Procedures to Evaluate Inflammatory and Pathological Changes During Allergic Airway Inflammation.

Cellular inflammation, with elevated levels of Th1/Th2 cytokines, airway mucus hypersecretion, and thickening of the airway smooth muscle, are characteristic features of the allergic lung. Assessment of pathophysiological changes in allergic lungs serves as an important tool to determine disease progression and understand the underlying mechanisms of pathogenesis. This can be achieved by evaluating the lung tissue for inflammation and airway structural changes along with the measurement of important pro-inflammatory mediators such as Th1/Th2 cytokines and eotaxins. This chapter describes procedures to histologically evaluate inflammatory and pathological changes observed during allergic airway inflammation using lung tissue from mice.

Pulmonary delivery of ORMDL3 short hairpin RNA - a potential tool to regulate allergen-induced airway inflammation.

Aim/Purpose: Exposure to various allergens has been shown to increase expression of ORMDL3 in the lung in models of allergic asthma. Studies using genetically modified (transgenic or knock out) mice have revealed some of the functions of ORMDL3 in asthma pathogenesis, although amid debate. The goal of this study was to use targeted post-transcriptional downregulation of ORMDL3 in allergen-challenged wild-type (WT) mice by RNA interference to further elucidate the functional role of ORMDL3 in asthma pathogenesis and evaluate a potential therapeutic option.Methods: Allergen (ovalbumin [OVA])-challenged WT mice were administered intranasally (i.n) with a single dose of five short hairpin RNA (shRNA) constructs with different target sequence for murine ORMDL3 cloned in a lentiviral vector or with the empty vector (control). Mice were evaluated for allergen-induced airway hyperresponsiveness (AHR) and various features of airway inflammation after 72 hours.Results: I.n administration of a single dose of ORMDL3 shRNAs to OVA-challenged mice resulted in reduction of ORMDL3 gene expression in the lungs associated with a significant reduction in AHR to inhaled methacholine and in the number of inflammatory cells recruited in the airways, specifically eosinophils, as well as in airway mucus secretion compared to OVA-challenged mice that received the empty vector. Administration of ORMDL3 shRNAs also significantly inhibited levels of IL-13, eotaxin-2 and sphingosine in the lungs. Additionally, ORMDL3 shRNAs significantly inhibited the allergen-mediated increase in monohexyl ceramides C22:0 and C24:0.Conclusions: Post-transcriptional down regulation of ORMDL3 in allergic lungs using i.n-delivered ORMDL3 shRNA (akin to inhaled therapy) attenuates development of key features of airway allergic disease, confirming the involvement of ORMDL3 in allergic asthma pathogenesis and serving as a model for a potential therapeutic strategy.

Regulation of Eosinophil Recruitment and Allergic Airway Inflammation by Tropomyosin Receptor Kinase A.

Eosinophilia is a hallmark of allergic airway inflammation (AAI). Identifying key molecules and specific signaling pathways that regulate eosinophilic inflammation is critical for development of novel therapeutics. Tropomycin receptor kinase A (TrkA) is the high-affinity receptor for nerve growth factor. AAI is associated with increased expression of TrkA by eosinophils; however, the functional role of TrkA in regulating eosinophil recruitment and contributing to AAI is poorly understood. This study identifies, to our knowledge, a novel mechanism of eotaxin-mediated activation of TrkA and its role in regulating eosinophil recruitment by using a chemical-genetic approach to specifically inhibit TrkA kinase activity with 1-NM-PP1 in TrkAF592A-knock-in (TrkA-KI) eosinophils. Blockade of TrkA by 1-NM-PP1 enhanced eosinophil spreading on VCAM-1 but inhibited eotaxin-1 (CCL11)-mediated eosinophil migration, calcium flux, cell polarization, and ERK1/2 activation, suggesting that TrkA is an important player in the signaling pathway activated by eotaxin-1 during eosinophil migration. Further, blockade of matrix metalloprotease with BB-94 inhibited eotaxin-1-induced TrkA activation and eosinophil migration, additively with 1-NM-PP1, indicating a role for matrix metalloproteases in TrkA activation. TrkA inhibition in Alternaria alternata-challenged TrkA-KI mice markedly inhibited eosinophilia and attenuated various features of AAI. These findings are indicative of a distinctive eotaxin-mediated TrkA-dependent signaling pathway, which, in addition to other TrkA-activating mediators, contributes to eosinophil recruitment during AAI and suggests that targeting the TrkA signaling pathway to inhibit eosinophil recruitment may serve as a therapeutic strategy for management of eosinophilic inflammation in allergic airway disease, including asthma.

