Blockade of trans PD-L1 interaction with CD80 augments antitumor immunity.

PD-L1 has two receptors: PD-1 and CD80. Previous reports assumed that PD-L1 and CD80 interacted in trans, but recent reports showed that only cis PD-L1/CD80 interactions existed, and prevention of cis PD-L1/CD80 interactions on antigen-presenting cells (APCs) reduced antitumor immunity via augmenting PD-L1/PD-1 and CD80/CTLA4 interactions between T and APCs. Here, using tumor-bearing mice capable of cis and trans or trans only PD-L1/CD80 interactions, we show that trans PD-L1/CD80 interactions do exist between tumor and T cells, and the effects of trans PD-L1/CD80 interactions require tumor cell expression of MHC-I and T cell expression of CD28. The blockade of PD-L1/CD80 interactions in mice with both cis and trans interactions or with only trans interactions augments antitumor immunity by expanding IFN-γ-producing CD8+ T cells and IFN-γ-dependent NOS2-expressing tumor-associated macrophages. Our studies indicate that although cis and trans PD-L1/CD80 interactions may have opposite effects on antitumor immunity, the net effect of blocking PD-L1/CD80 interactions in vivo augments CD8+ T cell-mediated antitumor immunity.

Asymmetrically Doping a Platinum Atom into a Au38 Nanocluster for Changing the Electron Configuration and Reactivity in Electrocatalysis.

It is an obstacle to precisely manipulate a doped heteroatom into a desired position in a metal nanocluster. Herein, we overcome this difficulty to obtain Pt1 Au37 (SCH2 Pht Bu)24 and Pt2 Au36 (SCH2 Pht Bu)24 nanoclusters via controllably doping Pt atoms into the kernels of Au38 (SCH2 Pht Bu)24 . We reveal that asymmetrical doping of one Pt atom into either of the cores of Au38 (SCH2 Pht Bu)24 elevates the relative energy of the HOMO (highest occupied molecular orbital) accompanied by one valence electron loss of Pt1 Au37 (SCH2 Pht Bu)24 , compared to Au38 (SCH2 Pht Bu)24 with 14 electrons, while symmetrical doping of two Pt atoms into the cores of Au38 (SCH2 Pht Bu)24 narrows the HOMO-LUMO gap (LUMO: lowest unoccupied molecular orbital) of Pt2 Au36 (SCH2 Pht Bu)24 with two valence electrons less. Consequently, Pt1 Au37 (SCH2 Pht Bu)24 shows an electron-spin-induced high activity for CO2 electroreduction, whereas Pt2 Au36 (SCH2 Pht Bu)24 is least efficient and Au38 (SCH2 Pht Bu)24 has a decent performance.

microRNA-142 guards against autoimmunity by controlling Treg cell homeostasis and function.

Regulatory T (Treg) cells are critical in preventing aberrant immune responses. Posttranscriptional control of gene expression by microRNA (miRNA) has recently emerged as an essential genetic element for Treg cell function. Here, we report that mice with Treg cell-specific ablation of miR-142 (hereafter Foxp3CremiR-142fl/fl mice) developed a fatal systemic autoimmune disorder due to a breakdown in peripheral T-cell tolerance. Foxp3CremiR-142fl/fl mice displayed a significant decrease in the abundance and suppressive capacity of Treg cells. Expression profiling of miR-142-deficient Treg cells revealed an up-regulation of multiple genes in the interferon gamma (IFNγ) signaling network. We identified several of these IFNγ-associated genes as direct miR-142-3p targets and observed excessive IFNγ production and signaling in miR-142-deficient Treg cells. Ifng ablation rescued the Treg cell homeostatic defect and alleviated development of autoimmunity in Foxp3CremiR-142fl/fl mice. Thus, our findings implicate miR-142 as an indispensable regulator of Treg cell homeostasis that exerts its function by attenuating IFNγ responses.

Molecular Dynamics Simulation of Ion Adsorption and Ligand Exchange on an Orthoclase Surface.

Orthoclase (K-feldspar) is one of the natural inorganic materials, which shows remarkable potential toward removing heavy metal ions from aqueous solutions. Understanding the interactions of the orthoclase and metal ions is important in the treatment of saline wastewater. In this paper, molecular dynamics simulations were used to prove the adsorption of different ions onto orthoclase. The adsorption isotherms show that orthoclase has remarkable efficiency in the removal of cations at low ion concentrations. Aluminol groups are the preferential adsorption sites of cations due to higher negative charges. The adsorption types and adsorption sites are influenced by the valence, radius, and hydration stability of ions. Monovalent cations can be adsorbed in the cavities, whereas divalent cations cannot. The hydrated cation may form an outer-sphere complex or an inner-sphere complex in association with the loss of hydration water. Na+, K+, and Ca2+ ions mainly undergo inner-sphere adsorption and Mg2+ ions prefer outer-sphere adsorption. On the basis of simulation results, the mechanism of ion removal in the presence of orthoclase is demonstrated at a molecular level.

