Transitional B cell cytokines predict renal allograft outcomes

Early immunological biomarkers that predict rejection and chronic allograft loss are needed to inform preemptive therapy and improve long-term outcomes. Here, we prospectively examined the ratio of interleukin-10 (IL-10) to tumor necrosis factor–α (TNFα) produced by transitional-1 B cells (T1B) 3 months after transplantation as a predictive biomarker for clinical and subclinical renal allograft rejection and subsequent clinical course. In both Training (n = 162) and Internal Validation (n = 82) Sets, the T1B IL-10/TNFα ratio 3 months after transplantation predicted both clinical and subclinical rejection anytime in the first year. The biomarker also predicted subsequent late rejection with a lead time averaging 8 months. Among biomarker high-risk patients, 60% had early rejection, of which 48% recurred later in the first posttransplant year. Among high-risk patients without early rejection, 74% developed rejection later in the first year. In contrast, only 5% of low-risk patients had early and 5% late rejection. The biomarker also predicted rejection in an External Validation Set (n = 95) and in key patient subgroups, confirming generalizability. Biomarker high-risk patients exhibited progressively worse renal function and decreased 5-year graft survival compared to low-risk patients. Treatment of B cells with anti-TNFα in vitro augmented the IL-10/TNFα ratio, restored regulatory activity, and inhibited plasmablast differentiation. To conclude, the T1B IL-10/TNFα ratio was validated as a strong predictive biomarker of renal allograft outcomes and provides a rationale for preemptive therapeutic intervention with TNF blockade

The Profile Improvement of Vocational School Teachers’ Competencies

This study is aimed to reveal the improvement in the competency of productive teachers of both state and private vocational high schools in Sleman Regency after participating in a self-development program in terms of psychological maturity and socio-cultural aspects. This study was carried out in two state vocational high schools SMKN 1 Sedayu and SMKN 1 Seyegan, and one private vocational high school SMK Muhammadiyah Pakem. It was a qualitative study in nature using interview and documentation as the means of collecting the data. Fifteen productive teachers of the three vocational high schools with expertise in Building Engineering Drawing (BED) were purposively selected to be the research subjects. The obtained data in the form of interview tapescripts, photos, and documents were triangulated to ensure data validity. The data were then analyzed systematically through three main stages including open coding, axial coding, and selective coding. The results show that through self-development, the BED productive teachers in state vocational high schools can improve their pedagogical and professional competencies. In addition, this program also develops their knowledge and skills in the areas of curriculum, expertise, technology, as well as teaching strategies and methods. Even so, in the case of BED productive teachers in private vocational high schools, this self-development program does not significantly improve their competencies

Two-dimensional SnS and SnSe as hosts of K-ion storage: a first-principles prediction

Potassium ion batteries (KIBs) have attracted remarkable consideration due to their intrinsic safety and huge availability of potassium. However, the large size of the K ion and low charge−discharge efficiency are the main obstacles to the progress of KIBs. To overcome these hurdles, we chose SnS and SnSe monolayers as K anodes for KIBs due to their layered structural assemblies, wider surface area to accommodate more K content, and high thermal stabilities. First-principles simulations were carried out to study the electronic properties and K storage capability of SnS and SnSe monolayers as anode materials for KIBs. We found that K adsorption enhances the electrical conductivity of both SnS and SnSe monolayers, which become metallic after the adsorption of a very minor concentration of K. The outcomes of the ab initio molecular dynamic simulations display the thermal stability of the host materials for KIBs. According to our calculations, the theoretical capacities of SnS and SnSe monolayers are 355 and 271 mA h/g, respectively. Consequently, we obtain very low average voltages of 0.45 V for SnS and 0.36 V for SnSe monolayers. In addition, the low diffusion barriers for the K-ion on SnS and SnSe monolayers are 0.14 and 0.16 eV, correspondingly, illustrating the fast ion transfer rate with rapid potassiation and depotassiation. These intriguing results suggest that SnS and SnSe monolayers could be promising anode materials for KIBs

B-cell-specific checkpoint molecules that regulate anti-tumour immunity.

