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Perineural invasion (PNI) is a biological characteristic commonly observed in pancreatic cancer. Although PNI plays a key role in pancreatic cancer metastasis, recurrence, and poor postoperative survival, its mechanism is largely unclarified. Clinical sample analysis and endoscopic ultrasonographic elasticity scoring indicated that cancer-associated fibroblasts (CAFs) were closely related to the occurrence of PNI. Furthermore, CAF-derived extracellular vesicles (EVs) were involved in PNI in dorsal root ganglion coculture and mouse sciatic nerve models. Next, we demonstrated that CAFs promoted PNI through extracellular vesicle transmission of PNI-associated transcript (PIAT). Mechanistically, PIAT specifically bound to YBX1 and blocked the YBX1-Nedd4l interaction to inhibit YBX1 ubiquitination and degradation. Furthermore, PIAT enhanced the binding of YBX1 and PNI-associated mRNAs in a 5-methylcytosine (m5C)–dependent manner. Mutation of m5C recognition motifs in YBX1 or m5C sites in downstream target genes reversed PIAT-mediated PNI. Consistent with these findings, analyses using a KPC mouse model demonstrated that the PIAT/YBX1 axis enhanced PNI through m5C modification. Clinical data suggested that the PIAT expression in the serum EVs of patients with pancreatic cancer was associated with the degree of neural invasion and prognosis. Our study revealed the important role of the PIAT/YBX1 signaling axis in the tumor microenvironment (TME) in promoting tumor cell PNI and provided a new target for precise interference with CAFs and RNA methylation in the TME to suppress PNI in pancreatic cancer. Editor's summary: Pancreatic cancer has a very poor prognosis and is often characterized by perineural invasion (PNI); however, the role that PNI plays in postoperative survival has been unexplored. Here, Zheng et al. evaluate the role PNI plays in pancreatic cancer prognosis and show that cancer-associated fibroblasts (CAFs) induce PNI in tumors through CAF-derived extracellular vesicles (EVs). They show that these EVs are packaged with PNI-associated transcript (PIAT) that enhances PNI in mouse models and induces worse survival. PIAT represents a potential target for reducing PNI in pancreatic cancer and perhaps improving survival for patients that requires further study. —Dorothy Hallberg [ABSTRACT FROM AUTHOR]

The creep behavior of composite wing leading edges resulting from nonequilibrium residual stresses and material viscoelasticity needs to be evaluated comprehensively as it significantly affects assembly. In this study, long-term creep monitoring of a composite wing leading edge used in an actual airplane for 710 h is conducted using embedded fiber Bragg grating arrays and a creep extraction algorithm. The spectra and Bragg wavelength shifts of two embedded arrays, which involve temperature, thermal expansion, and creep, are recorded and analyzed. The creep curve of the composite wing leading edge is reconstructed and further predicted using the creep extraction algorithm based on multiparameter decoupling and the Burgers model. This study elucidates the enlargement of the opening size in the composite wing leading edge by measuring the tensile strain above the neutral axis. The predicted creep time serves as a valuable reference for determining the appropriate assembly timing. [ABSTRACT FROM AUTHOR]

Wang He, Guangzheng Zhong, Ning Jiang, Bo Wang, Xinxiang Fan, Changhao Chen, Xu Chen, Jian Huang, and Tianxin Lin Original citation: J Clin Invest. 2018;128(2):861-875. https://doi.org/10.1172/JCI96218. Citation for this corrigendum: [...]

Patients with bladder cancer (BCa) with clinical lymph node (LN) metastasis have an extremely poor prognosis. VEGF-C has been demonstrated to play vital roles in LN metastasis in BCa. However, approximately 20% of BCa with LN metastasis exhibits low VEGF-C expression, suggesting a VEGF-C-independent mechanism for LN metastasis of BCa. Herein, we demonstrate that BCa cell-secreted exosome-mediated lymphangiogenesis promoted LN metastasis in BCa in a VEGF-C-independent manner. We identified an exosomal long noncoding RNA (lncRNA), termed lymph node metastasis-associated transcript 2 (LNMAT2), that stimulated human lymphatic endothelial cell (HLEC) tube formation and migration in vitro and enhanced tumor lymphangiogenesis and LN metastasis in vivo. Mechanistically, LNMAT2 was loaded to BCa cell-secreted exosomes by directly interacting with heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1). Subsequently, exosomal LNMAT2 was internalized by HLECs and epigenetically upregulated prospero homeobox 1 (PROX1) expression by recruitment of hnRNPA2B1 and increasing the H3K4 trimethylation level in the PROX1 promoter, ultimately resulting in lymphangiogenesis and lymphatic metastasis. Therefore, our findings highlight a VEGF-C-independent mechanism of exosomal lncRNA-mediated LN metastasis and identify LNMAT2 as a therapeutic target for LN metastasis in BCa., Introduction Bladder cancer (BCa), one of the most commonly diagnosed malignancies worldwide, is the leading cause of cancer-related death among men, with an estimated 550,000 new cases and 20,000 deaths [...]

