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Enhanced neovasculogenesis, especially vasculogenic mimicry (VM), contributes to the development of triple-negative breast cancer (TNBC). Breast tumor-initiating cells (BTICs) are involved in forming VM; however, the specific VM-forming BTIC population and the regulatory mechanisms remain undefined. We find that tumor endothelial marker 8 (TEM8) is abundantly expressed in TNBC and serves as a marker for VM-forming BTICs. Mechanistically, TEM8 increases active RhoC level and induces ROCK1-mediated phosphorylation of SMAD5, in a cascade essential for promoting stemness and VM capacity of breast cancer cells. ASB10, an estrogen receptor ERα trans-activated E3 ligase, ubiquitylates TEM8 for degradation, and its deficiency in TNBC resulted in a high homeostatic level of TEM8. In this work, we identify TEM8 as a functional marker for VM-forming BTICs in TNBC, providing a target for the development of effective therapies against TNBC targeting both BTIC self-renewal and neovasculogenesis simultaneously. Vasculogenic mimicry (VM) contributes to the development of triple-negative breast cancer. In this study, the authors show that TEM8 is expressed in VM-forming breast cancer stem cells and it promotes stemness and VM differentiation capacity through a RhoC/ROCK1/SMAD5 axis

Myristoylation is one of key post-translational modifications that involved in signal transduction, cellular transformation and tumorigenesis. Increasing evidence demonstrates that targeting myristoylation might provide a new strategy for eliminating cancers. However, the underlying mechanisms are still yielded unclear. In this study, we demonstrated that genetic inhibition of N-myristoyltransferase NMT1 suppressed initiation, proliferation and invasion of breast cancer cells either in vitro or in vivo. We identified ROS could negatively regulate NMT1 expression and NMT1 knockdown conversely promoted oxidative stress, which formed a feedback loop. Furthermore, inhibition of NMT1 caused degraded proteins increase and ER stress, which cross-talked with mitochondria to produce more ROS. And both of oxidative stress and ER stress could activate JNK pathway, leading to autophagy which abrogated breast cancer progression especially triple-negative breast cancer (TNBC). These studies provide a preclinical proof of concept for targeting NMT1 as a strategy to treat breast cancer.

Breast tumor initiating cells (BTICs) with ALDH+CD24−CD44+ phenotype are the most tumorigenic and invasive cell population in breast cancer. However, the molecular mechanisms are still unclear. Here, it is found that a negative immune regulator interleukin‐1 receptor type 2 (IL1R2) is upregulated in breast cancer (BC) tissues and especially in BTICs. BC patients with high IL1R2 expression have a poorer overall survival and relapse‐free survival. High IL1R2 promotes BTIC self‐renewal and BC cell proliferation and invasion. Mechanistically, IL1R2 is activated by IL1β, as demonstrated by the fact that IL1β induces the release of IL1R2 intracellular domain (icd‐IL1R2) and icd‐IL1R2 then interacts with the deubiquitinase USP15 at the UBL2 domain and promotes its activity, which finally induces BMI1 deubiquitination at lysine 81 and stabilizes BMI1 protein. In addition, IL1R2 neutralizing antibody can suppress the protein expression of both IL1R2 and BMI1, and significantly abrogates the promoting effect of IL1R2 on BTIC self‐renewal and BC cell growth both in vitro and in vivo. The current results indicate that blocking IL1R2 with neutralizing antibody provides a therapeutic approach to inhibit BC progression by targeting BTICs. Interleukin‐1 receptor type 2 (IL1R2) increases BMI1 deubiquitination and stability via binding and enhancing the activity of ubiquitin‐specific protease 15 (USP15) in cell nuclei, intrinsically promoting the self‐renewal of breast tumor initiating cells (BTICs) as well as breast cancer cell proliferation and invasion. Targeting IL1R2 with its neutralizing antibody inhibits the self‐renewal of BTICs, breast tumorigenesis, and cancer resistance to docetaxel.

