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  1. Article ; Online: Highlights of the Latest Developments in Radiopharmaceuticals for Infection Imaging and Future Perspectives

    Ekaterina Dadachova / Drauzio E. N. Rangel

    Frontiers in Medicine, Vol

    2022  Volume 9

    Abstract: COVID-19 pandemic has heightened the interest toward diagnosis and treatment of infectious diseases. Nuclear medicine with its powerful scintigraphic, single photon emission computer tomography (SPECT) and positron emission tomography (PET) imaging ... ...

    Abstract COVID-19 pandemic has heightened the interest toward diagnosis and treatment of infectious diseases. Nuclear medicine with its powerful scintigraphic, single photon emission computer tomography (SPECT) and positron emission tomography (PET) imaging modalities has always played an important role in diagnosis of infections and distinguishing them from the sterile inflammation. In addition to the clinically available radiopharmaceuticals there has been a decades-long effort to develop more specific imaging agents with some examples being radiolabeled antibiotics and antimicrobial peptides for bacterial imaging, radiolabeled anti-fungals for fungal infections imaging, radiolabeled pathogen-specific antibodies and molecular engineered constructs. In this opinion piece, we would like to discuss some examples of the work published in the last decade on developing nuclear imaging agents for bacterial, fungal, and viral infections in order to generate more interest among nuclear medicine community toward conducting clinical trials of these novel probes, as well as toward developing novel radiotracers for imaging infections.
    Keywords infection imaging ; antibiotics ; anti-fungals ; antimicrobial peptides ; antibodies ; HIV ; Medicine (General) ; R5-920
    Subject code 610
    Language English
    Publishing date 2022-02-01T00:00:00Z
    Publisher Frontiers Media S.A.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Usefulness of continuous probability distributions of rates for modelling radionuclide biokinetics in humans and animals

    Igor Shuryak / Ekaterina Dadachova

    Scientific Reports, Vol 9, Iss 1, Pp 1-

    2019  Volume 12

    Abstract: Abstract Modelling the biokinetics of radionuclide excretion or retention is important in nuclear medicine and following accidental/malicious radioactivity releases. Sums of discrete exponential decay rates are often used, but we hypothesized that ... ...

    Abstract Abstract Modelling the biokinetics of radionuclide excretion or retention is important in nuclear medicine and following accidental/malicious radioactivity releases. Sums of discrete exponential decay rates are often used, but we hypothesized that continuous probability distributions (CPD) of decay rates can describe the data more parsimoniously and robustly. We tested this hypothesis on diverse human and animal data sets involving various radionuclides (including plutonium, strontium, caesium) measured in the laboratory and in regions contaminated by the Fukushima and Chernobyl nuclear accidents. We used four models on each data set: mono-exponential (ME) with one discrete decay rate, bi-exponential (BE) with two rates, gamma-exponential (GE) with a Gamma distribution of stretched-exponential rates, and power-decay (PD) with a Gamma distribution of power-decay rates. Information-theoretic model selection suggested that radionuclide biokinetics, e.g. for plutonium in humans, are often better described by CPD models like GE and PD, than by discrete rates (ME and BE). Extrapolation of models fitted to data at short times to longer times was frequently more robust for CPD formalisms. We suggest that using a set of several CPD and discrete-rate models, and comparing them by information-theoretic methods, is a promising strategy to enhance the analysis of radionuclide excretion and retention kinetics.
    Keywords Medicine ; R ; Science ; Q
    Subject code 519
    Language English
    Publishing date 2019-02-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Characterization of IGF2R Molecular Expression in Canine Osteosarcoma as Part of a Novel Comparative Oncology Approach

    Charles Boisclair / Ryan Dickinson / Sabeena Giri / Ekaterina Dadachova / Valerie MacDonald-Dickinson

    International Journal of Molecular Sciences, Vol 24, Iss 1867, p

    2023  Volume 1867

    Abstract: Progress in prognostic factors, treatments, and outcome for both canine and human osteosarcoma (OS) has been minimal over the last three decades. Surface overexpression of the cation independent mannose-6-phosphate/insulin-like growth factor receptor ... ...

