Fabry-Perot-resonator-coupled metal pattern metamaterial for infrared suppression and radiative cooling.

The most intuitive approach for infrared stealth, namely, the indiscriminate suppression of thermal radiation, is often at the risk of overheating the target. Spectrally selective metamaterials may solve this problem by satisfying radiative cooling as well as infrared suppression. Therefore, we have designed and fabricated a broadband metamaterial by depositing a Fabry-Perot (F-P) resonator on top of a metal pattern. The composite structure has two absorption peaks, one originating from F-P resonance, the other from the magnetic resonance of the metal pattern, and they can be merged into the 5∼8 µm range through optimization. According to Kirchhoff's law, this results in high emissivity in the 5∼8 µm range (the best choice of nonatmospheric-window ranges) and low emissivity in the 3∼5 µm and 8∼14 µm ranges (the two atmospheric windows), satisfying both infrared suppression and radiative cooling. Energy dissipation distributions indicate apparent coupling of F-P resonance and magnetic resonance, but these two resonances are stronger at their respective intrinsic wavelengths. This paper reveals an alternative method for infrared suppression with radiative cooling, which is also meaningful in the design of broad/multiband absorbers.

TAK1 is a druggable kinase for diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common form of lymphoma, and up to 30% DLBCL patients eventually died by using first-line chemotherapy regimens. Currently, Bruton tyrosine kinase (BTK) inhibitor (ibrutinib) is one of the most promising medicine in clinical trials for DLBCL, to which about 25% of patients with relapsed or refractory DLBCL are responsive. Thus, it is urgent to discover new druggable targets for DLBCL, especially for patients who are unresponsive to first-line chemotherapy and ibrutinib. Here, we found that MAP 3K7 (TAK1) is required for DLBCL survival. Inhibition of TAK1 by small molecule 5Z7 or genetic silence could massively induce deaths of DLBCL cells. Mechanistically, TAK1 inhibition could dramatically reduce the nuclear factor kappa B (NF-κB) activity. Notably, ibrutinib-resistant DLBCL cells also respond to TAK1 inhibition. Database analysis showed that high expression of TAK1 in patients with DLBCL shows poor survival. A subtype of DLBCL patients showed that high expression of both TAK1 and BTK1 is poorly responsive to the current chemotherapy. Moreover, DLBCL cell line with high expression of both TAK1 and BTK1 is resistant to Dox. Simultaneously targeting TAK1 and BTK not only increases cellular toxicity of individual drug but also enhances the sensitivity to Dox. Taken together, we provide convincing evidence to show that kinase TAK1 is a druggable target in DLBCL. SIGNIFICANCE OF THE STUDY: Currently, there is still a significant portion of patients with DLBCL who are unresponsive to first-line chemotherapy. Thus, identification of novel druggable targets such as kinase is critical important. Here, we found that TAK1 inhibition promotes death of DLBCL cells through inhibition of chronic NF-κB signalling. Importantly, TAK1 inhibition overcomes ibrutinib resistance in DLBCL cells. Finally, DLBCL patients with high expression of both TAK1 and BTK showed extremely poor survival. In summary, we provide convincing results to demonstrate a potential important druggable kinase in DLBCL.

Targeting liquid-liquid phase separation in pancreatic cancer.

BACKGROUND: Accumulated evidence suggests a critical role of protein-mediated liquid-liquid phase separation (LLPS) in many key biological processes through organization of membrane-less compartments. However, the pathological role of protein-mediated LLPS remains elusive and it is unknown whether protein-mediated LLPS contributes to carcinogenesis. METHODS: HPDE6-C7, BxPC-3, PANC-1, AsPC-1 and CFPAC-1 cells were treated with the LLPS inhibitor, 1,6-hexanediol. Cell proliferation was determined by CCK8 assay. An atopic BxPC-3 xenograft mouse model was established and treated with 1,6-hexanediol. Gene expression profiling was achieved by RNA-sequencing. RESULTS: 1,6-hexanediol significantly inhibited cell proliferation and induced cell death in all tested pancreatic cancer cells (BxPC-3, PANC-1, AsPC-1 and CFPAC-1) but had a minimal effect on control cells (HPDE6-C7) at low doses. In an atopic BxPC-3 xenograft model, 1,6-hexanediol significantly limited pancreatic cancer growth. In whole genomic transcriptional analysis, 1,6-hexanediol significantly downregulated the expression of a set of genes that were enriched in cytokine-cytokine receptor interactions, WNT signaling pathway, ECM-receptor interaction, MAPK signaling pathway and focal adhesion. Furthermore, 1,6-hexanediol treatment specifically reduced the expression of MYC but not IL-6 and KLF5. CONCLUSIONS: Together, we provided evidence to demonstrate an important role of protein-mediated LLPS in pancreatic cancer. Cancer cells might be more addictive to LLPS and thus disruption of such a process might be a novel way to treat cancer.