Breast tumor‐initiating cells (BTICs) of triple‐negative breast cancer (TNBC) tissues actively repair DNA and are resistant to treatments including chemotherapy, radiotherapy, and targeted therapy. Herein, it is found that a previously reported secreted protein, sclerostin domain containing 1 (SOSTDC1), is abundantly expressed in BTICs of TNBC cells and positively correlated with a poor patient prognosis. SOSTDC1 knockdown impairs homologous recombination (HR) repair, BTIC maintenance, and sensitized bulk cells and BTICs to Olaparib. Mechanistically, following Olaparib treatment, SOSTDC1 translocates to the nucleus in an importin‐α dependent manner. Nuclear SOSTDC1 interacts with the N‐terminus of the nucleoprotein, chromatin helicase DNA‐binding factor (CHD1), to promote HR repair and BTIC maintenance. Furthermore, nuclear SOSTDC1 bound to β‐transducin repeat‐containing protein (β‐TrCP) binding motifs of CHD1 is found, thereby blocking the β‐TrCP‐CHD1 interaction and inhibiting β‐TrCP‐mediated CHD1 ubiquitination and degradation. Collectively, these findings identify a novel nuclear SOSTDC1 pathway in regulating HR repair and BTIC maintenance, providing insight into the TNBC therapeutic strategies. In this study, SOSTDC1 is identified as a potential target mediating BTICs resistance to Olaparib. SOSTDC1 is highly expressed in TNBC tissues and especially in the BTIC population. Nuclear translocation of SOSTDC1 mediated by importin‐α stabilizes CHD1 protein from ubiquitination, thereby promoting HR repair, BTIC maintenance, and Olaparib resistance in TNBC.

Targeted therapy based on ALK tyrosine kinase inhibitors (ALK-TKIs) has made significant achievements in individuals with EML4-ALK (echinoderm microtubule-associated protein-like 4 gene and the anaplastic lymphoma kinase gene) fusion positive nonsmall-cell lung cancer (NSCLC). However, a high fraction of patients receive inferior clinical response to such treatment in the initial therapy, and the exact mechanisms underlying this process need to be further investigated. In this study, we revealed a persistently activated PI3K/AKT signaling that mediates the drug ineffectiveness. We found that genetic or pharmacological inhibition of ALK markedly abrogated phosphorylated STAT3 and ERK, but it failed to suppress AKT activity or induce apoptosis, in EML4-ALK-positive H2228 cells. Furthermore, targeted RNA interference of PI3K pathway components restored sensitivity to TAE684 treatment at least partially due to increased apoptosis. Combined TAE684 with PI3K inhibitor synergistically inhibited the proliferation of EML4-ALK-positive cells in vitro and significantly suppressed the growth of H2228 xenografts in vivo, suggesting the potential clinical application of such combinatorial therapy regimens in patients with EML4-ALK positive lung cancer.

In article 1901728, Suling Liu and co‐workers report that the “decoy receptor” IL‐1 receptor 2 (IL1R2) is highly expressed on the most tumorigenic intermediate‐state breast tumor initiation cells (BTICs), which fall in between the epithelial‐like state and mesenchymal‐like state. IL‐1β in the tumor microenvironment activates the IL1R2 signaling pathway and then increases intermediate‐state BTIC self‐renewal and tumor progression, which can be specifically blocked by IL1R2 neutralizing antibody.

Under the dual pressures of global climate change and rapid urbanization, urban drainage systems (UDS) face severe challenges caused by extreme precipitation events and altered surface hydrological processes. The drainage paradigm is shifting toward resilient systems integrating grey and green infrastructure, necessitating a comprehensive review of the design and operation of grey infrastructure. This study systematically summarizes advances in urban stormwater process-wide regulation, focusing on drainage network design optimization, siting and control strategies for flow control devices (FCDs), and coordinated management of Quasi-Detention Basins (QDBs). Through graph theory-driven topological design, real-time control (RTC) technologies, and multi-objective optimization algorithms (e.g., genetic algorithms, particle swarm optimization), the research demonstrates that decentralized network layouts, dynamic gate regulation, and stormwater resource utilization significantly enhance system resilience and storage redundancy. Additionally, deep learning applications in flow prediction, flood assessment, and intelligent control exhibit potential to overcome limitations of traditional models. Future research should prioritize improving computational efficiency, optimizing hybrid infrastructure synergies, and integrating deep learning with RTC to establish more resilient and adaptive urban stormwater management frameworks.