    Abstract Progress in prognostic factors, treatments, and outcome for both canine and human osteosarcoma (OS) has been minimal over the last three decades. Surface overexpression of the cation independent mannose-6-phosphate/insulin-like growth factor receptor type 2 (IGF2R) has been proven to occur in human OS cells. Subsequently, radioimmunotherapy (RIT) targeting IGF2R has demonstrated promising preliminary results. The main aims of this study were to investigate the expression of IGF2R in spontaneously occurring canine OS cells using immunohistochemistry (IHC) on archived biopsy samples and to assess its prognostic significance. Thirty-four dogs were included in the study. All cases showed that 80–100% of OS cells stained positive for IGF2R. IGF2R overexpression alone was not shown to have prognostic significance using both visual and quantitative methods of IHC staining intensity. This study has established for the first time the consistent expression of IGF2R in spontaneously occurring canine OS. This comparative oncology approach will allow further investigation into RIT as a novel treatment modality; first in canines and then in humans with OS. In addition, further studies should be performed to assess the true prognostic significance of IGF2R overexpression.
    Keywords osteosarcoma ; canine ; IGF2R ; radioimmunotherapy ; immunohistochemistry ; comparative oncology ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 630
    Language English
    Publishing date 2023-01-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Targeting Melanin in Melanoma with Radionuclide Therapy

    Kevin J. H. Allen / Mackenzie E. Malo / Rubin Jiao / Ekaterina Dadachova

    International Journal of Molecular Sciences, Vol 23, Iss 9520, p

    2022  Volume 9520

    Abstract: Nearly 100,000 individuals are expected to be diagnosed with melanoma in the United States in 2022. Treatment options for late-stage metastatic disease up until the 2010s were few and offered only slight improvement to the overall survival. The ... ...

    Abstract Nearly 100,000 individuals are expected to be diagnosed with melanoma in the United States in 2022. Treatment options for late-stage metastatic disease up until the 2010s were few and offered only slight improvement to the overall survival. The introduction of B-RAF inhibitors and anti-CTLA4 and anti-PD-1/PD-L1 immunotherapies into standard of care brought measurable increases in the overall survival across all stages of melanoma. Despite the improvement in the survival statistics, patients treated with targeted therapies and immunotherapies are subject to very serious side effects, the development of drug resistance, and the high costs of treatment. This leaves room for the development of novel approaches as well as for the exploration of novel combination therapies for the treatment of metastatic melanoma. One such approach is targeting melanin pigment with radionuclide therapy. Advances in melanin-targeting radionuclide therapy of melanoma can be viewed from two spheres: (1) radioimmunotherapy (RIT) and (2) radiolabeled small molecules. The investigation of mechanisms of the action and efficacy of targeting melanin in melanoma treatment by RIT points to the involvement of the immune system such as complement dependent cytotoxicity. The combination of RIT with immunotherapy presents synergistic killing in mouse melanoma models. The field of radiolabeled small molecules is focused on radioiodinated compounds that have the ability to cross the cellular membranes to access intracellular melanin and can be applied in both therapy and imaging as theranostics. Clinical applications of targeting melanin with radionuclide therapies have produced encouraging results and clinical work is on-going. Continued work on targeting melanin with radionuclide therapy as a monotherapy, or possibly in combination with standard of care agents, has the potential to strengthen the current treatment options for melanoma patients.
    Keywords metastatic melanoma ; radioimmunotherapy ; melanin ; targeted radionuclide therapy ; benzamides ; nicotinamides ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 616
    Language English
    Publishing date 2022-08-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Quantitative Modeling of Microbial Population Responses to Chronic Irradiation Combined with Other Stressors.