Effect Of Dual sEH/COX-2 Inhibition on Allergen-Induced Airway Inflammation.

Arachidonic acid metabolites resulting from the cyclooxygenase (COX), lipoxygenase, and cytochrome P450 oxidase enzymatic pathways play pro- and anti-inflammatory roles in allergic airway inflammation (AAI) and asthma. Expression of COX-2 and soluble epoxide hydrolase (sEH) are elevated in allergic airways and their enzymatic products (e.g., prostaglandins and diols of epoxyeicosatrienoic acids, respectively) have been shown to participate in the pathogenesis of AAI. Here, we evaluated the outcome of inhibiting the COX-2 and sEH enzymatic pathways with a novel dual inhibitor, PTUPB, in A. alternata-induced AAI. Allergen-challenged mice were administered with 10 or 30 mg/kg of PTUPB, celecoxib (selective COX-2 inhibitor), t-TUCB (selective sEH inhibitor) or vehicle daily by gavage and evaluated for various features of AAI. PTUPB and t-TUCB at 30 mg/kg, but not celecoxib, inhibited eosinophilic infiltration and significantly increased levels of anti-inflammatory EETs in the lung tissue of allergen-challenged mice. t-TUCB significantly inhibited allergen-induced IL-4 and IL-13, while a less pronounced reduction was noted with PTUPB and celecoxib. Additionally, t-TUCB markedly inhibited eotaxin-2, an eosinophil-specific chemokine, which was only marginally reduced by PTUPB and remained elevated in celecoxib-treated mice. PTUPB or t-TUCB administration reversed allergen-induced reduction in levels of various lipid mediators in the lungs, with only a minimal effect noted with celecoxib. Despite the anti-inflammatory effects, PTUPB or t-TUCB did not reduce allergen-induced airway hyperresponsiveness (AHR). However, development of structural changes in the allergic airways, such as mucus hypersecretion and smooth muscle hypertrophy, was significantly inhibited by both inhibitors. Celecoxib, on the other hand, inhibited only airway smooth muscle hypertrophy, but not mucus hypersecretion. In conclusion, dual inhibition of COX-2 and sEH offers no additional advantage relative to sEH inhibition alone in attenuating various features associated with A. alternata-induced AAI, while COX-2 inhibition exerts only moderate or no effect on several of these features. Dual sEH/COX-2 inhibition may be useful in treating conditions where eosinophilic inflammation co-exists with pain-associated inflammation.

Galectin-1 is a new fibrosis protein in type 1 and type 2 diabetes.

Chronic exposure of tubular renal cells to high glucose contributes to tubulointerstitial changes in diabetic nephropathy. In the present study, we identified a new fibrosis gene called galectin-1 (Gal-1), which is highly expressed in tubular cells of kidneys of type 1 and type 2 diabetic mouse models. Gal-1 protein and mRNA expression showed significant increase in kidney cortex of heterozygous Akita+/- and db/db mice compared with wild-type mice. Mouse proximal tubular cells exposed to high glucose showed significant increase in phosphorylation of Akt and Gal-1. We cloned Gal-1 promoter and identified the transcription factor AP4 as binding to the Gal-1 promoter to up-regulate its function. Transfection of cells with plasmid carrying mutations in the binding sites of AP4 to Gal-1 promoter resulted in decreased protein function of Gal-1. In addition, inhibition of Gal-1 by OTX-008 showed significant decrease in p-Akt/AP4 and protein-promoter activity of Gal-1 and fibronectin. Moreover, down-regulation of AP4 by small interfering RNA resulted in a significant decrease in protein expression and promoter activity of Gal-1. We found that kidney of Gal-1-/- mice express very low levels of fibronectin protein. In summary, Gal-1 is highly expressed in kidneys of type 1 and 2 diabetic mice, and AP4 is a major transcription factor that activates Gal-1 under hyperglycemia. Inhibition of Gal-1 by OTX-008 blocks activation of Akt and prevents accumulation of Gal-1, suggesting a novel role of Gal-1 inhibitor as a possible therapeutic target to treat renal fibrosis in diabetes.-Al-Obaidi, N., Mohan, S., Liang, S., Zhao, Z., Nayak, B. K., Li, B., Sriramarao, P., Habib, S. L. Galectin-1 is a new fibrosis protein in type 1 and type 2 diabetes.

