Presenting clinical symptoms of post-COVID-19 breakthrough infection: Predictors of mortality in a Middle Eastern population.

Objective: Breakthrough COVID-19 infections are common following immunisation with various types of vaccines. The patterns of infections have not been well established. We aimed to analyse the signs and symptoms of post vaccination infections in addition to the need for hospital admission, ER visit and supplemental oxygen in relation to age and gender. Methods: A cross-sectional cohort study was conducted in JUH from March 2021 to August 2022, we interviewed 1479 individuals who are >15 years of age and got a breakthrough infection. The statistical analysis was performed using STATA statistical software. Results: Out of the 1479 cases, 50.2 % and 69.4 % were females and less than 45 years of age respectively. Symptoms of cough, fever and headache were reported by nearly 50 % of the patients, while one-third complained of dyspnoea. We found that participants older than 45 years had worse clinical outcomes (P-value < 0.001). 13 deaths were identified in this study due to breakthrough infection, 92.3 % of them were older than 45 years (P-value < 0.001). Participants ≥45 years who experienced a breakthrough infection of COVID-19 were 0.7 times less likely to be females using adjusted logistic regression. Conclusion: This study indicates that despite more severe symptoms reported in younger patients, the major clinical outcomes were worse among older patients, which makes age a major risk for poor outcomes regardless of symptoms. Thus, older people should be evaluated carefully when presenting with mild symptoms of COVID-19 breakthrough infection. The study also confirms that there is no difference in the incidence of COVID-19 breakthrough infections between males and females. Prospective studies are needed to risk stratify COVID-19 breakthrough infections, which should take into account variants of the virus and comorbidities.

Exploring the Potential Biological Activities of Pyrazole-Based Schiff Bases as Anti-Diabetic, Anti-Alzheimer's, Anti-Inflammatory, and Cytotoxic Agents: In Vitro Studies with Computational Predictions.

In this innovative research, we aim to reveal pyrazole-based Schiff bases as new multi-target agents. In this context, we re-synthesized three sets of pyrazole-based Schiff bases, 5a-f, 6a-f, and 7a-f, to evaluate their biological applications. The data from in vitro biological assays (including antioxidant and scavenging activities, anti-diabetes, anti-Alzheimer's, and anti-inflammatory properties) of the pyrazole-based Schiff bases 5a-f, 6a-f, and 7a-f showed that the six pyrazole-based Schiff bases 5a, 5d, 5e, 5f, 7a, and 7f possess the highest biological properties among the compounds evaluated. The cytotoxicity against lung (A549) and colon (Caco-2) human cancer types, as well as normal lung (WI-38) cell lines, was evaluated. The data from the cytotoxicity investigation demonstrated that the three Schiff bases 5d, 5e, and 7a are active against lung (A549) cells, while the two Schiff bases 5e and 7a exhibited the highest cytotoxicity towards colon (Caco-2) cells. Additionally, the enzymatic activities against caspase-3 and Bcl-2 of the six pyrazole-based Schiff bases 5a, 5d, 5e, 5f, 7a, and 7f were evaluated. Furthermore, we assessed the in silico absorption, distribution, metabolism, and toxicity (ADMT) properties of the more potent pyrazole-based Schiff bases. After modifying the structures of the six pyrazole-based Schiff bases, we plan to further extend the studies in the future.

Impact of Breathing Control Training Program on sonographic quantification of abdominal vasculature.

OBJECTIVES: To compare vascular scanning parameters (vessel diameter, peak systolic velocity, end-diastolic velocity, and resistive index) and scanning time before and after breathing control training program for selected abdominal vessels. METHODS: This study was pre and post quasi-experimental. The researchers designed a breathing training program that gives participants instructions through a video describing breathing maneuvers. Data were collected at the ultrasound laboratory/College of Health and Rehabilitation Sciences in Princess Nourah bint Abdul Rahman University, Riyadh, Saudi Arabia from January 2023 to November 2023. About 49 volunteers at the university participated in the study. Scanning was performed two times for the right renal artery, upper abdominal aorta, inferior vena cava, and superior mesenteric artery. Scanning time was measured before and after the program as well. A paired sample t-test was used to compare the parameters means and time before and after the program. RESULTS: The program had a significant effect on the following parameters: right renal artery peak systolic velocity (p=0.042), upper abdominal aortic peak systolic velocity, and resistive index (p=0.014, p=0.014 respectively), superior mesenteric artery and inferior vena cava diameters (p=0.010 and p=0.020). The scanning time was reduced significantly (p<0.001). CONCLUSION: The breathing training program saves time and improves ultrasound measurement quality. Hospitals and health centers should consider the importance of breathing control training programs before abdominal scanning.

