JMJD3 promotes survival of diffuse large B-cell lymphoma subtypes via distinct mechanisms.

JMJD3 (Jumonji domain containing-3), a histone H3 Lys27 (H3K27) demethylase, has been reported to be involved in the antigen-driven differentiation of germinal center B-cells. However, insight into the mechanism of JMJD3 in DLBCL (Diffuse large B-cell lymphoma) progression remains poorly understood. In this study, we investigated the subtype-specific JMJD3-dependent survival effects in DLBCL. Our data showed that in the ABC subtype, silencing-down of JMJD3 inhibited interferon regulatory factor 4 (IRF4) expression in a demethylase activity-dependent fashion. IRF4 reciprocally stimulated expression of JMJD3, forming a positive feedback loop that promoted survival in these cells. Accordingly, IRF4 expression was sufficient to rescue the pro-apoptotic effect of JMJD3 suppression in the ABC, but not in the GCB subtype. In contrast, ectopic overexpression of BCL-2 completely offset JMJD3-mediated survival in the GCB DLBCL cells. In vivo, treatment with siRNA to JMJD3 reduced tumor volume concordant with increased apoptosis in either subtype. This suggests it is a common target, though the distinctive signaling axes regulating DCBCL survival offer different strategic options for treating DLBCL subtypes

Immunostimulatory Activities of CpG-Oligodeoxynucleotides in Teleosts: Toll-Like Receptors 9 and 21

Toll-like receptors (TLRs) are pattern-recognition receptors that detect a wide variety of microbial pathogens for the initiation of host defense immunological responses. Thirteen TLRs have been identified in mammals, and teleosts contain 22 mammalian or non-mammalian TLRs. Of these, TLR9 and TLR21 are the cytosine-phosphate-guanosine-oligodeoxynucleotides (CpG-ODNs) recognition TLRs in teleosts. TLR9 is a mammalian TLR expressed in teleost but not in the avian species. TLR21 is a non-mammalian TLR expressed in both teleost and the avian species. Synthetic CpG-ODNs are potent immunostimulants that are being studied for their application against tumors, allergies, and infectious diseases, and as a vaccine adjuvant in humans. The immunostimulatory effects of CpG-ODNs as vaccine adjuvants and their antimicrobial function in domestic animals and teleosts are also being investigated. Most of our current knowledge about the molecular basis for the immunostimulatory activity of CpG-ODNs comes from earlier studies of the interaction between CpG-ODN and TLR9. More recent studies indicate that in addition to TLR9, TLR21 is another receptor for CpG-ODN recognition in teleosts to initiate immune responses. Whether these two receptors have differential functions in mediating the immunostimulatory activity of CpG-ODN in teleost has not been well-studied. Nevertheless, the existence of two recognition TLRs suggests that the molecular basis for the immunostimulatory activity of CpG-ODN in teleosts is different and more complex than in mammals. This article reviews the current knowledge of TLR9 and TLR21 activation by CpG-ODNs. The key points that need to be considered for CpG-ODNs as immunostimulants with maximum effectiveness in activation of immune responses in teleosts are discussed. This includes the structure/activity relationship of CpG-ODN activities for TLR9 and TLR21, the structure/functional relationship of these two TLRs, and differential expression levels and tissue distributions for these two TLRs

Cancer Associated Fibroblasts Promote Tumor Growth and Metastasis by Modulating the Tumor Immune Microenvironment in a 4T1 Murine Breast Cancer Model

BACKGROUND:Local inflammation associated with solid tumors commonly results from factors released by tumor cells and the tumor stroma, and promotes tumor progression. Cancer associated fibroblasts comprise a majority of the cells found in tumor stroma and are appealing targets for cancer therapy. Here, our aim was to determine the efficacy of targeting cancer associated fibroblasts for the treatment of metastatic breast cancer. METHODOLOGY/PRINCIPAL FINDINGS:We demonstrate that cancer associated fibroblasts are key modulators of immune polarization in the tumor microenvironment of a 4T1 murine model of metastatic breast cancer. Elimination of cancer associated fibroblasts in vivo by a DNA vaccine targeted to fibroblast activation protein results in a shift of the immune microenvironment from a Th2 to Th1 polarization. This shift is characterized by increased protein expression of IL-2 and IL-7, suppressed recruitment of tumor-associated macrophages, myeloid derived suppressor cells, T regulatory cells, and decreased tumor angiogenesis and lymphangiogenesis. Additionally, the vaccine improved anti-metastatic effects of doxorubicin chemotherapy and enhanced suppression of IL-6 and IL-4 protein expression while increasing recruitment of dendritic cells and CD8(+) T cells. Treatment with the combination therapy also reduced tumor-associated Vegf, Pdgfc, and GM-CSF mRNA and protein expression. CONCLUSIONS/SIGNIFICANCE:Our findings demonstrate that cancer associated fibroblasts promote tumor growth and metastasis through their role as key modulators of immune polarization in the tumor microenvironment and are valid targets for therapy of metastatic breast cancer

Benthic carbon mineralization in hadal trenches: Insights from in-situ determination of benthic oxygen consumption

