6–driven metastasis was predominantly mediated by Stat3 and to lesser extent by ERK1/2. Most importantly, pharmacologic inhibition of Jak1/2 by AZD1480 suppressed IL-6–induced signaling, migratory prostate cancer cell phenotypes, and metastatic dissemination of prostate cancer in vivo in nude mice. In conclusion, we demonstrate that the cytokine IL-6 directly promotes prostate cancer metastasis in vitro and in vivo via Jak–Stat3 signaling pathway, and that IL-6–driven metastasis can be effectively suppressed by pharmacologic targeting of Jak1/2 using Jak1/2 inhibitor AZD1480. Our results therefore provide a strong rationale for further development of Jak1/2 inhibitors as therapy for metastatic prostate cancer. Mol Cancer Ther; 13(5); 1246–58. ©2014 AACR.
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- 2023
8. Supplementary Materials and Methods and Supplementary Figures 1 through 3 from Pharmacologic Suppression of JAK1/2 by JAK1/2 Inhibitor AZD1480 Potently Inhibits IL-6–Induced Experimental Prostate Cancer Metastases Formation
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Marja T. Nevalainen, Dennis Huszar, Michael Zinda, Kalle Alanen, Tuomas Mirtti, David T. Hoang, Benjamin Leiby, Zhiyong Liao, Junaid Abdulghani, Ana L. Romero-Weaver, Paraskevi Vogiatzi, Pooja Talati, and Lei Gu
- Abstract
PDF - 295K, Suppl. Fig. 1. Autocrine IL-6 induces metastatic colonization of CWR22Rv1 human PC cells in the livers of mice in an experimental metastases assay. Figure 2. IL-6 induces a migratory phenotype in CWR22Rv1 PC cells. Suppl. Fig. 3. Pharmacological Jak1/2 inhibitor AZD1480 suppresses IL-6-activated Stat3 signaling in CWR22Rv1 PC cells and IL-6-induced migratory PC cell phenotype.
- Published
- 2023
9. Concise Guide to the Bionomics and Key Morphological Characteristics for Identifying Culex coronator (Dyar & Knab, 1906) – an Invasive Mosquito Species from the Neotropics
- Author
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Ana L. Romero-Weaver, Lawrence E. Reeves, Michael T. Riles, Yoosook Lee, and Bryan V. Giordano
- Subjects
General Medicine - Abstract
Culex coronator Dyar and Knab is a highly invasive Neotropical species, first described at the beginning of the 20th century in Trinidad and Tobago (Dyar and Knab 1906). This is an important invasive species in Florida, which needs to be carefully surveilled by mosquito control experts. This article is structured similar to those from Walter Reed Biosystematics Unit (WRBU) so that readers would obtain the similar level of details offered through WRBU species pages, which is widely used by anyone interested in mosquito biology, research, and education.
- Published
- 2023
10. Arboviral disease outbreaks, Aedes mosquitoes, and vector control efforts in the Pacific
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Sangwoo Seok, Camellia D. Raz, Julianna H. Miller, Ashley N. Malcolm, Maya D. Eason, Ana L. Romero-Weaver, Bryan V. Giordano, Christopher M. Jacobsen, Xiaodi Wang, Omar S. Akbari, Robyn Raban, Derrick K. Mathias, Eric P. Caragata, Adam E. Vorsino, Joanna C. Chiu, and Yoosook Lee
- Subjects
General Medicine - Abstract
Recurring outbreaks of mosquito-borne diseases, like dengue, in the Pacific region represent a major biosecurity risk to neighboring continents through potential introductions of disease-causing pathogens. Aedes mosquitoes, highly prevalent in this region, are extremely invasive and the predominant vectors of multiple viruses including causing dengue, chikungunya, and Zika. Due to the absence of vaccines for most of these diseases, Aedes control remains a high priority for public health. Currently, international organizations put their efforts into improving mosquito surveillance programs in the Pacific region. Also, a novel biocontrol method using Wolbachia has been tried in the Pacific region to control Aedes mosquito populations. A comprehensive understanding of mosquito biology is needed to assess the risk that mosquitoes might be introduced to neighboring islands in the region and how this might impact arboviral virus transmission. As such, we present a comprehensive review of arboviral disease outbreak records as well as Aedes mosquito biology research findings relevant to the Pacific region collected from both non-scientific and scientific sources.
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- 2023
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11. Multiple Novel Clades of Anopheline Mosquitoes Caught Outdoors in Northern Zambia
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Christine M. Jones, Ilinca I. Ciubotariu, Mbanga Muleba, James Lupiya, David Mbewe, Limonty Simubali, Twig Mudenda, Mary E. Gebhardt, Giovanna Carpi, Ashley N. Malcolm, Kyle J. Kosinski, Ana L. Romero-Weaver, Jennifer C. Stevenson, Yoosook Lee, and Douglas E. Norris
- Subjects
parasitic diseases - Abstract
Residual vector populations that do not come in contact with the most frequently utilized indoor-directed interventions present major challenges to global malaria eradication. Many of these residual populations are mosquito species about which little is known. As part of a study to assess the threat of outdoor exposure to malaria mosquitoes within the Southern and Central Africa International Centers of Excellence for Malaria Research, foraging female anophelines were collected outside households in Nchelenge District, northern Zambia. These anophelines proved to be more diverse than had previously been reported in the area. In order to further characterize the anopheline species, sequencing and phylogenetic approaches were utilized. Anopheline mosquitoes were collected from outdoor light traps, morphologically identified, and sent to Johns Hopkins Bloomberg School of Public Health for sequencing. Sanger sequencing from 115 field-derived samples yielded mitochondrial COI sequences, which were aligned with a homologous 488 bp gene segment from known anophelines (n = 140) retrieved from NCBI. Nuclear ITS2 sequences (n = 57) for at least one individual from each unique COI clade were generated and compared against NCBI’s nucleotide BLAST database to provide additional evidence for taxonomical identity and structure. Molecular and morphological data were combined for assignment of species or higher taxonomy. Twelve phylogenetic groups were characterized from the COI and ITS2 sequence data, including the primary vector species Anopheles funestus s.s. and An. gambiae s.s. An unexpectedly large proportion of the field collections were identified as An. coustani and An. sp. 6. Six phylogenetic groups remain unidentified to species-level. Outdoor collections of anopheline mosquitoes in areas frequented by people in Nchelenge, northern Zambia, proved to be extremely diverse. Morphological misidentification and underrepresentation of some anopheline species in sequence databases confound efforts to confirm identity of potential malaria vector species. The large number of unidentified anophelines could compromise the malaria vector surveillance and malaria control efforts not only in northern Zambia but other places where surveillance and control are focused on indoor-foraging and resting anophelines. Therefore, it is critical to continue development of methodologies that allow better identification of these populations and revisiting and cleaning current genomic databases.