Publisher Correction: The international staging system improves the IPI risk stratification in patients with diffuse large B-cell lymphoma treated with R-CHOP.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Retinoic acid receptor α expression exerts an anti-apoptosis effect on PC12 cells following oxygen-glucose deprivation.

It has been established that the primary form of neuron death following hypoxic ischemic brain damage is apoptosis. Imbalances in the expression of genes in the B-cell lymphoma 2 (Bcl-2) family located in the mitochondrion, and in the expression of their encoded proteins, are key events in the mitochondrial apoptotic pathway, which lead to damage of cellular structure and function. The present study aimed to explore the regulatory effect of retinoic acid receptor α (RAR-α) on the apoptosis of PC12 cells induced by oxygen-glucose deprivation (OGD) in the retinoic acid signaling pathway. Recombinant adenovirus RAR-α small interfering RNA (Ad-siRAR-α) was used to transduce PC12 cells, and the efficiency of RAR-α expression inhibition was detected by semi-quantitative reverse transcription polymerase chain reaction (RT-PCR). An empty adenovirus vector was transfected in PC12 cells, which were used as the control. Flow cytometry with Annexin V-propidium iodide (PI) and fluorescence probe JC-1 staining was used to detect the apoptosis rate and mitochondrial transmembrane potential (MMP), respectively, of PC12 cells after transduction with Ad-siRAR-α. Furthermore, the expression levels of key genes in the RAR-α and mitochondrial apoptotic pathway, Bcl-2 and Bcl-2-associated protein (Bax) were analyzed by RT-quantitative (q)PCR and western blot analysis. RAR-α mRNA expression was observed to be decreased in PC12 cells following OGD-induced injury, and this decrease can be reversed by 4 µmol/l ATRA treatment. After 36 h transfection with Ad-siRAR-α, RAR-α gene expression was significantly inhibited compared with the control (P<0.05). The results of Annexin V-PI, fluorescence probe JC-1 staining and flow cytometry demonstrated that the apoptosis rate significantly increased and MMP significantly decreased in OGD-induced PC12 cells following transduction with Ad-siRAR-α compared with the control (both P<0.05). RT-qPCR and western blot analysis indicated that Bax expression was significantly increased and Bcl-2 expression was significantly decreased in PC12 cells transduced with Ad-siRAR-α after OGD-induced injury at the mRNA and protein level (P<0.05). In conclusion, Ad-siRAR-α transduction could promote apoptosis in OGD-induced PC12 cells. This suggests that the expression of Bax and Bcl-2 in the mitochondrial apoptosis signaling pathway is, at least in part, mediated by RAR-α expression, thereby indicating that RAR-α expression exerts an anti-apoptotic effect on OGD-damaged PC12 cells.

High-Dose Tanshinone IIA Suppresses Migration and Proliferation While Promoting Apoptosis of Astrocytoma Cells Via Notch-1 Pathway.

Malignant astrocytoma is the most common malignant tumor with strong invasion in the central nervous system. Tanshinone IIA is an effective compound to suppress cell proliferation and promote cell apoptosis. However, there is little research about the role of tanshinone IIA in the treatment of astrocytoma. This study aimed to investigate the effect of tanshinone IIA on migration, proliferation and apoptosis of astrocytoma cells. The efficacy of tanshinone IIA on migration, proliferation and apoptosis of astrocytoma cells were evaluated by flow cytometry and the assays of plate clone formation, CCK-8, wound healing and transwell migration. The protein molecule and signaling pathway were detected by western blot. High-dose tanshinone IIA suppressed migration and proliferation of astrocytoma cells while promoting apoptosis of astrocytoma cells. The western blot results showed that there were high Notch-1 protein expression and low c-Myc, MMP-9 and Bcl-2 activation in the high-dose tanshinone IIA group compared with the control group. High-dose tanshinone IIA suppresses astrocytoma cell proliferation, migration while promoting apoptosis through Notch-1 pathway. Tanshinone IIA may be used to develop new drugs for the treatment of astrocytoma.

An Air-Stable Organoboron Compound, Dithienooxadiborepine: Preparation and Functionalization.

π-Conjugated organoboron molecules, which are easy to prepare, stable against moisture, and easy to functionalize, are scarce. Here, we report a one-pot synthesis of an air-stable organoboron compound, dithienooxadiborepine 1 in 17% yield on a 600 mg scale without separation or handling an air-sensitive intermediate. Dithienooxadiborepine 1 showed excellent stability under ambient conditions, allowing conventional column chromatography purification. Functionalization of 1 was realized via direct bromination using NBS and further Stille coupling reactions, giving access to longer π-conjugated molecules 5A and 5B. Single-crystal structures of compounds 4, 5A, and 5B not only unambiguously verified the chemical identity of dithienooxadiborepine 1 but also revealed that both the seven-member oxadiborepine ring and the 5-7-5 fused dithienooxadiborepine ring system are planar. UV-vis absorption and fluorescence emission measurements of 5A and 5B showed bathochromic shifted absorption and emission relative to 1, evidencing good π-conjugation. Cyclic voltammograms of 5A and 5B displayed two reduction peaks corresponding to two electron-accepting events at two boron atoms. These results proved dithienooxadiborepine 1 a potent π-conjugating building block for electron-accepting materials.