Interplay between Senescence and Macrophages in Diabetic Cardiomyopathy: A Review of the Potential Role of GDF-15 and Klotho.

Type 2 diabetes mellitus (T2DM) is a critical health problem, with 700 million diagnoses expected worldwide by 2045. Uncontrolled high blood glucose levels can lead to serious complications, including diabetic cardiomyopathy (DCM). Diabetes induces cardiovascular aging and inflammation, increasing cardiomyopathy risk. DCM is characterized by structural and functional abnormalities in the heart. Growing evidence suggests that cellular senescence and macrophage-mediated inflammation participate in the pathogenesis and progression of DCM. Evidence indicates that growth differentiation factor-15 (GDF-15), a protein that belongs to the transforming growth factor-beta (TGF-ß) superfamily, is associated with age-related diseases and exerts an anti-inflammatory role in various disease models. Although further evidence suggests that GDF-15 can preserve Klotho, a transmembrane antiaging protein, emerging research has elucidated the potential involvement of GDF-15 and Klotho in the interplay between macrophages-induced inflammation and cellular senescence in the context of DCM. This review explores the intricate relationship between senescence and macrophages in DCM while highlighting the possible contributions of GDF-15 and Klotho.

Liraglutide Attenuates Diabetic Cardiomyopathy via the ILK/PI3K/AKT/PTEN Signaling Pathway in Rats with Streptozotocin-Induced Type 2 Diabetes Mellitus.

One of the possible candidates for the treatment of diabetic cardiomyopathy is liraglutide, a glucagon-like peptide-1 receptor (GLP1R) agonist. In this study, the impacts of liraglutide on the integrin-linked kinase (ILK)-related PI3K/AKT axis in rats with type 2 diabetes induced via streptozotocin were examined. Twenty-four Wistar albino rats were distributed in four different groups, and a high-fat diet and streptozotocin were used to induce type 2 in two groups. Rats in the untreated control groups were administered 0.9% NaCl solution over a 6-week period, and those in the treatment groups were administered 0.9% NaCl for 3 weeks, followed by subcutaneous injection of liraglutide (150 µg/kg) for an additional 3 weeks. In the liraglutide-treated diabetic group, the heart-to-body weight ratio was significantly reduced, levels of cardiac biomarkers, troponin I and creatine-kinase-MB, were improved; activities of antioxidant enzymes, glutathione peroxidase and superoxide dismutase, were increased; and levels of malondialdehyde were decreased. Western blotting and immunohistochemical studies revealed increased levels of ILK, P-PI3K, P-AKT, and BCL2, as well as those of caspase 3, BAX, and P-PTEN, indicating mitigation of cardiomyocyte apoptosis. Our results show that liraglutide, by targeting GLP1Rs, enhances the expression of proteins in the ILK/PI3K/AKT/PTEN pathway and thereby exerts its cardioprotective effects in rats with DCM.

α1,3-fucosylation treatment improves cord blood CD34 negative hematopoietic stem cell navigation.

For almost two decades, clinicians have overlooked the diagnostic potential of CD34neg hematopoietic stem cells because of their limited homing capacity relative to CD34posHSCs when injected intravenously. This has contributed to the lack of appeal of using umbilical cord blood in HSC transplantation because its stem cell count is lower than bone marrow. The present study reveals that the homing and engraftment of CD34negHSCs can be improved by adding the Sialyl Lewis X molecule via α1,3-fucosylation. This unlocks the potential for using this more primitive stem cell to treat blood disorders because our findings show CD34negHSCs have the capacity to regenerate cells in the bone marrow of mice for several months. Furthermore, our RNA sequencing analysis revealed that CD34negHSCs have unique adhesion pathways, downregulated in CD34posHSCs, that facilitate interaction with the bone marrow niche. Our findings suggest that CD34neg cells will best thrive when the HSC resides in its microenvironment.

Clinical, Radiological, and Microbiologic Characteristics of Patients with Noncystic Fibrosis Bronchiectasis in a Tertiary Center at Jordan.