Assessment of eosinophils in gastrointestinal inflammatory disease of dogs.

BACKGROUND: Accurate identification of eosinophils in the gastrointestinal (GI) tract of dogs with eosinophilic GI disease (EGID) by histological evaluation is challenging. The currently used hematoxylin and eosin (H&E) staining method detects intact eosinophils but does not detect degranulated eosinophils, thus potentially underrepresenting the number of infiltrating eosinophils. OBJECTIVE: To develop a more sensitive method for identifying and quantifying both intact and degranulated eosinophils to diagnose EGID more accurately. METHODS: Endoscopically obtained paraffin-embedded intestinal biopsy specimens from dogs with GI signs were examined. The study groups were dogs with eosinophilic enteritis (EE), lymphoplasmacytic and mixed enteritis, and control dogs with GI signs but no histologic changes on tissue sections. Consecutive sections were immunolabeled with monoclonal antibodies (mAbs) against the eosinophil granule protein eosinophil peroxidase (Epx) and stained by H&E, respectively. The number of eosinophils was manually quantified and classified as intact or degranulated. RESULTS: The number of intact eosinophils detected in Epx mAb-labeled duodenal sections was significantly higher compared with that in H&E-stained sections, with a similar relationship noted in the colon and stomach. The Epx mAb allowed the unique assessment of eosinophil degranulation. The number of intact and degranulated eosinophils was significantly higher in duodenal lamina propria of the EE and mixed group compared to the control group. CONCLUSION: Immunohistochemical detection of Epx provides a more precise method to detect GI tract eosinophils compared to H&E staining and could be used as an alternative and reliable diagnostic tool for assessment of biopsy tissues from dogs with EGID.

FABP4 regulates eosinophil recruitment and activation in allergic airway inflammation.

Fatty acid binding protein 4 (FABP4), a member of a family of lipid-binding proteins, is known to play a role in inflammation by virtue of its ability to regulate intracellular events such as lipid fluxes and signaling. Studies have indicated a proinflammatory role for FABP4 in allergic asthma although its expression and function in eosinophils, the predominant inflammatory cells recruited to allergic airways, were not investigated. We examined expression of FABP4 in murine eosinophils and its role in regulating cell recruitment in vitro as well as in cockroach antigen (CRA)-induced allergic airway inflammation. CRA exposure led to airway recruitment of FABP4-expressing inflammatory cells, specifically eosinophils, in wild-type (WT) mice. FABP4 expression in eosinophils was induced by TNF-α as well as IL-4 and IL-13. FABP4-deficient eosinophils exhibited markedly decreased cell spreading/formation of leading edges on vascular cell adhesion molecule-1 and significantly decreased adhesion to intercellular adhesion molecule-1 associated with reduced ß2-integrin expression relative to WT cells. Furthermore, FABP4-deficient eosinophils exhibited decreased migration, F-actin polymerization, calcium flux, and ERK(1/2) phosphorylation in response to eotaxin-1. In vivo, CRA-challenged FABP4-deficient mice exhibited attenuated eosinophilia and significantly reduced airway inflammation (improved airway reactivity, lower IL-5, IL-13, TNF-α, and cysteinyl leukotriene C4 levels, decreased airway structural changes) compared with WT mice. In conclusion, expression of FABP4 in eosinophils is induced during conditions of inflammation and plays a proinflammatory role in the development of allergic asthma by promoting eosinophil adhesion and migration and contributing to the development of various aspects of airway inflammation.