- Published
- 2021
12. Evidence of Local Extinction and Reintroduction of Aedes aegypti in Exeter, California
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Lindsay P. Campbell, Lindsey K Mack, Tse-Yu Chen, Erin Taylor Kelly, Eva A. Buckner, Gregory C. Lanzaro, Kyle J. Kosinski, Rodrigo Rosario-Cruz, Ana L. Romero-Weaver, Melina Campos, Anthony J. Cornel, Geoffrey M. Attardo, Kirk Smith, Katherine K. Brisco, Crystal Grippin, Yoosook Lee, and Travis C. Collier
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0301 basic medicine ,Life on Land ,Range (biology) ,030231 tropical medicine ,Population ,Zoology ,Aedes aegypti ,Vaccine Related ,Population genomics ,03 medical and health sciences ,0302 clinical medicine ,Biodefense ,education ,education.field_of_study ,biology ,Prevention ,Knockdown resistance ,General Medicine ,biology.organism_classification ,Mosquito control ,Infectious Diseases ,Emerging Infectious Diseases ,Good Health and Well Being ,030104 developmental biology ,Local extinction ,Vector (epidemiology) - Abstract
Established populations of Aedes aegypti, a mosquito vector of multiple major arthropod-borne viruses, were first found in three California (CA) cities in 2013. From 2013 to April 2021, Ae. aegypti thwarted almost all control efforts to stop its spread and expanded its range to 308 cities, including Exeter, in 22 counties in CA. Population genomic analyses have suggested that multiple genetically distinct Ae. aegypti populations were introduced into CA. However Ae. aegypti collected for the first time in 2014 in Exeter, appeared to be different from three major genetic clusters found elsewhere in CA. Due to intense control efforts by the Delta Vector Control District (DVCD), Ae. aegypti was thought to have been eliminated from Exeter in 2015. Unfortunately, it was recollected in 2018. It was not clear if the reemergence of Ae. aegypti in Exeter was derived from the bottlenecked remnants of the original 2014 Exeter population or from an independent invasion from a different population derived from surrounding areas. The goal of this work was to determine which of these scenarios occurred (recovery after bottleneck or reintroduction after elimination) and if elimination and reintroduction occurred to identify the origin of the invading population using a population genomic approach. Our results support the reintroduction after elimination hypothesis. The source of reintroduction, however, was unexpectedly from the southern CA cluster rather than from other two geographically closer central CA genetic clusters. We also conducted a knockdown resistance mutation profile, which showed Exeter 2014 had the lowest level of resistant alleles compared to the other populations, could have contributed towards DVCD’s ability to locally eliminate Ae. aegypti in 2014.
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- 2021
- Full Text
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13. A Magnetic-Bead-Based Mosquito DNA Extraction Protocol for Next-Generation Sequencing
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Yoosook Lee, Kyle J. Kosinski, Tse Yu Chen, Eva A. Buckner, Adam E. Vorsino, Joanna C. Chiu, and Ana L. Romero-Weaver
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Protocol (science) ,Whole genome sequencing ,biology ,General Immunology and Microbiology ,Computer science ,General Chemical Engineering ,General Neuroscience ,Magnetic Phenomena ,High-Throughput Nucleotide Sequencing ,Aedes aegypti ,Computational biology ,DNA ,Sequence Analysis, DNA ,biology.organism_classification ,DNA extraction ,DNA sequencing ,General Biochemistry, Genetics and Molecular Biology ,chemistry.chemical_compound ,chemistry ,Aedes ,Magnetic bead ,Animals ,Throughput (business) - Abstract
A recently published DNA extraction protocol using magnetic beads and an automated DNA extraction instrument suggested that it is possible to extract high quality and quantity DNA from a well-preserved individual mosquito sufficient for downstream whole genome sequencing. However, reliance on an expensive automated DNA extraction instrument can be prohibitive for many laboratories. Here, the study provides a budget-friendly magnetic-bead-based DNA extraction protocol, which is suitable for low to medium throughput. The protocol described here was successfully tested using individual Aedes aegypti mosquito samples. The reduced costs associated with high quality DNA extraction will increase the application of high throughput sequencing to resource limited labs and studies.
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- 2021
14. Mosquito Control Priorities in Florida—Survey Results from Florida Mosquito Control Districts
- Author
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Eric Zeng, Daniel Killingsworth, Tse Yu Chen, Kyle J. Kosinski, Ana L. Romero-Weaver, Lindsay P. Campbell, Eric P. Caragata, Michael T. Riles, Rishi Kondapaneni, Benjamin T Allen, Brian M. Vazquez, Yoosook Lee, Ashley N. Malcolm, and Bryan V. Giordano
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0301 basic medicine ,Microbiology (medical) ,030231 tropical medicine ,vector control ,Survey result ,Arbovirus ,Article ,Invasive species ,mosquito control ,03 medical and health sciences ,0302 clinical medicine ,vectors ,parasitic diseases ,medicine ,Immunology and Allergy ,survey ,Molecular Biology ,Environmental planning ,General Immunology and Microbiology ,fungi ,State government ,Baseline data ,medicine.disease ,Mosquito control ,030104 developmental biology ,Infectious Diseases ,Geography ,control priority ,Florida ,Medicine ,Survey data collection ,Control methods - Abstract
Florida lies within a subtropical region where the climate allows diverse mosquito species including invasive species to thrive year-round. As of 2021, there are currently 66 state-approved Florida Mosquito Control Districts, which are major stakeholders for Florida public universities engaged in mosquito research. Florida is one of the few states with extensive organized mosquito control programs. The Florida State Government and Florida Mosquito Control Districts have long histories of collaboration with research institutions. During fall 2020, we carried out a survey to collect baseline data on the current control priorities from Florida Mosquito Control Districts relating to (1) priority control species, (2) common adult and larval control methods, and (3) major research questions to address that will improve their control and surveillance programs. The survey data showed that a total of 17 distinct mosquito species were considered to be priority control targets, with many of these species being understudied. The most common control approaches included truck-mounted ultra-low-volume adulticiding and biopesticide-based larviciding. The districts held interest in diverse research questions, with many prioritizing studies on basic science questions to help develop evidence-based control strategies. Our data highlight the fact that mosquito control approaches and priorities differ greatly between districts and provide an important point of comparison for other regions investing in mosquito control, particularly those with similar ecological settings, and great diversity of potential mosquito vectors, such as in Florida. Our findings highlight a need for greater alignment of research priorities between mosquito control and mosquito research. In particular, we note a need to prioritize filling knowledge gaps relating to understudied mosquito species that have been implicated in arbovirus transmission.
- Published
- 2021
15. Effects of Solar Particle Event-Like Proton Radiation and/or Simulated Microgravity on Circulating Mouse Blood Cells
- Author
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Ana L. Romero-Weaver, Liyong Lin, Alejandro Carabe-Fernandez, and Ann R. Kennedy
- Abstract
Astronauts traveling in space missions outside of low Earth orbit will be exposed for longer times to a microgravity environment. In addition, the increased travel time involved in exploration class missions will result in an increased risk of exposure to significant doses of solar particle event (SPE) radiation. Both conditions could significantly affect the number of circulating blood cells. Therefore, it is critical to determine the combined effects of exposure to both microgravity and SPE radiation. The purpose of the present study was to assess these risks by evaluating the effects of SPE-like proton radiation and/or microgravity, as simulated with the hindlimb unloading (HU) system, on circulating blood cells using mouse as a model system. The results indicate that exposure to HU alone caused minimal or no significant changes in mouse circulating blood cell numbers. The exposure of mice to SPE-like proton radiation with or without HU treatment caused a significant decrease in the number of circulating lymphocytes, granulocytes and platelets. The reduced numbers of circulating lymphocytes, granulocytes, and platelets, resulting from the SPE-like proton radiation exposure, with or without HU treatment, in mice suggest that astronauts participating in exploration class missions may be at greater risk of developing infections and thrombotic diseases; thus, countermeasures may be necessary for these biological endpoints.