BACKGROUND: Only a small number of the investigations that were carried out in the Middle East attempted to characterize patients with NCFB. In order to characterize patients with NCFB, as well as their etiologies, microbiological profiles, and outcomes, we therefore carried out this investigation. METHODS: This retrospective cohort study was carried out at the Jordan University Hospital (JUH), a tertiary facility located in Amman, Jordan. Non-cystic Fibrosis Bronchiectasis (NCFB) was defined as an HRCT scan typical for bronchiectasis along with a negative sweat chloride test to rule out cystic fibrosis. Patients' data were collected by the use of Electronic Medical Records (EMR) at our institution. Frequent exacerbation was defined as more than 2 exacerbations in 1 year of the onset of the diagnosis. RESULTS: A total of 79 patients were included, and 54.4% of them were female. The mean and standard deviation of the patient's age was 48.61 ± 19.62. The etiologies of bronchiectasis were evident in 79.7% of the sample. Asthma, Chronic Obstructive Pulmonary Diseases (COPD), and Kartagener syndrome were the most prevalent etiologies, accounting for related illnesses in 21.8%, 21.5%, and 13.9% of the patients, respectively. The most frequent bacteria cultured in our cohort were Pseudomonas and Candida Species. Moreover, 43 patients of the study cohort were frequent exacerbators, and 5 patients died. CONCLUSION: Our study supports the need to identify several bronchiectasis phenotypes linked to various causes. These findings provide information to clinicians for the early detection and treatment of bronchiectasis in Jordan.

Role of the integrin-linked kinase/TGF-ß/SMAD pathway in sitagliptin-mediated cardioprotective effects in a rat model of diabetic cardiomyopathy.

OBJECTIVES: Diabetic cardiomyopathy is a known complication of diabetes mellitus. Herein, we aimed to determine whether glycemic control mediated by sitagliptin, a dipeptidyl peptidase-4 inhibitor, can ameliorate diabetic myocardial abnormalities by modulating TGF-ß signaling via the SMAD and integrin-linked kinase (ILK) pathways. METHODS: Four groups of male Wistar albino rats were used, with six rats in each group. Two nondiabetic and two diabetic (produced by a single intraperitoneal dose of streptozotocin (55 mg/kg)) groups were administered either normal saline or sitagliptin (100 mg/kg) orally for 6 weeks. Subsequently, HW/BW ratios and cardiac enzymes were assessed, along with a histological examination of cardiac tissues. Levels of TGF-ß, collagen I, p-SMAD2/3, TNF-α, MMP-9, and ILK were detected. RESULTS: Compared with the diabetic control group, sitagliptin-treated diabetic rats exhibited considerably reduced HW/BW ratios and troponin I and creatine kinase-MB levels, with improvements in histopathological changes in cardiac tissues. TGF-ß, collagen I, p-SMAD2/3, TNF-α, and MMP-9 levels were significantly decreased in the sitagliptin-treated diabetic group, whereas ILK was elevated following sitagliptin treatment. CONCLUSION: Sitagliptin could afford cardioprotective effects for the first time by altering ILK-associated TGF-ß/SMAD signaling pathways. Thus, sitagliptin may be a promising therapeutic target for the prevention of diabetic cardiomyopathy.

The impact of COVID-19 on antibiotic resistance and clinical outcomes among critically ill patients.

BACKGROUND: There is conflicting evidence regarding the impact of the Coronavirus 2019 (COVID-19) pandemic on antimicrobial resistance, with few studies conducted in low- and middle-income countries. We investigated the impact of the COVID-19 pandemic on multidrug resistant organisms (MDROs) among critically ill patients and their clinical outcomes. METHODS: This was a retrospective observational study of patients admitted to the medical Intensive Care Unit at Jordan University Hospital and had blood, urine, or bronchoalveolar bacterial cultures taken during 2 time periods: prepandemic (ie, 1/2016 to 1/2019) and pandemic (ie, 1/2020 to 1/2023). We compared the clinical outcomes (ie, in-hospital deaths, the need for O2 devices, intubation, the length of hospital stay, and the occurrence of complications) and prevalence of MDROs between the 2 periods and conducted multivariate analyses. RESULTS: There were 1,254 patients (479 prepandemic and 775 postpandemic. The percentage of patients who had MDROs was significantly higher among patients with a culture taken during the pandemic (82.4%) compared to before it (17.6%) (P-value=.000). Multivariate analysis demonstrated that patients cultured during the pandemic were more than 3 times as likely to have an MDRO (odds ratio = 3.210; 95% confidence interval: 2.236-4.609). CONCLUSIONS: The increase in MDROs during the COVID-19 pandemic is an alarming threat to public health; thus, investigating the antibiotic resistance situation as the pandemic subsides is crucial.

