Lung metastasis is the major cause of breast cancer-related mortality. The neutrophil-associated inflammatory microenvironment aids tumor cells in metastatic colonization in lungs. Here, we show that ...tumor-secreted protease cathepsin C (CTSC) promotes breast-to-lung metastasis by regulating recruitment of neutrophils and formation of neutrophil extracellular traps (NETs). CTSC enzymatically activates neutrophil membrane-bound proteinase 3 (PR3) to facilitate interleukin-1β (IL-1β) processing and nuclear factor κB activation, thus upregulating IL-6 and CCL3 for neutrophil recruitment. In addition, the CTSC-PR3-IL-1β axis induces neutrophil reactive oxygen species production and formation of NETs, which degrade thrombospondin-1 and support metastatic growth of cancer cells in the lungs. CTSC expression and secretion are associated with NET formation and lung metastasis in human breast tumors. Importantly, targeting CTSC with compound AZD7986 effectively suppresses lung metastasis of breast cancer in a mouse model. Overall, our findings reveal a mechanism of how tumor cells regulate neutrophils in metastatic niches and support CTSC-targeting approaches for cancer treatment.
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•Tumor-secreted CTSC promotes breast-to-lung metastasis by regulating neutrophils•CTSC activates membrane-bound PR3 of neutrophils to upregulate IL-1β secretion•CTSC enhances neutrophil recruitment into metastatic niches and induces NETosis•Targeting CTSC with AZD7986 effectively inhibits lung metastasis in mice
Neutrophils play critical roles in cancer metastasis. Xiao et al. report the dual role of a tumor-secreted protease, CTSC, in recruiting neutrophils to metastatic niches and inducing neutrophils to form extracellular traps (NETs). These promote lung colonization of breast cancer and targeting CTSC inhibits lung metastasis in mice.
In cancer treatment, the unsatisfactory solid‐tumor penetration of nanomaterials limits their therapeutic efficacy. We employed an in vivo self‐assembly strategy and designed polymer–peptide ...conjugates (PPCs) that underwent an acid‐induced hydrophobicity increase with a narrow pH‐response range (from 7.4 to 6.5). In situ self‐assembly in the tumor microenvironment at appropriate molecular concentrations (around the IC50 values of PPCs) enabled drug delivery deeper into the tumor. A cytotoxic peptide KLAK, decorated with the pH‐sensitive moiety cis‐aconitic anhydride (CAA), and a cell‐penetrating peptide TAT were conjugated onto poly(β‐thioester) backbones to produce PT‐K‐CAA, which can penetrate deeply into solid tumors owing to its small size as a single chain. During penetration in vivo, CAA responds to the weak acid, leading to the self‐assembly of PPCs and the recovery of therapeutic activity. Therefore, a deep‐penetration ability for enhanced cancer therapy is provided by this in vivo assembly strategy.
Reaching new depths: Polymer–peptide conjugates (PPCs) designed to undergo an acid‐induced increase in hydrophobicity with a narrow pH‐response range (from pH 7.4 to 6.5) underwent in vivo self‐assembly in the tumor microenvironment (see picture). The PPCs in single‐chain form can penetrate deeply into the tumor and self‐assemble into nanoaggregates at molecular concentrations around the IC50 values of the PPCs for enhanced cancer therapy.
Direct detection of circularly polarized light (CPL) is a challenging task due to limited materials and ambiguous structure–property relationships that lead to low distinguishability of the light ...helicities. Perovskite ferroelectric semiconductors incorporating chirality provide new opportunities in dealing with this issue. Herein, a pair of 2D chiral perovskite ferroelectrics is reported, which have enhanced CPL detection performance due to interplays among lattice, photon, charge, spin, and orbit. The chirality‐transfer‐induced chiral&polar ferroelectric phase enhances the asymmetric nature of the photoactive sublattice and achieves a switchable self‐powered detection via the bulk photovoltaic effect. The single‐crystal‐based device exhibits a CPL‐sensitive detection performance under 430 nm with an asymmetric factor of 0.20 for left‐ and right‐CPL differentiation, about two times that of the pure chiral counterparts. The enhanced CPL detection performance is ascribed to the Rashba–Dresselhaus effect that originates from the bulk inversion asymmetry and strong spin–orbit coupling, shown with a large Rashba coefficient, which is demonstrated by density functional theory calculation and circularly polarized light excited photoluminescence measurement. These results provide new perspectives on chiral Rashba ferroelectric semiconductors for direct CPL detection and ferroelectrics‐based chiroptics and spintronics.
A pair of 2D chiral perovskite Rashba ferroelectric semiconductors is reported. The fabricated single‐crystal device responds to circularly polarized light (CPL) under 430 nm with an anisotropy factor of 0.20 for the left‐ and right‐CPL differentiation, about two times of reported pure chiral counterparts. The enhanced performance is ascribed to the Rashba–Dresselhaus effect with a large Rashba coefficient of 0.93 eV Å.
