Mesenchymal stromal cells (MSCs) are strongly immunosuppressive via producing nitric oxide (NO) and known to migrate into tumor sites to promote tumor growth, but the underlying mechanisms remain ...largely elusive. Here, we found that interferon alpha (IFNα)-secreting MSCs showed more dramatic inhibition effect on tumor progression than that of IFNα alone. Interestingly, IFNα-primed MSCs could also effectively suppress tumor growth. Mechanistically, we demonstrated that both IFNα and IFNβ (type I IFNs) reversed the immunosuppressive effect of MSCs on splenocyte proliferation. This effect of type I IFNs was exerted through inhibiting inducible NO synthase (iNOS) expression in IFNγ and TNFα-stimulated MSCs. Notably, only NO production was inhibited by IFNα; production of other cytokines or chemokines tested was not suppressed. Furthermore, IFNα promoted the switch from signal transducer and activator of transcription 1 (Stat1) homodimers to Stat1-Stat2 heterodimers. Studies using the luciferase reporter system and chromatin immunoprecipitation assay revealed that IFNα suppressed iNOS transcription through inhibiting the binding of Stat1 to iNOS promoter. Therefore, the synergistic anti-tumor effects of type I IFNs and MSCs were achieved by inhibiting NO production. This study provides essential information for understanding the mechanisms of MSC-mediated immunosuppression and for the development of better clinical strategies using IFNs and MSCs for cancer immunotherapy.
Abstract Background With the shift of our healthcare system toward a value-based system of reimbursement, complications such as surgical site infections (SSI) may not be reimbursed. The purpose of ...our study was to investigate the costs and risk factors of SSI for orthopedic trauma patients. Methods Through retrospective analysis, 1819 patients with isolated fractures were identified. Of those, 78 patients who developed SSIs were compared to 78 uninfected control patients. Patients were matched by fracture location, type of fracture, duration of surgery, and as close as possible to age, year of surgery, and type of procedure. Costs for treatment during primary hospitalization and initial readmission were determined and potential risk factors were collected from patient charts. A Wilcoxon test was used to compare the overall costs of treatment for case and control patients. Costs were further broken down into professional fees and technical charges for analysis. Risk factors for SSIs were analyzed through a chi-squared analysis. Results Median cost for treatment for patients with SSIs was $108,782 compared to $57,418 for uninfected patients ( p < 0.001). Professional fees and technical charges were found to be significantly higher for infected patients. No significant risk factors for SSIs were determined. Conclusions Our findings indicate the potential for financial losses in our new healthcare system due to uncompensated care. SSIs nearly double the cost of treatment for orthopedic trauma patients. There is no single driver of these costs. Reducing postoperative stay may be one method for reducing the cost of treating SSIs, whereas quality management programs may decrease risk of infection.
Summary
Background
INCB018424 is a novel, potent Janus kinase (JAK)1/JAK2 inhibitor that blocks signal transduction of multiple proinflammatory cytokines.
Objectives
To evaluate the safety, ...tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy of topical INCB018424 phosphate cream in patients with plaque psoriasis.
Methods
Topical INCB018424 phosphate 1·0% or 1·5% cream was applied once daily (QD) or twice daily (BID) for 4 weeks to 2–20% body surface area in five sequential cohorts of five patients aged 18–65 years. Target lesions were scored on a scale of 0–4 for erythema, scaling and thickness. Additionally, the overall disease activity in each patient was measured using Physician's Global Assessment. INCB018424 concentrations were measured in plasma, and cytokine stimulated phosphorylated signal transducer and activator of transcription 3 phosphorylation (pSTAT3) levels in peripheral blood cells were evaluated. Pretreatment and post‐treatment skin biopsies were compared with healthy skin, including evaluation of histopathology, immunohistochemistry and mRNA expression.
Results
Treatment with INCB018424 phosphate cream either 1·0% QD or 1·5% BID resulted in improvements in lesion scores. No significant inhibition of pSTAT3 in peripheral blood cells was observed following topical application, consistent with the generally low steady‐state plasma concentrations of INCB018424 measured. Transcriptional markers of immune cell lineage/activation in lesional skin were reduced by topical INCB018424, with correlations observed between clinical improvement and decreases in markers of T helper 17 lymphocyte activation, dendritic‐cell activation and epidermal hyperplasia. INCB018424 treatment reduced epidermal hyperplasia and dermal inflammation in most patient samples, with reductions in CD3, CD11c, Ki67 and keratin 16 observed by immunohistochemical analysis.
