scholarly journals BSTP Review of 12 Case Studies Discussing the Challenges, Pathology, Immunogenicity, and Mechanisms of Inhaled Biologics

2021 ◽  
pp. 019262332097609 ◽  
Author(s):  
A. Peter Hall ◽  
Jeffrey S. Tepper ◽  
Molly H. Boyle ◽  
Maurice G. Cary ◽  
Thierry G. Flandre ◽  
...  
Keyword(s):  
Case Studies ◽  
Immune Modulation ◽  
Complex Disease ◽  
Inflammatory Cell ◽  
Mode Of Delivery ◽  
Published Data ◽  
Differences Of Opinion ◽  
Fragment Antigen Binding ◽  
Novel Drug ◽  
Mononuclear Inflammatory Cell

The inhalation route is a relatively novel drug delivery route for biotherapeutics and, as a result, there is a paucity of published data and experience within the toxicology/pathology community. In recent years, findings arising in toxicology studies with inhaled biologics have provoked concern and regulatory challenges due, in part, to the lack of understanding of the expected pathology, mechanisms, and adversity induced by this mode of delivery. In this manuscript, the authors describe 12 case studies, comprising 18 toxicology studies, using a range of inhaled biotherapeutics (monoclonal antibodies, fragment antigen-binding antibodies, domain antibodies, therapeutic proteins/peptides, and an oligonucleotide) in rodents, nonhuman primates (NHPs), and the rabbit in subacute (1 week) to chronic (26 weeks) toxicology studies. Analysis of the data revealed that many of these molecules were associated with a characteristic pattern of toxicity with high levels of immunogenicity. Microscopic changes in the airways consisted of a predominantly lymphoid perivascular/peribronchiolar (PV/PB) mononuclear inflammatory cell (MIC) infiltrate, whereas changes in the terminal airways/alveoli were characterized by simple (“uncomplicated”) increases in macrophages or inflammatory cell infiltrates ranging from mixed inflammatory cell infiltration to inflammation. The PV/PB MIC changes were considered most likely secondary to immunogenicity, whereas simple increases in alveolar macrophages were most likely secondary to clearance mechanisms. Alveolar inflammatory cell infiltrates and inflammation were likely induced by immune modulation or stimulation through pharmacologic effects on target biology or type III hypersensitivity (immune complex disease). Finally, a group of experts provide introductory thoughts regarding the adversity of inhaled biotherapeutics and the basis for reasonable differences of opinion that might arise between toxicologists, pathologists, and regulators.

Identification of Antineoplastic Targets with Systems Approaches, Using Resveratrol as an In-Depth Case Study

2017 ◽  
Vol 23 (32) ◽  
pp. 4773-4793 ◽  
Author(s):  
Nivedita Singh ◽  
Sherry Freiesleben ◽  
Olaf Wolkenhauer ◽  
Yogeshwer Shukla ◽  
Shailendra K. Gupta
Keyword(s):  
Drug Target ◽  
Complex Disease ◽  
Biological Targets ◽  
Systems Approaches ◽  
Anticancer Mechanism ◽  
Genetic And Environmental Factors ◽  
Key Steps ◽  
Network Approaches ◽  
Novel Drug

The identification and validation of novel drug–target combinations are key steps in the drug discovery processes. Cancer is a complex disease that involves several genetic and environmental factors. High-throughput omics technologies are now widely available, however the integration of multi-omics data to identify viable anticancer drug-target combinations, that allow for a better clinical outcome when considering the efficacy-toxicity spectrum, is challenging. This review article provides an overview of systems approaches which help to integrate a broad spectrum of technologies and data. We focus on network approaches and investigate anticancer mechanism and biological targets of resveratrol using reverse pharmacophore mapping as an in-depth case study. The results of this case study demonstrate the use of systems approaches for a better understanding of the behavior of small molecule inhibitors in receptor binding sites. The presented network analysis approach helps in formulating hypotheses and provides mechanistic insights of resveratrol in neoplastic transformations.

