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Many immune‐mediated conditions are associated with a dysregulated imbalance toward a Th1 response leading to disease onset, severity, and damage. Many of the therapies such as immunomodulators or anti‐TNF‐α antibodies often fall short in preventing disease progression and ameliorating disease conditions. Thus, new therapies that can target inflammatory environments would have a major impact in preventing the progression of inflammatory diseases. We investigated the role of human stromal cells derived from the amniotic fluid (AFSCs), the placenta (PLSCs), and bone marrow‐derived mesenchymal stromal cells (BM‐MSCs) in modulating the inflammatory response of in vitro‐stimulated circulating blood‐derived immune cells. Immune cells were isolated from the blood of healthy individuals and stimulated in vitro with antigens to activate inflammatory responses to stimuli. AFSC, BM‐MSCs, and PLSCs were cocultured with stimulated leukocytes, neutrophils, or lymphocytes. Inflammatory cytokine production, neutrophil migration, enzymatic degranulation, T cell proliferation, and subsets were evaluated. Coculture of all three stromal cell types decreased the gene expression of inflammatory cytokines and enzymes such as IL‐1β, IFN‐γ, TNF‐α, neutrophil elastase, and the transcription factor NF‐κB in lipopolysaccharide‐stimulated leukocytes. With isolated phytohemagglutinin‐stimulated peripheral blood mononuclear cells, cells coculture leads to a decrease in lymphocyte proliferation. This effect correlated with decreased numbers of Th1 lymphocytes and decreased secreted levels of IFN‐γ. Perinatal cells suppress the proliferation of Th1 cells and their associated cytokines.

In this study, we attempt to target Arginine auxotrophy in glioblastoma multiforme (GBM) cells using a pegylated recombinant human Arginase I cobalt [HuArgI (Co)-PEG5000]. We tested and characterized the activity of HuArgI (Co)-PEG5000 on a panel of 9 GBM cell lines and on human fetal glial cells (SVG-p12). HuArgI (Co)-PEG5000 was cytotoxic to all GBM cells tested. SVG-p12 cells were not sensitive demonstrating the selective cytotoxicity of HuArgI (Co)-PEG5000-induced arginine deprivation. Addition of l -citrulline led to the rescue of 6 GBM cell lines but only at concentrations of 11.4 mM, reflecting the extent of arginine auxotrophy in GBM. The ability of l -citrulline to rescue cells was dependent on the expression of argininosuccinate synthetase-1 (ASS1) with the cells that were not rescued by l -citrulline being negative for ASS1 expression. Knocking-down ASS1 reversed the ability of l -citrulline to rescue GBM cells, further illustrating the dependence of arginine auxotrophy on ASS1 expression. Inhibition of autophagy increased cell sensitivity to HuArgI (Co)-PEG5000 indicating that, following arginine deprivation, autophagy plays a protective role in GBM cells. Analysis of the type of cell death revealed a lack of AnnexinV staining and caspase activation in HuArgI (Co)-PEG5000-treated cells, indicating that arginine deprivation induces caspase-independent, non-apoptotic cell death in GBM. We have shown that GBM cells are auxotrophic for arginine and can be selectively targeted using HuArgI (Co)-PEG5000-induced arginine depletion, thus demonstrating that l -Arginine deprivation is a potent and selective potential treatment for GBM.

Stress urinary incontinence (SUI) is a common urinary system disease that mostly affects women. Current treatments still do not solve the critical problem of urethral sphincter dysfunction. In recent years, there have been major developments in techniques to obtain, culture, and characterize autologous stem cells as well as many studies describing their applications for the treatment of SUI. In this paper, we review recent publications and clinical trials investigating the applications of several stem cell types as potential treatments for SUI and the underlying challenges of such therapy.

Inflammatory lung diseases affect millions of people worldwide. These diseases are caused by a number of factors such as pneumonia, sepsis, trauma, and inhalation of toxins. Pulmonary function testing (PFT) is a valuable functional methodology for better understanding mechanisms of lung disease, measuring disease progression, clinical diagnosis, and evaluating therapeutic interventions. Animal models of inflammatory lung diseases are needed that accurately recapitulate disease manifestations observed in human patients and provide an accurate prediction of clinical outcomes using clinically relevant pulmonary disease parameters. In this study, we evaluated a ferret lung inflammation model that closely represents multiple clinical manifestations of acute lung inflammation and injury observed in human patients. Lipopolysaccharide (LPS) from Pseudomonas aeruginosa was nebulized into ferrets for 7 repeated daily doses. Repeated exposure to nebulized LPS resulted in a restrictive pulmonary injury characterized using Buxco forced maneuver PFT system custom developed for ferrets. This is the first study to report repeated forced maneuver PFT in ferrets, establishing lung function measurements pre‐ and post‐injury in live animals. Bronchoalveolar lavage and histological analysis confirmed that LPS exposure elicited pulmonary neutrophilic inflammation and structural damage to the alveoli. We believe this ferret model of lung inflammation, with clinically relevant disease manifestations and parameters for functional evaluation, is a useful pre‐clinical model for understanding human inflammatory lung disease and for the evaluation of potential therapies. We developed a ferret model of lung inflammation, with clinically relevant disease manifestations and parameters for functional evaluation, which can be a useful pre‐clinical model for understanding human inflammatory lung disease and for evaluation of potential therapies.