Lymph node (LN) metastasis occurs frequently in pancreatic ductal adenocarcinoma (PDAC) and predicts poor prognosis for patients. The [KRAS.sup.G12D] mutation confers an aggressive PDAC phenotype that is susceptible to lymphatic dissemination. However, the regulatory mechanism underlying [KRAS.sup.G12D] mutation-driven LN metastasis in PDAC remains unclear. Herein, we found that PDAC with the [KRAS.sup.G12D] mutation ([KRAS.sup.G12D] PDAC) sustained extracellular vesicle-mediated (EV-mediated) transmission of heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) in a SUMOylation-dependent manner and promoted lymphangiogenesis and LN metastasis in vitro and in vivo. Mechanistically, hnRNPA1 bound with SUMO2 at the lysine 113 residue via [KRAS.sup.G12D]-induced hyperactivation of SUMOylation, which enabled its interaction with TSG101 to enhance hnRNPA1 packaging and transmission via EVs. Subsequently, SUMOylation induced EV-packaged-hnRNPA1 anchoring to the adenylateand uridylate-rich elements of PROX1 in lymphatic endothelial cells, thus stabilizing PROX1 mRNA. Importantly, impeding SUMOylation of EV-packaged hnRNPA1 dramatically inhibited LN metastasis of [KRAS.sup.G12D] PDAC in a genetically engineered [Kras.sup.G12D/+] [Trp53.sup.R172H/+] Pdx-1-Cre (KPC) mouse model. Our findings highlight the mechanism by which KRAS mutant-driven SUMOylation triggers EV-packaged hnRNPA1 transmission to promote lymphangiogenesis and LN metastasis, shedding light on the potential application of hnRNPA1 as a therapeutic target in patients with [KRAS.sup.G12D] PDAC., Introduction Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant digestive system cancers and represents the seventh leading cause of cancer-related death worldwide (1, 2). Accumulating reports have shown [...]

The prognosis for bladder cancer patients with lymph node (LN) metastasis is dismal and only minimally improved by current treatment modalities. Elucidation of the molecular mechanisms that underlie LN metastasis may provide clinical therapeutic strategies for LN-metastatic bladder cancer. Here, we report that a long noncoding RNA LINC00958, which we have termed bladder cancer-associated transcript 2 (BLACAT2), was markedly upregulated in LN-metastatic bladder cancer and correlated with LN metastasis. Overexpression of BLACAT2 promoted bladder cancer-associated lymphangiogenesis and lymphatic metastasis in both cultured bladder cancer cell lines and mouse models. Furthermore, we demonstrate that BLACAT2 epigenetically upregulated VEGF-C expression by directly associating with WDR5, a core subunit of human H3K4 methyltransferase complexes. Importantly, administration of an anti-VEGF-C antibody inhibited LN metastasis in BLACAT2-overexpressing bladder cancer. Taken together, these findings uncover a molecular mechanism in the lymphatic metastasis of bladder cancer and indicate that BLACAT2 may represent a target for clinical intervention in LN-metastatic bladder cancer., Introduction Bladder cancer is one of the most common genitourinary malignancies, with approximately 429,800 new cases and 165,100 deaths annually worldwide (1). Bladder cancer is categorized into 2 groups based [...]

Small ubiquitin-like modifier (SUMO) binding (termed SUMOylation) emerged as the inducer for the sorting of bioactive molecules into extracellular vesicles (EVs), triggering lymphangiogenesis and further driving tumor lymph node (LN) metastasis, but the precise mechanisms remain largely unclear. Here, we show that bladder cancer (BCa) cell-secreted EVs mediated intercellular communication with human lymphatic endothelial cells (HLECs) through transmission of the long noncoding RNA ELNAT1 and promoted lymphangiogenesis and LN metastasis in a SUMOylation-dependent manner in both cultured BCa cell lines and mouse models. Mechanistically, ELNAT1 induced UBC9 overexpression to catalyze the SUMOylation of hnRNPA1 at the lysine 113 residue, which mediated recognition of ELNAT1 by the endosomal sorting complex required for transport (ESCRT) and facilitated its packaging into EVs. EV-mediated ELNAT1 was specifically transmitted into HLECs and epigenetically activated SOX18 transcription to induce lymphangiogenesis. Importantly, blocking the SUMOylation of tumor cells by downregulating UBC9 expression markedly reduced lymphatic metastasis in EV-mediated, ELNATI-treated BCa in vivo. Clinically, EV-mediated ELNAT1 was correlated with LN metastasis and a poor prognosis for patients with BCa. These findings highlight a molecular mechanism whereby the EV-mediated ELNAT1/UBC9/SOX18 regulatory axis promotes lymphangiogenesis and LN metastasis in BCa in a SUMOylation-dependent manner and implicate ELNAT1 as an attractive therapeutic target for LN metastatic BCa., Introduction Bladder cancer (BCa) is one of the most prevalent malignancies in the genitourinary system (1). As seen in the infiltration of muscle, BCa develops into 2 distinct subtypes: non-muscle-invasive [...]

Impacts can degrade the strength of composite structures; thus, impact damages should be monitored and repaired. In this study, a novel composite consisting of carbon nanotube film and glass fiber-reinforced thermoplastic was thermoformed. The fabricated smart composite demonstrated self-sensing and self-healing capabilities for damage caused by low-energy impacts. Elastic deformation of the composite caused by a 0.5-J impact was monitored from the immediate change in resistance of approximately 0.25 Ω. Internal damage such as tears and debonding was detected in real time by monitoring the permanent resistance variation of approximately 0.4 Ω using a Wheatstone bridge with a 3-J impact on the smart composite. This difference occurs because a 3-J impact discontinues the conductive path of the carbon nanotubes and changes the total resistance of the smart composite. The internal damage caused by a 3-J impact was repaired through the Joule heat effect when 0.7 MPa and 55 V were applied to heat the composite to 330°C. A three-point bending test demonstrated that the self-healing efficiency of the smart composite reached 87% in terms of flexural strength. [ABSTRACT FROM AUTHOR]