    Igor Shuryak / Ekaterina Dadachova

    PLoS ONE, Vol 11, Iss 1, p e

    2016  Volume 0147696

    Abstract: Microbial population responses to combined effects of chronic irradiation and other stressors (chemical contaminants, other sub-optimal conditions) are important for ecosystem functioning and bioremediation in radionuclide-contaminated areas. ... ...

    Abstract Microbial population responses to combined effects of chronic irradiation and other stressors (chemical contaminants, other sub-optimal conditions) are important for ecosystem functioning and bioremediation in radionuclide-contaminated areas. Quantitative mathematical modeling can improve our understanding of these phenomena. To identify general patterns of microbial responses to multiple stressors in radioactive environments, we analyzed three data sets on: (1) bacteria isolated from soil contaminated by nuclear waste at the Hanford site (USA); (2) fungi isolated from the Chernobyl nuclear-power plant (Ukraine) buildings after the accident; (3) yeast subjected to continuous γ-irradiation in the laboratory, where radiation dose rate and cell removal rate were independently varied. We applied generalized linear mixed-effects models to describe the first two data sets, whereas the third data set was amenable to mechanistic modeling using differential equations. Machine learning and information-theoretic approaches were used to select the best-supported formalism(s) among biologically-plausible alternatives. Our analysis suggests the following: (1) Both radionuclides and co-occurring chemical contaminants (e.g. NO2) are important for explaining microbial responses to radioactive contamination. (2) Radionuclides may produce non-monotonic dose responses: stimulation of microbial growth at low concentrations vs. inhibition at higher ones. (3) The extinction-defining critical radiation dose rate is dramatically lowered by additional stressors. (4) Reproduction suppression by radiation can be more important for determining the critical dose rate, than radiation-induced cell mortality. In conclusion, the modeling approaches used here on three diverse data sets provide insight into explaining and predicting multi-stressor effects on microbial communities: (1) the most severe effects (e.g. extinction) on microbial populations may occur when unfavorable environmental conditions (e.g. fluctuations of temperature and/or ...
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2016-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Comparative Molecular Characterization and Pharmacokinetics of IgG1-Fc and Engineered Fc Human Antibody Variants to Insulin-like Growth Factor 2 Receptor (IGF2R)

    Chandra B. Prabaharan / Sabeena Giri / Kevin J. H. Allen / Katrina E. M. Bato / Therese R. Mercado / Mackenzie E. Malo / Jorge L. C. Carvalho / Ekaterina Dadachova / Maruti Uppalapati

    Molecules, Vol 28, Iss 5839, p

    2023  Volume 5839

    Abstract: Novel therapeutic approaches are much needed for the treatment of osteosarcoma. Targeted radionuclide therapy (TRT) and radioimmunotherapy (RIT) are promising approaches that deliver therapeutic radiation precisely to the tumor site. We have previously ... ...

    Abstract Novel therapeutic approaches are much needed for the treatment of osteosarcoma. Targeted radionuclide therapy (TRT) and radioimmunotherapy (RIT) are promising approaches that deliver therapeutic radiation precisely to the tumor site. We have previously developed a fully human antibody, named IF3, that binds to insulin-like growth factor 2 receptor (IGF2R). IF3 was used in TRT to effectively inhibit tumor growth in osteosarcoma preclinical models. However, IF3’s relatively short half-life in mice raised the need for improvement. We generated an Fc-engineered version of IF3, termed IF3δ, with amino acid substitutions known to enhance antibody half-life in human serum. In this study, we confirmed the specific binding of IF3δ to IGF2R with nanomolar affinity, similar to wild-type IF3. Additionally, IF3δ demonstrated binding to human and mouse neonatal Fc receptors (FcRn), indicating the potential for FcRn-mediated endocytosis and recycling. Biodistribution studies in mice showed a higher accumulation of IF3δ in the spleen and bone than wild-type IF3, likely attributed to abnormal spleen expression of IGF2R in mice. Therefore, the pharmacokinetics data from mouse xenograft models may not precisely reflect their behavior in canine and human patients. However, the findings suggest both IF3 and IF3δ as promising options for the RIT of osteosarcoma.
    Keywords osteosarcoma (OS) ; insulin-like growth factor 2 receptor (IGF2R) ; monoclonal antibodies ; neonatal Fc receptor (FcRn) ; radioimmunotherapy (RIT) ; Organic chemistry ; QD241-441
    Subject code 616
    Language English
    Publishing date 2023-08-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Radioimmunotherapy of fungal diseases