Cardioprotective Effects of the GRK2 Inhibitor Paroxetine on Isoproterenol-Induced Cardiac Remodeling by Modulating NF-κB Mediated Prohypertrophic and Profibrotic Gene Expression.

Pathological cardiac remodeling is associated with cardiovascular disease and can lead to heart failure. Nuclear factor-kappa B (NF-κB) is upregulated in the hypertrophic heart. Moreover, the expression of the G-protein-coupled receptor kinase 2 (GRK2) is increased and linked to the progression of heart failure. The inhibitory effects of paroxetine on GRK2 have been established. However, its protective effect on IκBα/NFκB signaling has not been elucidated. This study investigated the cardioprotective effect of paroxetine in an animal model of cardiac hypertrophy (CH), focusing on its effect on GRK2-mediated NF-κB-regulated expression of prohypertrophic and profibrotic genes. Wistar albino rats were administered normal saline, paroxetine, or fluoxetine, followed by isoproterenol to induce CH. The cardioprotective effects of the treatments were determined by assessing cardiac injury, inflammatory biomarker levels, histopathological changes, and hypertrophic and fibrotic genes in cardiomyocytes. Paroxetine pre-treatment significantly decreased the HW/BW ratio (p < 0.001), and the expression of prohypertrophic and profibrotic genes Troponin-I (p < 0.001), BNP (p < 0.01), ANP (p < 0.001), hydroxyproline (p < 0.05), TGF-ß1 (p < 0.05), and αSMA (p < 0.01) as well as inflammatory markers. It also markedly decreased pIκBα, NFκB(p105) subunit expression (p < 0.05) and phosphorylation. The findings suggest that paroxetine prevents pathological cardiac remodeling by inhibiting the GRK2-mediated IκBα/NF-κB signaling pathway.

Evidence-Based Strategies to Enhance Weight Management Programs for Adult Military Beneficiaries: A Narrative Review.

INTRODUCTION: Overweight and obesity trends are on the rise among both civilian and military beneficiaries. The purpose of this narrative review was to evaluate nutrition, behavioral, lifestyle, pharmacotherapy, and alternative approaches to weight management (WM) among adults with a focus toward identifying gaps and evidence-based strategies that could support or enhance current and future WM programming among military adult beneficiaries. MATERIALS AND METHODS: A trained research team identified publications (January 2013-January 2020) for abstract review using key search terms and inclusion criteria. Two independent researchers conducted both the abstract review and full-paper bias scoring using selected Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. All eligible studies were assessed for bias and categorized based on key themes. The study was registered in PROSPERO, the international prospective register of systematic reviews. RESULTS: The research team identified 741 articles, with 278 meeting final inclusion criteria. The mean bias score was 7.5 ± 3.9 (score of 0-13; higher indicating fewer bias factors), with 64% scoring ≥9. Factors contributing to low bias included intervention compliance, dropout rate, and inability to blind participants. The most common published weight-loss interventions included a combination of therapies (59%), diet/supplement (17%), other approaches (12%), behavior change (7%), and exercise (6%). Themes identified to improve WM outcomes included leveraging technology, increasing intervention interactions, community support, emphasis on early weight loss, pharmacotherapy risk-benefit, enhanced behavioral component, resistance exercise, mindfulness, and benefits of quality-of-life measures. CONCLUSIONS: Reviewers identified several validated tools and techniques to augment and update existing WM programming to improve health and weight outcomes. The review affirmed use of individualized dietary patterns and not a "one-size-fits-all approach" as well as incorporating more comprehensive and team-approached treatments to make the best use of tools and strategies to enhance outcomes.

The prevalence of anxiety and depression in bronchiectasis patients and their association with disease severity: a cross-sectional study.

Bronchiectasis is a chronic lung disease characterized by recurrent respiratory symptoms. Several studies demonstrated that psychological comorbidities are common in patients with bronchiectasis. The aim of this study is to investigate the prevalence of anxiety and depression in bronchiectasis patients and assess their association with disease severity. In this cross-sectional study, we included patients diagnosed with bronchiectasis. The study was conducted using an interviewer-administered questionnaire via phone calls and data collected from the electronic medical records at JUH. The questionnaire included patients' demographics and disease characteristics. Anxiety and depression were assessed using GAD7 and PHQ9 respectively. Bronchiectasis disease severity was assessed using BSI and FACED score. The total number of included patients was 133. Moreover, 53.4% of the participants were females while the rest were males (46.6%). PHQ9 demonstrated that 65.4% of the patients had depression. Regarding anxiety, GAD7 scale showed that 54.1% of the patients had anxiety. Pearson correlation showed that bronchiectasis severity index was significantly associated only with PHQ9 depression scores (r = 0.212, P value = 0.014). The prevalence of depression and anxiety is high among patients with bronchiectasis. We believe that patients affected with bronchiectasis should be screened for depression to improve their quality of life.

