Cancer‐associated fibroblasts (CAFs), a major component of the tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC), play an important role in tumorigenesis, metastasis, and ...chemoresistance. Tumor‐derived small extracellular vesicles (sEVs), which mediate cell‐to‐cell communication between cancer cells and fibroblasts, are also critical for cancer progression and metastasis. However, it remains unclear how PDAC cell‐derived sEVs activate fibroblasts, which contributes to tumor progression. Here, we report that ezrin (EZR) expression in PDAC cell‐derived sEVs (sEV‐EZR) can activate fibroblasts, resulting in increased migration ability and high expression of α‐SMA, PDGFRB, and high production of extracellular matrix in fibroblasts. Reciprocally, sEV‐EZR‐activated fibroblasts enhanced PDAC cell proliferation, invasion, and metastasis to the liver in animal models. Conversely, fibroblasts treated with PDAC cell‐derived sEVs with EZR knockdown resulted in the reduced metastatic ability of PDAC. Mechanistically, we demonstrated that PDAC cell‐derived sEV‐EZR increases the STAT3 and YAP‐1 signaling pathways to induce fibroblast activation, and the activated fibroblasts promote PDAC cell proliferation, invasion, and liver metastasis. Inhibition of the STAT3 and YAP‐1 signaling pathways by gene knockdown can abrogate sEV‐EZR‐induced effects. These findings suggest that targeting the interaction between PDAC cell‐derived sEV‐EZR and fibroblasts is a potential therapeutic strategy for PDAC.
PDAC cell‐derived sEVs can activate fibroblasts through activating STAT3 and YAP‐1 signaling, resulting in increased migration ability and high expression of α‐SMA, PDGFRB, and high production of extracellular matrix in fibroblasts. Reciprocally, sEV‐EZR‐activated fibroblasts enhanced PDAC cell proliferation, invasion, and metastasis to the liver. Inhibition of the STAT3 and YAP‐1 signaling pathways can abrogate sEV‐EZR‐induced effects. Thus, targeting sEV‐EZR may contribute to improve adjuvant PDAC therapies.
•The lump solution method is generalized.•The CDGKS-like equation is derived through the generalized bilinear method.•The new rogue wave solution is constructed by using “3-2-2” neural network model.
...Under investigation in this paper is the (2+1)-dimensional Caudrey-Dodd-Gibbon-Kotera-Sawada-like (CDGKS-like) equation. Based on bilinear neural network method, the generalized lump solution, classical lump solution and the novel analytical solution are constructed by giving some specific activation functions in the single hidden layer neural network model and the “3-2-2” neural network model. By means of symbolic computation, these analytical solutions and corresponding rogue waves are obtained with the help of Maple software. These results fill the blank of the CDGKS-like equation in the existing literature. Via various three-dimensional plots, curve plots, density plots and contour plots, dynamical characteristics of these waves are exhibited. The effective methods used in this paper is helpful to study the nonlinear evolution equations in plasmas, mathematical physics, electromagnetism and fluid dynamics.
Abstract
Van der Waals heterobilayers of transition metal dichalcogenides with spin–valley coupling of carriers in different layers have emerged as a new platform for exploring spin/valleytronic ...applications. The interlayer coupling was predicted to exhibit subtle changes with the interlayer atomic registry. Manually stacked heterobilayers, however, are incommensurate with the inevitable interlayer twist and/or lattice mismatch, where the properties associated with atomic registry are difficult to access by optical means. Here, we unveil the distinct polarization properties of valley-specific interlayer excitons using epitaxially grown, commensurate WSe
2
/MoSe
2
heterobilayers with well-defined (AA and AB) atomic registry. We observe circularly polarized photoluminescence from interlayer excitons, but with a helicity opposite to the optical excitation. The negative circular polarization arises from the quantum interference imposed by interlayer atomic registry, giving rise to distinct polarization selection rules for interlayer excitons. Using selective excitation schemes, we demonstrate the optical addressability for interlayer excitons with different valley configurations and polarization helicities.
KRAS mutations are the earliest events found in approximately 90% of pancreatic ductal adenocarcinomas (PDACs). However, little is known as to why KRAS mutations preferentially occur in PDACs and ...what processes/factors generate these mutations. While abnormal carbohydrate metabolism is associated with a high risk of pancreatic cancer, it remains elusive whether a direct relationship between KRAS mutations and sugar metabolism exists. Here, we show that under high-glucose conditions, cellular O-GlcNAcylation is significantly elevated in pancreatic cells that exhibit lower phosphofructokinase (PFK) activity than other cell types. This post-translational modification specifically compromises the ribonucleotide reductase (RNR) activity, leading to deficiency in dNTP pools, genomic DNA alterations with KRAS mutations, and cellular transformation. These results establish a mechanistic link between a perturbed sugar metabolism and genomic instability that induces de novo oncogenic KRAS mutations preferentially in pancreatic cells.