scholarly journals Updates on the understanding and management of thyroid eye disease

2021 ◽  
Vol 13 ◽  
pp. 251584142110277
Author(s):  
Clara J. Men ◽  
Andrea L. Kossler ◽  
Sara T. Wester
Keyword(s):  
Autoimmune Diseases ◽  
Immune Modulation ◽  
Complex Disease ◽  
Vision Loss ◽  
Treatment Options ◽  
Thyroid Stimulating Hormone ◽  
Thyroid Eye Disease ◽  
Eye Disease ◽  
Signaling Complex ◽  
Clinical Trial Results

Thyroid eye disease (TED) is a complex disease associated with myriad clinical presentations, including facial disfigurement, vision loss, and decreased quality of life. Traditionally, steroid therapy and/or radiation therapy were commonly used in the treatment of active TED. While these therapies can help reduce inflammation, they often do not have a sustainable, significant long-term effect on disease outcomes, including proptosis and diplopia. Recent advances in our understanding of the pathophysiology of TED have shifted the focus of treatment toward targeted biologic therapies. Biologics have the advantage of precise immune modulation, which can have better safety profiles and greater efficacy compared to traditional approaches. For instance, the insulin-like growth factor-1 receptor (IGF-1R) has been found to be upregulated in TED patients and to colocalize with the thyroid-stimulating hormone receptor (TSHR), forming a signaling complex. Teprotumumab is an antibody targeted against IGF-1R. By inhibiting the IGF-1R/TSHR signaling pathway, teprotumumab may reduce the production of proinflammatory cytokines, hyaluronan secretion, and orbital fibroblast activation in patients with TED. Due to promising phase II and III clinical trial results, teprotumumab has become the first biologic US Food and Drug Administration (FDA)-approved for the treatment of TED. In addition, there are currently ongoing studies looking at the use of antibodies targeting the neonatal Fc receptor (FcRn) in various autoimmune diseases, including TED. FcRn functions to transport immunoglobulin G (IgG) and prevent their lysosomal degradation. By blocking the recycling of IgG, this approach may dampen the body’s immune response, in particular the pathogenic IgG implicated in some autoimmune diseases. Advances in our understanding of the pathophysiology of TED, therefore, are leading to more targeted therapeutic options, and we are entering an exciting new phase in the management of TED. This review will cover recent insights into the understanding of TED pathophysiology and novel treatment options as well as ongoing studies of new potential treatment options for TED.

scholarly journals Pathogenicity of severe fever with thrombocytopenia syndrome virus in mice regulated in type I interferon signaling

2020 ◽  
Vol 36 (1) ◽  
Author(s):  
Seok-Chan Park ◽  
Jun Young Park ◽  
Jin Young Choi ◽  
Sung-Geun Lee ◽  
Seong Kug Eo ◽  
...  
Keyword(s):  
Inflammatory Cell ◽  
Type I Interferon ◽  
Coagulation Necrosis ◽  
White Pulp ◽  
Type I ◽  
Interferon Signaling ◽  
Viral Shedding ◽  
Mononuclear Inflammatory Cell ◽  
Severe Fever ◽  
Deficient Mice