The relatively low capacity and capacity fade of spinel LiMn2O4 (LMO) limit its application as a cathode material for lithium‐ion batteries. Extending the potential window of LMO below 3 V to access ...double capacity would be fantastic but hard to be realized, as it will lead to fast capacity loss due to the serious Jahn–Teller distortion. Here using experiments combined with extensive ab initio calculations, it is proved that there is a cooperative effect among individual Jahn–Teller distortions of Mn3+O6 octahedrons in LMO, named as cooperative Jahn–Teller distortion (CJTD) in the text, which is the difficulty to access the capacity beyond one lithium intercalation. It is further proposed that the cationic disordering (excess Li at Mn sites and Li/Mn exchange) can intrinsically suppress the CJTD of Mn3+O6 octahedrons. The cationic disordering can break the symmetry of Mn3+ arrangements to disrupt the correlation of distortions arising from individual JT centers and prevent the Mn3+O bonds distorting along one direction. Interestingly, with the suppressed CJTD, the original octahedral vacancies in spinel LMO are activated and can serve as extra Li‐ion storage sites to access the double capacity with good reversible cycling stability in microsized LMO.
Using experiments and ab initio calculations, the capacity is doubled by suppressing the cooperative Jahn–Teller distortion (CJTD) in spinel LiMn2O4 (LMO). It is further shown that the cationic disordering can intrinsically suppress CJTD because it can break the symmetry of Mn3+ arrangements to disrupt the correlation of distortions arising from individual JT centers and prevent the Mn3+O bonds distorting along one direction.
Shape is an important quality index of cold rolling strip. Up to now, many problems in the shape control domain have not been solved satisfactorily, and a review on the research progress in the shape ...control domain can help to seek new breakthrough directions. In the past 10 years, researches and applications of shape control models, shape control means, shape detection technology, and shape con- trol system have achieved significant progress. In the aspect of shape control models, the researches in the past improve the accuracy, speed and robustness of the models. The intelligentization of shape control models should be strengthened in the future. In the aspect of the shape control means, the researches in the past focus on the roll opti- mization, mill type selection, process optimization, local strip shape control, edge drop control, and so on. In the future, more attention should be paid to the coordination control of both strip shape and other quality indexes, and the refinement of control objective should be strengthened. In the aspects of shape detection technology and shape control system, some new types of shape detection meters and shape control systems are developed and have successfully indus- trial applications. In the future, the standardization of shape detection technology and shape control system should be promoted to solve the problem of compatibility. In general,the four expected development trends of shape control for cold roiling strip in the future are intelligentization, coordi- nation, refinement, and standardization. The proposed research provides new breakthrough directions for improv- ing shape quality.
Accumulating evidence suggests that M2-polarized tumor-associated macrophages (TAMs) play an important role in cancer progression and metastasis, making M2 polarization of TAMs an ever more appealing ...target for therapeutic intervention. Astragaloside IV (AS-IV), a saponin component isolated from Astragali radix, has been reported to inhibit the invasion and metastasis of lung cancer, but its effects on TAMs during lung cancer progression have not been investigated.
Human THP-1 monocytes were induced to differentiate into M2 macrophages through treatments with IL-4, IL-13, and phorbol myristate acetate (PMA). We used the lung cancer cell lines A549 and H1299 cultured in conditioned medium from M2 macrophages (M2-CM) to investigate the effects of AS-IV on tumor growth, invasion, migration, and angiogenesis of lung cancer cells. Macrophage subset distribution, M1 and M2 macrophage-associated markers, and mRNA expression were analyzed by flow cytometry and quantitative PCR. The activation of adenosine monophosphate-activated protein kinase (AMPK) signaling pathways that mediate M2-CM-promoted tumor migration was detected using western blotting.
Here we found that AS-IV significantly inhibited IL-13 and IL-4-induced M2 polarization of macrophages, as illustrated by reduced expression of CD206 and M2-associated genes, and that AS-IV suppressed the M2-CM-induced invasion, migration, and angiogenesis of A549 and H1299 cells. In vivo experiments demonstrated that AS-IV greatly inhibited tumor growth and reduced the number of metastases of Lewis lung cancer. The percentage of M2 macrophages was decreased in tumor tissue after AS-IV treatment. Furthermore, AS-IV inhibited AMPKα activation in M2 macrophages, and silencing of AMPKα partially abrogated the inhibitory effect of AS-IV.
AS-IV reduced the growth, invasion, migration, and angiogenesis of lung cancer by blocking the M2 polarization of macrophages partially through the AMPK signaling pathway, which appears to play an important role in AS-IV's ability to inhibit the metastasis of lung cancer.
Hybrid metal halides (HMHs) based phase transition materials have received widespread attention due to their excellent performance and potential applications in energy harvesting, optoelectronics, ...ferroics, and actuators. Nevertheless, effectively regulating the properties of phase transitions is still a thorny problem. In this work, two chiral lead‐free HMHs (R‐3FP)2SbCl5 (1; 3FP=3‐fluoropyrrolidinium) and (R‐3FP)2SbBr5 (2) were synthesized. By replacing the halide ions in the inorganic skeleton, the phase transition temperature of 2 changes with an increase of about 20 K, compared with 1. Meanwhile, both compounds display reversible dielectric switching properties. Through crystal structure analysis and Hirshfeld surface analysis, their phase transitions are ascribed to the disorder of the cations and deformation of the inorganic chains.