Alterations in Patients' Clinical Outcomes and Respiratory Viral Pathogen Activity following the COVID-19 Pandemic.

BACKGROUND: Before the COVID-19 pandemic, respiratory pathogens such as influenza, parainfluenza, and respiratory syncytial virus were the most commonly detected viruses among hospitalized patients with respiratory tract infections. METHODS: This was a retrospective observational study of inpatients and outpatients who attended Jordan University Hospital and underwent Nasopharyngeal Aspiration (NPA) in the periods from December 2017 to December 2018 and from December 2021 to December 2022. The results of multiplex respiratory pathogen real-time PCR tests for nasopharyngeal swab specimens were extracted from the electronic-based molecular diagnostic laboratory record of JUH. We compared the prevalence of the detected viruses as well as the patients' characteristics and outcomes between the two periods. RESULTS: The total number of included patients was 695. Our analysis showed that a higher percentage of patients with hypertension and diabetes presented before the pandemic compared to the same period after it (p-value < 0.001). The need for O2 devices, white blood cell counts, diastolic blood pressure, and the length of hospital stay were significantly higher among patients who presented before the pandemic (p-value < 0.050). Influenza H1N1 (8.70% vs. 4.03%), influenza B (1.67% vs. 0.25%), parainfluenza (1.00% vs. 0.00%), human metapneumovirus (5.35% vs. 0.76%), adenoviruses (6.35% vs. 3.02%), and coronaviruses (8.70% vs. 3.53%) were detected with higher frequency in the period before the pandemic (p-value = 0.011, 0.045, 0.045, 0.000, 0.035, 0.004). These results were similar in terms of changes in the detection rates of viruses after matching the number of tested patients between the periods before and after the pandemic. CONCLUSIONS: We have demonstrated a reduction in the detection of several viruses, which might be due to the increase in public awareness toward infection protection measures after the COVID-19 pandemic.

Gold and Silver Chains from Tetrahydrothiophenocucurbit[6]uril as Au or Ag-Nanoparticles.

Tetrahydrothiophenocucurbit[5 and 6]uril has been synthesized from tetrathiophenoglycoluril diether, providing thioether functionality at the exterior equatorial position of the cucurbituril cage. This functionality has been investigated for chemical modification through sulfoxide formation and subsequent Pummerer rearrangement to the acetoxy derivative of the tetrahydrothiophenocucurbit[5]uril. Nanoparticles of Au and Ag were prepared in the presence of tetrahydrothiophenocucurbit[6]uril, which curiously led to the formation of nanoparticle chains, growing in length over days to weeks.

Significant photocatalytic decomposition of malachite green dye in aqueous solutions utilizing facilely synthesized barium titanate nanoparticles.

The release of malachite green dye into water sources has detrimental effects on the liver, kidneys, and respiratory system. Additionally, this dye can impede photosynthesis and disrupt the growth and development of plants. As a result, in this study, barium titanate nanoparticles (BaTiO3) were facilely synthesized using the Pechini sol-gel method at 600 °C (abbreviated as EA600) and 800 °C (abbreviated as EA800) for the efficient removal of malachite green dye from aqueous media. The Pechini sol-gel method plays a crucial role in the production of barium titanate nanoparticles due to its simplicity and ability to precisely control the crystallite size. The synthesized barium titanate nanoparticles were characterized by several instruments, such as X-ray diffraction (XRD), high-resolution transmission electron microscopy (HR-TEM), Fourier transform infrared spectroscopy, and a diffuse reflectance spectrophotometer. The XRD analysis confirmed that the mean crystallite size of the EA600 and EA800 samples is 14.83 and 22.27 nm, respectively. Furthermore, the HR-TEM images confirmed that the EA600 and EA800 samples exhibit irregular and polyhedral structures, with mean diameters of 45.19 and 72.83 nm, respectively. Additionally, the synthesized barium titanate nanoparticles were utilized as catalysts for the effective photocatalytic decomposition of malachite green dye in aqueous media. About 99.27 and 93.94% of 100 mL of 25 mg/L malachite green dye solution were decomposed using 0.05 g of the EA600 and EA800 nanoparticles within 80 min, respectively. The effectiveness of synthesized BaTiO3 nanoparticles as catalysts stems from their unique characteristics, including small crystallite sizes, a low rate of hole/electron recombination owing to ferroelectric properties, high chemical stability, and the ability to be regenerated and reused multiple times without any loss in efficiency.

