Biofilm infections can induce chronic inflammation and stall the normal orchestrated course of wound-healing cascades. Herein, pH-switchable antimicrobial hydrogel with nanofiber networks for biofilm eradication and rescuing stalled healing in chronic wounds is reported on the basis of the self-assembly of a designed octapeptide (IKFQFHFD) at neutral pH. This hydrogel is biocompatible and exhibits an acidic pH (pathological environment of infected chronic wounds)-switchable broad-spectrum antimicrobial effect via a mechanism involving cell wall and membrane disruption. The antimicrobial activity of hydrogel is derived from its acidic pH-dependent nanofiber network destabilization and activated release of IKFQFHFD, which is antimicrobial only at acidic pH due to the antimicrobial peptide-like molecular structure. In addition, supramolecular nanofiber networks loaded with drugs of cypate (photothermal agent) and proline (procollagen component) are further developed. In vitro experiments show that loaded drugs exhibit acidic pH (pH ∼ 5.5)-responsive release profiles, and synergistic biofilm eradication and subsequent healing cascade activation of cells proliferation are achieved on the basis of the supramolecular nanofiber networks. Remarkably, the nanofiber networks of hydrogel enable in vivo complete healing of MRSA biofilm infected wound in diabetic mice within 20 days, showing great potential as promising chronic wound dressings. The proposed synergistic strategy for eradicating biofilm and activating subsequent healing cascades may offer a powerful modality for the management of clinical chronic wounds.

Developing predictive biomarkers that can detect the tipping point before metastasis of hepatocellular carcinoma (HCC), is critical to prevent further irreversible deterioration. To discover such early-warning signals or biomarkers of pulmonary metastasis in HCC, we analyse time-series gene expression data in spontaneous pulmonary metastasis mice HCCLM3-RFP model with our dynamic network biomarker (DNB) method, and identify CALML3 as a core DNB member. All experimental results of gain-of-function and loss-of-function studies show that CALML3 could indicate metastasis initiation and act as a suppressor of metastasis. We also reveal the biological role of CALML3 in metastasis initiation at a network level, including proximal regulation and cascading influences in dysfunctional pathways. Our further experiments and clinical samples show that DNB with CALML3 reduced pulmonary metastasis in liver cancer. Actually, loss of CALML3 predicts shorter overall and relapse-free survival in postoperative HCC patients, thus providing a prognostic biomarker and therapy target in HCC.

BackgroundHepatocellular carcinoma (HCC) develops in a complex microenvironment characterized by chronic inflammation. In recent years, cholesterol metabolic abnormalities have been implicated the importance in cancer cell physiology. This study was designed to investigate the relationship between inflammation and cholesterol accumulation in HCC cells.MethodsHuman HCC cells HepG2 and Huh7 were cultured and stimulated with lipopolysaccharide (LPS) for 24 h. The changes of HCC cells related to cholesterol metabolism including intracellular cholesterol concentrations, cholesterol uptake, and the expression of cholesterol-related genes 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), LDL receptor (LDLR), sterol regulatory element-binding transcription factor 2 (SREBF2), and proprotein convertase subtilisin/kexin 9 (PCSK9) were comparatively analyzed. Simultaneously, the effects of nuclear factor-kappa B (NF-κB) signaling pathway on cholesterol metabolism were clarified by knocking-down of nuclear factor kappa-B kinase subunit alpha (IKKα) and TGF-beta-activated kinase 1 and MAP3K7-binding protein 3 (TAB3) via RNAi and microRNA (miR)-195. Subsequently, the roles of cholesterol accumulation in LPS induced pro-inflammatory effects were further investigated.ResultsPro-inflammatory factor LPS significantly increased intracellular cholesterol accumulation by upregulating the expression of HMGCR, LDLR, and SREBF2, while downregulating the expression of PCSK9. These effects were revealed to depend on NF-κB signaling pathway by knocking-down and overexpression of IKKα and TAB3. Additionally, miR-195, a regulator directly targeting IKKα and TAB3, blocked the effects of cholesterol accumulation, further supporting the critical role of pro-inflammation NF-κB signaling in regulating cholesterol accumulation. Intriguingly, the accumulation of cholesterol conversely exerted an augmented pro-inflammation effects by further activating NF-κB signaling pathway.ConclusionsThese results indicated that pro-inflammation effects of NF-κB signaling could be augmented by a positive feedback via enhancing the cholesterol accumulation in liver cancer cells.

Summary The discovery that mutations in the EGFR gene are detected in up to 50% of lung adenocarcinoma patients, along with the development of highly efficacious epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), has revolutionized the treatment of this frequently occurring lung malignancy. Indeed, the clinical success of these TKIs constitutes a critical milestone in targeted cancer therapy. Three generations of EGFR-TKIs are currently approved for the treatment of EGFR mutation-positive non-small cell lung cancer (NSCLC). The first-generation TKIs include erlotinib, gefitinib, lapatinib, and icotinib; the second-generation ErbB family blockers include afatinib, neratinib, and dacomitinib; whereas osimertinib, approved by the FDA on 2015, is a third-generation TKI targeting EGFR harboring specific mutations. Compared with the first- and second-generation TKIs, third-generation EGFR inhibitors display a significant advantage in terms of patient survival. For example, the median overall survival in NSCLC patients receiving osimertinib reached 38.6 months. Unfortunately, however, like other targeted therapies, new EGFR mutations, as well as additional drug-resistance mechanisms emerge rapidly after treatment, posing formidable obstacles to cancer therapeutics aimed at surmounting this chemoresistance. In this review, we summarize the molecular mechanisms underlying resistance to third-generation EGFR inhibitors and the ongoing efforts to address and overcome this chemoresistance. We also discuss the current status of fourth-generation EGFR inhibitors, which are of great value in overcoming resistance to EGFR inhibitors that appear to have greater therapeutic benefits in the clinic.