- Published
- 2014
16. Orally administered fructose increases the numbers of peripheral lymphocytes reduced by exposure of mice to gamma or SPE-like proton radiation
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Ana L. Romero-Weaver, Liyong Lin, Ann R. Kennedy, and J. Ni
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Radiation ,Ecology ,business.industry ,Health, Toxicology and Mutagenesis ,medicine.medical_treatment ,Astronomy and Astrophysics ,Granulocyte ,medicine.disease ,Agricultural and Biological Sciences (miscellaneous) ,Article ,Peripheral ,Ionizing radiation ,Radiation therapy ,Haematopoiesis ,medicine.anatomical_structure ,Immune system ,Radiation sickness ,Immunology ,medicine ,Bone marrow ,business - Abstract
Exposure of the whole body or a major portion of the body to ionizing radiation can result in Acute Radiation Sickness (ARS), which can cause symptoms that range from mild to severe, and include death. One of the syndromes that can occur during ARS is the hematopoietic syndrome, which is characterized by a reduction in bone marrow cells as well as the number of circulating blood cells. Doses capable of causing this syndrome can result from conventional radiation therapy and accidental exposure to ionizing radiation. It is of concern that this syndrome could also occur during space exploration class missions in which astronauts could be exposed to significant doses of solar particle event (SPE) radiation. Of particular concern is the reduction of lymphocytes and granulocytes, which are major components of the immune system. A significant reduction in their numbers can compromise the immune system, causing a higher risk for the development of infections which could jeopardize the success of the mission. Although there are no specific countermeasures utilized for the ARS resulting from exposure to space radiation(s), granulocyte colony-stimulating factor (G-CSF) has been proposed as a countermeasure for the low number of neutrophils caused by SPE radiation, but so far no countermeasure exists for a reduced number of circulating lymphocytes. The present study demonstrates that orally administered fructose significantly increases the number of peripheral lymphocytes reduced by exposure of mice to 2 Gy of gamma- or SPE-like proton radiation, making it a potential countermeasure for this biological end-point.
- Published
- 2014
17. Interferon: Cellular Executioner or White Knight?
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Anthony J. Scarzello, Stephen G. Maher, Ana L. Romero-Weaver, and Ana M. Gamero
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Cell signaling ,medicine.medical_treatment ,Apoptosis ,Cell fate determination ,Biology ,p38 Mitogen-Activated Protein Kinases ,Biochemistry ,Interferon-gamma ,Interferon ,Drug Discovery ,medicine ,Humans ,Immunologic Factors ,STAT1 ,Cell Proliferation ,Janus Kinases ,Pharmacology ,Immunity, Cellular ,Cell growth ,Interleukins ,Organic Chemistry ,JAK-STAT signaling pathway ,Proto-Oncogene Proteins c-crk ,Phosphoproteins ,Receptor, Insulin ,STAT Transcription Factors ,Cytokine ,Virus Diseases ,Antibody Formation ,Interferon Type I ,Immunology ,Insulin Receptor Substrate Proteins ,biology.protein ,Cancer research ,Cytokines ,Molecular Medicine ,Interferons ,Signal transduction ,Signal Transduction ,medicine.drug - Abstract
Interferons (IFNs) are a family of pleiotropic cytokines that typically exhibit antiviral, antiproliferative, antitumor, and immunomodulatory properties. While their complex mechanisms of action remain unclear, IFNs are used clinically in the treatment of viral infections, such as hepatitis B and hepatitis C, and remain the primary treatment for a limited number of malignancies, such as melanoma, hairy cell leukemia, and non-Hodgkin's lymphoma and in autoimmune diseases such as multiple sclerosis. IFNs not only regulate somatic cell growth and division but also influence cell survival through the modulation of apoptosis. Paradoxically, IFNs are described to be both pro- and anti-apoptotic in nature. The biological effects of IFNs are primarily mediated via activation of the JAK/STAT pathway, formation of the ISGF3 and STAT1:STAT1 protein complexes, and the subsequent induction of IFN-stimulated genes. However, the activation of JAK/STAT-independent signal transduction pathways also contribute to IFN-mediated responses. To further demonstrate the complexity of the downstream events following stimulation, oligonucleotide microarray studies have shown that in excess of 300 genes are induced following treatment with IFN, some of which are crucial to the induction of apoptosis and cell growth control. In this review we describe the recent advances made in elucidating the various signaling pathways that are activated by IFNs and how these diverse signals contribute to the regulation of cell growth and apoptosis and inhibition of viral replication. Furthermore, we highlight the role of specific signaling molecules and the function(s) of particular IFN-stimulated genes that have been implicated in determining cell fate in response to IFN, as well as the clinical experience of IFN immunotherapy.
- Published
- 2007
18. Effect of Gender on the Radiation Sensitivity of Murine Blood Cells
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Paul C. Billings, Ana L. Romero-Weaver, and Ann R. Kennedy
- Subjects
Article - Abstract
Space travel beyond the Earth’s protective magnetosphere risks exposing astronauts to ionizing radiation, such as that generated during a solar particle event (SPE). Ionizing radiation has well documented effects on blood cells and it is generally assumed that these effects contribute to the hematopoietic syndrome (HS), observed in animals and humans, following exposure to total body irradiation (TBI). The purpose of the current study was to assess the role of gender on the effects of gamma radiation on blood cells. C3H/HeN mice were irradiated with a 137Cs gamma source. Radiation had similar effects on white blood cells (WBCs), lymphocytes, and granulocytes in male and female C3H/HeN mice, while red blood cell (RBC) counts and hematocrit values remained stable following radiation exposure. Non-irradiated male mice had 13% higher platelet counts, compared with their female counterparts, and showed enhanced recovery of platelets on day 16 following radiation exposure. Hence, gender differences influence the response of platelets to TBI exposure.