Enhancer RNAs: a missing regulatory layer in gene transcription.

Enhancers and super-enhancers exert indispensable roles in maintaining cell identity through spatiotemporally regulating gene transcription. Meanwhile, active enhancers and super-enhancers also produce transcripts termed enhancer RNAs (eRNAs) from their DNA elements. Although enhancers have been identified for more than 30 years, widespread transcription from enhancers are just discovered by genome-wide sequencing and considered as the key to understand longstanding questions in gene transcription. RNA-transcribed enhancers are marked by histone modifications such as H3K4m1/2 and H3K27Ac, and enriched with transcription regulatory factors such as LDTFs, P300, CBP, BRD4 and MED1. Those regulatory factors might constitute a Mega-Trans-like complex to potently activate enhancers. Compared to mRNAs, eRNAs are quite unstable and play roles at local. Functionally, it has been shown that eRNAs promote formation of enhancer-promoter loops. Several studies also demonstrated that eRNAs help the binding of RNA polymerase II (RNAPII) or transition of paused RNAPII by de-association of the negative elongation factor (NELF) complex. Nevertheless, these proposed mechanisms are not universally accepted and still under controversy. Here, we comprehensively summarize the reported findings and make perspectives for future exploration. We also believe that super-enhancer derived RNAs (seRNAs) might be informative to understand the nature of super-enhancers.

A Tumor-Specific Super-Enhancer Drives Immune Evasion by Guiding Synchronous Expression of PD-L1 and PD-L2.

PD-L1 and PD-L2 are important targets for immune checkpoint blockade, but how tumor cells achieve their expression remains to be addressed. Here, we find that PD-L1 and PD-L2 are co-expressed in cancer cell lines and tissues across different cancer types. In breast cancer, MDA-MB-231 and SUM-159 cells show high expression of both PD-L1 and PD-L2. The expression of both PD-L1 and PD-L2 is greatly reduced upon treatment of inhibitors of super-enhancers. Bioinformatic analysis identifies a potential super-enhancer (PD-L1L2-SE) that is located between the CD274 and CD273 genes. Genetic deletion of PD-L1L2-SE profoundly reduces the expression of PD-L1 and PD-L2. PD-L1L2-SE-deficient cancer cells fail to generate immune evasion and are sensitive to T cell-mediated killing. Notably, epigenetic activation of such a region (PD-L1L2-SE) is correlated with PD-L1 and PD-L2. Taken together, we identify a super-enhancer (PD-L1L2-SE) that is responsible for the overexpression of PD-L1 and PD-L2 as well as immune evasion in cancer.

A super-enhancer maintains homeostatic expression of Regnase-1.

Regnase-1 is not only a key component in maintaining intracellular homeostasis but also a critical negative regulator in preventing autoimmune diseases and cancer development. To keep homeostatic state, Regnase-1 has to be maintained at a desired level in multiple cell types. However, the molecular mechanism of keeping a certain transcriptional level of Reganase-1 is largely unknown. In this study, we found a super-enhancer (Reg-1-SE) around Regnase-1 gene is able to control the homeostatic expression of Regnase-1. Functional inhibition of super-enhancers through BRD4 inhibitors or genetic silence of key components such as BRD4 and MED1 significantly downregulates Regnase-1 expression at multiple cell types. Consistently, treatment of JQ1 or I-BET-762 dramatically decreases the protein level of Regnase-1. By analyzing Regnase-1 gene, the distribution of H3K27Ac is highly enriched at a 8 kb DNA region around the second intron. Several DNA elements at the second intron are highly conserved between different species. Deletion of the second intron by CRISPR-Cas9 technology significantly reduces the expression of Regnase-1. JQ1 or I-BET-762 failed to further downregulate the expression of Regnase-1 in cells without the second intron. Our result reveals a novel molecular mechanism by which a super-enhancer around the second intron regulates the expression of Regnase-1, and in turn maintains a desired level of Regnase-1.