Cystic fibrosis (CF) is associated with exaggerated and prolonged inflammation in the lungs, which contributes to lung injury, airway mucus obstruction, bronchiectasis, and loss of lung function. This hyperinflammatory phenotype appears to be caused by an imbalance between the pro- and antiinflammatory regulatory pathways, with heightened proinflammatory stimuli, a decreased counter-regulatory response, and reduced effectiveness of immune cell function and inflammatory resolution. Thus, therapies that can target this inflammatory environment would have a major impact on preventing the progression of lung disease. Because of the complex phenotype of CF inflammation, current antiinflammatory regimens have proven to be inadequate for the targeting of these multiple dysregulated pathways and effects. Several approaches using cell therapies have shown potential therapeutic benefit for the treatment of CF inflammation. This review provides an overview of the immune dysfunctions in CF and current therapeutic regimens; explores the field of cell therapy as a treatment for CF inflammation; and focuses on the various cell types used, their immunomodulatory functions, and the current approaches to mitigate the inflammatory response and reduce the long-term damage for patients with CF.

A study on the immune and cytokine dysfunction in cystic fibrosis (CF), is presented. CF is hallmarked by chronic bacterial infectionsm persistent inflammation and mucus plugging of small airways causing obstruction and bronchiectasis. Here, discusses that loss of cystic fibrosis transmemrbane conductance regulator (CFTR) ion channel function leads to dehydration of the airway surface liquid, resulting in a dense mucus layer that adheres tightly to the lungepithelium which also increased susceptibility to chronic infections. However, evidence also shows that chronic inflammation in CF happens before birth, independently of infection. Furthermore, evaluation on the inflammatory acute-phase reactant profiles reactant profiles in circulating blood leukocytes from patients with stable CF and control healty donors, is also emphasized.

Chronic inflammation is associated with many pulmonary conditions such as Cystic Fibrosis (CF), chronic obstructive pulmonary disease (COPD), asthma and acute respiratory distress syndrome (ARDS). Often, patients with inflammatory lung disease exhibit increased immune cell counts in their lungs such as neutrophils, macrophages and T cells accompanied by elevated levels of pro-inflammatory cytokines such as IFN-γ, IL-6, IL-8, IL-1β and neutrophil elastase (NE). Increased immune cell numbers and increased levels of their associated cytokines in the pulmonary environment of these patients do not necessarily correlate with increased efficiency to clear bacteria and resolve the inflammatory response. Thus, patients exhibit a progressive cycle of chronic inflammation, lung fibrosis and reduction in lung function. As many studies have shown, immune cells in patients with inflammatory lung disease might be dysregulated and often lead to disease worsening and contribute to the progressive loss of lung function. Therapeutic regimens for these diseases mainly rely on the use of anti-inflammatory drugs such as corticosteroids, ibuprofen and azithromycin to mitigate the inflammatory response and improve lung function. However, the use of these drug regimens has been associated with serious adverse events such as growth retardation, and often presents challenges to establish precise doses in patients. Thus, therapeutic regimens provide symptom management in an attempt to slow the progression of the disease however; it is the repeated cycles of inflammation, injury and fibrosis that cause the chronic, life-threatening manifestations that ultimately lead to respiratory failure. Thus, therapies that can target this inflammatory environment and disrupt the destructive cycle of infection, inflammation and fibrosis would have a major impact in preventing the progression of lung disease. We hypothesized that immune-modulatory cell therapy can be an effective treatment for inflammatory lung disease, such as CF, to prevent ongoing inflammation and improve lung function. Perinatal stem cells have anti-inflammatory properties that make them a promising cell therapeutic approach for treating inflammation in lung disease. In Aim 1, we demonstrated that perinatal cells, particularly placental stem cells (PLSCs) have potent suppressive properties on the proliferation of lymphocytes as well as on the levels of acute phase reactants such as NE, NF-κB, IL-1β, TNF, IL-6 and IFN-γ. PLSCs decreased the percentage of pro-inflammatory Th1 cells and reduced their function to secrete IFN-γ in healthy derived immune cells stimulated in vitro. In Aim 2 we first confirmed that the administration of PLSCs to immune cells derived from CF patients also decreased the level of IFN-γ, suggesting that PLSCs have consistent therapeutic effects that are exerted via the Th1 branch of the immune response. Next we demonstrated that PLSCs primed with CF derived from supernatant of mucopurulent material (SMM) showed a superior suppressive effect on lymphocytes, describing a new approach to generate PLSCs with potent disease specific properties that make them useful candidates for targeted CF therapy. We found that PLSCs secreted factors, conditioned media (CM) and exosomes was not successful in sustaining the suppressive effects observed in the presence of PLSCs, thus we concluded that in our in vitro immunoassay settings, cell-to-cell contact is required between immune cells and PLSCs to achieve the desired immunomodulation. In Aim 3, we were successful in establishing an LPS acute lung injury model and pulmonary function testing methodology using a novel ferret model. We demonstrated that repeated does of 1mg/ml LPS triggered an inflammatory response characterized by increased neutrophilia in the lung and reduced lung function. We found that the administration of PLSCs in LPS ferrets could reduce lung inflammation but did not rescue pulmonary function at the doses and duration of the injury evaluated. In conclusion, these studies highlighted the immunomodulatory properties of PLSCs and enhanced our understanding of the potential interactions with the immune system in vitro and in vivo. This work devised new insights about the immune properties of cell therapy, and highlighted characteristics that should be taken into account for the development of a successful targeted therapy.