- Published
- 2014
19. Broad-spectrum antibiotic or G-CSF as potential countermeasures for impaired control of bacterial infection associated with an SPE exposure during spaceflight
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Drew Weissman, Minghong Li, Liyong Lin, Jenine K. Sanzari, Ann R. Kennedy, Ana L. Romero-Weaver, Houping Ni, Eric S. Diffenderfer, A Carabe-Fernandez, and Veronica M. Holmes
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medicine.drug_class ,Antibiotics ,lcsh:Medicine ,Biology ,medicine.disease_cause ,Spaceflight ,law.invention ,03 medical and health sciences ,Mice ,Antibiotic resistance ,Immune system ,law ,Granulocyte Colony-Stimulating Factor ,medicine ,Enrofloxacin ,Animals ,Circadian rhythm ,Solar Activity ,lcsh:Science ,030304 developmental biology ,0303 health sciences ,Multidisciplinary ,030306 microbiology ,Pseudomonas aeruginosa ,lcsh:R ,Bacterial Infections ,Space Flight ,3. Good health ,Granulocyte colony-stimulating factor ,Anti-Bacterial Agents ,13. Climate action ,Immunology ,lcsh:Q ,Female ,medicine.drug ,Fluoroquinolones ,Research Article - Abstract
A major risk for astronauts during prolonged space flight is infection as a result of the combined effects of microgravity, situational and confinement stress, alterations in food intake, altered circadian rhythm, and radiation that can significantly impair the immune system and the body’s defense systems. We previously reported a massive increase in morbidity with a decrease in the ability to control a bacterial challenge when mice were maintained under hindlimb suspension (HS) conditions and exposed to solar particle event (SPE)-like radiation. HS and SPE-like radiation treatment alone resulted in a borderline significant increase in morbidity. Therefore, development and testing of countermeasures that can be used during extended space missions in the setting of exposure to SPE radiation becomes a serious need. In the present study, we investigated the efficacy of enrofloxacin (an orally bioavailable antibiotic) and Granulocyte colony stimulating factor (G-CSF) (Neulasta) on enhancing resistance to Pseudomonas aeruginosa infection in mice subjected to HS and SPE-like radiation. The results revealed that treatment with enrofloxacin or G-CSF enhanced bacterial clearance and significantly decreased morbidity and mortality in challenged mice exposed to suspension and radiation. These results establish that antibiotics, such as enrofloxacin, and G-CSF could be effective countermeasures to decrease the risk of bacterial infections after exposure to SPE radiation during extended space flight, thereby reducing both the risk to the crew and the danger of mission failure.
- Published
- 2014
20. Potential Beneficial Effects of Si-Wu-Tang on White Blood Cell Numbers and the Gastrointestinal Tract of γ-Ray Irradiated Mice
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Jin, Ni, Ana L, Romero-Weaver, and Ann R, Kennedy
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lymphocytes ,white blood cells ,gamma radiation ,Original Article ,granulocytes ,gastrointestinal tract ,fibrinogen ,monocytes ,Si-Wu-Tang - Abstract
Si-Wu-Tang (SWT) is a decoction consisting of a mixture of ingredients of Rehmanniae Radix, Angelica Radix, Chuanxiong Rhizoma and Paeoniae Radix. As a traditional Chinese herbal decoction, SWT has been widely used for the treatment of diseases characterized as blood and/or energy deficit. The present study was performed to evaluate the effects of SWT on the different populations of circulating white blood cells (WBCs) and gastrointestinal changes in γ-ray irradiated mice. Female mice were treated daily with orally administered SWT seven days before irradiation, until one day before irradiation or until one day before sample collection. WBC counts were determined from peripheral blood samples taken from the mice at different times post-irradiation. Hematoxylin and eosin (H&E) staining, as well as immunohistochemical analysis of fibrinogen, were utilized to evaluate the effects of SWT in the intestines of mice after radiation exposure. The results of the present studies demonstrate that SWT has protective effects against radiation damage to circulating WBCs, specifically to lymphocytes, and to the gastrointestinal tract of the irradiated animals.
- Published
- 2014
21. Cutting Edge Therapies for Cancer in the 21st Century
- Author
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Shilpa Gupta, Ana L. Romero-Weaver, Chiara Stella Di Stadio, Emili Rippa, Rounak Nande, Philippe G. Frank, Juan Carlos Trivino Pardo, Caterina Cinti, Giuseppina Miselli, Elaine Hardman, Michael P. Lisanti, Faizan Alawi, Marja T. Nevalainen, Paraskevi Vogiatzi, David T. Hoang, Candace M. Howard, Zoran Culig, John J. Sauk, Paolo Arcari, Theodore R. Witte, Filomena Altieri, Sucharitha Balasubramaniam, Ilaria Naldi, Pipitska Valsamaki, Johannes F. Fahrmann, Marco Durante, Daniela Trani, Laslo Otvos, Maria Irene Scarano, Sonia Godoy-Tundidor, Gloria Bonuccelli, Pier Paolo Claudio, and Monia Taranta
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,Medicine ,Cancer ,Edge (geometry) ,business ,medicine.disease - Published
- 2014
22. PHARMACOLOGICAL SUPPRESSION OF JAK1/2 BY JAK1/2 INHIBITOR AZD1480 POTENTLY INHIBITS IL-6-INDUCED EXPERIMENTAL PROSTATE CANCER METASTASES FORMATION
- Author
-
Ana L. Romero-Weaver, Tuomas Mirtti, Benjamin E. Leiby, Junaid Abdulghani, Paraskevi Vogiatzi, Zhiyong Liao, David T. Hoang, Kalle Alanen, Dennis Huszar, Michael Zinda, Marja T. Nevalainen, Pooja Talati, and Lei Gu
- Subjects
Male ,STAT3 Transcription Factor ,Cancer Research ,MAP Kinase Signaling System ,medicine.medical_treatment ,Gene Expression ,Mice, Nude ,Article ,Metastasis ,Prostate cancer ,Mice ,Prostate ,Cell Movement ,Cell Line, Tumor ,medicine ,Cell Adhesion ,Animals ,Humans ,Neoplasm Metastasis ,Cell adhesion ,Interleukin 6 ,Janus kinase 2 ,biology ,Janus kinase 1 ,Interleukin-6 ,Prostatic Neoplasms ,Janus Kinase 1 ,Janus Kinase 2 ,medicine.disease ,3. Good health ,Disease Models, Animal ,Cytokine ,medicine.anatomical_structure ,Phenotype ,Pyrimidines ,Oncology ,biology.protein ,Cancer research ,Pyrazoles - Abstract
Metastatic prostate cancer is lethal and lacks effective strategies for prevention or treatment, requiring novel therapeutic approaches. Interleukin-6 (IL-6) is a cytokine that has been linked with prostate cancer pathogenesis by multiple studies. However, the direct functional roles of IL-6 in prostate cancer growth and progression have been unclear. In the present study, we show that IL-6 is produced in distant metastases of clinical prostate cancers. IL-6–activated signaling pathways in prostate cancer cells induced a robust 7-fold increase in metastases formation in nude mice. We further show that IL-6 promoted migratory prostate cancer cell phenotype, including increased prostate cancer cell migration, microtubule reorganization, and heterotypic adhesion of prostate cancer cells to endothelial cells. IL-6–driven metastasis was predominantly mediated by Stat3 and to lesser extent by ERK1/2. Most importantly, pharmacologic inhibition of Jak1/2 by AZD1480 suppressed IL-6–induced signaling, migratory prostate cancer cell phenotypes, and metastatic dissemination of prostate cancer in vivo in nude mice. In conclusion, we demonstrate that the cytokine IL-6 directly promotes prostate cancer metastasis in vitro and in vivo via Jak–Stat3 signaling pathway, and that IL-6–driven metastasis can be effectively suppressed by pharmacologic targeting of Jak1/2 using Jak1/2 inhibitor AZD1480. Our results therefore provide a strong rationale for further development of Jak1/2 inhibitors as therapy for metastatic prostate cancer. Mol Cancer Ther; 13(5); 1246–58. ©2014 AACR.