Regulation of eosinophil recruitment and allergic airway inflammation by heparan sulfate proteoglycan (HSPG) modifying enzymes.

BACKGROUND: HSPGs are glycoproteins containing covalently attached heparan sulfate (HS) chains which bind to growth factors, chemokines, etc., and regulate various aspects of inflammation including cell recruitment. We previously showed that deletion of endothelial N-acetylglucosamine N-deacetylase-N-sulfotransferase-1 (Ndst1), an enzyme responsible for N-sulfation during HS biosynthesis, reduces allergic airway inflammation (AAI). Here, we investigated the importance of O-sulfation mediated by uronyl 2-O-sulfotransferase (Hs2st) in development of AAI relative to N-sulfation. METHODS: Mice deficient in endothelial and leukocyte Hs2st (Hs2stf/fTie2Cre+) or Ndst1 (Ndst1f/fTie2Cre+) and WT mice were challenged with Alternaria alternata and evaluated for airway inflammation. Trafficking of murine eosinophils on lung endothelial cells was examined in vitro under conditions of flow. RESULTS: Exposure to Alternaria decreased expression level of Hs2st in WT mice while level of Ndst1 remained unchanged. Compared to WT mice, Alternaria-challenged Hs2stf/fTie2Cre+ mice exhibited significantly increased eosinophils in the bone marrow, bronchoalveolar lavage fluid [BALF] and lung tissue associated with persistent airway hyperresponsiveness, airway mucus hypersecretion and elevated Th2 cytokines. In contrast, Alternaria-challenged Ndst1f/fTie2Cre+ mice exhibited a marked reduction in airway eosinophilia, mucus secretion and smooth muscle mass compared to WT counterparts. While BALF eotaxins were lower in Alternaria-challenged Hs2stf/fTie2Cre+ relative to WT mice, they were not reduced to background levels as in allergen-challenged Ndst1f/fTie2Cre+ mice. Trafficking of murine eosinophils under conditions of flow in vitro was similar on Hs2st-deficient and WT endothelial cells. Expression of ZO-1 in Hs2st-deficient lung blood vessels in control and allergen-challenged mice was significantly lower than in WT counterparts. CONCLUSIONS: Our study demonstrates that allergen exposure reduces expression of Hs2st; loss of uronyl 2-O-sulfation in endothelial and leukocyte HSPG amplifies recruitment of eosinophils likely due to a compromised vascular endothelium resulting in persistent inflammation whereas loss of N-sulfation limits eosinophilia and attenuates inflammation underscoring the importance of site-specific sulfation in HSPG to their role in AAI.

Knob protein enhances epithelial barrier integrity and attenuates airway inflammation.

BACKGROUND: Altered epithelial physical and functional barrier properties along with TH1/TH2 immune dysregulation are features of allergic asthma. Regulation of junction proteins to improve barrier function of airway epithelial cells has the potential for alleviation of allergic airway inflammation. OBJECTIVE: We sought to determine the immunomodulatory effect of knob protein of the adenoviral capsid on allergic asthma and to investigate its mechanism of action on airway epithelial junction proteins and barrier function. METHODS: Airway inflammation, including junction protein expression, was evaluated in allergen-challenged mice with and without treatment with knob. Human bronchial epithelial cells were exposed to knob, and its effects on expression of junction proteins and barrier integrity were determined. RESULTS: Administration of knob to allergen-challenged mice suppressed airway inflammation (eosinophilia, airway hyperresponsiveness, and IL-5 levels) and prevented allergen-induced loss of airway epithelial occludin and E-cadherin expression. Additionally, knob decreased expression of TH2-promoting inflammatory mediators, specifically IL-33, by murine lung epithelial cells. At a cellular level, treatment of human bronchial epithelial cells with knob activated c-Jun N-terminal kinase, increased expression of occludin and E-cadherin, and enhanced epithelial barrier integrity. CONCLUSION: Increased expression of junction proteins mediated by knob leading to enhanced epithelial barrier function might mitigate the allergen-induced airway inflammatory response, including asthma.

Inhibition of soluble epoxide hydrolase attenuates eosinophil recruitment and food allergen-induced gastrointestinal inflammation.