Abstract Severe fever with thrombocytopenia syndrome (SFTS) is an emerging zoonotic disease, which causes high fever, thrombocytopenia, and death in humans and animals in East Asian countries. The pathogenicity of SFTS virus (SFTSV) remains unclear. We intraperitoneally infected three groups of mice: wild-type (WT), mice treated with blocking anti-type I interferon (IFN)-α receptor antibody (IFNAR Ab), and IFNAR knockout (IFNAR−/−) mice, with four doses of SFTSV (KH1, 5 × 105 to 5 × 102 FAID50). The WT mice survived all SFTSV infective doses. The IFNAR Ab mice died within 7 days post-infection (dpi) with all doses of SFTSV except that the mice were infected with 5 × 102 FAID50 SFTSV. The IFNAR−/− mice died after infection with all doses of SFTSV within four dpi. No SFTSV infection caused hyperthermia in any mice, whereas all the dead mice showed hypothermia and weight loss. In the WT mice, SFTSV RNA was detected in the eyes, oral swabs, urine, and feces at 5 dpi. Similar patterns were observed in the IFNAR Ab and IFNAR−/− mice after 3 dpi, but not in feces. The IFNAR Ab mice showed viral shedding until 7 dpi. The SFTSV RNA loads were higher in organs of the IFNAR−/− mice compared to the other groups. Histopathologically, coagulation necrosis and mononuclear inflammatory cell infiltration in the liver and white pulp atrophy in the spleen were seen as the main lesions in the IFN signaling lacking mice. Immunohistochemically, SFTSV antigens were mainly detected in the marginal zone of the white pulp of the spleen in all groups of mice, but more viral antigens were observed in the spleen of the IFNAR−/− mice. Collectively, the IFN signaling-deficient mice were highly susceptible to SFTSV and more viral burden could be demonstrated in various excreta and organs of the mice when IFN signaling was inhibited.

Vasculitis in MRL/1pr Mice: Model of Cell-Mediated Autoimmunity

1989 ◽  
Vol 17 (1_part_2) ◽  
pp. 122-128 ◽  
Author(s):  
Carolyn F. Moyer ◽  
Carol L. Reinisch
Keyword(s):  
Inflammatory Cell ◽  
Interleukin 1 ◽  
Function Evaluation ◽  
Lymphocyte Function ◽  
Mice Model ◽  
Experimental Conditions ◽  
Accessory Function ◽  
Accessory Cells ◽  
C3h Mice ◽  
Mononuclear Inflammatory Cell

The destruction of vascular smooth muscle cells (VSMC) in autoimmune arteritis is a poorly understood phenomenon. To approach this problem, VSMC cultures were established. The interaction of these cells (from normal or autoimmune mice) with lymphocytes was then evaluated. Specifically, splenocytes from MRL/1pr or C3H mice were co-cultivated with MRL/1pr or C3H VSMCs. Massive mononuclear inflammatory cell clusters enveloped MRL/1pr VSMCs which culminated in the detachment of MRL/1pr VSMCs from the culture plate. In contrast, the interaction of splenocytes from normal or autoimmune mice did not destroy normal VSMCs. Further investigation indicated that MRL/1pr VSMCs spontaneously expressed both Ia–k and Ia–d, as assessed by fluorescence microscopy and flow cytometry, and released interleukin-1-like factors–-characteristics of accessory cells to T-lymphocyte function. Evaluation of VSMCs accessory function in antigen presentation suggests that these cells may present antigen under specific experimental conditions. As a result of these studies, a novel mechanism of autoimmune vasculitis is proposed. Our hypothesis is that defective biological function of VSMCs from autoimmune mice stimulates a mononuclear inflammatory cell response which culminates in VSMC autodestruction.

Pathology of End-stage Remodeling in a Family of Cats with Hypertrophic Cardiomyopathy

2005 ◽  
Vol 42 (4) ◽  
pp. 458-467 ◽  
Author(s):  
M. F. Cesta ◽  
C. J. Baty ◽  
B. W. Keene ◽  
I. W. Smoak ◽  
D. E. Malarkey
Keyword(s):  
Heart Failure ◽  
Hypertrophic Cardiomyopathy ◽  
Inflammatory Cell ◽  
Interventricular Septum ◽  
Coronary Vessels ◽  
Left Ventricular ◽  
Coronary Vessel ◽  
End Stage ◽  
Mononuclear Inflammatory Cell ◽  
Fractional Shortening