- Published
- 2014
23. Kinetics of neutrophils in mice exposed to radiation and/or granulocyte colony-stimulating factor treatment
- Author
-
Ana L. Romero-Weaver, Liyong Lin, Eric S. Diffenderfer, X. S. Wan, and Ann R. Kennedy
- Subjects
Neutropenia ,Time Factors ,Filgrastim ,Neutrophils ,Biophysics ,Biology ,Granulocyte ,Neutrophil Activation ,Article ,Polyethylene Glycols ,Leukocyte Count ,Mice ,Granulocyte Colony-Stimulating Factor ,medicine ,Relative biological effectiveness ,Animals ,Radiology, Nuclear Medicine and imaging ,Solar Activity ,Myelopoiesis ,Mice, Inbred ICR ,Radiation ,medicine.disease ,Recombinant Proteins ,Granulocyte colony-stimulating factor ,Haematopoiesis ,Disease Models, Animal ,Radiation Injuries, Experimental ,medicine.anatomical_structure ,Gamma Rays ,Immunology ,Absolute neutrophil count ,Tetradecanoylphorbol Acetate ,Female ,Protons ,Reactive Oxygen Species ,Pegfilgrastim ,Relative Biological Effectiveness ,medicine.drug - Abstract
Astronauts have the potential to develop the hematopoietic syndrome as a result of exposure to radiation from a solar particle event (SPE) during exploration class missions. This syndrome is characterized by a reduction in the number of circulating blood cells (cytopenias). In the present study the effects of SPE-like proton and γ radiation on the kinetics of circulating neutrophils were evaluated during a one-month time period using mice as a model system. The results revealed that exposure to a 2 Gy dose of either SPE-like proton or γ radiation significantly decreased the number of circulating neutrophils, with two nadirs observed on day 4 and day 16 postirradiation. Low circulating neutrophil count (neutropenia) is particularly important because it can increase the risk of astronauts developing infections, which can compromise the success of the mission. Thus, two granulocyte colony-stimulating factors (G-CSFs), filgrastim and pegfilgrastim were evaluated as countermeasures for this endpoint. Both forms of G-CSF significantly increased neutrophil counts in irradiated mice, however, the effect of pegfilgrastim was more potent and lasted longer than filgrastim. Using the expression of CD11b, CD18 and the production of reactive oxygen species (ROS) as markers of neutrophil activation, it was determined that the neutrophils in the irradiated mice treated with pegfilgrastim were physiologically active. Thus, these results suggest that pegfilgrastim could be a potential countermeasure for the reduced number of circulating neutrophils in irradiated animals.
- Published
- 2013
24. Effect of SPE-like Proton or Photon Radiation on the Kinetics of Mouse Peripheral Blood Cells and Radiation Biological Effectiveness Determinations
- Author
-
Eric S. Diffenderfer, Ann R. Kennedy, Liyong Lin, X.S. Wan, and Ana L. Romero-Weaver
- Subjects
Mice, Inbred ICR ,Photons ,Blood Cells ,Proton ,Chemistry ,Kinetics ,Photon radiation ,Radiation ,Radiation Dosage ,Agricultural and Biological Sciences (miscellaneous) ,Peripheral blood ,Toxicology ,Blood cell ,Mice ,medicine.anatomical_structure ,Space and Planetary Science ,White blood cell ,Solar particle event ,medicine ,Biophysics ,Animals ,Female ,Protons ,Research Articles - Abstract
Exploration missions outside low-Earth orbit are being planned; therefore, it is critical to understand the risk astronauts would be exposed to in the space environment, especially during extravehicular activities (EVAs). Reductions in white blood cell (WBC) numbers can occur as a result of exposure to solar particle event (SPE) radiation. The aim of the present study was to determine the duration of the effects on blood cell numbers from exposure to a single whole-body dose of SPE-like proton radiation or photon radiation as well as to determine the radiation biological effectiveness (RBE) values at those times when radiation exposure causes blood cell numbers to experience the most critical effects when using mice as a model. Our results indicate that both types of radiation cause significant reductions in the numbers of all blood cell types at different times post-irradiation. The RBE values were not significantly different from 1.0. These results indicate that the risk estimations for astronauts from exposure of mice to SPE-like proton radiation are comparable to those previously made for doses of standard reference radiations, suggesting that countermeasures should be developed for the decreases in blood cell counts observed following the exposure of mice to SPE radiation. Key Words: Proton radiation—Gamma radiation—Blood cell counts—Solar particle event. Astrobiology 13, 570–577.
- Published
- 2013
25. Leukocyte activity is altered in a ground based murine model of microgravity and proton radiation exposure
- Author
-
Liyong Lin, Jenine K. Sanzari, Gabrielle James, Eric S. Diffenderfer, Gabriel Krigsfeld, Ann R. Kennedy, and Ana L. Romero-Weaver
- Subjects
Anatomy and Physiology ,Mouse ,Lymphocyte ,lcsh:Medicine ,Lymphocyte Activation ,Mice ,Immune Physiology ,lcsh:Science ,Immune Response ,Immunity, Cellular ,Multidisciplinary ,Physics ,Animal Models ,Radiation Injuries, Experimental ,medicine.anatomical_structure ,Hindlimb Suspension ,Astronauts ,Medicine ,Research Article ,T cell ,Immune Cells ,Radiation Biophysics ,Immunology ,Biophysics ,Spleen ,Biology ,Immune system ,Model Organisms ,Immunity ,White blood cell ,medicine ,Animals ,Humans ,Lymphocyte Count ,Weightlessness Simulation ,Cell Proliferation ,Cell growth ,Monocyte ,lcsh:R ,Radiobiology ,Immune Defense ,Space Flight ,Immune System ,lcsh:Q ,Clinical Immunology ,T-Lymphocytes, Cytotoxic - Abstract
Immune system adaptation during spaceflight is a concern in space medicine. Decreased circulating leukocytes observed during and after space flight infer suppressed immune responses and susceptibility to infection. The microgravity aspect of the space environment has been simulated on Earth to study adverse biological effects in astronauts. In this report, the hindlimb unloading (HU) model was employed to investigate the combined effects of solar particle event-like proton radiation and simulated microgravity on immune cell parameters including lymphocyte subtype populations and activity. Lymphocytes are a type of white blood cell critical for adaptive immune responses and T lymphocytes are regulators of cell-mediated immunity, controlling the entire immune response. Mice were suspended prior to and after proton radiation exposure (2 Gy dose) and total leukocyte numbers and splenic lymphocyte functionality were evaluated on days 4 or 21 after combined HU and radiation exposure. Total white blood cell (WBC), lymphocyte, neutrophil, and monocyte counts are reduced by approximately 65%, 70%, 55%, and 70%, respectively, compared to the non-treated control group at 4 days after combined exposure. Splenic lymphocyte subpopulations are altered at both time points investigated. At 21 days post-exposure to combined HU and proton radiation, T cell activation and proliferation were assessed in isolated lymphocytes. Cell surface expression of the Early Activation Marker, CD69, is decreased by 30% in the combined treatment group, compared to the non-treated control group and cell proliferation was suppressed by approximately 50%, compared to the non-treated control group. These findings reveal that the combined stressors (HU and proton radiation exposure) result in decreased leukocyte numbers and function, which could contribute to immune system dysfunction in crew members. This investigation is one of the first to report on combined proton radiation and simulated microgravity effects on hematopoietic, specifically immune cells.
