BackgroundPancreatic cancer is characterised by the accumulation of a fibro-inflammatory stroma. Within this stromal reaction, myeloid cells are a predominant population. Distinct myeloid subsets have been correlated with tumour promotion and unmasking of anti-tumour immunity.ObjectiveThe goal of this study was to determine the effect of myeloid cell depletion on the onset and progression of pancreatic cancer and to understand the relationship between myeloid cells and T cell-mediated immunity within the pancreatic cancer microenvironment.MethodsPrimary mouse pancreatic cancer cells were transplanted into CD11b-diphtheria toxin receptor (DTR) mice. Alternatively, the iKras* mouse model of pancreatic cancer was crossed into CD11b-DTR mice. CD11b+ cells (mostly myeloid cell population) were depleted by diphtheria toxin treatment during tumour initiation or in established tumours.ResultsDepletion of myeloid cells prevented KrasG12D-driven pancreatic cancer initiation. In pre-established tumours, myeloid cell depletion arrested tumour growth and in some cases, induced tumour regressions that were dependent on CD8+ T cells. We found that myeloid cells inhibited CD8+ T-cell anti-tumour activity by inducing the expression of programmed cell death-ligand 1 (PD-L1) in tumour cells in an epidermal growth factor receptor (EGFR)/mitogen-activated protein kinases (MAPK)-dependent manner.ConclusionOur results show that myeloid cells support immune evasion in pancreatic cancer through EGFR/MAPK-dependent regulation of PD-L1 expression on tumour cells. Derailing this crosstalk between myeloid cells and tumour cells is sufficient to restore anti-tumour immunity mediated by CD8+ T cells, a finding with implications for the design of immune therapies for pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an exuberant inflammatory desmoplastic response. The PDAC microenvironment is complex, containing both pro-and antitumorigenic elements, and remains to be fully characterized. Here, we show that sensory neurons, an under-studied cohort of the pancreas tumor stroma, play a significant role in the initiation and progression of the early stages of PDAC. Using a well-established autochthonous model of PDAC (PKC), we show that inflammation and neuronal damage in the peripheral and central nervous system (CNS) occurs as early as the pancreatic intraepithelial neoplasia (PanIN) 2 stage. Also at the PanIN2 stage, pancreas acinar-derived cells frequently invade along sensory neurons into the spinal cord and migrate caudally to the lower thoracic and upper lumbar regions. Sensory neuron ablation by neonatal capsaicin injection prevented perineural invasion (PNI), astrocyte activation, and neuronal damage, suggesting that sensory neurons convey inflammatory signals from Kras-induced pancreatic neoplasia to the CNS. Neuron ablation in PKC mice also significantly delayed PanIN formation and ultimately prolonged survival compared with vehicle-treated controls (median survival, 7.8 vs. 4.5 mo; P = 0.001). These data establish a reciprocal signaling loop between the pancreas and nervous system, including the CNS, that supports inflammation associated with oncogenic Kras-induced neoplasia. Thus, pancreatic sensory neurons comprise an important stromal cell population that supports the initiation and progression of PDAC and may represent a potential target for prevention in high-risk populations.sensory neuron | pancreatic ductal adenocarcinoma | tumorigenesis | inflammation | PanIN P ancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with a median survival of ∼6 mo from diagnosis (National Cancer Institute). A number of unique features distinguish PDAC from other carcinomas, but the most striking is the exuberant desmoplastic infiltrate within tumors. This compartment exhibits an array of cell types, including activated myofibroblasts and myeloid-derived cells. Indeed, this inflammatory infiltrate is present at the inception of neoplasia and accumulates at a near exponential rate during progression to carcinoma and tumor formation. It provides a complex balance of pro-and antitumorigenic signals to neoplastic cells (and also to each other) that is a focus of intense investigation. The pancreas tumor microenvironment has been studied previously, but new tools [genetically engineered mouse models (GEMs) that faithfully recapitulate the salient features of human PDAC] now allow for a careful dissection of the stroma. Using these models, we showed that generalized inflammation is required for the development of precancerous pancreatic intraepithelial neoplasias (1) and that Hedgehog-dependent stromal elements, including activated myofibroblasts, serve to constrain tumor growth and spread (2). Other cellular components of the pancreatic inflammatory str...