Prevalence of food allergies in the United States is on the rise. Eosinophils are recruited to the intestinal mucosa in substantial numbers in food allergen-driven gastrointestinal (GI) inflammation. Soluble epoxide hydrolase (sEH) is known to play a pro-inflammatory role during inflammation by metabolizing anti-inflammatory epoxyeicosatrienoic acids (EETs) to pro-inflammatory diols. We investigated the role of sEH in a murine model of food allergy and evaluated the potential therapeutic effect of a highly selective sEH inhibitor (trans-4-{4-[3-(4-trifluoromethoxyphenyl)-ureido]-cyclohexyloxy}-benzoic acid [t-TUCB]). Oral exposure of mice on a soy-free diet to soy protein isolate (SPI) induced expression of intestinal sEH, increased circulating total and antigen-specific IgE levels, and caused significant weight loss. Administration of t-TUCB to SPI-challenged mice inhibited IgE levels and prevented SPI-induced weight loss. Additionally, SPI-induced GI inflammation characterized by increased recruitment of eosinophils and mast cells, elevated eotaxin 1 levels, mucus hypersecretion, and decreased epithelial junction protein expression. In t-TUCB-treated mice, eosinophilia, mast cell recruitment, and mucus secretion were significantly lower than in untreated mice and SPI-induced loss of junction protein expression was prevented to variable levels. sEH expression in eosinophils was induced by inflammatory mediators TNF-α and eotaxin-1. Treatment of eosinophils with t-TUCB significantly inhibited eosinophil migration, an effect that was mirrored by treatment with 11,12-EET, by inhibiting intracellular signaling events such as ERK (1/2) activation and eotaxin-1-induced calcium flux. These studies suggest that sEH induced by soy proteins promotes allergic responses and GI inflammation including eosinophilia and that inhibition of sEH can attenuate these responses.

Team science and the physician-scientist in the age of grand health challenges.

Despite remarkable advances in medical research, clinicians face daunting challenges from new diseases, variations in patient responses to interventions, and increasing numbers of people with chronic health problems. The gap between biomedical research and unmet clinical needs can be addressed by highly talented interdisciplinary investigators focused on translational bench-to-bedside medicine. The training of talented physician-scientists comfortable with forming and participating in multidisciplinary teams that address complex health problems is a top national priority. Challenges, methods, and experiences associated with physician-scientist training and team building were explored at a workshop held at the Second International Conference on One Medicine One Science (iCOMOS 2016), April 24-27, 2016, in Minneapolis, Minnesota. A broad range of scientists, regulatory authorities, and health care experts determined that critical investments in interdisciplinary training are essential for the future of medicine and healthcare delivery. Physician-scientists trained in a broad, nonlinear, cross-disciplinary manner are and will be essential members of science teams in the new age of grand health challenges and the birth of precision medicine. Team science approaches have accomplished biomedical breakthroughs once considered impossible, and dedicated physician-scientists have been critical to these achievements. Together, they translate into the pillars of academic growth and success.

Regulation of Eosinophil Recruitment and Activation by Galectins in Allergic Asthma.

Eosinophils are differentiated granulocytes that are recruited from the bone marrow to sites of inflammation via the vascular system. Allergic asthma is characterized by the presence of large numbers of eosinophils in the lungs and airways. Due to their capacity to rapidly release inflammatory mediators such as cytokines, chemokines, growth factors, and cytotoxic granule proteins upon stimulation, eosinophils play a critical role in pro-inflammatory processes in allergen-exposed lungs. Identifying key players and understanding the molecular mechanisms directing eosinophil trafficking and recruitment to inflamed airways is a key to developing therapeutic strategies to limit their influx. Recent studies have brought to light the important role of glycans and glycan binding proteins in regulating recruitment of eosinophils. In addition to the role of previously identified eosinophil- and endothelial-expressed adhesion molecules in mediating eosinophil trafficking and recruitment to the inflamed airways, studies have also indicated a role for galectins (galectin-3) in this process. Galectins are mammalian lectins expressed by various cell types including eosinophils. Intracellularly, they can regulate biological processes such as cell motility. Extracellularly, galectins interact with ß-galactosides in cell surface-expressed glycans to regulate cellular responses like production of inflammatory mediators, cell adhesion, migration, and apoptosis. Eosinophils express galectins intracellularly or on the cell surface where they interact with cell surface glycoconjugate receptors. Depending on the type (galectin-1, -3, etc.) and location (extracellular or intracellular, endogenous or exogenously delivered), galectins differentially regulate eosinophil recruitment, activation, and apoptosis and thus exert a pro- or anti-inflammatory outcome. Here, we have reviewed information pertaining to galectins (galectin-1, -3 -9, and -10) that are expressed by eosinophils themselves and/or other cells that play a role in eosinophil recruitment and function in the context of allergic asthma and their potential use as disease biomarkers or therapeutic targets for immunomodulation.

