Tumor-secreted FGF21 acts as an immune suppressor by rewiring cholesterol metabolism of CD8T cells.

Tumors employ diverse strategies for immune evasion. Unraveling the mechanisms by which tumors suppress anti-tumor immunity facilitates the development of immunotherapies. Here, we have identified tumor-secreted fibroblast growth factor 21 (FGF21) as a pivotal immune suppressor.

A Single-Atom Manganese Nanozyme Mn-N/C Promotes Anti-Tumor Immune Response via Eliciting Type I Interferon Signaling.

Tumor microenvironment (TME)-induced nanocatalytic therapy is a promising strategy for cancer treatment, but the low catalytic efficiency limits its therapeutic efficacy. Single-atom catalysts (SACs) are a new type of nanozyme with incredible catalytic efficiency. Here, a single-atom manganese (Mn)-N/C nanozyme is constructed.

Cancer CD39 drives metabolic adaption and mal-differentiation of CD4 T cells in patients with non-small-cell lung cancer.

While ectonucleotidase CD39 is a cancer therapeutic target in clinical trials, its direct effect on T-cell differentiation in human non-small-cell lung cancer (NSCLC) remains unclear. Herein, we demonstrate that human NSCLC cells, including tumor cell lines and primary tumor cells from clinical patients, efficiently drive the metabolic adaption of human CD4 T cells, instructing differentiation of regulatory T cells while inhibiting effector T cells. Of importance, NSCLC-induced T-cell mal-differentiation primarily depends on cancer CD39, as this can be fundamentally blocked by genetic depletion of CD39 in NSCLC.

Mitophagy bridges DNA sensing with metabolic adaption to expand lung cancer stem-like cells.

While previous studies have identified cancer stem-like cells (CSCs) as a crucial driver for chemoresistance and tumor recurrence, the underlying mechanisms for populating the CSC pool remain unclear. Here, we identify hypermitophagy as a feature of human lung CSCs, promoting metabolic adaption via the Notch1-AMPK axis to drive CSC expansion. Specifically, mitophagy is highly active in CSCs, resulting in increased mitochondrial DNA (mtDNA) content in the lysosome.

Protection of Regulatory T Cells from Fragility and Inactivation in the Tumor Microenvironment.

Fragility of regulatory T (Treg) cells manifested by the loss of neuropilin-1 (NRP1) and expression of IFNγ undermines the immune suppressive functions of Treg cells and contributes to the success of immune therapies against cancers. Intratumoral Treg cells somehow avoid fragility; however, the mechanisms by which Treg cells are protected from fragility in the tumor microenvironment are not well understood. Here, we demonstrate that the IFNAR1 chain of the type I IFN (IFN1) receptor was downregulated on intratumoral Treg cells.

A novel transfer learning model for traditional herbal medicine prescription generation from unstructured resources and knowledge.

Traditional Chinese medicine (TCM) is an essential part of the world's traditional medicine. However, there are still many issues in the promotion and development of TCM, such as a lot of unique TCM treatments are taught only between the master and an apprentice in practice, it takes dozens of years for a TCM practitioner to master them and the complicated TCM treatment principles. Intelligent TCM models, as a promising method, can overcome these issues.

Activation of p38α stress-activated protein kinase drives the formation of the pre-metastatic niche in the lungs.

Primary tumor-derived factors (TDFs) act upon normal cells to generate a pre-metastatic niche, which promotes colonization of target organs by disseminated malignant cells. Here we report that TDFs-induced activation of the p38α kinase in lung fibroblasts plays a critical role in the formation of a pre-metastatic niche in the lungs and subsequent pulmonary metastases. Activation of p38α led to inactivation of type I interferon signaling and stimulation of expression of fibroblast activation protein (FAP).

Depalmitoylation rewires FLT3-ITD signaling and exacerbates leukemia progression.

Internal tandem duplication within FLT3 (FLT3-ITD) is one of the most frequent mutations in acute myeloid leukemia (AML) and correlates with a poor prognosis. Whereas the FLT3 receptor tyrosine kinase is activated at the plasma membrane to transduce PI3K/AKT and RAS/MAPK signaling, FLT3-ITD resides in the endoplasmic reticulum and triggers constitutive STAT5 phosphorylation. Mechanisms underlying this aberrant FLT3-ITD subcellular localization or its impact on leukemogenesis remain poorly established.

Immune suppressive activity of myeloid-derived suppressor cells in cancer requires inactivation of the type I interferon pathway.

Myeloid-derived suppressor cells (MDSC) are pathologically activated neutrophils and monocytes with potent immune suppressive activity. These cells play an important role in accelerating tumor progression and undermining the efficacy of anti-cancer therapies. The natural mechanisms limiting MDSC activity are not well understood.

[Study on chemical bibenzyls in Dendrobium gratiosissimum].

