No abstract

T cells are key mediators of graft tolerance/rejection, development of autoimmunity, and the anticancer response. Consequently, differentially modifying the T cell response is a major therapeutic target. Most immunomodulatory approaches have focused on cytotoxic agents, cytokine modulation, monoclonal antibodies, mitogen activation, adoptive cell therapies (including CART cells). However, these approaches do not persistently reorient the systemic immune response thus necessitating continual therapy. Previous murine studies from our laboratory demonstrated that the adoptive transfer of polymer-grafted (PEGylated) allogeneic leukocytes resulted in the induction of a persistent and systemic tolerogenic state. Further analyses demonstrated that miRNA isolated from the secretome of polymermodified or control allogeneic responses effectively induced either a tolerogenic (TA1 miRNA) or proinflammatory (IA1 miRNA) response both in vitro and in vivo that was both systemic and persistent. In a murine Type 1 diabetes autoimmune model, the tolerogenic TA1 therapeutic effectively attenuated the disease process via the systemic upregulation of regulatory T cells while simultaneously downregulating T effector cells. In contrast, the proinflammatory IA1 therapeutic enhanced the anticancer efficacy of naïve PBMC by increasing inflammatory T cells and decreasing regulatory T cells. The successful development of this secretome miRNA approach may prove useful treating both autoimmune diseases and cancer.

While our previous studies have demonstrated that polymer-grafting to MHC disparate leukocytes inhibits CD4 cell proliferation, the effects of PEGylation on the alloproliferation of CD8 cytotoxic T cells (CTL) was not examined. As shown here, PEGylation of allogeneic leukocytes prevents the generation of the CTL response responsible for acute rejection. The loss of CTL proliferation is consequent to the polymer-based attenuation of allorecognition and the induction of T regulatory cells (Tregs). Interestingly, the Tregs are primarily generated via the differentiation of non-proliferating naive T cells. Importantly, the Tregs are functional and effectively induce a tolerogenic environment when transferred to an alloresponsive environment. The use of polymer-modified leukocytes provides a unique approach to effectively maximize the biologic production of functional Tregs both in vitro and in vivo. By using this approach it may be possible to attenuate unwanted alloresponses (e.g., graft rejection) or to treat autoimmune diseases.

Studies have shown that rapid rehabilitation surgery has a positive effect on recovery after major orthopedic surgery. However, very few studies have examined the impact of fast track surgery on physical and psychological rehabilitation in patients who have undergone total hip replacement. This study aimed to investigate the value of the rapid rehabilitation surgical model for patients undergoing total hip arthroplasty during the perioperative period. We conducted a prospective cohort study that included patients who underwent total hip arthroplasty at our hospital from January 2015 to December 2018. We divided the patients into 2 groups – the rapid rehabilitation group and the conventional rehabilitation group – and compared their length of hospital stay, time to off-bed activity, pain score, Self-Rating Anxiety Scale scores, Self-Rating Depression Scale scores, complication rate, and rate of satisfaction during hospitalization. A total of 348 patients were included in the study. Of these, 180 received rapid rehabilitation nursing and 168 patients received conventional nursing. Compared with the patients in the conventional rehabilitation group, those in the rapid rehabilitation group had shorter hospital stays (11.5 ± 1.2 day vs 15.5 ± 2.3 day, P = .021), resumed off-bed activities sooner (20.5 ± 3.4 hours vs 61.8 ± 4.7 hours, P = .001, had less postoperative pain (4.0 ± 1.2 vs 6.5 ± 1.1, P < .001), and lower anxiety and depression scores (anxiety score: 24.4 ± 2.1 vs 47.9 ± 2.9; depression score: 25.8 ± 1.8 vs 43.7 ± 1.7, P < .001). The application of rapid rehabilitation surgery in total hip arthroplasty can accelerate patients’ postoperative recovery, relieve anxiety and depression, and increase the patient's satisfaction with the treatment.

While ABO/Rh(D) red blood cells (RBC)-matched transfusions are generally considered as safe, a significant risk of alloimmunization to non-A/B blood group antigens exists; especially in chronically transfused patients. Indeed, alloimmunization to non-A/B antigens can be so severe that RBC transfusion can no longer be safely administered without the risk of a potentially deadly immune haemolytic reaction. Currently, no satisfactory solutions exist either to prevent blood group alloimmunization or to cost-effectively treat patients with severe alloimmunization. To address this problem, we have pioneered the immunocamouflage of donor RBC. The immunocamouflaged (stealth) RBC is manufactured by the covalent grafting of biologically safe polymers to RBC membrane proteins. As a result of the grafted polymer, non-A/B blood group antigens are biophysically and immunologically masked. Of particular interest is the immunocamouflage of the Rh(D) antigen which could be used to improve blood inventory and transfusion safety. The polymer-modified RBCs are morphologically normal and, in mice, exhibit normal in vivo survival at immunoprotective grafting concentration. In this chapter, we explore both the biophysical and immunological consequences of the grafted polymers, explore the conditions in which they might be appropriately used, and describe the technology necessary to manufacture functional transfusable units of these cells within the clinical setting.

