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Indoleamine-2,3-dioxygenase (IDO) inhibitors have entered clinical trials based on their ability to restore anti-tumor immunity in preclinical studies. However, the mechanisms leading to constitutive expression of IDO in human tumors are largely unknown. Here we analyzed the pathways mediating constitutive IDO expression in human cancer. IDO-positive tumor cells and tissues showed basal phosphorylation and acetylation of STAT3 as evidenced by western blotting and immunoprecipitation. Inhibition of IL-6 or STAT3 using siRNA and/or pharmacological inhibitors reduced IDO mRNA and protein expression as well as kynurenine formation. In turn, IDO enzymatic activity activated the AHR as shown by the induction of AHR target genes. IDO-mediated AHR activation induced IL-6 expression, while inhibition or knockdown of the AHR reduced IL-6 expression. IDO activity thus sustains its own expression via an autocrine AHR–IL-6–STAT3 signaling loop. Inhibition of the AHR–IL-6–STAT3 signaling loop restored T-cell proliferation in mixed leukocyte reactions performed in the presence of IDO-expressing human cancer cells. Identification of the IDO-AHR-IL-6-STAT3 signaling loop maintaining IDO expression in human cancers reveals novel therapeutic targets for the inhibition of this core pathway promoting immunosuppression of human cancers. The relevance of the IDO-AHR-IL-6-STAT3 transcriptional circuit is underscored by the finding that high expression of its members IDO, STAT3 and the AHR target gene CYP1B1 is associated with reduced relapse-free survival in lung cancer patients.

Nyquist sinc-pulse shaping provides spectral efficiencies close to the theoretical limit. In this paper we discuss the analogy to optical orthogonal frequency division multiplexing and compare both techniques with respect to spectral efficiency and peak to average power ratio. We then show that using appropriate algorithms, Nyquist pulse shaped modulation formats can be encoded on a single wavelength at speeds beyond 100 Gbit/s in real-time. Finally we discuss the proper reception of Nyquist pulses. ©2011 Optical Society of America

Epigenetic mechanisms have emerged as links between prenatal environmental exposure and disease risk later in life. Here, we studied epigenetic changes associated with maternal smoking at base pair resolution by mapping DNA methylation, histone modifications, and transcription in expectant mothers and their newborn children. We found extensive global differential methylation and carefully evaluated these changes to separate environment associated from genotype‐related DNA methylation changes. Differential methylation is enriched in enhancer elements and targets in particular “commuting” enhancers having multiple, regulatory interactions with distal genes. Longitudinal whole‐genome bisulfite sequencing revealed that DNA methylation changes associated with maternal smoking persist over years of life. Particularly in children prenatal environmental exposure leads to chromatin transitions into a hyperactive state. Combined DNA methylation, histone modification, and gene expression analyses indicate that differential methylation in enhancer regions is more often functionally translated than methylation changes in promoters or non‐regulatory elements. Finally, we show that epigenetic deregulation of a commuting enhancer targeting c‐Jun N‐terminal kinase 2 (JNK2) is linked to impaired lung function in early childhood.

A practical scheme to perform the fast Fourier transform in the optical domain is introduced. Optical real-time FFT signal processing is performed at speeds far beyond the limits of electronic digital processing, and with negligible energy consumption. To illustrate the power of the method we demonstrate an optical 400 Gbit/s OFDM receiver. It performs an optical real-time FFT on the consolidated OFDM data stream, thereby demultiplexing the signal into lower bit rate subcarrier tributaries, which can then be processed electronically.

Background: Cardiac surgery often represents the only treatment option in patients with infective endocarditis (IE). However, IE surgery may lead to a sudden release of inflammatory mediators, which is associated with the severity of postoperative organ dysfunction. We investigated the impact of hemoadsorption during IE surgery on postoperative organ dysfunction. Methods: This multi-center, randomized, non-blinded, controlled trial assigned patients undergoing cardiac surgery for IE to hemoadsorption [integration of CytoSorb® to cardiopulmonary bypass (CPB)] or control. The Primary outcome (ΔSOFA) was defined as the difference between the mean total postoperative sequential organ failure assessment score (SOFA), calculated maximally to the 9th postoperative day, and the basal SOFA score. The analysis was by modified intention-to-treat. A predefined inter-group comparison was done using a linear mixed model for ΔSOFA including surgeon and baseline SOFA as fixed effect covariates and with the surgical center as random effect. The SOFA score assesses dysfunction in six organ systems, each scored from zero to four. Higher scores indicate worsening dysfunction. Secondary outcomes were 30-day mortality, durations of mechanical ventilation, vasopressor and renal replacement therapy. Cytokines were measured in the first 50 patients. Results: Between January 17, 2018 and January 31, 2020, A total of 288 patients were randomly assigned to hemoadsorption (n=142) or control (n=146). Four patients in the hemoadsorption and two in the control group were excluded as they did not undergo surgery. The primary outcome ΔSOFA did not differ between the hemoadsorption and the control group (1.79 ± 3.75 and 1.93 ± 3.53, respectively, 95% CI: −1.30 to 0.83, p=0.6766). Mortality at 30 days (21% hemoadsorption vs 22% control, p=0.782), the durations of mechanical ventilation, vasopressor and renal replacement therapy did not differ between groups. Levels of IL-1β and IL-18 at the end of CPB were significantly lower in the hemoadsorption than in the control group. Conclusions: This randomized trial failed to demonstrate a reduction in postoperative organ dysfunction through intraoperative hemoadsorption in patients undergoing cardiac surgery for IE. Although hemoadsorption reduced plasma cytokines at the end of CPB, there was no difference in any of the clinically relevant outcome points.