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•Pancreatic cells exhibit lower phosphofructokinase activity than other cell types•High glucose elevates O-GlcNAcylation and genomic alterations in pancreatic cells•Reduction of RNR activity leads to nucleotide pool imbalance and KRAS mutations•PFK activity alters the sensitivity to high-glucose-induced genomic effects
Most pancreatic ductal adenocarcinomas contain activated KRAS mutations required for cancer initiation and maintenance. Here, Hu et al. show that high glucose promotes O-GlcNAcylation on ribonucleotide reductase, leading to nucleotide pool imbalance and KRAS mutations preferentially in pancreatic cells.
The design of multicomponent materials has captured considerable attention due to its extraordinary ability to tailor functional properties. However, how a single element affects the behavior of the ...overall material has yet to be explored in depth. In this study, the heteroepitaxy of high entropy (Fe, Co, Ni, Cr, Mn)3O4 films with varying strain states are investigated in magnetic performance. It is discovered that the high entropy oxide thin film with compressive strain exhibits an effect of crystalline magnetic anisotropy. Diverse analyses provide a detailed understanding of high entropy magnetic oxide systems, including X‐ray diffraction, reciprocal space mapping, macroscopic magnetic characterization, X‐ray absorption spectroscopy (XAS), etc. Notably, the element‐specific XAS technique proves effective in uncovering the origin of the crystalline magnetic anisotropy. Due to the substrate‐induced epitaxial strain, the eg orbitals of Mn3+ form different energy levels, leading to different preferred electron occupancy. The exploration of magnetic properties in epitaxial high entropy oxide film is then raveled. By navigating the complexities introduced by the random atom distribution and intricate magnetic interactions, this study pioneers novel methodologies for probing the core physics of high entropy oxides.
In a strain‐driven local environment, the magnetic properties of high entropy oxide (Fe, Co, Ni, Cr, Mn)3O4 induced by individual elements are discovered. By utilizing atomic‐spatial‐resolution scanning transmission electron microscopy and element‐specific X‐ray absorption techniques, a thorough understanding of the high entropy oxide can be achieved, establishing a novel methodology for investigating the magnetic origin of high entropy oxides.
Tumor cells with diverse phenotypes and biological behaviors are influenced by stromal cells through secretory factors or direct cell-cell contact. Pancreatic ductal adenocarcinoma (PDAC) is ...characterized by extensive desmoplasia with fibroblasts as the major cell type. In the present study, we observe enrichment of myofibroblasts in a juxta-tumoral position with tumor cells undergoing epithelial-mesenchymal transition (EMT) that facilitates invasion and correlates with a worse clinical prognosis in PDAC patients. Direct cell-cell contacts forming heterocellular aggregates between fibroblasts and tumor cells are detected in primary pancreatic tumors and circulating tumor microemboli (CTM). Mechanistically, ATP1A1 overexpressed in tumor cells binds to and reorganizes ATP1A1 of fibroblasts that induces calcium oscillations, NF-κB activation, and activin A secretion. Silencing ATP1A1 expression or neutralizing activin A secretion suppress tumor invasion and colonization. Taken together, these results elucidate the direct interplay between tumor cells and bound fibroblasts in PDAC progression, thereby providing potential therapeutic opportunities for inhibiting metastasis by interfering with these cell-cell interactions.
The efficacy of treatment of Helicobacter pylori infection has decreased steadily because of increasing resistance to clarithromycin, metronidazole, and levofloxacin. Resistance to amoxicillin is ...generally low, and high intragastric pH increases the efficacy of amoxicillin, so we investigated whether a combination of a high-dose proton pump inhibitor and amoxicillin (dual therapy) was more effective than standard first-line or rescue therapies in eradicating H pylori.
We performed a large-scale multihospital trial to compare the efficacy of a high-dose dual therapy (HDDT) with that of standard therapies in treatment-naive (n = 450) or treatment-experienced (n = 168) patients with H pylori infection. Treatment-naive patients were randomly assigned to groups given HDDT (rabeprazole 20 mg and amoxicillin 750 mg, 4 times/day for 14 days, group A1), sequential therapy for 10 days (group B1), or clarithromycin-containing triple therapy for 7 days (group C1). Treatment-experienced patients were randomly assigned to groups given HDDT for 14 days (group A2), sequential therapy for 10 days (B2), or levofloxacin-containing triple therapy for 7 days (C2). H pylori infection was detected by using the (13)C-urea breath test. We evaluated factors associated with treatment outcomes.