The main objective of the current study was to adapt the Cultural Assessment for Risk of Suicide measure (CARS; Chu et al., 2013) for use with adolescents (CARS-A). Utilizing The Adult to Adolescent Measure Adaptation Model (AA-MAM), the study demonstrated the utility of qualitative methodologies in the adaptations of measures for use with the adolescent population. Methods: (1) the conceptual model was developed through comparing the adolescents relevant literature to the adult developed constructs to confirm construct equivalence; (2) Content validity of the measure was established through monitoring the degree of agreement between five expert reviewers using the Content Validity Index (CVI); (3) experiential equivalence and exploration of new constructs was established through concept elicitation interviews with 20 adolescents from the target population; (4) Item performance was assessed through cognitive interviews with 50 adolescents, aiming to detect problems in comprehension, retrieval, judgment or response. Results: the results illustrated the applicability of the primary four constructs of the CARS measure for adolescents with the addition of three main subdomains: peer conflict/victimization, academic stress and intergenerational cultural dissonance. Minor revisions in the domain of idioms of distress were performed to reflect the adolescent’s literature. The Content Validity Index for items resulted in the removal of 8 items from the original item pool and the revision of 5 items. The CVI-S was 0.8, which indicated an adequate level of agreement between the experts regarding the relevance of the items. The concept elicitation interviews with adolescents further confirmed the relevance of the developed constructs and informed the development of additional 6 items. Finally, two phases of Cognitive Interviews (CI) informed the revision of 19 items, the removal of 20 items from the original item pool, and changes to the measure organization and structure. The adaptation process resulted in 46 items and 2 brief supplements for sexual and gender minority stress and acculturative stress. Conclusions: the The Adult to Adolescent Measure Adaptation Model developed for the purpose of the current study is a useful framework through which adult measures can be adapted for use with adolescents, facilitates the early identification of problems in items, and constructs prior to conducting large-scale validation studies.

Malignant astrocytomas are highly invasive into adjacent and distant regions of the normal brain. Understanding and targeting cancer cell invasion is an important therapeutic approach. Cell invasion is a complex process that replies on many signaling pathways including the mitogen-activated protein (MAP) kinase (MAPK). In many cell lines, the use of MAPK-targeted drugs proved to be a potential method to inhibit cancer cell motility. In the present study, we use a recombinant anthrax lethal toxin (LeTx), which selectively inhibits the MAPK pathway, in order to target invasion. LeTx proved ineffective on cell survival in astrocytoma (as well as normal cells). However, astrocytoma cells that were treated with LeTx showed a significant decrease in cell motility as seen by wound healing as well as random 2D motility in serum. The cells also showed a decrease in invasion across a collagen matrix. The effect of LeTx on cell migration was mediated though the deregulation of Rho GTPases, which play a role in cell motility. Finally, the effect of LeTx on cell migration and Rho GTPases was mimicked by the inhibition of the MAPK pathway. In this study, we describe for the first time the effect of the LeTx on cancer cell motility and invasion not cell survival making it a potentially selective brain tumor invasion inhibitor.

Introduction: The delivery of cell therapies may be an important frontier to treat different respiratory diseases in the near future. However, the cell size, delivery conditions, cell viability, and effect in the pulmonary function are critical factors. We performed a proof-of-concept experiment using ex vivo lungs and novel subglottic airway device that allows for selective lobar isolation and administration of drugs and biologics in liquid solution deep into the lung tissues, while simultaneously ventilating the rest of the lung lobes. Methods: We used radiolabeled cells and positron emission tomography-computed tomography (PET-CT) imaging to demonstrate the feasibility of high-yield cell delivery to a specifically targeted lobe. This study proposes an alternative delivery method of live cells labeled with radioactive isotope into the lung parenchyma and tracks the cell delivery using PET-CT imaging. The technique combines selective lobar isolation and lobar infusion to carry large particles distal to the trachea, subtending bronchial segments and reaching alveoli in targeted regions. Results: The solution with cells and carrier achieved a complete and homogeneous lobar distribution. An increase in tissue density was shown on the computed tomography (CT) scan, and the PET-CT imaging demonstrated retention of the activity at central, peripheral lung parenchyma, and pleural surface. The increase in CT density and metabolic activity of the isotope was restricted to the desired lobe only without leak to other lobes. Conclusion: The selective lobe delivery is targeted and imaging-guided by bronchoscopy and CT to a specific diseased lobe during mechanical ventilation. The feasibility of high-yield cell delivery demonstrated in this study will lead to the development of potential novel therapies that contribute to lung health.