Branched-chain amino acid (BCAA) metabolism is potentially linked with development of pancreatic ductal adenocarcinoma (PDAC)
. BCAA transaminase 2 (BCAT2) was essential for the collateral lethality ...conferred by deletion of malic enzymes in PDAC and the BCAA-BCAT metabolic pathway contributed to non-small-cell lung carcinomas (NSCLCs) other than PDAC
. However, the underlying mechanism remains undefined. Here we reveal that BCAT2 is elevated in mouse models and in human PDAC. Furthermore, pancreatic tissue-specific knockout of Bcat2 impedes progression of pancreatic intraepithelial neoplasia (PanIN) in LSL-Kras
; Pdx1-Cre (KC) mice. Functionally, BCAT2 enhances BCAA uptake to sustain BCAA catabolism and mitochondrial respiration. Notably, BCAA enhances growth of pancreatic ductal organoids from KC mice in a dose-dependent manner, whereas addition of branched-chain α-keto acid (BCKA) and nucleobases rescues growth of KC organoids that is suppressed by BCAT2 inhibitor. Moreover, KRAS stabilizes BCAT2, which is mediated by spleen tyrosine kinase (SYK) and E3 ligase tripartite-motif-containing protein 21 (TRIM21). In addition, BCAT2 inhibitor ameliorates PanIN formation in KC mice. Of note, a lower-BCAA diet also impedes PDAC development in mouse models of PDAC. Thus, BCAT2-mediated BCAA catabolism is critical for development of PDAC harbouring KRAS mutations. Targeting BCAT2 or lowering dietary BCAA may have translational significance.
A major challenge for traditional cancer therapy, including surgical resection, chemoradiotherapy, and immunotherapy, is how to induce tumor cell death and leverage the host immune system at the same ...time. Here, a myeloid‐derived suppressor cell (MDSC) membrane‐coated iron oxide magnetic nanoparticle (MNP@MDSC) to overcome this conundrum for cancer therapy is developed. In this study, MNP@MDSC demonstrates its superior performance in immune evasion, active tumor‐targeting, magnetic resonance imaging, and photothermal therapy (PTT)‐induced tumor killing. Compared with red blood cell membrane‐coated nanoparticles (MNPs@RBC) or naked MNPs, MNP@MDSCs are much more effective in active tumor‐targeting, a beneficial property afforded by coating MNP with membranes from naturally occurring MDSC, thus converting the MNP into “smart” agents that like to accumulate in tumors as the source MDSCs. Once targeted to the tumor microenvironment, MNPs@MDSC can act as a PTT agents for enhanced antitumor response by inducing immunogenic cell death, reprogramming the tumor infiltrating macrophages, and reducing the tumor's metabolic activity. These benefits, in combination with the excellent biocompatibility and pharmacological kinetics characteristics, make MNP@MDSC a promising, multimodal agent for cancer theranostics.
Myeloid‐derived suppressor cell (MDSC) membranes are collected from tumor‐bearing mice and further used for magnetic Fe3O4 nanoparticle (MNP) coating. The resulting MDSC‐mimicking nanoparticles (MNP@MDSC) demonstrate superior performance in immune evasion, active tumor‐targeting, magnetic resonance imaging, photothermal therapy‐induced tumor killing, and excellent biocompatibility and pharmacological kinetics characteristics. These benefits make MNP@MDSC a promising, multimodal agent for cancer theranostics.
Immune checkpoint blockade therapy is revolutionizing the traditional treatment model of multiple tumor types, but remains ineffective for a large subset of patients. Photodynamic therapy (PDT) has ...been shown to induce cancer cell death and provoke an immune response, and may represent a potential strategy to synergize with immune checkpoint blockade therapy. However, the limited tissue penetration of exciting light for conventional PDT largely hinders its application in the clinic and its further combination with immunotherapy. Here, a serrated packing covalent organic framework (COF), COF‐606, with excellent two‐photon absorption (2PA) property and photostability, largely avoids aggregation‐caused quenching, therefore offering high reactive oxygen species (ROS) generation efficiency; it is used as a 2PA photosensitizer for PDT in deep tumor tissue. COF‐606 induced PDT is shown to be efficient in inducing immunogenic cell death, provoking an immune response and normalizing the immunosuppressive status for the first time. This makes it possible to combine 2PA induced PDT using COF with programmed cell death protein 1 immune checkpoint blockade therapy. Such combination leads to strong abscopal tumor‐inhibiting efficiency and long‐lasting immune memory effects, standing as a promising combinatorial therapeutic strategy for cancer treatment.