In the intention-to-treat analysis, H pylori was eradicated in 95.3% of patients in group A1 (95% confidence interval CI, 91.9%-98.8%), 85.3% in B1 (95% CI, 79.6%-91.1%), and 80.7% in group C1 (95% CI, 74.3%-87.1%). Infection was eradicated in 89.3% of patients in group A2 (95% CI, 80.9%-97.6%), 51.8% in group B2 (95% CI, 38.3%-65.3%), and 78.6% (95% CI, 67.5%-89.7%) in group C2. The efficacy of HDDT was significantly higher than that of currently recommended regimens, irrespective of CYP2C19 genotype. Bacterial resistance to drugs was associated with treatment failure. There were no significant differences between groups in adverse events or patient adherence.
HDDT is superior to standard regimens as empirical first-line or rescue therapy for H pylori infection, with similar safety profiles and tolerability. ClinicalTrials.gov number: NCT01163435.
This work presents polymer photovoltaic devices based on poly(3-hexylthiophene) (P3HT) and TiO2 nanorod hybrid bulk heterojunctions. Interface modification of a TiO2 nanorod surface is conducted to ...yield a very promising device performance of 2.20% with a short circuit current density (J sc) of 4.33 mA/cm2, an open circuit voltage (V oc) of 0.78 V, and a fill factor (FF) of 0.65 under simulated A.M. 1.5 illumination (100 mW/cm2). The suppression of recombination at P3HT/TiO2 nanorod interfaces by the attachment of effective ligand molecules substantially improves device performance. The correlation between surface photovoltage and hybrid morphology is revealed by scanning Kelvin probe microscopy. The proposed method provides a new route for fabricating low-cost, environmentally friendly polymer/inorganic hybrid bulk heterojunction photovoltaic devices.
Over 90% of patients with pancreatic ductal adenocarcinoma (PDAC) have oncogenic KRAS mutations. Nevertheless, mutated KRAS alone is insufficient to initiate pancreatic intraepithelial neoplasia ...(PanIN), the precursor of PDAC. The identities of the other factors/events required to drive PanIN formation remain elusive. Here, optic‐clear 3D histology is used to analyze entire pancreases of 2‐week‐old Pdx1‐Cre; LSL‐KrasG12D/+ (KC) mice to detect the earliest emergence of PanIN and observed that the occurrence is independent of physical location. Instead, it is found that the earliest PanINs overexpress Muc4 and associate with αSMA+ fibroblasts in both transgenic mice and human specimens. Mechanistically, KrasG12D/+ pancreatic cells upregulate Muc4 through genetic alterations to increase proliferation and fibroblast recruitments via Activin A secretion and consequently enhance cell transformation for PanIN formation. Inhibition of Activin A signaling using Follistatin (FST) diminishes early PanIN‐associated fibroblast recruitment, effectively curtailing PanIN initiation and growth in KC mice. These findings emphasize the vital role of interactions between oncogenic KrasG12D/+‐driven genetic alterations and induced microenvironmental changes in PanIN initiation, suggesting potential avenues for early PDAC diagnostic and management approaches.
This study found that early PanIN cells express elevated levels of Muc4, specifically the oncogenic Muc4/X variant, and are closely associated with αSMA+ fibroblasts. This is observed in KrasG12D/+ transgenic mice and human pancreatic specimens with early PanINs. Importantly, upregulated Muc4 expression and Activin A secretion are identified as critical factors driving PanIN initiation in pancreatic cells with KrasG12D/+ mutation.
The search for topological superconductors (TSCs) is one of the most urgent contemporary problems in condensed matter systems. TSCs are characterized by a full superconducting gap in the bulk and ...topologically protected gapless surface (or edge) states. Within each vortex core of TSCs, there exists the zero-energy Majorana bound states, which are predicted to exhibit non-Abelian statistics and to form the basis of the fault-tolerant quantum computation. To date, no stoichiometric bulk material exhibits the required topological surface states (TSSs) at the Fermi level (EF) combined with fully gapped bulk superconductivity. We report atomic-scale visualization of the TSSs of the noncentrosymmetric fully gapped superconductor PbTaSe2. Using quasi-particle scattering interference imaging, we find two TSSs with a Dirac point at E ≅ 1.0 eV, of which the inner TSS and the partial outer TSS cross EF, on the Pb-terminated surface of this fully gapped superconductor. This discovery reveals PbTaSe2 as a promising candidate for TSC.
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