The role of B cells in anti-tumour immunity is still debated and, accordingly, immunotherapies have focused on targeting T and natural killer cells to inhibit tumour growth1,2. Here, using high-throughput flow cytometry as well as bulk and single-cell RNA-sequencing and B-cell-receptor-sequencing analysis of B cells temporally during B16F10 melanoma growth, we identified a subset of B cells that expands specifically in the draining lymph node over time in tumour-bearing mice. The expanding B cell subset expresses the cell surface molecule T cell immunoglobulin and mucin domain 1 (TIM-1, encoded by Havcr1) and a unique transcriptional signature, including multiple co-inhibitory molecules such as PD-1, TIM-3, TIGIT and LAG-3. Although conditional deletion of these co-inhibitory molecules on B cells had little or no effect on tumour burden, selective deletion of Havcr1 in B cells both substantially inhibited tumour growth and enhanced effector T cell responses. Loss of TIM-1 enhanced the type 1 interferon response in B cells, which augmented B cell activation and increased antigen presentation and co-stimulation, resulting in increased expansion of tumour-specific effector T cells. Our results demonstrate that manipulation of TIM-1-expressing B cells enables engagement of the second arm of adaptive immunity to promote anti-tumour immunity and inhibit tumour growth

Risk factors in the development of stem cell therapy

Stem cell therapy holds the promise to treat degenerative diseases, cancer and repair of damaged tissues for which there are currently no or limited therapeutic options. The potential of stem cell therapies has long been recognised and the creation of induced pluripotent stem cells (iPSC) has boosted the stem cell field leading to increasing development and scientific knowledge. Despite the clinical potential of stem cell based medicinal products there are also potential and unanticipated risks. These risks deserve a thorough discussion within the perspective of current scientific knowledge and experience. Evaluation of potential risks should be a prerequisite step before clinical use of stem cell based medicinal products

A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma

<p>Abstract</p> <p>Background</p> <p>Ipilimumab, a fully human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4, has demonstrated an improvement in overall survival in two phase III trials of patients with advanced melanoma. The primary objective of the current trial was to prospectively explore candidate biomarkers from the tumor microenvironment for associations with clinical response to ipilimumab.</p> <p>Methods</p> <p>In this randomized, double-blind, phase II biomarker study (ClinicalTrials.gov NCT00261365), 82 pretreated or treatment-naïve patients with unresectable stage III/IV melanoma were induced with 3 or 10 mg/kg ipilimumab every 3 weeks for 4 doses; at Week 24, patients could receive maintenance doses every 12 weeks. Efficacy was evaluated per modified World Health Organization response criteria and safety was assessed continuously. Candidate biomarkers were evaluated in tumor biopsies collected pretreatment and 24 to 72 hours after the second ipilimumab dose. Polymorphisms in immune-related genes were also evaluated.</p> <p>Results</p> <p>Objective response rate, response patterns, and safety were consistent with previous trials of ipilimumab in melanoma. No associations between genetic polymorphisms and clinical activity were observed. Immunohistochemistry and histology on tumor biopsies revealed significant associations between clinical activity and high baseline expression of FoxP3 (p = 0.014) and indoleamine 2,3-dioxygenase (p = 0.012), and between clinical activity and increase in tumor-infiltrating lymphocytes (TILs) between baseline and 3 weeks after start of treatment (p = 0.005). Microarray analysis of mRNA from tumor samples taken pretreatment and post-treatment demonstrated significant increases in expression of several immune-related genes, and decreases in expression of genes implicated in cancer and melanoma.</p> <p>Conclusions</p> <p>Baseline expression of immune-related tumor biomarkers and a post-treatment increase in TILs may be positively associated with ipilimumab clinical activity. The observed pharmacodynamic changes in gene expression warrant further analysis to determine whether treatment-emergent changes in gene expression may be associated with clinical efficacy. Further studies are required to determine the predictive value of these and other potential biomarkers associated with clinical response to ipilimumab.</p

An Observational Cohort Study of the Kynurenine to Tryptophan Ratio in Sepsis: Association with Impaired Immune and Microvascular Function

