Search

Dengue virus (DENV) infection causes a characteristic pathology in humans involving dysregulation of the vascular system. In some patients with dengue hemorrhagic fever (DHF), vascular pathology can become severe, resulting in extensive microvascular permeability and plasma leakage into tissues and organs. Mast cells (MCs), which line blood vessels and regulate vascular function, are able to detect DENV in vivo and promote vascular leakage. Here, we showed that an MC-derived protease, tryptase, is consequential for promoting vascular permeability during DENV infection through inducing breakdown of endothelial cell tight junctions. Injected tryptase alone was sufficient to induce plasma loss from the circulation and hypovolemic shock in animals. A potent tryptase inhibitor, nafamostat mesylate, blocked DENV-induced vascular leakage in vivo. Importantly, in 2 independent human dengue cohorts, tryptase levels correlated with the grade of DHF severity. This study defines an immune mechanism by which DENV can induce vascular pathology and shock., Introduction In humans, dengue virus (DENV) causes an acute viral infection that manifests as a broad spectrum of disease: from asymptomatic infection to a mild febrile illness, dengue fever (DF), [...]

Liver cancers consist primarily of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Immune checkpoint inhibitors have emerged as promising therapeutic agents against liver cancers. Programmed cell death protein 1 (PD‐1) is an immunoinhibitory receptor present on T cells that interacts with its ligand programmed death‐ligand 1 (PD‐L1) found on cancer cells. Blocking PD‐1/PD‐L1 binding improves T‐cell survival, proliferation and cytotoxicity, which enhances their antitumor activity. Better understanding of the molecular mechanisms governing PD‐1/PD‐L1 response is essential to the development of predictive markers and therapeutic combinations that could improve the efficiency of anti‐PD‐1/PD‐L1 treatment. Chemokine‐like factor (CKLF)–like MARVEL transmembrane domain–containing 6 (CMTM6) has been recently identified as a major regulator of PD‐L1. Another member in the CMTM family, CKLF‐like MARVEL transmembrane domain–containing 4 (CMTM4), has been shown to compensate for the effects of CMTM6 when CMTM6 is lost. Interestingly, we found that CMTM4 is the major regulator of PD‐L1 in the context of liver cancer. Up‐regulated CMTM4 in patients with HCC and ICC is associated with poor patient survival, potentially due to its function in stabilizing PD‐L1 expression, hence facilitating escape from T cell–mediated cytotoxicity. We confirmed the role of CMTM4 as a positive regulator of PD‐L1 in multiple HCC and ICC cell lines and demonstrated that CMTM4 stabilizes PD‐L1 through posttranslational mechanisms. In vivo, suppression of Cmtm4 inhibited HCC growth and increased CD8+ T‐cell infiltration in immunocompetent mice. Furthermore, we found that depletion of CMTM4 sensitized HCC tumor to anti‐PD‐L1 treatment compared with control. This suggests that CMTM4 expression level could be a predictive marker for patient response to anti‐PD‐L1 treatment, and CMTM4 depletion can potentially be used to enhance the clinical benefits of anti‐PD‐L1 immunotherapy in patients with liver cancer. [ABSTRACT FROM AUTHOR]

Abstract: Red/near‐infrared dyes are highly demanded for biological applications but most of them are far from satisfactory. In this work, a series of red/near‐infrared fluorophores based on electron‐withdrawing benzo[1,2‐b:4,5‐b′]dithiophene 1,1,5,5‐tetraoxide (BDTO) are synthesized and characterized. They possess both aggregation‐induced emission, and hybridized local and charge‐transfer characteristics. Crystallographic, spectroscopic, electrochemical and computational results reveal that the oxidation of benzo[1,2‐b:4,5‐b′]dithiophene to BDTO can endow the fluorophores with greatly red‐shifted emission, enhanced emission efficiency, reduced energy levels, enlarged two‐photon absorption cross section, and increased reactive oxygen species generation efficiency. The nanoparticles fabricated with a near‐infrared fluorophore TPA‐BDTO show high photostability and biocompatibility with good performance in targeted photodynamic ablation of cancer cells and two‐photon fluorescence imaging of intravital mouse brain vasculature. [ABSTRACT FROM AUTHOR]

Cell cycle inhibitors have a long history as cancer treatment. Here, we report that these inhibitors combated cancer partially via the stimulator of IFN genes (STING) signaling pathway. We demonstrated that paclitaxel (microtubule stabilizer), palbociclib (cyclin-dependent kinase 4/6 inhibitor), and AZD1152 and GSK1070916 (aurora kinase B inhibitors) have anticancer functions beyond arresting the cell cycle. They consistently caused cytosolic DNA accumulation and DNA damage, which inadvertently triggered the cytosolic DNA sensor DEAD-box helicase 41 (DDX41) and activated STING to secrete pro-inflammatory senescence-associated secretory phenotype factors (SASPs). Interestingly, we found that DDX41 was a transcriptional target of HIF. Hypoxia induced expression of DDX41 through HIF-1, making hypoxic hepatocellular carcinoma (HCC) cells more sensitive to the antimitotic agents in STING activation and SASP production. The SASPs triggered immune cell infiltration in tumors for cancer clearance. The treatment with cell cycle inhibitors, especially paclitaxel, extended survival by perturbing mouse HCC growth when used in combination with anti-PD-1. We observed a trend that paclitaxel suppressed Sting wild-type HCC more effectively than Sting-KO HCC, suggesting that STING might contribute to the antitumor effects of paclitaxel. Our study revealed the immune-mediated tumor-suppressing properties of cell cycle inhibitors and suggested combined treatment with immunotherapy as a potential therapeutic approach.

The skin is one of the most physiologically important organs where the organism comes into contact with the external environment and is often a site where pathogen entry first occurs. Thus, a better understanding of the specialized cellular behavior of the immune system in the skin may be important for the improved treatment of diseases. Here, we describe in detail a procedure to image the dorsal mouse ear skin, using a customized ear stage and its associated coverslip holder, with an upright multiphoton microscope. As a demonstrative example, we describe the specific protocol for visualizing robust neutrophil trafficking in albino lysozyme-EGFP mice in response to zymosan particles. Instructive sections are provided for the mouse ear preparation, intradermal delivery of zymosan, design and use of the custom ear stage, as well as a solution for the uninterrupted live imaging of mice during prolonged sessions within a dark box. The mouse ear is easily accessible for imaging, and unlike most other organs, does not require any invasive surgery to be performed.