- Published
- 2013
26. Effects of selenomethionine in irradiated human thyroid epithelial cells and tumorigenicity studies
- Author
-
Zhaozong Zhou, X. Steven Wan, Jeffrey H. Ware, Paul M. Newberne, Ana L. Romero-Weaver, and Ann R. Kennedy
- Subjects
Cancer Research ,Pathology ,medicine.medical_specialty ,Iron ,Thyroid Gland ,Medicine (miscellaneous) ,chemistry.chemical_element ,Mice, Nude ,Biology ,Antioxidants ,Article ,Cell Line ,Mice ,medicine ,Animals ,Humans ,Irradiation ,Clonogenic assay ,Selenomethionine ,Nutrition and Dietetics ,Thyroid ,Epithelial Cells ,Molecular biology ,Transformation (genetics) ,medicine.anatomical_structure ,Oncology ,chemistry ,Nonlinear Dynamics ,Cell culture ,Gamma Rays ,Toxicity ,Regression Analysis ,Human thyroid ,Protons ,Selenium ,Biomarkers - Abstract
The objectives of the present study were to characterize γ -ray, 1 GeV/n proton, and 1 GeV/n iron ion radiation-induced adverse biological effects in terms of toxicity and transformation of HTori-3 human thyroid epithelial cells; to evaluate the ability of L-selenomethionine (SeM) to protect against radiation-induced transformation when present at different times during the assay period; and to evaluate the tumorigenicity of HTori-3 cells derived from anchorage-independent colonies following iron ion radiation exposure. Cell survival was determined by a clonogenic assay, transformation was measured by a soft agar colony formation assay, and the tumorigenic potential of the cells was determined by injecting them subcutaneously into athymic nude mice and monitoring tumor formation. The results demonstrate that exposure of HTori-3 cells to γ -ray, proton, or iron ion radiation resulted in decreased clonogenic survival, which persisted for weeks after the radiation exposure. Treatment with SeM initiated up to 7 days after the radiation exposure conferred significant protection against radiation-induced anchorage-independent growth. HTori-3 cells derived from all evaluated anchorage-independent colonies formed tumors when injected into athymic nude mice, indicating that these cells are tumorigenic and that anchorage-independent colony growth is a reliable surrogate endpoint biomarker for the radiation-induced malignant transformation of HTori-3 cells.
- Published
- 2011
27. Analysis of white blood cell counts in mice after gamma- or proton-radiation exposure
- Author
-
Jeffrey H. Ware, Ann R. Kennedy, Ana L. Romero-Weaver, Jolaine M. Wilson, James M. Slater, Andrew J. Wroe, Peter Koss, Jenine K. Sanzari, Steve Rightnar, Casey Maks, X. Steven Wan, and Daila S. Gridley
- Subjects
Endpoint Determination ,Biophysics ,Biology ,Radiation ,Article ,Andrology ,Leukocyte Count ,Mice ,Proton radiation ,White blood cell ,Relative biological effectiveness ,medicine ,Leukocytes ,Animals ,Radiology, Nuclear Medicine and imaging ,Mice, Inbred ICR ,business.industry ,Gamma ray ,Dose-Response Relationship, Radiation ,medicine.anatomical_structure ,Increased risk ,Gamma Rays ,Solar particle event ,Female ,Protons ,Nuclear medicine ,business ,Dose rate ,Relative Biological Effectiveness - Abstract
In the coming decades human space exploration is expected to move beyond low-Earth orbit. This transition involves increasing mission time and therefore an increased risk of radiation exposure from solar particle event (SPE) radiation. Acute radiation effects after exposure to SPE radiation are of prime importance due to potential mission-threatening consequences. The major objective of this study was to characterize the dose–response relationship for proton and γ radiation delivered at doses up to 2 Gy at high (0.5 Gy/min) and low (0.5 Gy/h) dose rates using white blood cell (WBC) counts as a biological end point. The results demonstrate a dose-dependent decrease in WBC counts in mice exposed to high- and low-dose-rate proton and γ radiation, suggesting that astronauts exposed to SPE-like radiation may experience a significant decrease in circulating leukocytes.
- Published
- 2011
28. Acute effects of solar particle event radiation
- Author
-
Drew Weissman, Gabriel Krigsfeld, Eric S. Diffenderfer, Jenine K. Sanzari, Ana L. Romero-Weaver, L.L. Lin, X. Steven Wan, Ann R. Kennedy, and Keith A. Cengel
- Subjects
Disseminated intravascular coagulation ,Oral Session 12: Countermeasure and Transportation Code ,Radiation ,business.industry ,Health, Toxicology and Mutagenesis ,Gamma ray ,Acute Radiation Syndrome ,Pharmacology ,medicine.disease ,Relative biological effectiveness ,Medicine ,Hypogravity ,Radiology, Nuclear Medicine and imaging ,Retching ,Animal studies ,medicine.symptom ,business ,Nuclear medicine - Abstract
A major solar particle event (SPE) may place astronauts at significant risk for the acute radiation syndrome (ARS), which may be exacerbated when combined with other space flight stressors, such that the mission or crew health may be compromised. The National Space Biomedical Research Institute (NSBRI) Center of Acute Radiation Research (CARR) is focused on the assessment of risks of adverse biological effects related to the ARS in animals exposed to space flight stressors combined with the types of radiation expected during an SPE. The CARR studies are focused on the adverse biological effects resulting from exposure to the types of radiation, at the appropriate energies, doses and dose-rates, present during an SPE (and standard reference radiations: gamma rays or electrons). All animal studies described have been approved by the University of PA IACUC. Some conclusions from recent CARR investigations are as follows: (i) the relative biological effectiveness (RBE) values for SPE-like protons compared with standard reference radiations (gammas or electrons) for white blood cells (WBCs) vary greatly between mice, ferrets and pigs, with the RBE values being greater in ferrets than those in mice, and considerably greater in pigs compared with those in ferrets or mice [1, 2]. This trend for the data suggests that the RBE values for WBCs in humans could be considerably greater than those observed in small mammals, and SPE proton radiation may be far more hazardous to humans than previously estimated from small animal studies. (ii) Very low doses of SPE proton radiation (25 cGy) increase blood clotting times in ferrets, and the low SPE-like dose rate has more severe effects than high dose rate radiation [3]. (iii) Results from pig and ferret studies suggest that disseminated intravascular coagulation is a major cause of death at doses near the LD50 level for SPE-like proton and gamma radiation. (iv) Exposure to SPE-like proton or gamma radiation, in combination with simulated microgravity (hindlimb suspension), leads to a very high level of morbidity/mortality in mice given a bacterial challenge with non-toxic levels of Pseudomonas aeruginosa or Klebsiella pneumoniae; the threshold for this effect was 1.5 Gy. (v) T-cell activation was reduced in mice exposed to SPE-like radiation with or without simulated hypogravity (either partial weight suspension or hindlimb suspension) (e.g. [4]). (vi) Radiation and simulated hypogravity had synergistic effects on immune system biological endpoints (e.g. [5]). (vii) Pigs exposed to simulated SPE radiation exhibited increases in intracranial pressure that remained elevated over the 90-day experimental period. (viii) A major sparing effect of SPE-like low dose rate radiation (compared with the results for high dose rate radiation) was observed for ferret emesis parameters, such that the differences between the results for ferret exposure to low dose rate radiation (50 cGy/h) and controls were not statistically significant (for doses up to 2 Gy). For high dose rate SPE proton radiation, the threshold value for retching was 75 cGy, and for ferret vomiting, it was 1 Gy.
