A secreted PD-L1 splice variant that covalently dimerizes and mediates immunosuppression

Targeting immune checkpoint pathways, such as programmed death ligand-1 (PD-L1, also known as CD274 or B7-H1) or its receptor programmed cell death-1 (PD-1) has shown improved survival for patients with numerous types of cancers, not limited to lung cancer, melanoma, renal cell carcinoma, and Hodgkin lymphoma. PD-L1 is a co-inhibitory molecule whose expression on the surface of tumor cells is associated with worse prognosis in many tumors. Here we describe a splice variant (secPD-L1) that does not splice into the transmembrane domain, but instead produces a secreted form of PD-L1 that has a unique 18 amino acid tail containing a cysteine that allows it to homodimerize and more effectively inhibit lymphocyte function than monomeric soluble PD-L1. We show that recombinant secPD-L1 can dimerize and inhibit T-cell proliferation and IFN-gamma production in vitro. The secPD-L1 variant is expressed by malignant cells in vitro that also express high levels of full-length PD-L1. Transcriptomic analysis of gene expression across The Cancer Genome Atlas found the strongest association of secPD-L1 with full-length PD-L1, but also with subsets of immunologic genes, such as in myeloid-derived suppressor cells. Moreover, the splice variant is also expressed in normal tissues and within normal peripheral blood cells it is preferentially expressed in activated myeloid cells. This is the first report of a form of secreted PD-L1 that homodimerizes and is functionally active. SecPD-L1 may function as a paracrine negative immune regulator within the tumor, since secPD-L1 does not require a cell-to-cell interaction to mediate its inhibitory effect

Peak Stir Zone Temperatures during Friction Stir Processing

The stir zone (SZ) temperature cycle was measured during the friction stir processing (FSP) of NiAl bronze plates. The FSP was conducted using a tool design with a smooth concave shoulder and a 12.7-mm step-spiral pin. Temperature sensing was accomplished using sheathed thermocouples embedded in the tool path within the plates, while simultaneous optical pyrometry measurements of surface temperatures were also obtained. Peak SZ temperatures were 990 ⁰Cto 1015 ⁰C (0.90 to 0.97 TMelt) and were not affected by preheating to 400⁰C, although the dwell time above 900 ⁰C was increased by the preheating. Thermocouple data suggested little variation in peak temperature across the SZ, although thermocouples initially located on the advancing sides and at the centerlines of the tool traverses were displaced to the retreating sides, precluding direct assessment of the temperature variation across the SZ. Microstructure-based estimates of local peak SZ temperatures have been made on these and on other similarly processed materials. Altogether, the peak-temperature determinations from these different measurement techniques are in close agreement

The influence of carotenoid and chlorophyll content on the oxidative processes in the selected vegetable oils

Purpose: More than 100 plant species have been classified as oil products, but only a few of them are used in industrial production. In the available literature, there are no studies that would describe the relationship between the content of plant dyes and their impact on auto-oxidative processes. Therefore, this study aimed to determine dye composition and to define their effect on the acid value, peroxide value and quality assessment of selected refined and unrefined oils. Materials and methods: Twenty samples from different manufacturers were evaluated. Oils were purchased from retail trade of the Bialystok city. The total colour, acid, and peroxide values were determined in accordance with the Polish Standards PN-ISO 3960: 1996, PN-A-86934: 1995 and PN-ISO 3960: 1996, respectively. Results: Statistically significant differences of total colour values between both groups were found (p=0.002). The acid value of refined oils was lower than in an unrefined group (p=0.02). A positive statistically significant correlation was noticed between the total colour value and the acid value in the refined group (R=0.65, p=0.04). No significant effect of plant dyes on the acid or peroxide value of unrefined oils was observed. Conclusions: Refined and unrefined oils purchased in the city of Bialystok mostly met the standard values with the exception of cold-pressed oil from black cumin seeds, where the acid and peroxide value exceeded the values set in Codex Alimentarius

Association of pediatric psoriasis severity with excess and central adiposity: an international cross-sectional study

Item does not contain fulltextOBJECTIVE: To investigate the relationship of excess and central adiposity with pediatric psoriasis severity. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, cross-sectional study of 409 psoriatic children. Psoriasis was classified as mild (worst Physician's Global Assessment score /=3 with body surface area >10%). Children were enrolled from 9 countries between June 19, 2009, and December 2, 2011. MAIN OUTCOME MEASURES: Excess adiposity (body mass index percentile) and central adiposity (waist circumference percentile and waist to height ratio). RESULTS: Excess adiposity (body mass index >/=85th percentile) occurred in 37.9% of psoriatic children (n=155) vs 20.5% of controls (n=42) but did not differ significantly by severity. The odds ratio (95% CI) of obesity (body mass index >/=95th percentile) overall in psoriatic children vs controls was 4.29 (1.96-9.39) and was higher with severe (4.92; 2.20-10.99) than with mild (3.60; 1.56-8.30) psoriasis, particularly in the United States (7.60; 2.47-23.34, and 4.72; 1.43-15.56, respectively). Waist circumference above the 90th percentile occurred in 9.3% of the control (n=19), 14.0% of the mild psoriasis (n=27), and 21.2% of the of severe psoriasis (n=43) participants internationally; this incidence was highest in the United States (12.0% [n=13], 20.8% [16], and 31.1% [32], respectively). Waist to height ratio was significantly higher in psoriatic (0.48) vs control (0.46) children but was unaffected by psoriasis severity. Children with severe psoriasis at its worst, but mild at enrollment, showed no significant difference in excess or central adiposity from children whose psoriasis remained severe. CONCLUSIONS: Globally, children with psoriasis have excess adiposity and increased central adiposity regardless of psoriasis severity. The increased metabolic risks associated with excess and central adiposity warrant early monitoring and lifestyle modification. Trial Registration: clinicaltrials.gov Identifier: NCT0087994