End-stage hypertrophic cardiomyopathy (ES-HCM), affecting 5-10% of human hypertrophic cardiomyopathy (HCM) patients, is characterized by relative thinning of the ventricular walls and septum with dilation of the ventricular lumen, decreased fractional shortening, and progression to heart failure. C. J. Baty and others recently documented similar progressive changes to ES-HCM in a family of four cats through serial echocardiograms. At the time of heart failure, these cats exhibited changes similar to those exhibited by human ES-HCM patients. Our objectives were to describe the pathologic alterations associated with ES-HCM and investigate the pathogenesis in three of the four cats. Grossly, there was left atrial dilation with relative thinning of the interventricular septum (IVS) and left ventricular free wall (LVFW). The left atrium contained large thrombi in two of the three cats, and all three cats died following thromboembolization of the aortic bifurcation. Histologically, all three cats had subendocardial and myocardial fibrosis, predominantly of the IVS and LVFW, and one cat had acute, multifocal, myocardial infarcts with mononuclear inflammatory cell infiltrates. The pathogenesis of ES-HCM is uncertain, but theories implicate occlusion of the coronary blood flow by thickening of the coronary vessels, coronary vascular thromboembolism or coronary vessel spasm, apoptosis of myocytes, and myocardial hypertrophy beyond the ability of the vasculature to supply blood. Apoptosis assays did not reveal any apoptotic myocytes. Considering the hypercoagulative state of these cats, coronary vascular thromboembolism could be a major contributing factor. We cannot exclude apoptosis or coronary vessel spasm on the basis of the data presented.

scholarly journals Kidney osteoclast factors and matrix metalloproteinase expression in a mice model of diet-induced obesity and diabetes

2019 ◽  
Author(s):  
Francine dos Santos-Macedo ◽  
Bianca Martins-Gregorio ◽  
Elan Cardozo Paes-de-Almeida ◽  
Leonardo de Souza Mendonça ◽  
Rebeca de Souza Azevedo ◽  
...  
Keyword(s):  
Inflammatory Cell ◽  
Renal Tissue ◽  
Inflammatory Cell Infiltrate ◽  
Mice Model ◽  
Diet Induced Obesity ◽  
Obesity And Diabetes ◽  
Underlying Mechanisms ◽  
Mononuclear Inflammatory Cell ◽  
High Sucrose

ABSTRACTThe role of RANKL/RANK/OPG system on bone remodeling is well known, and there is evidence that it is also important to cardiovascular and kidney pathology, although the underlying mechanisms are not elucidated so far. Thus, we investigated in a mice model of diet-induced obesity and diabetes if renal histopathological changes are associated with the expression of RANKL/RANK/OPG system and matrix metalloproteinases (MMPs). Three months old C57BL/6 mice were fed with control (AIN93M) or high-fat high sucrose (HFHS) diets for 21 weeks (CEUA/UFF #647/15). The HFHS group showed weight gain (+35%, P=0.0001), increased epididymal, inguinal and retroperitoneal fat pad weight (+121 %, P = 0.0006; +287 %, P = 0.0007 and; +286 %, P < 0.0001, respectively), and hyperglycemia (+43%, P=0.02). The kidney of some HFHS fed mice displayed mononuclear inflammatory cell infiltrate (40%), perivascular fibrosis (20%), and focal tubule mineralization (20%). Glomeruli hypertrophy was not detected. Unexpectedly, OPG, RANK, MMP-2 and MMP-9 expression was not altered in HFHS groups (Western blot analysis). In conclusion, the expression of RANKL/RANK/OPG system proteins and MMPs was not influenced by diet-induced obesity and diabetes in the kidney of male C57BL/6 mice, although some adverse histopathological remodeling is noticed in the renal tissue.

scholarly journals The biosecurity risks of seeds in a botanic garden context

2021 ◽  
pp. 147-162
Author(s):  
Sara Redstone ◽  
Adrian Fox
Keyword(s):  
Case Studies ◽  
Published Data ◽  
Botanic Garden ◽  
Seed Systems ◽  
Long Term Storage ◽  
Naturally Occurring ◽  
Awareness Raising ◽  
The Difference ◽  
Term Storage