The science behind One Health: at the interface of humans, animals, and the environment.

Humans face a grand quality-of-life challenge as growing demands for resources for an ever-expanding population threaten the existence of wildlife populations, degrade land, and pollute air and water. Public investment and policy decisions that will shape future interactions of humans, animals, and the environment need scientific input to help find common ground for durable and sustainable success. The Second International Conference on One Medicine One Science brought together a broad range of scientists, trainees, regulatory authorities, and health experts from 34 countries to inform and discuss the human impacts of air quality; the complexities of water quality, access, and conflicts; the opportunities and uncertainties in precision medicine; and the role of science communication in health policy formulation. Workshops focused on the roles and development of physician-scientists and multidisciplinary teams in complex problem solving, Big Data tools for analysis and visualization, international policy development processes, and health models that benefit animals and humans. Key realizations were that local and regional health challenges at the interface of humans, animals, and the environment are variations of the same overarching conflicts and that international gatherings provide new opportunities for investigation and policy development that are broadly applicable.

Assessment of eosinophil peroxidase as a potential diagnostic and prognostic marker in dogs with inflammatory bowel disease.

OBJECTIVE To evaluate a method for identifying intact and degranulated eosinophils in the small intestine of dogs with inflammatory bowel disease (IBD) by use of a monoclonal antibody (mAb) against eosinophil peroxidase (EPX). ANIMALS 11 untreated dogs with IBD, 5 dogs with IBD treated with prednisolone, and 8 control dogs with no clinical evidence of gastrointestinal tract disease and no immunosuppressive treatment. PROCEDURES 4-µm-thick sections of paraffin-embedded tissues from necropsy specimens were immunostained with EPX mAb. Stained intact and degranulated eosinophils in consecutive microscopic fields (400X magnification) of the upper (villus tips) and lower (between the muscularis mucosae and crypts) regions of the lamina propria of the jejunum were manually counted. RESULTS Compared with control and treated IBD dogs, untreated IBD dogs had a significantly higher number of degranulated eosinophils in the lower region of the lamina propria. However, no significant differences were detected in the number of intact eosinophils in this region among groups. In the upper region of the lamina propria, untreated IBD dogs had a significantly higher number of degranulated and intact eosinophils, compared with control and treated IBD dogs. Number of degranulated and intact eosinophils did not differ significantly between control and treated IBD dogs. CONCLUSIONS AND CLINICAL RELEVANCE Immunohistologic analysis with EPX mAb yielded prominent granule staining that allowed reliable morphological identification of degranulated and intact eosinophils, which may provide a strategy for quantitative and selective evaluation of eosinophils in gastrointestinal biopsy specimens and a potential method to diagnose IBD and evaluate treatment outcome.

Regulation of eosinophilia and allergic airway inflammation by the glycan-binding protein galectin-1.