Sodium‐ion batteries (NIBs) have attracted more and more attention as economic alternatives for lithium‐ion batteries (LIBs). Sodium super ionic conductor (NASICON) structure materials, known for high conductivity and chemical diffusion coefficient of Na+ (≈10−14 cm2 s−1), are promising electrode materials for NIBs. However, NASICON structure materials often suffer from low electrical conductivity (<10−4 S cm−1), which hinders their electrochemical performance. Here high performance sodium storage performance in Na3V2(PO4)3 (NVP) is realized by optimizing nanostructure and rational surface engineering. A N, B codoped carbon coated three‐dimensional (3D) flower‐like Na3V2(PO4)3 composite (NVP@C‐BN) is designed to enable fast ions/electrons transport, high‐surface controlled energy storage, long‐term structural integrity, and high‐rate cycling. The conductive 3D interconnected porous structure of NVP@C‐BN greatly releases mechanical stress from Na+ extraction/insertion. In addition, extrinsic defects and active sites introduced by the codoping heteroatoms (N, B) both enhance Na+ and e− diffusion. The NVP@C‐BN displays excellent electrochemical performance as the cathode, delivering reversible capacity of 70% theoretical capacity at 100 C after 2000 cycles. When used as anode, the NVP@C‐BN also shows super long cycle life (38 mA h g−1 at 20 C after 5000 cycles). The design provides a novel approach to open up possibilities for designing high‐power NIBs.

Glycogen synthase kinase (GSK)3␤ is a ser-thr kinase that is phosphorylated by the kinase Akt. Although Akt has been shown to regulate platelet function and arterial thrombosis, its effectors in platelets remain unknown. We show here that agonist-dependent phosphorylation of GSK3␤ in platelets is Akt dependent. To determine whether GSK3␤ regulates platelet function, platelets from mice lacking a single allele of GSK3␤ were compared with those of wild-type (WT) controls. GSK3␤ ؉/؊ platelets demonstrated enhanced agonist-dependent aggregation, dense granule secretion, and fibrinogen binding, compared with WT platelets. Treatment of human platelets with GSK3 inhibitors renders them more sensitive to agonist-induced aggregation, suggesting that GSK3 suppresses platelet function in vitro. Finally, the effect of GSK3␤ on platelet function in vivo was evaluated using 2 thrombosis models in mice. In the first, 80% of GSK3␤ ؉/؊ mice (n ‫؍‬ 10) formed stable occlusive thrombi after ferric chloride carotid artery injury, whereas the majority of wild-type mice (67%) formed no thrombi (n ‫؍‬ 15). In a disseminated thrombosis model, deletion of a single allele of GSK3␤ in mice conferred enhanced sensitivity to thrombotic insult. Taken together, these results suggest that GSK3␤ acts as a negative regulator of platelet function in vitro and in vivo. IntroductionPlatelet activation is critical for hemostasis, as is evident from the identification of patients with bleeding disorders attributed to defects in platelet surface receptors or intracellular signaling molecules. [1][2][3][4][5][6][7][8][9][10][11] The activation of platelets is also a central factor contributing to arterial thrombosis. Inhibitors of platelet agonists such as thrombin or adenosine diphosphate (ADP), or antagonists for their cell surface receptors, have been shown to inhibit platelet aggregation and reduce arterial thrombosis in both mouse models and humans. 4,12,13 Thus, the signaling pathways by which these agonists activate platelets are under intense scrutiny, as they may suggest potential new risk factors for thrombosis or therapeutic targets. One signaling pathway of recent interest is the activation of the ser-thr kinases PI3K and Akt. Both thrombin and ADP activate G protein-coupled receptors on the platelet surface, which in turn have been shown to activate multiple isoforms of PI3K 14 and Akt. 13,15 Deletion of PI3K␥ in mice, 16,17 inhibition of PI3K␤ in human platelets, 18 and deletion of either Akt1 19 or Akt2 13 have all been shown to result in defective platelet aggregation and reduced sensitivity to thrombosis in various models. Therefore, the effectors of Akt are likely to play important roles in regulating platelet activation and thrombosis. However, of the dozens of Akt substrates identified to date, it is unclear which are present and functional in platelets.As in other cells, there are likely to be several Akt effectors in platelets. NOS3 is one candidate effector of Akt in platelets that has been shown to positively regulate platelet ...