Using current diagnostic criteria, primary mediastinal B cell lymphoma (PMBL) cannot be distinguished from other types of diffuse large B cell lymphoma (DLBCL) reliably. We used gene expression profiling to develop a more precise molecular diagnosis of PMBL. PMBL patients were considerably younger than other DLBCL patients, and their lymphomas frequently involved other thoracic structures but not extrathoracic sites typical of other DLBCLs. PMBL patients had a relatively favorable clinical outcome, with a 5-yr survival rate of 64% compared with 46% for other DLBCL patients. Gene expression profiling strongly supported a relationship between PMBL and Hodgkin lymphoma: over one third of the genes that were more highly expressed in PMBL than in other DLBCLs were also characteristically expressed in Hodgkin lymphoma cells. PDL2, which encodes a regulator of T cell activation, was the gene that best discriminated PMBL from other DLBCLs and was also highly expressed in Hodgkin lymphoma cells. The genomic loci for PDL2 and several neighboring genes were amplified in over half of the PMBLs and in Hodgkin lymphoma cell lines. The molecular diagnosis of PMBL should significantly aid in the development of therapies tailored to this clinically and pathogenetically distinctive subgroup of DLBCL.

Recent compelling evidence has lead to renewed interest in the role of antibodies and immune complexes in the pathogenesis of several autoimmune disorders, such as rheumatoid arthritis. These immune complexes, consisting of autoantibodies to selfantigens, can mediate inflammatory responses largely through binding and activating the immunoglobulin Fc receptors (FcRs). Using cell-based structure activity relationships with cultured human mast cells, we have identified the small molecule R406 [N4-(2,2-dimethyl-3-oxo-4H-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine] as a potent inhibitor of immunoglobulin E (IgE)-and IgG-mediated activation of Fc receptor signaling (EC 50 for degranulation ϭ 56 -64 nM). Here we show that the primary target for R406 is the spleen tyrosine kinase (Syk), which plays a key role in the signaling of activating Fc receptors and the B-cell receptor (BCR). R406 inhibited phosphorylation of Syk substrate linker for activation of T cells in mast cells and B-cell linker protein/SLP65 in B cells. R406 bound to the ATP binding pocket of Syk and inhibited its kinase activity as an ATP-competitive inhibitor (K i ϭ 30 nM). Furthermore, R406 blocked Syk-dependent FcR-mediated activation of monocytes/macrophages and neutrophils and BCR-mediated activation of B lymphocytes. R406 was selective as assessed using a large panel of Sykindependent cell-based assays representing both specific and general signaling pathways. Consistent with Syk inhibition, oral administration of R406 to mice reduced immune complex-mediated inflammation in a reverse-passive Arthus reaction and two antibody-induced arthritis models. Finally, we report a first-inhuman study showing that R406 is orally bioavailable, achieving exposures capable of inhibiting Syk-dependent IgE-mediated basophil activation. Collectively, the results show R406 potential for modulating Syk activity in human disease.

<p><strong>Abstract.</strong> To tackle the problem of severe air pollution, China has implemented active clean air policies in recent years. As a consequence, the emissions of major air pollutants have decreased and the air quality has substantially improved. Here, we quantified China's anthropogenic emission trends from 2010–2017 and identified the major driving forces of these trends by using a combination of bottom-up emission inventory and Index Decomposition Analysis (IDA) approaches. The relative change rates of China's anthropogenic emissions during 2010–2017 are estimated as follows: −62 % for SO<sub>2</sub>, −17 % for NO<sub>x</sub>, +11 % for NMVOC, +1 % for NH<sub>3</sub>, −27 % for CO, −38 % for PM<sub>10</sub>, −35 % for PM<sub>2.5</sub>, −27 % for BC, −35 % for OC, and +18 % for CO<sub>2</sub>. The IDA results suggest that emission control measures are the main drivers of this reduction, in which the pollution controls on power plants and industries are the most effective mitigation measures. The emission reduction rates markedly accelerated after the year 2013, confirming the effectiveness of China's Clean Air Action that was implemented in 2013. We estimated that during 2013–2017, China's anthropogenic emissions decreased by 59 % for SO<sub>2</sub>, 21 % for NO<sub>x</sub>, 23 % for CO, 36 % for PM<sub>10</sub>, 33 % for PM<sub>2.5</sub>, 28 % for BC, and 32 % for OC. NMVOC emissions increased by 11 % and NH<sub>3</sub> emissions remained stable from 2010–2017, representing the absence of effective mitigation measures for NMVOC and NH<sub>3</sub> in current policies. The relative contributions of different sectors to emissions have significantly changed after several years' implementation of clean air policies, indicating that it is paramount to introduce new policies to enable further emission reductions in the future.</p>

The inactivated EV71 vaccine elicited EV71-specific immune responses and protection against EV71-associated hand, foot, and mouth disease. (Funded by the National Basic Research Program and others; ClinicalTrials.gov number, NCT01569581.).