    JoshuaDNosanchuk / EkaterinaDadachova

    Frontiers in Microbiology, Vol

    the therapeutic potential of cytocidal radiation delivered by antibody targeting fungal cell surface antigens

    2012  Volume 2

    Abstract: Radioimmunotherapy is the targeted delivery of cytocidal radiation to cells via specific antibody. Although mature for the treatment of cancer, RIT of infectious diseases is in pre-clinical development. However, as there is an obvious and urgent need for ...

    Abstract Radioimmunotherapy is the targeted delivery of cytocidal radiation to cells via specific antibody. Although mature for the treatment of cancer, RIT of infectious diseases is in pre-clinical development. However, as there is an obvious and urgent need for novel approaches to treat infectious diseases, RIT can provide us with a powerful approach to combat serious diseases, including invasive fungal infections. For example, RIT has proven more effective than standard amphotericin B for the treatment of experimental cryptococcosis. This review will discuss the concepts of RIT, its applications for infectious diseases, and the strides made to date to bring RIT of infectious diseases to fruition. Finally, we will discuss the potential of PAN-FUNGAL RIT, the targeting of conserved fungal cell surface antigens by RIT, as a treatment modality for fungi prior to the formal microbiological identification of the specific pathogen. In sum, RIT provides a mechanism for the targeted killing of drug susceptible or resistant fungi irrespective of the host immune status and may dramatically reduce the length of therapy currently required for many invasive fungal diseases.
    Keywords Candida ; Cryptococcus ; Fungi ; Histoplasma ; Radioimmunotherapy ; Monoclonal antibody ; beta-glucan ; Heat shock protein 60 ; Microbiology ; QR1-502 ; Science ; Q
    Subject code 630
    Language English
    Publishing date 2012-01-01T00:00:00Z
    Publisher Frontiers Media S.A.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Radioimmunotherapy Targeting IGF2R on Canine-Patient-Derived Osteosarcoma Tumors in Mice and Radiation Dosimetry in Canine and Pediatric Models

    Jaline Broqueza / Chandra B. Prabaharan / Kevin J. H. Allen / Rubin Jiao / Darrell R. Fisher / Ryan Dickinson / Valerie MacDonald-Dickinson / Maruti Uppalapati / Ekaterina Dadachova

    Pharmaceuticals, Vol 15, Iss 10, p

    2022  Volume 10

    Abstract: Background: Osteosarcoma (OS) has an overall patient survival rate of ~70% with no significant improvements in the last two decades, and novel effective treatments are needed. OS in companion dogs is phenotypically close to human OS, which makes a ... ...