Galectin-1 (Gal-1), a glycan-binding protein with broad antiinflammatory activities, functions as a proresolving mediator in autoimmune and chronic inflammatory disorders. However, its role in allergic airway inflammation has not yet been elucidated. We evaluated the effects of Gal-1 on eosinophil function and its role in a mouse model of allergic asthma. Allergen exposure resulted in airway recruitment of Gal-1-expressing inflammatory cells, including eosinophils, as well as increased Gal-1 in extracellular spaces in the lungs. In vitro, extracellular Gal-1 exerted divergent effects on eosinophils that were N-glycan- and dose-dependent. At concentrations ≤0.25 µM, Gal-1 increased eosinophil adhesion to vascular cell adhesion molecule-1, caused redistribution of integrin CD49d to the periphery and cell clustering, but inhibited ERK(1/2) activation and eotaxin-1-induced migration. Exposure to concentrations ≥1 µM resulted in ERK(1/2)-dependent apoptosis and disruption of the F-actin cytoskeleton. At lower concentrations, Gal-1 did not alter expression of adhesion molecules (CD49d, CD18, CD11a, CD11b, L-selectin) or of the chemokine receptor CCR3, but decreased CD49d and CCR3 was observed in eosinophils treated with higher concentrations of this lectin. In vivo, allergen-challenged Gal-1-deficient mice exhibited increased recruitment of eosinophils and CD3(+) T lymphocytes in the airways as well as elevated peripheral blood and bone marrow eosinophils relative to corresponding WT mice. Further, these mice had an increased propensity to develop airway hyperresponsiveness and displayed significantly elevated levels of TNF-α in lung tissue. This study suggests that Gal-1 can limit eosinophil recruitment to allergic airways and suppresses airway inflammation by inhibiting cell migration and promoting eosinophil apoptosis.

Limited hydrolysis combined with controlled Maillard-induced glycation does not reduce immunoreactivity of soy protein for all sera tested.

Combining proteolysis and Maillard-induced glycation was investigated to reduce the immunoreactivity of soy protein. Soy protein was hydrolyzed by Alcalase following response surface methodology utilizing three variables, temperature, time, and enzyme:substrate ratio, with the degree of hydrolysis (DH) and percent reduction in immunoreactivity as response variables. Western blots and ELISA were used to evaluate immunoreactivity using human sera. Data were fitted to appropriate models and prediction equations were generated to determine optimal hydrolysis conditions. The hydrolysate produced under optimized conditions was subjected to glycation with dextran. Hydrolysate produced under optimal conditions had 7.8% DH and a percent reduction in immunoreactivity ranging from 20% to 52%, depending on the sera used. Upon glycation, immunoreactivity was further reduced only when using serum that had the highest soy-specific IgE. This work revealed limitations and provided premises for future studies intended to prove the potency of the combined modification approach to produce a hypoallergenic protein ingredient.

Tumor eosinophil infiltration and improved survival of colorectal cancer patients: Iowa Women's Health Study.

The role of the innate immune response in colorectal cancer is understudied. We examined the survival of colorectal cancer patients in relation to eosinophils, innate immune cells, infiltrating the tumor. Tissue microarrays were constructed from paraffin-embedded tumor tissues collected between 1986 and 2002 from 441 post-menopausal women diagnosed with colorectal cancer in the Iowa Women's Health Study. Tissue microarrays were stained with an eosinophil peroxidase antibody. Eosinophils in epithelial and stromal tissues within the tumor (called epithelial and stromal eosinophils, hereafter) were counted and scored into three and four categories, respectively. In addition, the degree of eosinophil degranulation (across epithelial and stromal tissues combined) was quantified and similarly categorized. We used Cox regression to estimate the hazard ratios and 95% confidence interval for all-cause and colorectal cancer death during 5-year follow-up after diagnosis and during follow-up through 2011 ('total follow-up'). The hazard ratios associated with eosinophil scores were adjusted for age of diagnosis, SEER (Surveillance, Epidemiology, and End Results) stage, tumor grade, body mass, and smoking history. High tumor stromal eosinophil score was inversely correlated with age and stage, and was associated with a decreased risk for all-cause and colorectal cancer death: hazard ratios (95% confidence intervals) were 0.61 (0.36-1.02; P-trend=0.02) and 0.48 (0.24-0.93; P-trend=0.01), respectively, during the 5-year follow-up for the highest vs lowest category. The inverse associations also existed for total follow-up for all-cause and colorectal cancer death for the highest vs lowest stromal eosinophil score: hazard ratios (95% confidence intervals) were 0.72 (0.48-1.08; P-trend=0.04) and 0.61 (0.34-1.12; P-trend=0.04), respectively. Further adjustment for treatment, comorbidities, additional lifestyle factors, tumor location, or molecular markers did not markedly change the associations, while adjustment for cytotoxic T cells slightly attenuated all associations. The infiltration of tumors with eosinophils, especially in stromal tissue, may be an important prognostic factor in colorectal cancer.