We study the field-ionization threshold behavior when a Rydberg atom is ionized by a short single-cycle pulse field. Both hydrogen and sodium atoms are considered. The required threshold field amplitude is found to scale inversely with the binding energy when the pulse duration becomes shorter than the classical Rydberg period, and, thus, more weakly bound electrons require larger fields for ionization. This threshold scaling behavior is confirmed by both three-dimensional classical trajectory Monte Carlo simulations and numerically solving the time-dependent Schrödinger equation. More surprisingly, the same scaling behavior in the short pulse limit is also followed by the ionization thresholds for much lower bound states, including the hydrogen ground state. An empirical formula is obtained from a simple model, and the dominant ionization mechanism is identified as a nonzero spatial displacement of the electron. This displacement ionization should be another important mechanism beyond the tunneling ionization and the multiphoton ionization. In addition, an "ionization window" is shown to exist for the ionization of Rydberg states, which may have potential applications to selectively modify and control the Rydberg-state population of atoms and molecules.

The standard closed-orbit theory is extended for the photodetachment of negative ions in a timedependent electric field. The time-dependent photodetachment rate is specifically studied in the presence of a single-cycle terahertz pulse, based on exact quantum simulations and semiclassical analysis. We find that the photodetachment rate is unaffected by a weak terahertz field, but oscillates complicatedly when the terahertz pulse gets strong enough. Three types of closed classical orbits are identified for the photoelectron motion in a strong single-cycle terahertz pulse, and their connections with the oscillatory photodetachment rate are established quantitatively by generalizing the standard closed-orbit theory to a time-dependent form. By comparing the negative hydrogen and fluorine ions, both the in-phase and antiphase oscillations can be observed, depending on a simple geometry of the contributed closed classical orbits. On account of its generality, the presented theory provides an intuitive understanding from a time-dependent viewpoint for the photodetachment dynamics driven by an external electric field oscillating at low frequency.

Objectives LncRNA nuclear‐enriched abundant transcript 1 (NEAT1) participates in the development and progression of multiple malignancies. However, the molecular mechanism by which NEAT1 contributes to colorectal cancer (CRC) remains unclear. Methods The association between lncRNA NEAT1 expression and clinicopathological characteristics and prognosis in patients with CRC was analysed by TCGA RNA‐sequencing data. MTT, colony formation, flow cytometry, transwell assays and a xenograft tumour model were used to assess the functions of NEAT1. Bioinformatics and spearman correlation analysis were used to identify the NEAT1‐specific binding with miRNAs, and luciferase gene report and RIP assays were performed to confirm the interaction between miR‐193a‐3p (miR‐193a) and NEAT1 in CRC cells. Results Upregulation of NEAT1 expression was significantly correlated with TNM stage, poor survival and tumour recurrence in patients with CRC, and acted as an independent prognostic factor for tumour recurrence. Knockdown of NEAT1 suppressed cell proliferation, colony formation abilities and invasive potential and induced cell apoptosis, but overexpression of NEAT1 reversed these effects. Furthermore, NEAT1 was confirmed to act as a sponge of miR‐193a, and knockdown of NEAT1 attenuated miR‐193a inhibitor‐induced tumour promoting effects and L17RD expression in CRC cells. miR‐193a harboured negative correlation with NEAT1 and IL17RD expression in CRC specimens. In vivo experiment further validated the inhibitory effects of NEAT1 knockdown on xenograft tumour growth. Conclusion Our findings demonstrate that lncRNA NEAT1 acts as an oncogenic role in CRC cells by sponging miR‐193a and may represent a potential marker for CRC patients.

Triggering receptor expressed on myeloid cells 2 (TREM2) is involved in nonmalignant pathological processes. However, TREM2’s function in malignant diseases, especially in hepatocellular carcinoma (HCC) remains unknown. In the present study, we report that TREM2 is a novel tumor suppressor in HCC. TREM2 expression was obviously decreased in hepatoma cells (especially metastatic HCC cells), and in most human HCC tissues (especially extrahepatic metastatic tumors). Reduced tumor TREM2 expression was correlated with poor prognosis of HCC patients, and with aggressive pathological features (BCLC stage, tumor size, tumor encapsulation, vascular invasion, and tumor differentiation). TREM2 knockdown substantially promoted cell growth, migration, and invasion in vitro and in vivo, while TREM2 overexpression produced the opposite effect. TREM2 suppressed HCC metastasis by inhibiting epithelial-mesenchymal transition, accompanied by abnormal expression of epithelial and mesenchymal markers. Further study revealed that downregulation of TREM2 in HCC was regulated by miR-31-5p. Moreover, by directly interacting with β-catenin, TREM2 attenuated oncogenic and metastatic behaviors by inhibiting Akt and GSK3β phosphorylation, and activating β-catenin. TREM2 suppressed carcinogenesis and metastasis in HCC by targeting the PI3K/Akt/β-catenin pathway. Thus, we propose that TREM2 may be a candidate prognostic biomarker in malignant diseases and TREM2 restoration might be a prospective strategy for HCC therapy.