A novel biocompatible covalent organic framework with excellent two‐photon absorption properties is used for cancer photodynamic therapy to overcome the low penetration depth of traditional photodynamic therapy. This treatment induces immunogenic cell death, alleviates immunosuppression, and further enhances the effectiveness of PD‐1‐based immunotherapy in a poorly immunogenic breast cancer mouse model.
The commercial ceramic nanoparticle coated microporous polyolefin separators used in lithium batteries are still vulnerable under external impact, which may cause short circuits and consequently ...severe safety threats, because the protective ceramic nanoparticle coating layers on the separators are intrinsically brittle. Here, a nacre‐inspired coating on the separator to improve the impact tolerance of lithium batteries is reported. Instead of a random structured ceramic nanoparticle layer, ion‐conductive porous multilayers consisting of highly oriented aragonite platelets are coated on the separator. The nacre‐inspired coating can sustain external impact by turning the violent localized stress into lower and more uniform stress due to the platelet sliding. A lithium‐metal pouch cell using the aragonite platelet coated separator exhibits good cycling stability under external shock, which is in sharp contrast to the fast short circuit of a lithium‐metal pouch cell using a commercial ceramic nanoparticle coated separator.
A nacre‐inspired coating is fabricated to improve the impact tolerance of the separator in a lithium battery via efficient energy dissipation. Remarkably, the pouch cell using the nacre‐inspired porous aragonite platelet coated separator performs with much lower instantaneous open‐circuit voltage change and faster voltage recovery than the cell using the commercial ceramic nanoparticle coated separator under external impaction.
Background This study aimed to investigate the incidence and long-term survival outcomes of occult lung cancer between 2004 and 2015. Methods A total of 2958 patients were diagnosed with occult lung ...cancer in the 305,054 patients with lung cancer. The entire cohort was used to calculate the crude incidence rate. Eligible 52,472 patients (T1-xN0M0, including 2353 occult lung cancers) were selected from the entire cohort to perform survival analyses after translating T classification according to the 8th TNM staging system. Cancer-specific survival curves for different T classifications were presented. Results The crude incidence rate of occult lung cancer was 1.00 per 100 patients, and it was reduced between 2004 and 2015 1.4 per 100 persons in 2004; 0.6 per 100 persons in 2015; adjusted risk ratio = 0.437, 95% confidence interval (CI) 0.363-0.527. In the survival analysis, there were 2206 death events in the 2353 occult lung cancers. The results of the multivariable analysis revealed that the prognoses with occult lung cancer were similar to patients with stage T3N0M0 (adjusted hazard ratio = 1.054, 95% CI 0.986-1.127, p = 0.121). Adjusted survival curves presented the same results. In addition, adjusted for other confounders, female, age less than or equai to 72 years, surgical treatment, radiotherapy, adenocarcinoma, and non-squamous and non-adenocarcinoma non-small cell carcinoma were independent protective prognostic factors (all p < 0.05). Conclusions Occult lung cancer was uncommon. However, the cancer-specific survival of occult lung cancer was poor, therefore, we should put the assessment of its prognoses on the agenda. Timely surgical treatment and radiotherapy could improve survival outcomes for those patients. Besides, we still need more research to confirm those findings. Keywords: Occult lung cancer, Incidence, Survival, Surveillance, Epidemiology, And end results database
Gliomas are the most common central nervous system tumors. They show malignant characteristics indicating rapid proliferation and a high invasive capacity and are associated with a poor prognosis. In ...our previous study, p68 was overexpressed in glioma cells and correlated with both the degree of glioma differentiation and poor overall survival. Downregulating p68 significantly suppressed proliferation in glioma cells. Moreover, we found that the p68 gene promoted glioma cell growth by activating the nuclear factor‐κB signaling pathway by a downstream molecular mechanism that remains incompletely understood. In this study, we found that dual specificity phosphatase 5 (DUSP5) is a downstream target of p68, using microarray analysis, and that p68 negatively regulates DUSP5. Upregulating DUSP5 in stably expressing cell lines (U87 and LN‐229) suppressed proliferation, invasion, and migration in glioma cells in vitro, consistent with the downregulation of p68. Furthermore, upregulating DUSP5 inhibited ERK phosphorylation, whereas downregulating DUSP5 rescued the level of ERK phosphorylation, indicating that DUSP5 might negatively regulate ERK signaling. Additionally, we show that DUSP5 levels were lower in high‐grade glioma than in low‐grade glioma. These results suggest that the p68‐induced negative regulation of DUSP5 promoted invasion by glioma cells and mediated the activation of the ERK signaling pathway.
