Elucidating the importance and regulation of key enhancers for human MEIS1 expression.

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.

Passively Q-switched Tm:YAP laser with a tantalum aluminum carbide saturable absorber.

Tantalum aluminum carbide (Ta4AlC3) phase ceramic (MAX) material has attracted much attention because of its high conductivity, high strength, corrosion resistance, and good optical properties. However, there are too few reports on lasers with Ta4AlC3-based saturable absorbers (SAs). We prepared and characterized a Ta4AlC3-based SA whose nonlinear absorption performances were achieved at a 2 µm waveband range and which was used in a passively Q-switched (PQS) Tm:YAP laser. In the PQS mode, a maximum average output power of 0.78 W was achieved with the central output wavelength of 1991.86 nm from a PQS Tm:YAP laser, corresponding to a pulse duration of 926 ns at 143.8 kHz.

Differential Leukocyte MicroRNA Responses Following Pan T Cell, Allorecognition and Allosecretome-Based Therapeutic Activation.

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).

Impacts of the perioperative fast track surgery concept on the physical and psychological rehabilitation of total hip arthroplasty: A prospective cohort study of 348 patients.

ABSTRACT: 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 ±â€Š1.2 day vs 15.5 ±â€Š2.3 day, P = .021), resumed off-bed activities sooner (20.5 ±â€Š3.4 hours vs 61.8 ±â€Š4.7 hours, P = .001, had less postoperative pain (4.0 ±â€Š1.2 vs 6.5 ±â€Š1.1, P < .001), and lower anxiety and depression scores (anxiety score: 24.4 ±â€Š2.1 vs 47.9 ±â€Š2.9; depression score: 25.8 ±â€Š1.8 vs 43.7 ±â€Š1.7, 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.

Enhancing the pro-inflammatory anti-cancer T cell response via biomanufactured, secretome-based, immunotherapeutics.

T lymphocytes play a critical role in the pro-inflammatory anti-cancer response; hence, significant pharmacologic efforts have been made to enhance the endogenous T cell response. Unfortunately, significant toxicity arises consequent to pan T cell activation. In contrast, the less robust T cell alloresponse has also demonstrated an anti-cancer effect, but poses an inherent risk of GvHD. To overcome the GvHD risk, an acellular pro-inflammatory agent (IA1) has been biomanufactured from the secretome of the allorecognition response. To assess IA1's immunomodulatory activity, T cell proliferation and differentiation were determined in vitro. The pro-inflammatory properties of the IA1 therapeutic were mediated by the miRNA-enriched fractions. Moreover, cross-species efficacy was observed consequent to the evolutionary conservation of miRNA. IA1 exerted no toxicity to resting PBMC but induced significant proliferation of resting CD3+ (CD4+ and CD8+) T cells and skewed the response towards a pro-inflammatory state (i.e., increased Teff:Treg ratio). Crucially, IA1-activated PBMC demonstrated a potent inhibition of cancer cell (HeLa and SH-4 melanoma) proliferation relative to the resting PBMC. The anti-proliferation effect of IA1-activated PBMC was noted within ˜12 h versus 4-5 days for resting cells. A second biomanufactured therapeutic (IA2; produced using HeLa cells) surprisingly demonstrated direct toxicity to cancer cells but was less effective than IA1 in inducing a cell-mediated response. This study demonstrates that miRNA-enriched therapeutics can be biomanufactured from the secretome and can induce a potent pro-inflammatory, anti-cancer, effect on resting lymphocytes.