Description: Nature Medicine 21, 1337 (2015). doi:10.1038/nm.3957 Authors: Muhammad S Alam, Matthias M Gaida, Frank Bergmann, Felix Lasitschka, Thomas Giese, Nathalia A Giese, Thilo Hackert, Ulf Hinz, S Perwez Hussain, Serguei V Kozlov & Jonathan D Ashwell Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive neoplasm characterized by a marked fibro-inflammatory microenvironment, the presence of which can promote both cancer induction and growth. Therefore, selective manipulation of local cytokines is an attractive, although unrealized, therapeutic approach. T cells possess a unique mechanism of p38 mitogen-activated protein kinase (MAPK) activation downstream of T cell receptor (TCR) engagement through the phosphorylation of Tyr323 (pY323). This alternative p38 activation pathway is required for pro-inflammatory cytokine production. Here we show in human PDAC that a high percentage of infiltrating pY323+ T cells was associated with large numbers of tumor necrosis factor (TNF)-α− and interleukin (IL)-17–producing CD4+ tumor-infiltrating lymphocytes (TILs) and aggressive disease. The growth of mouse pancreatic tumors was inhibited by genetic ablation of the alternative p38 pathway, and transfer of wild-type CD4+ T cells, but not those lacking the alternative pathway, enhanced tumor growth in T cell–deficient mice. Notably, a plasma membrane–permeable peptide derived from GADD45-α, the naturally occurring inhibitor of p38 pY323+ (ref. 7), reduced CD4+ TIL production of TNF-α, IL-17A, IL-10 and secondary cytokines, halted growth of implanted tumors and inhibited progression of spontaneous KRAS-driven adenocarcinoma in mice. Thus, TCR-mediated activation of CD4+ TILs results in alternative p38 activation and production of protumorigenic factors and can be targeted for therapeutic benefit.

Description: Toll-like receptors (TLR) are overexpressed on many types of cancer cells, including colorectal cancer cells, but little is known about the functional relevance of these immune regulatory molecules in malignant settings. Here, we report frequent single-nucleotide polymorphisms (SNP) in the flagellin receptor TLR5 and the TLR downstream effector molecules MyD88 and TIRAP that are associated with altered survival in a large cohort of Caucasian patients with colorectal cancer (n = 613). MYD88 rs4988453, a SNP that maps to a promoter region shared with the acetyl coenzyme-A acyl-transferase-1 (ACAA1), was associated with decreased survival of patients with colorectal cancer and altered transcriptional activity of the proximal genes. In the TLR5 gene, rs5744174/F616L was associated with increased survival, whereas rs2072493/N592S was associated with decreased survival. Both rs2072493/N592S and rs5744174/F616L modulated TLR5 signaling in response to flagellin or to different commensal and pathogenic intestinal bacteria. Notably, we observed a reduction in flagellin-induced p38 phosphorylation, CD62L shedding, and elevated expression of interleukin (IL)-6 and IL-1β mRNA in human primary immune cells from TLR5 616LL homozygote carriers, as compared with 616FF carriers. This finding suggested that the well-documented effect of cytokines like IL-6 on colorectal cancer progression might be mediated by TLR5 genotype-dependent flagellin sensing. Our results establish an important link between TLR signaling and human colorectal cancer with relevance for biomarker and therapy development. Cancer Res; 73(24); 7232–42. ©2013 AACR.

Description: Gemcitabine has limited clinical benefits in pancreatic ductal adenocarcinoma. The solvent-based traditional taxanes docetaxel and paclitaxel have not shown clinical results superior to gemcitabine. Nab-paclitaxel, a water-soluble albumin-bound paclitaxel, may carry superior distribution properties into the tumor microenvironment and has shown efficacy in multiple tumor types. We evaluated nab-paclitaxel effects compared with gemcitabine or docetaxel. For pancreatic ductal adenocarcinoma cells AsPC-1, BxPC-3, MIA PaCa-2 and Panc-1, gemcitabine IC 50 ranged from 494nM to 23.9 μM; docetaxel IC 50 range was from 5 to 34nM; nab-paclitaxel IC 50 range was from 243nM to 4.9 μM. Addition of IC 25 dose of docetaxel or nab-paclitaxel decreased gemcitabine IC 50 . Net tumor growth inhibition after gemcitabine, docetaxel or nab-paclitaxel was 67, 31 and 72%, which corresponded with intratumoral proliferative and apoptotic indices. Tumor stromal density was decreased by nab-paclitaxel and to a lesser extent by docetaxel as measured through reduction in α-smooth muscle actin, S100A4 and collagen 1 expression. Animal survival was prolonged after nab-paclitaxel treatment (41 days, P 〈 0.002) compared with gemcitabine (32 days, P = 0.005), docetaxel (32 days, P = 0.005) and controls (20 days). Survival in nab-paclitaxel/gemcitabine and docetaxel/gemcitabine sequential treatment groups was not superior to nab-paclitaxel alone. Low-dose combination of gemcitabine with nab-paclitaxel or docetaxel was more effective compared with controls or gemcitabine alone but not superior to regular dose nab-paclitaxel alone. Combination treatment of gemcitabine+nab-paclitaxel or gemcitabine+docetaxel increased gemcitabine concentration in plasma and tumor. The superior antitumor activity of nab-paclitaxel provides a strong rationale for considering nab-paclitaxel as first-line monotherapy in pancreatic ductal adenocarcinoma.