    Abstract Background: Osteosarcoma (OS) has an overall patient survival rate of ~70% with no significant improvements in the last two decades, and novel effective treatments are needed. OS in companion dogs is phenotypically close to human OS, which makes a comparative oncology approach to developing new treatments for OS very attractive. We have recently created a novel human antibody, IF3 to IGF2R, which binds to this receptor on both human and canine OS tumors. Here, we evaluated the efficacy and safety of radioimmunotherapy with 177 Lu-labeled IF3 of mice bearing canine-patient-derived tumors and performed canine and human dosimetry calculations. Methods: Biodistribution and microSPECT/CT imaging with 111 In-IF3 was performed in mice bearing canine OS Gracie tumors, and canine and human dosimetry calculations were performed based on these results. RIT of Gracie-tumor-bearing mice was completed with 177 Lu-IF3. Results: Biodistribution and imaging showed a high uptake of 111 In-IF3 in the tumor and spleen. Dosimetry identified the tumor, spleen and pancreas as the organs with the highest uptake. RIT was very effective in abrogating tumor growth in mice with some spleen-associated toxicity. Conclusions: These results demonstrate that RIT with 177 Lu-IF3 targeting IGF2R on experimental canine OS tumors effectively decreases tumor growth. However, because of the limitations of murine models, careful evaluation of the possible toxicity of this treatment should be performed via nuclear imaging and image-based dosimetry in healthy dogs before clinical trials in companion dogs with OS can be attempted.
    Keywords osteosarcoma ; IGF2R ; radioimmunotherapy ; canine-patient-derived Gracie tumors ; human dosimetry ; canine dosimetry ; Medicine ; R ; Pharmacy and materia medica ; RS1-441
    Subject code 630
    Language English
    Publishing date 2022-12-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: Cryptococcus neoformans as a Model for Radioimmunotherapy of Infections

    Ekaterina Dadachova / Arturo Casadevall

    Interdisciplinary Perspectives on Infectious Diseases, Vol

    2011  Volume 2011

    Keywords Infectious and parasitic diseases ; RC109-216 ; Internal medicine ; RC31-1245 ; Medicine ; R ; DOAJ:Internal medicine ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
    Language English
    Publishing date 2011-01-01T00:00:00Z
    Publisher Hindawi Publishing Corporation
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: Safety Evaluation of an Alpha-Emitter Bismuth-213 Labeled Antibody to (1→3)-β-Glucan in Healthy Dogs as a Prelude for a Trial in Companion Dogs with Invasive Fungal Infections

    Muath Helal / Kevin J. H. Allen / Hilary Burgess / Rubin Jiao / Mackenzie E. Malo / Matthew Hutcheson / Ekaterina Dadachova / Elisabeth Snead

    Molecules, Vol 25, Iss 3604, p

    2020  Volume 3604

    Abstract: Background : With the limited options available for therapy to treat invasive fungal infections (IFI), radioimmunotherapy (RIT) can potentially offer an effective alternative treatment. Microorganism-specific monoclonal antibodies have shown promising ... ...

    Abstract Background : With the limited options available for therapy to treat invasive fungal infections (IFI), radioimmunotherapy (RIT) can potentially offer an effective alternative treatment. Microorganism-specific monoclonal antibodies have shown promising results in the experimental treatment of fungal, bacterial, and viral infections, including our recent and encouraging results from treating mice infected with Blastomyces dermatitidis with 213 Bi-labeled antibody 400-2 to (1→3)-β-glucan. In this work, we performed a safety study of 213 Bi-400-2 antibody in healthy dogs as a prelude for a clinical trial in companion dogs with acquired invasive fungal infections and later on in human patients with IFI. Methods : Three female beagle dogs (≈6.1 kg body weight) were treated intravenously with 155.3, 142.5, or 133.2 MBq of 213 Bi-400-2 given as three subfractions over an 8 h period. RBC, WBC, platelet, and blood serum biochemistry parameters were measured periodically for 6 months post injection. Results : No significant acute or long-term side effects were observed after RIT injections; only a few parameters were mildly and transiently outside reference change value limits, and a transient atypical morphology was observed in the circulating lymphocyte population of two dogs. Conclusions : These results demonstrate the safety of systemic 213 Bi-400-2 administration in dogs and provide encouragement to pursue evaluation of RIT of IFI in companion dogs.
    Keywords radioimmunotherapy ; bismuth-213 ; invasive fungal infections ; 1-3-beta-glucan ; dogs ; Organic chemistry ; QD241-441
    Subject code 630
    Language English
    Publishing date 2020-08-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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