Both endothelial and immune dysfunction contribute to the high mortality rate in human sepsis, but the underlying mechanisms are unclear. In response to infection, interferon-γ activates indoleamine 2,3-dioxygenase (IDO) which metabolizes the essential amino acid tryptophan to the toxic metabolite kynurenine. IDO can be expressed in endothelial cells, hepatocytes and mononuclear leukocytes, all of which contribute to sepsis pathophysiology. Increased IDO activity (measured by the kynurenine to tryptophan [KT] ratio in plasma) causes T-cell apoptosis, vasodilation and nitric oxide synthase inhibition. We hypothesized that IDO activity in sepsis would be related to plasma interferon-γ, interleukin-10, T cell lymphopenia and impairment of microvascular reactivity, a measure of endothelial nitric oxide bioavailability. In an observational cohort study of 80 sepsis patients (50 severe and 30 non-severe) and 40 hospital controls, we determined the relationship between IDO activity (plasma KT ratio) and selected plasma cytokines, sepsis severity, nitric oxide-dependent microvascular reactivity and lymphocyte subsets in sepsis. Plasma amino acids were measured by high performance liquid chromatography and microvascular reactivity by peripheral arterial tonometry. The plasma KT ratio was increased in sepsis (median 141 [IQR 64–235]) compared to controls (36 [28–52]); p<0.0001), and correlated with plasma interferon-γ and interleukin-10, and inversely with total lymphocyte count, CD8+ and CD4+ T-lymphocytes, systolic blood pressure and microvascular reactivity. In response to treatment of severe sepsis, the median KT ratio decreased from 162 [IQR 100–286] on day 0 to 89 [65–139] by day 7; p = 0.0006) and this decrease in KT ratio correlated with a decrease in the Sequential Organ Failure Assessment score (p<0.0001). IDO-mediated tryptophan catabolism is associated with dysregulated immune responses and impaired microvascular reactivity in sepsis and may link these two fundamental processes in sepsis pathophysiology

A Short Review of Hydrophilic Surface Modification Methods for Low Density Poly Ethylene

In this review, the effect of chemicals, flame radiation, grafting and their combination on the surface of low density polyethylene (LDPE)were studied.Like the most of the polymers, LDPE is inherently hydropolic; we explored the possible options for redenring the polymer surface hydrophilic without changes in bulk properties of the polymer producing improved wettability mainly due to introduction of function group moieties. It was concluded that wettability was associated with concentration and types of functional groups and consequent changes in the contact angle. It was also found that each method for introducing hydrophilicity has advantages and disadvantages of its own and a combination of methods can be applied catering a specific demand. This introduction of wettability would greatly benefit in enhancing innovative use of LDPE in industrial end products like wetting agents, protective films, anti-static fibers, antifogging surfaces, printable polymers and many others related goods

Characterization of Functionalized Low Density Polyethylene/Polyaniline Nano Fiber Composite

Nano composite based on polyaniline (PANI) nano fibers filler and chromic acid functionalized low density polyethylene (LDPE) matrix with biocompatibility and low percolation threshold value was prepared via twin screw extrusion process. Density measurement, Fourier Transform Infrared Spectroscopy (FTIR), Field Emission Electron Microscopy (FESEM), Energy-dispersive X-ray spectroscopy (EDX), X-ray crystallography (XRD), Brunauer, Emmett and Teller analysis (BET), Thermo Gravimetric (TGA), Differential Scanning Calorimetery (DSC) and Four-Probe Conductivity measurements are reported. As low density polyethylene functionalization renders LDPE more biocompatible, it also facilitates conductivity due to carbon carbon double bonds, sulfonic, and carbonyl group moieties. PANI nano fibers also assist in charge transfer mechanism of resultant composite. Overall results indicate the formation of highly stable nanocomposite materials, with good physiochemical properties and conductivity. The resultant blend may prove beneficial as a low cost biocompatible and electrically simulated nerve tissue repair scaffolds

Sulfonation of Low-density Polyethylene and Its Impact on Polymer Properties

Sulfonation of polymers is of great importance for the packaging industry mainly due to its effect on the alteration of surface functionality of polymer films. In this study we customized liquid phase sulfonation of low-density polyethylene (LDPE) swelling the polymer by using a combination of polar and nonpolar solvents. Swollen polymer was treated with sulfuric acid of varying concentrations with continuous mixing for in-depth sulfonation of the polymer. Presence of cyclohexane and ethanol, as polar and nonpolar reagents, not only kept the batch under isothermal conditions but also homogenously influenced in-depth functionalization of LDPE. The durability of the sulfonated polymer was determined by grinding the test samples 30 days after the reaction. Fourier transform-infrared spectroscopy indicated presence of functional group moieties, which is also supported by increase of 5% and 1.35% in density and sulfur contents of the polymer, respectively. Contact angle measurements indicate 30° decrease in values of the sulfonated polymer which corresponds with decrease in carbon to hydrogen ratio (from 5.9 to 5.3) and increase in sulfur to carbon ratio (up to 0.0184) resulting from the sulfonation of the polymer. Differential scanning calorimetery results indicate almost linear reduction in the crystallinity of LDPE with an increase in acid concentration used for the sulfonation reaction