Description: Rapid and efficient enzymatic degradation of plant biomass into fermentable sugars is a major challenge for the sustainable production of biochemicals and biofuels. Enzymes that are more thermostable (up to 70°C) use shorter reaction times for the complete saccharification of plant polysaccharides compared to hydrolytic enzymes of mesophilic fungi such as Trichoderma and Aspergillus species. The genus Myceliophthora contains four thermophilic fungi producing industrially relevant thermostable enzymes. Within this genus, isolates belonging to M. heterothallica were recently separated from the well-described species M. thermophila . We evaluate here the potential of M. heterothallica isolates to produce efficient enzyme mixtures for biomass degradation. Compared to the other thermophilic Myceliophthora species, isolates belonging to M. heterothallica and M. thermophila grew faster on pretreated spruce, wheat straw, and giant reed. According to their protein profiles and in vitro assays after growth on wheat straw, (hemi-)cellulolytic activities differed strongly between M. thermophila and M. heterothallica isolates. Compared to M. thermophila , M. heterothallica isolates were better in releasing sugars from mildly pretreated wheat straw (with 5% HCl) with a high content of xylan. The high levels of residual xylobiose revealed that enzyme mixtures of Myceliophthora species lack sufficient β-xylosidase activity. Sexual crossing of two M. heterothallica showed that progenies had a large genetic and physiological diversity. In the future, this will allow further improvement of the plant biomass-degrading enzyme mixtures of M. heterothallica .

Description: BAY60-6583 [2-({6-amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]pyridin-2-yl}sulfanyl)acetamide] is the most potent and selective adenosine A 2B receptor (A 2B AR) agonist known to date. Therefore, it has been widely used for in vitro and in vivo experiments. In the present study, we investigated the binding and functional properties of BAY60-6583 in various native and recombinant cell lines with different A 2B AR expression levels. In cAMP accumulation and calcium mobilization assays, BAY60-6583 was found to be significantly less efficacious than adenosine or the adenosine derivative NECA. When it was tested in human embryonic kidney (HEK)293 cells, its efficacy correlated with the A 2B expression level of the cells. In Jurkat T cells, BAY60-6583 antagonized the agonistic effect of NECA and adenosine as determined in cAMP accumulation assays. On the basis of these results, we conclude that BAY60-6583 acts as a partial agonist at adenosine A 2B receptors. At high levels of the physiologic agonist adenosine, BAY60-6583 may act as an antagonist and block the effects of adenosine at A 2B receptors. This has to be considered when applying the A 2B -selective "agonist" BAY60-6583 in pharmacological studies, and previous research results may have to be reinterpreted.

Description: Tropospheric water vapor is one of the most important trace gases of the Earth's climate system, and its temporal and spatial distribution is critical for the genesis of clouds and precipitation. Due to the pronounced dynamics of the atmosphere and the nonlinear relation of air temperature and saturated vapor pressure, it is highly variable, which hampers the development of high-resolution and three-dimensional maps of regional extent. With their complementary high temporal and spatial resolutions, Global Navigation Satellite Systems (GNSS) meteorology and Interferometric Synthetic Aperture Radar (InSAR) satellite remote sensing represent a significant alternative to generally sparsely distributed radio sounding observations. In addition, data fusion with collocation and tomographical methods enables the construction of detailed maps in either two or three dimensions. Finally, by assimilation of these observation-derived datasets with dynamical regional atmospheric models, tropospheric water vapor fields can be determined with high spatial and continuous temporal resolution. In the following, a collection of basic and processed datasets, obtained with the above-listed methods, is presented that describes the state and course of atmospheric water vapor for the extent of the GNSS Upper Rhine Graben Network (GURN) region. The dataset contains hourly 2D fields of integrated water vapor (IWV) and 3D fields of water vapor density (WVD) for four multi-week, variable season periods between April 2016 and October 2018 at a spatial resolution of (2.1 km)2. Zenith total delay (ZTD) from GNSS and collocation and refractivities are provided as intermediate products. InSAR (Sentinel-1A/B)-derived double differential slant total delay phases (ddSTDPs) and GNSS-based ZTDs are available for March 2015 to July 2019. The validation of data assimilation with five independent GNSS stations for IWV shows improving Kling–Gupta efficiency (KGE) scores for all seasons, most notably for summer, with collocation data assimilation (KGE = 0.92) versus the open-cycle simulation (KGE = 0.69). The full dataset can be obtained from https://doi.org/10.1594/PANGAEA.936447 (Fersch et al., 2021).

Description: Atmospheric water vapor (WV) is one of the driving constituents of the atmosphere. The modelling and forecasting of WV and derived quantities like precipitable water is reliable on regional scales but challenging on small scales because of its high spatial and temporal variation. Interferometric synthetic aperture radar (InSAR) can be exploited to retrieve integrated atmospheric water vapor (IWV) from path delay observations along the radar line of sight. InSAR-derived IWV maps feature a very high spatial resolution but the double-differential interferometric observations only provide changes of IWV between acquisition times and with respect to a certain spatial reference. In this study we present a method to derive the absolute IWV by combining ERA5 numerical weather model data with differential path delay observations from InSAR time series. We propose different functional approaches to merge the regional trend of WV from ERA5 with the high resolution IWV signal from InSAR. We apply this to a Sentinel-1 Persistent Scatterer InSAR time series in the Upper Rhine Graben and validate against IWV observations at GNSS stations of the Upper Rhine Graben Network.