Conclusions
Topical INCB018424 dosed for 28 days QD or BID is pharmacologically active in patients with active psoriasis and modulates proinflammatory cytokines in the pathogenesis of psoriatic lesions.
What's already known about this topic?
Cytokines are implicated in the pathogenesis of psoriasis, and Janus kinase (JAK) inhibitors have efficacy in psoriasis.
Many of the cytokines implicated in the pathogenesis of psoriasis signal via the JAK–signal transducer and activator of transcription (STAT) pathway.
What does this study add?
This study showed that the topical JAK1/JAK2 inhibitor INCB018424 is pharmacologically active in patients with active psoriasis, modulates proinflammatory cytokines, and is well tolerated.
JAK–STAT inhibition with INCB018424 cream may represent a new treatment option in psoriasis.
ABSTRACT The LAMOST-Kepler project was designed to obtain high-quality, low-resolution spectra of many of the stars in the Kepler field with the Large Sky Area Multi Object Fiber Spectroscopic ...Telescope (LAMOST) spectroscopic telescope. To date 101,086 spectra of 80,447 objects over the entire Kepler field have been acquired. Physical parameters, radial velocities, and rotational velocities of these stars will be reported in other papers. In this paper we present MK spectral classifications for these spectra determined with the automatic classification code MKCLASS. We discuss the quality and reliability of the spectral types and present histograms showing the frequency of the spectral types in the main table organized according to luminosity class. Finally, as examples of the use of this spectral database, we compute the proportion of A-type stars that are Am stars, and identify 32 new barium dwarf candidates.
Altered transforming growth factor (TGF)-β expression levels have been linked to a variety of human respiratory diseases, including bronchopulmonary dysplasia and pulmonary fibrosis. However, a ...causative role for aberrant TGF-β in neonatal lung diseases has not been defined in primates.
Exogenous and transient TGF-β1 overexpression in fetal monkey lung was achieved by transabdominal ultrasound-guided fetal intrapulmonary injection of adenoviral vector expressing TGF-β1 at the second or third trimester of pregnancy. The lungs were then harvested near term, and fixed for histology and immunohistochemistry.
Lung hypoplasia was observed where TGF-β1 was overexpressed during the second trimester. The most clearly marked phenotype consisted of severe pulmonary and pleural fibrosis, which was independent of the gestational time point when TGF-β1 was overexpressed. Increased cell proliferation, particularly in α-smooth muscle actin-positive myofibroblasts, was detected within the fibrotic foci. But epithelium to mesenchyme transdifferentiation was not detected. Massive collagen fibres were deposited on the inner and outer sides of the pleural membrane, with an intact elastin layer in the middle. This induced fibrotic pathology persisted even after adenoviral-mediated TGF-β1 overexpression was no longer evident.
Therefore, overexpression of TGF-β1 within developing fetal monkey lung results in severe and progressive fibrosis in lung parenchyma and pleural membrane, in addition to pulmonary hypoplasia.
The role of fatty acid synthase (FASN) on de novo fatty acid synthesis has been well established. In monogastrics, unlike acetyl-coenzyme A carboxylase, FASN is primarily controlled at the ...transcriptional level. However, no data exist on ruminant mammary cells evaluating effects of FASN knockdown on mRNA expression of lipogenic genes. Inhibition of FASN in mammary cells by C75-mediated interference, a synthetic inhibitor of FASN activity, and short hairpin RNA–mediated interference markedly reduced cellular triglyceride content at least in part by decreasing the expression of genes related to triglyceride synthesis (GPAT, AGPAT6, and DGAT2) and enhancing the expression of lipolysis-related genes (ATGL and HSL). Consistent with the markedly lower expression of genes related to lipid droplet formation and secretion (TIP47, ADFP, BTN1A1, and XDH), cellular lipid droplets also were reduced sharply after incubation with C75 or adenovirus-short-hairpin-RNA. The results underscored the essential role of FASN in the overall process of milk-fat formation in goat mammary epithelial cells.