This study experimentally investigated the spreading behavior of droplets impacting wetted cylindrical surfaces. The temporal evolution of spreading dimensions along the circumferential and axial directions of the cylinder was measured. The effects of fluid type, impact velocity, cylinder diameter, and impact position on the spreading dimensions were analyzed. The findings show that the droplet velocity minimally influences the spreading dimensions. The spreading dimensions increase with cylinder diameter but remain nearly unchanged when the cylinder diameter exceeds four times the droplet diameter. The spreading characteristics of droplets under eccentric impact were also examined, revealing that forward spreading is significantly greater than backward spreading. Additionally, the phenomenon of one-sided spreading during eccentric impacts was investigated, and it was found that the critical condition for one-sided spreading is largely independent of the impact velocity.

The main objective of this experiment was to study the metabolism of arginine in juvenile largemouth bass ( Micropterus salmoides ). A total of 300 healthy fish (average weight of 25 ± 0.5 g) were randomly assigned to ten groups. Experimental fish were orally administered or intraperitoneally injected with 0.9% sodium chloride, arginine, arginine-aspartate, citrulline, and glutamate solutions, respectively. They were euthanized at 10, 30, 60, 120, and 240 min after oral administration or intraperitoneal injection, and various tissue samples were subsequently collected for analysis. The results revealed that serum ornithine and citrulline concentrations of largemouth bass were significantly increased by oral administration of arginine or arginine-aspartate ( P  < 0.05). Intraperitoneal injection of arginine or arginine-aspartate solution significantly elevated the concentrations of ornithine and citrulline in the serum, liver, kidney, and muscles ( P  < 0.05). The concentrations of citrulline, ornithine, and arginine in serum and muscle increased significantly at 4 h after intraperitoneal injection of glutamate ( P  < 0.05). Intraperitoneal injection of citrulline significantly increased the concentrations of ornithine and arginine in the serum and muscles ( P  < 0.05). The research findings demonstrate that both free and small peptide forms of arginine were rapidly degraded to ornithine due to the high arginase activity in various tissues of largemouth bass. Additionally, the pathway of synthesizing citrulline from glutamate and then arginine from citrulline may exist in largemouth bass, but the exact location of this synthesis process may differ from that found in mammals.

Background Layered double hydroxide lactate nanosheets (LDH-lactate-NS) are powerful carriers for delivering macro-molecules into intact plant cells. In the past few years, some studies have been carried out on DNA/RNA transformation and plant disease resistance, but little attention has been paid to these factors during LDH-lactate-NS synthesis and delamination, nor has their relationship to the DNA adsorption capacity or transformation efficiency of plant cells been considered. Results Since the temperature during delamination alters particle sizes and zeta potentials of LDH-lactate-NS products, we compared the LDH-lactate-NS stability, DNA adsorption rate and delivery efficiency of fluorescein isothiocyanate isomer I (FITC) of them, found that the LDH-lactate-NS obtained at 25 °C has the best characters for delivering biomolecules into plant cell. To understand the potential side effects and cytotoxicity of LDH-lactate-NS to plants, we compared the root growth rate between the Arabidopsis thaliana seedlings grown in the culture medium with 1–300 μg/mL LDH-lactate-NS and equivalent raw material, Mg(lactate) 2 and Al (lactate) 3 . Phenotypic analysis showed LDH in a range of 1–300 μg/mL can enhance the root elongation, whereas the same concentration of raw materials dramatically inhibited root elongation, suggesting the nanocrystallization has a dramatical de-toxic effect to Mg(lactate) 2 and Al (lactate) 3. Since enhancing of root elongation by LDH is an unexpected phenomenon, we further designed experiments to investigate influence of LDH to Arabidopsis seedlings. We further used the gravitropic bending test, qRT-PCR analysis of auxin transport proteins, non-invasive micro-test technology and liquid chromatography-mass spectrometry to investigate the auxin transport and distribution in Arabidopsis root. Results indicated that LDH-lactate-NS affect root growth by increasing the polar auxin transport. Conclusions Optimal synthesized LDH-lactate-NS can delivery biomolecules into intact plant cells with high efficiency and low cytotoxity. The working solution of LDH-lactate-NS can promote root elongation via increase the polar auxin transport in Arabidopsis roots.