Purpose-Development of a radiosensitivity predictive assay is a central goal of radiation oncology. We reasoned a gene expression model could be developed to predict intrinsic radiosensitivity and treatment response in patients.Methods and Materials-Radiosensitivity (determined by survival fraction at 2 Gy) was modeled as a function of gene expression, tissue of origin, ras status (mut/wt), and p53 status (mut/wt) in 48 human cancer cell lines. Ten genes were identified and used to build a rank-based linear regression algorithm to predict an intrinsic radiosensitivity index (RSI, high index = radioresistance). This model was applied to three independent cohorts treated with concurrent chemoradiation: head-and-neck cancer (HNC, n = 92); rectal cancer (n = 14); and esophageal cancer (n = 12).Results-Predicted RSI was significantly different in responders (R) vs. nonresponders (NR) in the rectal (RSI R vs. NR 0.32 vs. 0.46, p = 0.03), esophageal (RSI R vs. NR 0.37 vs. 0.50, p = 0.05) and combined rectal/esophageal (RSI R vs. NR 0.34 vs. 0.48, p = 0.001511) cohorts. Using a threshold RSI of 0.46, the model has a sensitivity of 80%, specificity of 82%, and positive predictive value of 86%. Finally, we evaluated the model as a prognostic marker in HNC. There was an improved 2-year locoregional control (LRC) in the predicted radiosensitive group (2-year LRC 86% vs. 61%, p = 0.05).Conclusions-We validate a robust multigene expression model of intrinsic tumor radiosensitivity in three independent cohorts totaling 118 patients. To our knowledge, this is the first time that a systems biology-based radiosensitivity model is validated in multiple independent clinical datasets.

Purpose The discovery of effective biomarkers is a fundamental goal of molecular medicine. Developing a systems-biology understanding of radiosensitivity can enhance our ability of identifying radiation-specific biomarkers. Methods and Materials Radiosensitivity, as represented by the Survival Fraction at 2 Gy (SF2) was modeled in 48 human cancer cell lines. We apply a linear regression algorithm that integrates gene expression with biological variables including: ras status (mut/wt), tissue of origin (TO) and p53 status (mut/wt). Results The biomarker discovery platform is a network representation of the top 500 genes identified by linear regression. This network was reduced to a 10-hub network that includes: c-Jun, HDAC1, RELA (p65 subunit of NFKB), PKC-beta, SUMO-1, c-Abl, STAT1, AR, CDK1 and IRF1. Nine targets associated with radiosensitization drugs link to the network, demonstrating clinical relevance. Furthermore, the model identifies four significant radiosensitivity clusters of terms and genes. Ras was a dominant variable in the analysis along with TO and their interaction with gene expression but not p53. Overrepresented biological pathways differed between clusters but included: DNA repair, cell cycle, apoptosis and metabolism. The c-Jun network hub was validated using a knockdown approach in 8 human cell lines representing lung, colon and breast cancers. Conclusions We developed a novel radiation-biomarker discovery platform using a systems biology modeling approach. We propose this platform will play a central role in the integration of biology into clinical radiation oncology practice.