Glasgow prognostic score is superior to other inflammation-based scores in predicting survival of diffuse large B-cell lymphoma.

Inflammation-based prognostic scores, such as the glasgow prognostic score (GPS), prognostic index (PI), prognostic nutritional index (PNI), neutrophil lymphocyte ratio (NLR) and platelet lymphocyte ratio (PLR) were related to survival in many solid tumors. Recent study showed that GPS can be used to predict outcome in diffuse large B-cell lymphoma (DLBCL). However, other inflammation related scores had not been reported and it also remained unknown which of them was the most useful to evaluate the survival in DLBCLs. In this retrospective study, a number of 252 newly diagnosed and histologically proven DLBCLs from January 2003 to December 2014 were included. The high GPS, high PI, high NLR, high PLR and low PNI were all associated with poor overall survival (p < 0.05) and event-free survival (p < 0.05) in univariate analysis. Multivariate analysis indicated that GPS (HR = 1.781, 95% CI = 1.065-2.979, p = 0.028) remained an independent prognostic predictor in DLBCL. The c-index of GPS (0.735, 95% CI = 0.645-0.824) was greater than that of PI (0.710, 95% CI = 0.621-0.799, p = 0.602), PNI (0.600, 95% CI = 0.517-0.683, p = 0.001), PLR (0.599, 95% CI = 0.510-0.689, p = 0.029) and NLR (0.572, 95% CI = 0.503-0.642, p = 0.005) by Harrell's concordance index. Especially in DLBCLs treated with R-CHOP, GPS still remained the most powerful prognostic score when comparing with others (p = 0.001 and p < 0.001, respectively for OS and EFS). In conclusion, it is indicated that inflammation-based prognostic scores such as GPS, PI, NLR, PNI and PLR all could be used to predict the outcome of DLBCLs. Among them, GPS is the most powerful indicator in predicting survival in DLBCLs, even in the rituximab era.

The international staging system improves the IPI risk stratification in patients with diffuse large B-cell lymphoma treated with R-CHOP.

The international staging system (ISS), based on serum beta-2 microglobulin and albumin, is used to predict survival in multiple myeloma, but its prognostic significance in diffuse large B-cell lymphoma (DLBCL) remains unknown. Herein, we retrospectively analyzed 215 de novo DLBCL patients. According to ISS, there were 90 of 215 (41.9%) patients in stage I, 98 of 215 (45.6%) in stage II and 27 of 215 (12.6%) in stage III group. Patients with ISS stage II/III showed shorter overall survival (OS) and event free survival (EFS) than those with stage I treated with R-CHOP (p = 0.012 and p = 0.043, respectively), but not those treated with CHOP regimen (p > 0.05). Multivariable analysis revealed that ISS, independent of IPI, indicated different survival in both OS (HR, 5.690; 95% CI, 1.270-25.495, p = 0.023) and EFS (HR, 2.116; 95% CI, 1.005-4.455, p = 0.049) in DLBCL patients treated with R-CHOP. ISS could identify patients with better outcome in intermediate-high/high IPI risk patients (p < 0.05). Our data suggests that advanced ISS stage is associated with inferior outcome in DLBCL patients treated with R-CHOP. ISS could identify a subgroup of DLBCL patients with superior outcome from high IPI risk patients, which may help to avoid intensive therapy.

Low prognostic nutritional index predicts poor outcome in diffuse large B-cell lymphoma treated with R-CHOP.

Prognostic nutritional index (PNI), based on serum albumin concentration and the absolute peripheral lymphocyte count, has been used to predict survival in various tumors. Whether PNI can predict prognosis in patients with diffuse large B-cell lymphoma (DLBCL) remains unknown. We retrospectively analyzed 253 patients with newly diagnosed DLBCL in the present study. The PNI was calculated as: albumin (g/L) + 5 × total lymphocyte count × 10(9)/L. All patients were divided in low and high groups according to the analysis of receiver operating characteristic (ROC) curve. Low PNI was associated with more unfavorable clinical features (p < 0.05). Patients with low PNI tended to have worse event-free survival (EFS) and overall survival (OS) (EFS, p = 0.001; OS, p < 0.001). For patients treated with R-CHOP, PNI proved to be predictive for survival (EFS, p = 0.001; OS, p < 0.001), while no significant effect was found in DLBCL patients who received CHOP chemotherapy (EFS, p = 0.496; OS, p = 0.125). Multivariate analysis showed that low PNI is an independent adverse predictor of OS and EFS, especially in DLBCL patients treated with R-CHOP. In conclusion, this study suggests that PNI is an effective prognostic factor in DLBCL patients treated with R-CHOP.