- Published
- 2014
29. Resistance to IFN-alpha-induced apoptosis is linked to a loss of STAT2
- Author
-
Faruk Sheikh, Ana M. Gamero, Raymond P. Donnelly, Hsiang-Wen Wang, Anthony J. Scarzello, Håkan C. Steen, Ana L. Romero-Weaver, and Veronica L. Hall
- Subjects
Cancer Research ,Programmed cell death ,Apoptosis ,Transfection ,Jurkat cells ,Article ,TNF-Related Apoptosis-Inducing Ligand ,Jurkat Cells ,Tumor Cells, Cultured ,Gene silencing ,Humans ,Gene Silencing ,Phosphorylation ,Molecular Biology ,Regulation of gene expression ,Cell Nucleus ,biology ,Cytochrome c ,Interferon-alpha ,STAT2 Transcription Factor ,Protein-Tyrosine Kinases ,Mitochondria ,Oncology ,Drug Resistance, Neoplasm ,biology.protein ,Cancer research ,Signal transduction ,Gene Deletion ,Signal Transduction - Abstract
Type I IFNs (IFN-α/β) are pleitropic cytokines widely used in the treatment of certain malignancies, hepatitis B and C, and multiple sclerosis. IFN resistance is a challenging clinical problem to overcome. Hence, understanding the molecular mechanism by which IFN immunotherapy ceases to be effective is of translational importance. In this study, we report that continuous IFN-α stimulation of the human Jurkat variant H123 led to resistance to type I IFN–induced apoptosis due to a loss of signal transducers and activators of transcription 2 (STAT2) expression. The apoptotic effects of IFN-α were hampered as STAT2-deficient cells were defective in activating the mitochondrial-dependent death pathway and ISGF3-mediated gene activation. Reconstitution of STAT2 restored the apoptotic effects of IFN-α as measured by the loss of mitochondrial membrane potential, cytochrome c release from mitochondria, caspase activation, and ultimately cell death. Nuclear localization of STAT2 was a critical event as retention of tyrosine-phosphorylated STAT2 in the cytosol was not sufficient to activate apoptosis. Furthermore, silencing STAT2 gene expression in Saos2 and A375S.2 tumor cell lines significantly reduced the apoptotic capacity of IFN-α. Altogether, we show that STAT2 is a critical mediator in the activation of type I IFN–induced apoptosis. More importantly, defects in the expression or nuclear localization of STAT2 could lessen the efficacy of type I IFN immunotherapy. Mol Cancer Res; 8(1); 80–92
- Published
- 2010
30. IFNalpha and IFNlambda differ in their antiproliferative effects and duration of JAK/STAT signaling activity
- Author
-
Darren P. Baker, Ana L. Romero-Weaver, Stephen G. Maher, Anthony J. Scarzello, Faruk Sheikh, Ana M. Gamero, and Raymond P. Donnelly
- Subjects
Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Apoptosis ,stat ,Article ,Amino Acid Chloromethyl Ketones ,Mice ,Internal medicine ,Cell Line, Tumor ,medicine ,Animals ,Humans ,STAT1 ,STAT2 ,Cell Proliferation ,Pharmacology ,biology ,Janus kinase 1 ,Dose-Response Relationship, Drug ,Interleukins ,JAK-STAT signaling pathway ,Interferon-alpha ,Janus Kinase 1 ,Staurosporine ,HaCaT ,Kinetics ,Endocrinology ,Cytokine ,STAT1 Transcription Factor ,Oncology ,biology.protein ,Cancer research ,Molecular Medicine ,Cytokines ,Interferons ,Signal transduction ,Signal Transduction - Abstract
Interferon (IFN)lambda, also known as IL-28A, IL-28B or IL-29, is a new type III IFN, which like type I IFN(alpha/beta), activates common elements of the JAK/STAT signaling pathway and exhibits antiproliferative activity. Currently, IFNalpha is used in the treatment of certain forms of cancer, but its antitumor effects are limited and associated with high toxicity. In this study, we determined whether IFNlambda induced the same level of cell growth inhibition relative to IFNalpha. To this effect HaCaT cells, which are typically growth inhibited by IFNalpha, underwent apoptosis in response to IFNlambda. Next, in contrast to IFNalpha stimulation, IFNlambda prolonged the duration of activated STAT1 and STAT2. Furthermore, the kinetics of IFN-stimulated genes was different as IFNlambda induced a delayed but stronger induction of IFN-responsive genes. Components of the JAK/STAT pathway remained essential for the antiproliferative effects of IFNalpha and IFNlambda. IFNlambda-induced persistence of STAT activation required de novo protein synthesis and was in part due to a delay in STAT2 inactivation. Thus our data demonstrate that the duration of IFNlambda signaling is different from that of IFNalpha, and that IFNlambda could be a suitable cytokine to evaluate for cancer therapy.
- Published
- 2008
31. A Mutation in the SH2 Domain of STAT2 Prolongs Tyrosine Phosphorylation of STAT1 and Promotes Type I IFN-induced Apoptosis
- Author
-
Ana L. Romero-Weaver, Ana M. Gamero, Ming Zhou, Stephen G. Maher, Anthony J. Scarzello, Angel Qin, Timothy D. Veenstra, Raymond P. Donnelly, and Faruk Sheikh
- Subjects
Transcription, Genetic ,Amino Acid Motifs ,Molecular Sequence Data ,Apoptosis ,Protein tyrosine phosphatase ,SH2 domain ,src Homology Domains ,chemistry.chemical_compound ,Cell Line, Tumor ,Humans ,STAT1 ,Amino Acid Sequence ,Tyrosine ,Phosphorylation ,STAT3 ,Phosphotyrosine ,Molecular Biology ,Conserved Sequence ,Janus Kinases ,Cell Nucleus ,biology ,Tyrosine phosphorylation ,STAT2 Transcription Factor ,Cell Biology ,Articles ,STAT1 Transcription Factor ,chemistry ,Interferon Type I ,Mutation ,Cancer research ,biology.protein ,Janus kinase - Abstract
Type I interferons (IFN-α/β) induce apoptosis in certain tumor cell lines but not others. Here we describe a mutation in STAT2 that confers an apoptotic effect in tumor cells in response to type I IFNs. This mutation was introduced in a conserved motif, PYTK, located in the STAT SH2 domain, which is shared by STAT1, STAT2, and STAT3. To test whether the tyrosine in this motif might be phosphorylated and affect signaling, Y631 of STAT2 was mutated to phenylalanine (Y631F). Although it was determined that Y631 was not phosphorylated, the Y631F mutation conferred sustained signaling and induction of IFN-stimulated genes. This prolonged IFN response was associated with sustained tyrosine phosphorylation of STAT1 and STAT2 and their mutual association as heterodimers, which resulted from resistance to dephosphorylation by the nuclear tyrosine phosphatase TcPTP. Finally, cells bearing the Y631F mutation in STAT2 underwent apoptosis after IFN-α stimulation compared with wild-type STAT2. Therefore, this mutation reveals that a prolonged response to IFN-α could account for one difference between tumor cell lines that undergo IFN-α–induced apoptosis compared with those that display an antiproliferative response but do not die.