This report describes the synthesis of two cyclic RGD (Arg-Gly-Asp) conjugates, HYNIC-2PEG 4 -dimer (HYNIC = 6-hydrazinonicotinyl; 2PEG 4 -dimer = E[PEG 4 -c(RGDfK)] 2 ; and PEG 4 = 15-amino-4,7,10,13-tetraoxapentadecanoic acid) and HYNIC-3PEG 4 -dimer (3PEG 4 -dimer = PEG 4 -E [PEG 4 -c(RGDfK)] 2 ), and evaluation of their 99m Tc complexes [ 99m Tc(HYNIC-2PEG 4 -dimer) (tricine)(TPPTS)] ( 99m Tc-2PEG 4 -dimer: TPPTS = trisodium triphenylphosphine-3,3′,3″-trisulfonate) and [ 99m Tc(HYNIC-3PEG 4 -dimer)(tricine)(TPPTS)] ( 99m Tc-3PEG 4 -dimer) as novel radiotracers for imaging integrin α v β 3 expression in athymic nude mice bearing U87MG glioma and MDA-MB-435 breast cancer xenografts. The integrin α v β 3 binding affinities of RGD peptides were determined by competitive displacement of 125 I-c(RGDyK) on U87MG glioma cells. It was found that the two PEG 4 linkers between RGD motifs in HYNIC-2PEG 4 -dimer (IC 50 = 2.8 ± 0.5 nM) and HYNIC-3PEG 4 -dimer (IC 50 = 2.4 ± 0.7 nM) are responsible for their higher integrin α v β 3 binding affinity than that of HYNIC-PEG 4 -dimer (PEG 4 -dimer = PEG 4 -E[c(RGDfK)] 2 ; IC 50 = 7.5 ± 2.3 nM). Addition of extra PEG 4 linker in HYNIC-3PEG 4 -dimer has little impact on integrin α v β 3 binding affinity. 99m Tc-2PEG 4 -dimer and 99m Tc-3PEG 4 -dimer were prepared in high yield with >95% radiochemical purity and the specific activity of > 10 Ci/μmol. Biodistribution studies clearly demonstrated that PEG 4 linkers are particularly useful for improving the tumor uptake and clearance kinetics of 99m Tc-2PEG 4 -dimer and 99m Tc-3PEG 4 -dimer from non-cancerous organs. It was also found that there was a linear relationship between the tumor size and radiotracer tumor uptake expressed as %ID (percentage of the injected dose) in U87MG glioma and MDA-MB-435 breast tumor models. The blocking experiment showed that the tumor uptake of 99m Tc-2PEG 4 -dimer is integrin α v β 3 -mediated. In the metabolism study, 99m Tc-2PEG 4 -dimer had high metabolic stability during its excretion from renal and hepatobiliary routes. 99m Tc-3PEG 4 -dimer also remained intact during thee excretion from the renal route, but, had ~30% metabolism during the excretion from the hepatobiliary route. Planar imaging studies in U87MG glioma and MDA-MB-435 breast tumor models showed that the tumors of ~5 mm in diameter could be readily visualized with excellent contrast. Thus, 99m Tc-3PEG 4 -dimer is a very promising radiotracer for the early detection of integrin α v β 3 -positive tumors, and may have the potential for non-invasive monitoring of tumor growth or treatment efficacy.

The development of a successful radiation sensitivity predictive assay has been a major goal of radiation biology for several decades. We have developed a radiation classifier that predicts the inherent radiosensitivity of tumor cell lines as measured by survival fraction at 2 Gy (SF2), based on gene expression profiles obtained from the literature. Our classifier correctly predicts the SF2 value in 22 of 35 cell lines from the National Cancer Institute panel of 60, a result significantly different from chance (P = 0.0002). In our approach, we treat radiation sensitivity as a continuous variable, significance analysis of microarrays is used for gene selection, and a multivariate linear regression model is used for radiosensitivity prediction. The gene selection step identified three novel genes (RbAp48, RGS19, and R5PIA) of which expression values are correlated with radiation sensitivity. Gene expression was confirmed by quantitative real-time PCR. To biologically validate our classifier, we transfected RbAp48 into three cancer cell lines (HS-578T, MALME-3M, and MDA-MB-231). RbAp48 overexpression induced radiosensitization (1.5-to 2-fold) when compared with mock-transfected cell lines. Furthermore, we show that HS-578T-RbAp48 overexpressors have a higher proportion of cells in G 2 -M (27% versus 5%), the radiosensitive phase of the cell cycle. Finally, RbAp48 overexpression is correlated with dephosphorylation of Akt, suggesting that RbAp48 may be exerting its effect by antagonizing the Ras pathway. The implications of our findings are significant. We establish that radiation sensitivity can be predicted based on gene expression profiles and we introduce a genomic approach to the identification of novel molecular markers of radiation sensitivity. (Cancer Res 2005; 65(16): 7169-76)