Facile synthesis and characterization of Fe3O4/analcime nanocomposite for the efficient removal of Cu(II) and Cd(II) ions from aqueous media.

In the water purification field, heavy metal pollution is a problem that causes severe risk aversion. This study aimed to examine the disposal of cadmium and copper ions from aqueous solutions by a novel Fe3O4/analcime nanocomposite. A field emission scanning electron microscope (FE-SEM), Fourier transform infrared spectroscopy (FT-IR), and X-ray diffraction were used to characterize the synthesized products. The FE-SEM images showed that the analcime and Fe3O4 samples consist of polyhedral and quasi-spherical shapes with average diameters of 923.28 and 28.57 nm, respectively. Besides, the Fe3O4/analcime nanocomposite consists of polyhedral and quasi-spherical shapes with average diameters of 1100.00 nm. The greatest uptake capability of the Fe3O4/analcime nanocomposite toward the copper and cadmium ions is 176.68 and 203.67 mg/g, respectively. The pseudo-second-order kinetic model and Langmuir equilibrium isotherm best describe the uptake of copper and cadmium ions using the Fe3O4/analcime nanocomposite. The uptake of copper and cadmium ions using the Fe3O4/analcime nanocomposite is exothermic and chemical in nature.

Functionalization of Silica Nanoparticles by 5-Chloro-8-quinolinol as a New Nanocomposite for the Efficient Removal and Preconcentration of Al3+ Ions from Water Samples.

In this work, silica nanoparticles were modified by 5-chloro-8-quinolinol as a new nanocomposite for the efficient elimination and preconcentration of Al3+ ions from several water sources. The fabricated composite was characterized utilizing XRD, SEM, FT-IR, TEM, CHN elemental analyzer, and N2 adsorption/desorption analyzer. The XRD demonstrated the existence of a wide peak at 2θ = 30°. Also, all the peaks of silica were severely reduced, which confirms the success of loading the 5-chloro-8-quinolinol on the surface of the silica. The SEM and TEM images demonstrated that the composite resembled cotton, and this confirms that 5-chloro-8-quinolinol was successfully loaded on the silica surface. The specific surface area, the average pore size, and the total pore volume of the synthesized composite are 80.53 m2/g, 3.26 nm, and 0.185 cc/g, respectively. In addition, the greatest uptake capacity of the synthesized composite toward aluminum ions is 95.06 mg/g. The results indicated that the adsorption of aluminum ions onto the silica/5-chloro-8-quinolinol composite follows the Langmuir isotherm and pseudo-second-order model. Moreover, the adsorption of aluminum ions by the silica/5-chloro-8-quinolinol composite is spontaneous, chemical, and thermodynamically favorable. The values of % recovery were more than 97%, whereas the values of % RSD were less than 3.5%. Hence, this confirms the effectiveness of the proposed method in the determination of aluminum ions in real water samples.

CD34+ HSPCs-derived exosomes contain dynamic cargo and promote their migration through functional binding with the homing receptor E-selectin.

Exosomes are tiny vesicles released by cells that carry communications to local and distant locations. Emerging research has revealed the role played by integrins found on the surface of exosomes in delivering information once they reach their destination. But until now, little has been known on the initial upstream steps of the migration process. Using biochemical and imaging approaches, we show here that exosomes isolated from both leukemic and healthy hematopoietic stem/progenitor cells can navigate their way from the cell of origin due to the presence of sialyl Lewis X modifications surface glycoproteins. This, in turn, allows binding to E-selectin at distant sites so the exosomes can deliver their messages. We show that when leukemic exosomes were injected into NSG mice, they traveled to the spleen and spine, sites typical of leukemic cell engraftment. This process, however, was inhibited in mice pre-treated with blocking E-selectin antibodies. Significantly, our proteomic analysis found that among the proteins contained within exosomes are signaling proteins, suggesting that exosomes are trying to deliver active cues to recipient cells that potentially alter their physiology. Intriguingly, the work outlined here also suggests that protein cargo can dynamically change upon exosome binding to receptors such as E-selectin, which thereby could alter the impact it has to regulate the physiology of the recipient cells. Furthermore, as an example of how miRNAs contained in exosomes can influence RNA expression in recipient cells, our analysis showed that miRNAs found in KG1a-derived exosomes target tumor suppressing proteins such as PTEN.