Nineteen compounds were isolated and structurally characterized from an ethanol extract of Dendrobium gratiossimum, including dendrogratiol A(1), DDB-1(2), 3,4-dihydroxyl-5,3',4'-trimethoxybibenzyl(3), amoenylin(4), chrysotoxine(5), DTB(6), 3,4,4'-trihydroxyl-5,3'-dimethoxybenzyl(7), 3-methylgiga(8), aloifol(9), gigantol tetramethyl ether(10), batatasin Ⅲ(11), moscatilin(12), moniliformine(13), gigantol(14), DMB(15), flavanthrinin(16), cannithrene-2(17), 3,4-dihydroxyl-5,4'-dimethoxystilbene(18) and 4-hydroxy-3,5,4'-trimethoxystilbene(19). 1 was a new compound, and 2-10, 16, 18 and 19 were obtained from this plant species for the first time. In vitro cytotoxic and antiviral activities of these isolates were evaluated, which displayed that 4 showed moderate cytotoxicity against human hepatoma cell line HepG2 with the IC_(50) of 10.

Dynamics of calling activity to toll-free numbers in China.

The quantitative understanding of human behavior is a key issue in modern science. Recently, inhomogeneous human activities have been described by bursts (consecutive activities separated by long periods of inactivity) and characterized by fat-tailed inter-event time (interval between two activities) distributions. However, the dynamics between number of activities and activity duration are still unclear.

The PKR-Like Endoplasmic Reticulum Kinase Promotes the Dissemination of Myc-Induced Leukemic Cells.

Hyperactive oncogenic Myc stimulates protein synthesis that induces the unfolded protein response, which requires the function of the eukaryotic translation initiation factor 2-alpha kinase 3, also known as protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK). Activated PERK acts to limit mRNA translation, enable proper protein folding, and restore the homeostasis in the endoplasmic reticulum. Given that Myc activation contributes to many types of lymphoid and myeloid human leukemias, we used a mouse model to examine the importance of PERK in development and progression of Myc-induced leukemias.

An Interferon-Driven Oxysterol-Based Defense against Tumor-Derived Extracellular Vesicles.

Tumor-derived extracellular vesicles (TEV) "educate" healthy cells to promote metastases. We found that melanoma TEV downregulated type I interferon (IFN) receptor and expression of IFN-inducible cholesterol 25-hydroxylase (CH25H). CH25H produces 25-hydroxycholesterol, which inhibited TEV uptake.

Targeting Myeloid-derived Suppressor Cells and Programmed Death Ligand 1 Confers Therapeutic Advantage of Ablative Hypofractionated Radiation Therapy Compared With Conventional Fractionated Radiation Therapy.

Purpose: Ablative hypofractionated radiation therapy (AHFRT) presents a therapeutic advantage compared with conventional fractionated radiation therapy (CFRT) for primary and oligometastatic cancers. However, the underlying mechanisms remain largely unknown. In the present study, we compared the immune alterations in response to AHFRT versus CFRT and examined the significance of immune regulations contributing to the efficacy of AHFRT.

Downregulation of the IFNAR1 chain of type 1 interferon receptor contributes to the maintenance of the haematopoietic stem cells.

Recent studies demonstrated that prolonged exposure of haematopoietic stem cells (HSCs) to type I interferons (IFN) stimulates HSCs entrance into cell cycle, continuous proliferation and eventual exhaustion, which could be prevented by ablation of the Ifnar1 chain of IFN receptor. Given that levels IFNAR1 expression can be robustly affected by IFN-independent ubiquitination and downregulation of IFNAR1 in response to activation of protein kinases such as protein kinase R-like endoplasmic reticulum kinase (PERK) and casein kinase 1α (CK1α), we aimed to determine the role of IFNAR1 downregulation in the maintenance of HSCs. Mice harboring the ubiquitination-deficient Ifnar1 allele displayed greater levels of haematopoietic cell progenitors but reduced numbers of the long-term HSCs compared with wild type mice and animals lacking Ifnar1.

Therapeutic Elimination of the Type 1 Interferon Receptor for Treating Psoriatic Skin Inflammation.

Phototherapy with UV light is a standard treatment for psoriasis, yet the mechanisms underlying the therapeutic effects are not well understood. Studies in human and mouse keratinocytes and in the skin tissues from human patients and mice showed that UV treatment triggers ubiquitination and downregulation of the type I IFN receptor chain IFNAR1, leading to suppression of IFN signaling and an ensuing decrease in the expression of inflammatory cytokines and chemokines. The severity of imiquimod-induced psoriasiform inflammation was greatly exacerbated in skin of mice deficient in IFNAR1 ubiquitination (Ifnar1(SA)).

Type I interferons mediate pancreatic toxicities of PERK inhibition.

The great preclinical promise of the pancreatic endoplasmic reticulum kinase (PERK) inhibitors in neurodegenerative disorders and cancers is marred by pancreatic injury and diabetic syndrome observed in PERK knockout mice and humans lacking PERK function and suffering from Wolcott-Rallison syndrome. PERK mediates many of the unfolded protein response (UPR)-induced events, including degradation of the type 1 interferon (IFN) receptor IFNAR1 in vitro. Here we report that whole-body or pancreas-specific Perk ablation in mice leads to an increase in IFNAR1 protein levels and signaling in pancreatic tissues.