The as-produced isomer mixture of the organic photovoltaic device acceptor material bis-60PCBM has been purified into its constituents by peak-recycling HPLC, and those individual isomers were ...characterised by UV-Vis absorption spectroscopy and cyclic voltammetry. A total of 18 isomers were purified from the mixture to a standard exceeding 99.5% with respect to other isomers. The HOMOs, LUMOs, and HOMO-LUMO gaps of the purified isomers vary from -5.673 to -5.444 eV, -3.901 to -3.729 eV, and 1.664 to 1.883 eV, respectively. We also find a correlation between HPLC retention time and the relative positions of the addends; in that generally the closer the addends are to each other the longer the retention time of the isomer, and vice versa.
We search for lepton-flavor-violating τ^{-}→e^{-}α and τ^{-}→μ^{-}α decays, where α is an invisible spin-0 boson. The search uses electron-positron collisions at 10.58 GeV center-of-mass energy with ...an integrated luminosity of 62.8 fb^{-1}, produced by the SuperKEKB collider and collected with the Belle II detector. We search for an excess in the lepton-energy spectrum of the known τ^{-}→e^{-}νover ¯_{e}ν_{τ} and τ^{-}→μ^{-}νover ¯_{μ}ν_{τ} decays. We report 95% confidence-level upper limits on the branching-fraction ratio B(τ^{-}→e^{-}α)/B(τ^{-}→e^{-}νover ¯_{e}ν_{τ}) in the range (1.1-9.7)×10^{-3} and on B(τ^{-}→μ^{-}α)/B(τ^{-}→μ^{-}νover ¯_{μ}ν_{τ}) in the range (0.7-12.2)×10^{-3} for α masses between 0 and 1.6 GeV/c^{2}. These results provide the most stringent bounds on invisible boson production from τ decays.
This volume examines trends in inequality in the People's Republic of China. It contains findings on inequality nationwide, as well as within the rural and urban sectors, with an emphasis on public ...policy considerations. Several chapters focus on inequality of income; others analyse poverty, inequality in wealth, and the distribution of wages. Attention is given to groups such as migrants, women, and the elderly, as well as the relationship between income and health care funding and the impact of the rural tax reform. All contributors to this volume make use of a large, nationwide survey of Chinese households, the product of long-term co-operation between Chinese and international researchers that is unique in its scope and duration. Using these data, the contributors examine changes in inequality from 1988 to 2002.
A novel aggregated multiposition noncontact mapping (AMP-NCM) algorithm is proposed to diagnose cardiac arrhythmias.
The purpose of this study was to computationally determine an accuracy threshold ...and to compare the accuracy and clinical utility of AMP-NCM to gold standard contact mapping.
In a cellular automata model, the number of catheter positions and chamber coverage were varied to establish accuracy requirements for clinically relevant AMP-NCM. This guided the clinical study protocol. In a prospective cohort of patients with atrial tachycardia (AT), noncontact mapping (NCM) recordings from a single position (SP) and multiple positions were compared to contact mapping with a high-density multipolar catheter using morphology and timing differences of reconstructed signals. Identification of AT mechanisms and ablation targets using both AMP-NCM and contact mapping were randomly evaluated by 5 blinded reviewers.
AMP-NCM accuracy was asymptotic at 60 catheter positions in computational modeling. Twenty patients (age 65 ± 12 years; 19 male) with 26 ATs (5 focal, 21 reentrant) were studied. Morphologic correlation of signals derived from AMP-NCM was significantly better than those from SP-NCM compared to contact signals (median 0.93 vs 0.76; P <.001). AMP-NCM generated maps more rapidly than contact mapping (3 ± 1 minutes vs 13 ± 6 minutes; P <.001) and correctly diagnosed AT mechanisms in 25 of 26 maps (96%). Overall, 80% of arrhythmia mechanisms were correctly identified using AMP-NCM by blinded reviewers.
Once 60 catheter positions were achieved, AMP-NCM successfully diagnosed mechanisms of AT and identified treatment sites equal to gold standard contact mapping in 3 minutes of procedural time.
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