We found that the function of the DUSP5 gene is to act as the downstream signaling pathway of p68 using global microarray gene expression analysis, and revealed that p68 negatively regulated the DUSP5 gene. Our discovery provides novel insight into the mode of negative regulation in cancer cells and represents a new facet in the complexities of p68 gene tumor‐promoting function.
Cyclooxygenase-2 (COX-2) was stated to be overexpression in various human malignancies associating with angiogenesis, metastasis and chemoresistence. Pancreatic ductal adenocarcinoma (PDAC) is a ...lethal disease displaying many of these characteristics. A common abnormality of PDAC is overexpression of specificity protein-1 (Sp1), which was said to correlate with malignant phenotypes of human cancers. Using RNA-seq data from The Cancer Genome Atlas (TCGA), we found that Sp1 expression was positively correlated with that of COX-2 in PDAC, and that the inhibition or overexpression of Sp1 in PDAC cells leads to decreased or elevated COX-2 expression. Luciferase reporter gene and chromatin immunoprecipitation (ChIP) assays revealed that elevated transcription of COX-2 requires Sp1 binding to sequence positions around -245/-240 of COX-2 promoter. Activated epidermal growth factor receptor (EGFR) and downstream p38 mitogen-activated protein kinase (p38-MAPK) were also profoundly altered in PDAC. The inhibition of EGFR/p38-MAPK signaling resulted in reduced Sp1 activation, decreased COX-2 and vascular endothelial growth factor (VEGF) expression. Thus, Sp1 could transcriptionally activate COX-2 expression in a process relies on activated EGFR/p38-MAPK signaling. Finally, we found that the inhibition of COX-2 leads to decreased angiogenesis in a process dependent on VEGF, which link COX-2 to angiogenesis in PDAC.
T-cell immunoglobulin mucin 3 (TIM3) is a negative immune checkpoint and plays a crucial part in tumor-induced immune suppression. However, the mechanism of TIM3 in regulating immunosuppression in ...head and neck squamous cell carcinoma (HNSCC) was still not quite clear.
We carried out the immunohistochemistry staining of HNSCC tissue microarrays. Through quantification of the histoscore, we performed the correlation analysis among the TIM3, Galectin-9, Foxp3, CD68 and CD163. The effects of TIM3 on regulatory T cells (Tregs) and macrophages were detected by utilizing the Tgfbr1/Pten 2cKO HNSCC mouse model. Flow cytometry were used to analysis the percent of Tregs, macrophages and IFN-γ.
We demonstrated the close association among TIM3/Galectin-9 pathway, regulatory T cell marker (Foxp3) and macrophage marker (CD68, CD163) in human HNSCC. In the transgenic HNSCC mouse model, blockade of TIM3 by the anti-TIM3 monoclonal antibody induced a reduction of CD4
CD25
Foxp3
Tregs. Meanwhile, the population of TIM3
Tregs was also decreased. However, the population of CD206
macrophages was not significantly declined. The increased IFN-γ production on CD8
T cells in anti-TIM3 treatment mice showed that the antitumor immune response was enhanced through suppression of these negative immune factors.
The present study demonstrated that TIM3 was associated with the immunosuppression in HNSCC. And targeting TIM3 can enhance anti-tumor immune response by decreasing Tregs in HNSCC.
Mare volcanics on the Moon are the key record of thermo-chemical evolution throughout most of lunar history
. Young mare basalts-mainly distributed in a region rich in potassium, rare-earth elements ...and phosphorus (KREEP) in Oceanus Procellarum, called the Procellarum KREEP Terrane (PKT)
-were thought to be formed from KREEP-rich sources at depth
. However, this hypothesis has not been tested with young basalts from the PKT. Here we present a petrological and geochemical study of the basalt clasts from the PKT returned by the Chang'e-5 mission
. These two-billion-year-old basalts are the youngest lunar samples reported so far
. Bulk rock compositions have moderate titanium and high iron contents with KREEP-like rare-earth-element and high thorium concentrations. However, strontium-neodymium isotopes indicate that these basalts were derived from a non-KREEP mantle source. To produce the high abundances of rare-earth elements and thorium, low-degree partial melting and extensive fractional crystallization are required. Our results indicate that the KREEP association may not be a prerequisite for young mare volcanism. Absolving the need to invoke heat-producing elements in their source implies a more sustained cooling history of the lunar interior to generate the Moon's youngest melts.
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