- Published
- 2007
32. Ground-based microgravity and proton radiation exposure alters leukocyte activity
- Author
-
Jenine K. Sanzari, Gabrielle James, Liyong Lin, Eric S. Diffenderfer, Ann R. Kennedy, Gabriel Krigsfeld, and Ana L. Romero-Weaver
- Subjects
Radiation ,Cell growth ,Health, Toxicology and Mutagenesis ,Monocyte ,Lymphocyte ,Cell ,Poster Session 02: Cancer Risk ,Biology ,Spaceflight ,law.invention ,medicine.anatomical_structure ,Immune system ,Immunity ,law ,White blood cell ,Immunology ,medicine ,Radiology, Nuclear Medicine and imaging - Abstract
Immune system adaptation during spaceflight is a concern in space medicine. Decreased circulating leukocytes observed during and after space flight infer suppressed immune responses and susceptibility to infection. The microgravity aspect of the space environment has been simulated on Earth to study adverse biological effects in astronauts. In this report, the hindlimb unloading (HU) model was employed to investigate the combined effects of solar particle event-like proton radiation and simulated microgravity on immune cell parameters, including lymphocyte subtype populations and activity. Lymphocytes are a type of white blood cell critical for adaptive immune responses and T lymphocytes are regulators of cell-mediated immunity, controlling the entire immune response. Mice were suspended prior to and after proton radiation exposure (0 or 2 Gy doses) and total leukocyte numbers and splenic lymphocyte functionality were evaluated on days 4 or 21 after combined HU and radiation exposure. Total white blood cell (WBC), lymphocyte, neutrophil and monocyte counts are reduced by ∼65, 70, 55 and 70%, respectively, compared with the non-treated control group 4 days after combined exposure. Splenic lymphocyte subpopulations are altered at both time points investigated. At 21 days post-exposure to combined HU and proton radiation, T-cell activation and proliferation were assessed in isolated lymphocytes. Cell surface expression of the Early Activation Marker, CD69, is decreased by 30% in the combined treatment group, compared with the non-treated control group and cell proliferation was suppressed by ∼50%, compared with the non-treated control group. These findings reveal that the combined stressors (HU and proton radiation exposure) induce decreased leukocyte numbers and function, contributing to immune system dysfunction in crew members. This research was supported by the NIH Training Grant 2T32CAO9677 and the National Space Biomedical Research Institute (NSBRI) Center of Acute Radiation Research (CARR) grant. The NSBRI is funded through the National Aeronautics and Space Administration (NASA) Class Code (NCC) 9-58. The authors declare that this work has been published: Sanzari JK, Romero-Weaver AL, James G, Krigsfeld G, Lin L, Diffenderfer ES, Kennedy AR. Leukocyte activity is altered in a ground based murine model of microgravity and proton radiation exposure. PLoS One. 2013;8(8):e71757. doi:10.1371/journal.pone.0071757.
- Published
- 2014
33. Broad-spectrum antibiotic or G-CSF as potential countermeasures for impaired control of bacterial infection associated with an SPE exposure during spaceflight.
- Author
-
Minghong Li, Veronica Holmes, Houping Ni, Jenine K Sanzari, Ana L Romero-Weaver, Liyong Lin, Alejandro Carabe-Fernandez, Eric S Diffenderfer, Ann R Kennedy, and Drew Weissman
- Subjects
Medicine ,Science - Abstract
A major risk for astronauts during prolonged space flight is infection as a result of the combined effects of microgravity, situational and confinement stress, alterations in food intake, altered circadian rhythm, and radiation that can significantly impair the immune system and the body's defense systems. We previously reported a massive increase in morbidity with a decrease in the ability to control a bacterial challenge when mice were maintained under hindlimb suspension (HS) conditions and exposed to solar particle event (SPE)-like radiation. HS and SPE-like radiation treatment alone resulted in a borderline significant increase in morbidity. Therefore, development and testing of countermeasures that can be used during extended space missions in the setting of exposure to SPE radiation becomes a serious need. In the present study, we investigated the efficacy of enrofloxacin (an orally bioavailable antibiotic) and Granulocyte colony stimulating factor (G-CSF) (Neulasta) on enhancing resistance to Pseudomonas aeruginosa infection in mice subjected to HS and SPE-like radiation. The results revealed that treatment with enrofloxacin or G-CSF enhanced bacterial clearance and significantly decreased morbidity and mortality in challenged mice exposed to suspension and radiation. These results establish that antibiotics, such as enrofloxacin, and G-CSF could be effective countermeasures to decrease the risk of bacterial infections after exposure to SPE radiation during extended space flight, thereby reducing both the risk to the crew and the danger of mission failure.
- Published
- 2015
- Full Text
- View/download PDF
34. Leukocyte activity is altered in a ground based murine model of microgravity and proton radiation exposure.
- Author
-
Jenine K Sanzari, Ana L Romero-Weaver, Gabrielle James, Gabriel Krigsfeld, Liyong Lin, Eric S Diffenderfer, and Ann R Kennedy
- Subjects
Medicine ,Science - Abstract
Immune system adaptation during spaceflight is a concern in space medicine. Decreased circulating leukocytes observed during and after space flight infer suppressed immune responses and susceptibility to infection. The microgravity aspect of the space environment has been simulated on Earth to study adverse biological effects in astronauts. In this report, the hindlimb unloading (HU) model was employed to investigate the combined effects of solar particle event-like proton radiation and simulated microgravity on immune cell parameters including lymphocyte subtype populations and activity. Lymphocytes are a type of white blood cell critical for adaptive immune responses and T lymphocytes are regulators of cell-mediated immunity, controlling the entire immune response. Mice were suspended prior to and after proton radiation exposure (2 Gy dose) and total leukocyte numbers and splenic lymphocyte functionality were evaluated on days 4 or 21 after combined HU and radiation exposure. Total white blood cell (WBC), lymphocyte, neutrophil, and monocyte counts are reduced by approximately 65%, 70%, 55%, and 70%, respectively, compared to the non-treated control group at 4 days after combined exposure. Splenic lymphocyte subpopulations are altered at both time points investigated. At 21 days post-exposure to combined HU and proton radiation, T cell activation and proliferation were assessed in isolated lymphocytes. Cell surface expression of the Early Activation Marker, CD69, is decreased by 30% in the combined treatment group, compared to the non-treated control group and cell proliferation was suppressed by approximately 50%, compared to the non-treated control group. These findings reveal that the combined stressors (HU and proton radiation exposure) result in decreased leukocyte numbers and function, which could contribute to immune system dysfunction in crew members. This investigation is one of the first to report on combined proton radiation and simulated microgravity effects on hematopoietic, specifically immune cells.
- Published
- 2013
- Full Text
- View/download PDF
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