Seeds present a naturally occurring package of germplasm with ideal attributes for collection, distribution and, in the case of orthodox seed, long term storage. From a phytosanitary perspective seeds are often considered a relatively low-risk option for movement of germplasm across borders. Most published data are concerned with diseases of commercial crops and little is known about the risks associated with wild collected, non-commercial seeds. However, there is demonstrable risk associated with the movement of any plant germplasm which can pose a risk to both crops and the wider environment. Presented here are a discussion on seed standards and the difference between seed borne and seed transmitted pathogens, with case studies presented to highlight the risks associated with informal seed systems and wild collected seeds in particular. Additionally, suggestions on how to address phytosanitary issues are presented including awareness raising measures aimed at improving biosecurity procedures during collection and before long-term storage of seed accessions.

scholarly journals Modeling Error in Quantitative Macro-Comparative Research

2009 ◽  
pp. 86-114 ◽  
Author(s):  
Salvatore Babones
Keyword(s):  
Comparative Research ◽  
Fixed Effects ◽  
Multilevel Models ◽  
Published Data ◽  
Science Literature ◽  
Cross Sectional ◽  
Random Effects Models ◽  
Large Panels ◽  
Differences Of Opinion ◽  
Spurious Results

Much quantitative macro-comparative research (QMCR) relies on a common set of published data sources to answer similar research questions using a limited number of statistical tools. Since all researchers have access to much the same data, one might expect quick convergence of opinion on most topics. In reality, of course, differences of opinion abound and persist. Many of these differences can be traced, implicitly or explicitly, to the different ways researchers choose to model error in their analyses. Much careful attention has been paid in the political science literature to the error structures characteristic of time series cross-sectional (TSCE) data, but much less attention has been paid to the modeling of error in broadly cross-national research involving large panels of countries observed at limited numbers of time points. Here, and especially in the sociology literature, multilevel modeling has become a hegemonic – but often poorly understood – research tool. I argue that widely-used types of multilevel models, commonly known as fixed effects models (FEMs) and random effects models (REMs), can produce wildly spurious results when applied to trended data due to mis-specification of error. I suggest that in most commonly-encountered scenarios, difference models are more appropriate for use in QMC.

scholarly journals Potential application of mesenchymal stem cells and their exosomes in lung injury: an emerging therapeutic option for COVID-19 patients

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Sara Al-Khawaga ◽  
Essam M. Abdelalim
Keyword(s):  
Stem Cells ◽  
Clinical Trials ◽  
Mesenchymal Stem Cells ◽  
Lung Injury ◽  
Therapeutic Option ◽  
Mode Of Delivery ◽  
Effective Therapy ◽  
Published Data ◽  
Global Public Health ◽  
Challenges And Opportunities

Abstract The COVID-19 pandemic has negatively impacted the global public health and the international economy; therefore, there is an urgent need for an effective therapy to treat COVID-19 patients. Mesenchymal stem cells (MSCs) have been proposed as an emerging therapeutic option for the SARS-CoV-2 infection. Recently, numerous clinical trials have been registered to examine the safety and efficacy of different types of MSCs and their exosomes for treating COVID-19 patients, with less published data on the mechanism of action. Although there is no approved effective therapy for COVID-19 as of yet, MSC therapies showed an improvement in the treatment of some COVID-19 patients. MSC’s therapeutic effect is displayed in their ability to reduce the cytokine storm, enhance alveolar fluid clearance, and promote epithelial and endothelial recovery; however, the safest and most effective route of MSC delivery remains unclear. The use of poorly characterized MSC products remains one of the most significant drawbacks of MSC-based therapy, which could theoretically promote the risk for thromboembolism. Optimizing the clinical-grade production of MSCs and establishing a consensus on registered clinical trials based on cell-product characterization and mode of delivery would aid in laying the foundation for a safe and effective therapy in COVID-19. In this review, we shed light on the mechanistic view of MSC therapeutic role based on preclinical and clinical studies on acute lung injury and ARDS; therefore, offering a unique correlation and applicability in COVID-19 patients. We further highlight the challenges and opportunities in the use of MSC-based therapy.

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