This article reports a pair of 1D lead‐free hybrid metal halides: (R‐3FP)2SbCl5 (1; 3FP=3‐fluoropyrrolidinium) and (R‐3FP)2SbBr5 (2) exhibit high temperature triggered structural phase transition and dielectric switching properties. By halogen substitution in the inorganic framework, the dielectric switch temperature of 2 increased about 20 K, compared with 1.
The process of nitrite-dependent anaerobic methane oxidation (n-damo) was recently discovered and shown to be mediated by "Candidatus Methylomirabilis oxyfera" (M. oxyfera). Here, evidence for n-damo ...in three different freshwater wetlands located in southeastern China was obtained using stable isotope measurements, quantitative PCR assays, and 16S rRNA and particulate methane monooxygenase gene clone library analyses. Stable isotope experiments confirmed the occurrence of n-damo in the examined wetlands, and the potential n-damo rates ranged from 0.31 to 5.43 nmol CO2 per gram of dry soil per day at different depths of soil cores. A combined analysis of 16S rRNA and particulate methane monooxygenase genes demonstrated that M. oxyfera-like bacteria were mainly present in the deep soil with a maximum abundance of 3.2 × 107 gene copies per gram of dry soil. It is estimated that ∼0.51 g of CH4 m-2 per year could be linked to the n-damo process in the examined wetlands based on the measured potential n-damo rates. This study presents previously unidentified confirmation that the n-damo process is a previously overlooked microbial methane sink in wetlands, and n-damo has the potential to be a globally important methane sink due to increasing nitrogen pollution.
Multiferroics refer to materials with two or more ferroic orders in one phase within a specific temperature range, including ferroelectricity, ferroelasticity, and ferromagnetism which have been ...widely used in sensors, actuators, and memory devices. Among them, hybrid perovskites exhibiting multiferroicity are generally limited to low dimensions (0D–2D). Designing 3D lead‐free perovskite multiferroics remains a challenge due to Goldschmidt's tolerance factor limitation. Here, a multiferroic perovskite (R‐3AP)RbBr3 (1; 3AP = 3‐ammoniopyrrolidinium) is successfully synthesized by introducing homochirality to the 3D ferroelectric (Rac‐3AP)RbBr3, achieving both ferroelasticity and ferroelectricity. Compound 1 undergoes a structure phase transition at 401 K belonging to Aizu notation 432F2(s), which has 12 ferroelectric equivalent polarization directions and 6 polar axes. Furthermore, 1 exhibits reversible second harmonic generation switching effects. Moreover, while the temperature varies, the reversible and rapid changes of ferroelastic domains in 1 are observed using a polarizing microscope, indicating that it is a ferroelastic material. This work provides a practical method for designing and synthesizing molecule‐based multiferroics.
The work reports a 3D perovskite multiferroics (R‐3AP)RbBr3 (1) based on the 3D rubidium‐based ferroelectric (Rac‐3AP)RbBr3 by using the homochirality strategy. Compound 1 exhibits 432F2(s) ferroelectric–ferroelastic phase transition at 401 K. In addition, 1 exhibits a second harmonic generation (SHG) switch and multi‐axis ferroelectricity with a saturation polarization (Ps) value of 1.21 µC·cm−2.
Glioblastoma is the most common lethal malignant intracranial tumor with a low 5‐year survival rate. Currently, the maximal safe surgical resection, followed by high‐dose radiotherapy (RT), is a ...standard treatment for glioblastoma. However, high‐dose radiation to the brain is associated with brain injury and results in a high fatality rate. Here, integrated pharmaceutics (named D‐iGSNPs) composed of gold sub‐nanometer particles (GSNPs), blood‐brain barrier (BBB) penetration peptide iRGD, and cell cycle regulator α‐difluoromethylornithine is designed. In both simulated BBB and orthotopic murine GL261 glioblastoma models, D‐iGSNPs are proved to have a beneficial effect on the BBB penetration and tumor targeting. Meanwhile, data from cell and animal experiments reveal that D‐iGSNPs are able to sensitize RT. More importantly, the synergy of D‐iGSNPs with low‐dose RT can exhibit an almost equal therapeutic effect with that of high‐dose RT. This study demonstrates the therapeutic advantages of D‐iGSNPs in boosting RT, and may provide a facile approach to update the current treatment of glioblastoma.
Multifunctionalized gold sub‐nanometer particles (D‐iGSNPs) are designed to sensitize radiotherapy against glioblastoma, which is modified with cyclopeptide iRGD and cell cycle regulator α‐difluoromethylornithine. With small size and iRGD modification, the D‐iGSNPs can easily penetrate through the blood‐brain barrier and target the glioma, which make radiotherapy more effective toward glioblastoma.
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