Advancing One Health Policy and Implementation Through the Concept of One Medicine One Science.

Numerous interspecies disease transmission events, Ebola virus being a recent and cogent example, highlight the complex interactions between human, animal, and environmental health and the importance of addressing medicine and health in a comprehensive scientific manner. The diversity of information gained from the natural, social, behavioral, and systems sciences is critical to developing and sustainably promoting integrated health approaches that can be implemented at the local, national, and international levels to meet grand challenges. The Concept of One Medicine One Science (COMOS) as outlined herein describes the interplay between scientific knowledge that underpins health and medicine and efforts toward stabilizing local systems using 2 linked case studies: the food system and emerging infectious disease. Forums such as the International Conference of One Medicine One Science (iCOMOS), where science and policy can be debated together, missing pieces identified, and science-based collaborations formed among industry, governmental, and nongovernmental policy makers and funders, is an essential step in addressing global health. The expertise of multiple disciplines and research foci to support policy development is critical to the implementation of one health and the successful achievement of global health security goals.

Los numerosos acontecimientos de transmisión de enfermedades entre especies, de los cuales el virus del Ébola es un ejemplo claro y reciente, ponen de manifiesto las complejas interacciones que existen entre la salud humana, animal y medioambiental, así como la importancia de abordar la medicina y la salud de una manera científica e integral. La diversidad de la información obtenida de las ciencias naturales, sociales, conductuales y de los sistemas es fundamental para el desarrollo y fomento sostenibles de enfoques integrados de salud que puedan implementarse a nivel local, nacional e internacional para atender los grandes retos. El concepto de Una medicina una ciencia (Concept of One Medicine One Science, COMOS) esbozado aquí describe la interrelación entre el conocimiento científico que sustenta la salud y la medicina, y los esfuerzos hacia la estabilización de los sistemas locales por medio de dos estudios de casos relacionados: el sistema alimentario y las enfermedades infecciosas emergentes. Los foros como la Conferencia internacional de una medicina una ciencia (International Conference of One Medicine One Science, iCOMOS), donde se hace posible el debate conjunto de la ciencia y la política, la identificación de eslabones perdidos, y la formación de colaboraciones basadas en la ciencia entre los formuladores y fundadores de políticas industriales, gubernamentales y no gubernamentales, representan un paso decisivo para abordar el tema de la salud mundial. La experiencia de múltiples disciplinas y enfoques de investigación para apoyar el desarrollo de políticas es fundamental para la implementación de una salud y el logro de los objetivos relativos a la seguridad de la salud mundial.

One Medicine One Science: a framework for exploring challenges at the intersection of animals, humans, and the environment.

Characterizing the health consequences of interactions among animals, humans, and the environment in the face of climatic change, environmental disturbance, and expanding human populations is a critical global challenge in today's world. Exchange of interdisciplinary knowledge in basic and applied sciences and medicine that includes scientists, health professionals, key sponsors, and policy experts revealed that relevant case studies of monkeypox, influenza A, tuberculosis, and HIV can be used to guide strategies for anticipating and responding to new disease threats such as the Ebola and Chickungunya viruses, as well as to improve programs to control existing zoonotic diseases, including tuberculosis. The problem of safely feeding the world while preserving the environment and avoiding issues such as antibiotic resistance in animals and humans requires cooperative scientific problem solving. Food poisoning outbreaks resulting from Salmonella growing in vegetables have demonstrated the need for knowledge of pathogen evolution and adaptation in developing appropriate countermeasures for prevention and policy development. Similarly, pesticide use for efficient crop production must take into consideration bee population declines that threaten the availability of the two-thirds of human foods that are dependent on pollination. This report presents and weighs the objective merits of competing health priorities and identifies gaps in knowledge that threaten health security, to promote discussion of major public policy implications such that they may be decided with at least an underlying platform of facts.