Myeloid ecotropic virus insertion site 1 (MEIS1) is essential for normal hematopoiesis and is a critical factor in the pathogenesis of a large subset of acute myeloid leukemia (AML). Despite the clinical relevance of MEIS1, its regulation is largely unknown. To understand the transcriptional regulatory mechanisms contributing to human MEIS1 expression, we created a knock-in green florescent protein (GFP) reporter system at the endogenous MEIS1 locus in a human AML cell line. Using this model, we have delineated and dissected a critical enhancer region of the MEIS1 locus for transcription factor (TF) binding through in silico prediction in combination with oligo pull-down, mass-spectrometry and knockout analysis leading to the identification of FLI1, an E-twenty-six (ETS) transcription factor, as an important regulator of MEIS1 transcription. We further show direct binding of FLI1 to the MEIS1 locus in human AML cell lines as well as enrichment of histone acetylation in MEIS1-high healthy and leukemic cells. We also observe a positive correlation between high FLI1 transcript levels and worse overall survival in AML patients. Our study expands the role of ETS factors in AML and our model constitutes a feasible tool for a more detailed understanding of transcriptional regulatory elements and their interactome.

Objective: To compare different nasal cavity nursing methods on mechanically ventilated patients. Methods: According to acute physiology and chronic health evaluation (APACHEII), 615 cases of mechanically ventilated patients were divided into group A, group B and group C by stratified random method. Traditional oral nursing plus aspirating secretions from oral cavity and nasal cavity q6h were done in group A. Based on methods in group A, normal saline was used for cleaning nasal cavity in group B. Besides the methods in group A, atomizing nasal cleansing a6h was also used in group C. Incidence rate of Ventilator-Associated Pneumonia (VAP) and APACHE II scores after administrating were compared. The correlation between APACHE II score and outcomes was analyzed by Spearman-rank correlation. Results: In group A, incidence of VAP was 36.76%, group B was 30.24%, group C was 20.38%, and the difference was statistically significant. APACHE II scores in group C were significantly lower compared with group A and B. APACHE II score was negatively correlated with clinical outcomes. Conclusions: For mechanically ventilated patients, nasal nursing can’t be ignored and the new atomizing nasal cleaning is an effective method for VAP prevention.

Effective immunomodulation of T-cell responses is critical in treating both autoimmune diseases and cancer. Our previous studies have demonstrated that secretomes derived from control or methoxypolyethylene glycol mixed lymphocyte alloactivation assays exerted potent immunomodulatory activity that was mediated by microRNAs (miRNA). The immunomodulatory effects of biomanufactured miRNA-based allo-secretome therapeutics (SYN, TA1, IA1 and IA2) were compared to Pan T-cell activators (PHA and anti-CD3/CD28) and lymphocyte alloactivation. The differential effects of these activation strategies on resting peripheral blood mononuclear cells (PBMC) were assessed via T-cell proliferation, subset analysis and miRNA expression profiles. Mitogen-induced PBMC proliferation (> 85%) significantly exceeded that arising from either allostimulation (~ 30%) or the pro-inflammatory IA1 secretome product (~ 12%). Consequent to stimulation, the ratio of CD4 to CD8 cells of the resting PBMC (CD4:CD8; 1.7 ± 0.1) decreased in the Pan T cell, allrecognition and IA1 activated cells (averages of 1.1 ± 0.2; 1.2 ± 0.1 and 1.0 ± 0.1). These changes arose consequent to the expansion of both CD4+CD8+ and CD4–CD8– populations as well as the shrinkage of the CD4 subset and the expansion of the CD8 T cells. Importantly, these activation strategies induced vastly different miRNA expression profiles which were associated with significant differences in cellular differentiation and biological function. These findings support the concept that the “differential patterns of miRNA expression” regulate the biologic immune response in a “lock and key” manner. The biomanufacturing of miRNA-enriched secretome biotherapeutics may be a successful therapeutic approach for the systemic treatment of autoimmune diseases (TA1) and cancer (IA1).