Hadal trenches have been proposed as depocenters of organic material and hot spots for organic matter mineralization. In this study, we for the first time quantified the total benthic O-2 uptake in hadal trenches using in situ chamber incubations. Three trenches in the tropical Pacific were targeted and exhibited relatively high diagenetic activity given the great water depths, that is, the Mariana Trench (2.0x10(2)molO(2)m(-2)d(-1), 10,853m), the Mussau Trench (2.70.1x10(2)molO(2)m(-2)d(-1), 7,011m), and the New Britain Trench (6.00.1x10(2)molO(2)m(-2)d(-1), 8,225m). Combined with the analyses of total organic carbon and C-13 of total organic carbon in the sediments and previously published in situ O-2 microprofiles from hadal settings, we suggest that hadal benthic carbon mineralization partly is governed by the surface production and also is linked to the distance from land. Therefore, we highlight that terrestrial organic matter can be of importance in sustaining benthic communities in some hadal settings. Plain Language Summary Hadal trenches that refer to seafloor areas covered by a water column with depths >6,000m have been proposed as depocenters of organic material and hot spots for organic matter mineralization. We applied in situ benthic chamber incubation techniques within three trenches in the tropical Pacific Ocean (the Mariana Trench, the Mussau Trench, and the New Britain Trench) and thereby reported the first benthic total O-2 uptake rates measured in hadal settings. The benthic carbon mineralization rates generally show a positive correlation with the net primary production in respective provinces and the sedimentary total organic carbon (TOC) level. Analyses of TOC contents and C-13 of TOC indicated a downslope transport of sediment containing a large amount of terrestrial organic matter, possibly via mass-wasting events to the axis of New Britain Trench off the New Britain Island. Therefore, we speculate that both surface production regimes and the distance from land are closely connected with the benthic carbon mineralization rate at the trench axes. The elevated organic carbon turnover rate may in part result from preferential concentration of relatively labile organic matter in the surface sediments of trench axes or efficient utilization of refractory terrestrial material under extreme pressure

The sustainable materials roadmap

Over the past 150 years, our ability to produce and transform engineered materials has been responsible for our current high standards of living, especially in developed economies. However, we must carefully think of the effects our addiction to creating and using materials at this fast rate will have on the future generations. The way we currently make and use materials detrimentally affects the planet Earth, creating many severe environmental problems. It affects the next generations by putting in danger the future of the economy, energy, and climate. We are at the point where something must drastically change, and it must change now. We must create more sustainable materials alternatives using natural raw materials and inspiration from nature while making sure not to deplete important resources, i.e. in competition with the food chain supply. We must use less materials, eliminate the use of toxic materials and create a circular materials economy where reuse and recycle are priorities. We must develop sustainable methods for materials recycling and encourage design for disassembly. We must look across the whole materials life cycle from raw resources till end of life and apply thorough life cycle assessments (LCAs) based on reliable and relevant data to quantify sustainability. We need to seriously start thinking of where our future materials will come from and how could we track them, given that we are confronted with resource scarcity and geographical constrains. This is particularly important for the development of new and sustainable energy technologies, key to our transition to net zero. Currently 'critical materials' are central components of sustainable energy systems because they are the best performing. A few examples include the permanent magnets based on rare earth metals (Dy, Nd, Pr) used in wind turbines, Li and Co in Li-ion batteries, Pt and Ir in fuel cells and electrolysers, Si in solar cells just to mention a few. These materials are classified as 'critical' by the European Union and Department of Energy. Except in sustainable energy, materials are also key components in packaging, construction, and textile industry along with many other industrial sectors. This roadmap authored by prominent researchers working across disciplines in the very important field of sustainable materials is intended to highlight the outstanding issues that must be addressed and provide an insight into the pathways towards solving them adopted by the sustainable materials community. In compiling this roadmap, we hope to aid the development of the wider sustainable materials research community, providing a guide for academia, industry, government, and funding agencies in this critically important and rapidly developing research space which is key to future sustainability.journal articl

Ganglioside GD2 is a potential candidate marker for lung cancer stem cells

Objective To explore the feasibility of ganglioside GD2 as a marker for lung cancer stem cells (LCSCs). Methods Cancer stem cells (CSCs) of lung cancer cell lines were enriched by spheroid culturing in vitro; The expression of stemness-related genes and GD3 synthase (GD3S) in LCSCs were detected by RT-qPCR and Western blot; The expression of GD2 and other stemness phenotypes in lung cancer cell line A549 were detected by flow cytometry; Cell proliferation was detected by CCK8 assay; Cell invasion and migration in vitro were examined by Transwell and wound healing assays; The oncogenicity of different subpopulations in cell line A549 was compared with tumor xenograft model. Results CSCs of A549 cell were successfully enriched by and the percentage of GD2+ cells was 0.57% in adherent cell, but the percentage of GD2+ cells was able to increase to 20.4% after spheroid culturing. In comparison with GD2- A549 cells, GD2+ A549 cells showed significantly enhanced cell proliferation (P＜0.05),invasion (P＜0.05) and migration ability (P＜0.01) in vitro. There was a close association between GD2 and two other LCSCs phenotypes, and the expression level of GD2 was positively correlated with the expression of CD44 (P＜0.01) and EpCAM (P＜0.001). The results in vivo indicated that tumors formed by GD2+ A549 cells grew faster (P＜0.001) and were more malignant (P＜0.01) as compared to GD2- A549 cells. Conclusions Ganglioside GD2 is a potential marker for LCSCs to identify cancer stem cells, providing a novel strategy of GD2-targeted lung cancer immunothearapy