Single-cell landscape of intratumoral heterogeneity and tumor microenvironment remolding in pre-nodal metastases of breast cancer.

BACKGROUND: The metastasis of cancer cells is influenced by both their intrinsic characteristics and the tumor microenvironment (TME). However, the molecular mechanisms underlying pre-nodal metastases of breast cancer remain unclear. METHODS: We integrated a total of 216,963 cells from 54 samples across 6 single-cell datasets to profile the cellular landscape differences between primary tumors and pre-nodal metastases. RESULTS: We revealed three distinct metastatic epithelial cell subtypes (Epi1, Epi2 and Epi3), which exhibited different metastatic mechanisms. Specifically, the marker gene KCNK15 of the Epi1 subtype exhibited increased gene expression along the cell differentiation trajectory and was specifically regulated by the transcription factor ASCL1. In the Epi3 subtype, we highlighted NR2F1 as a regulator targeting the marker gene MUCL1. Additionally, we found that the Epi2 and Epi3 subtypes shared some regulons, such as ZEB1 and NR2C1. Similarly, we identified specific subtypes of stromal and immune cells in the TME, and discovered that vascular cancer-associated fibroblasts might promote capillary formation through CXCL9+ macrophages in pre-nodal metastases. All three subtypes of metastatic epithelial cells were associated with poor prognosis. CONCLUSIONS: In summary, this study dissects the intratumoral heterogeneity and remodeling of the TME in pre-nodal metastases of breast cancer, providing novel insights into the mechanisms underlying breast cancer metastasis.

Two-dimensional Janus monolayers SPtAZ2 (A = Si and Ge; Z = N, P, and As): insight into their photocatalytic properties via first-principles calculations.

As a derivative of the two-dimensional material family, two-dimensional Janus materials have garnered widespread attention in recent years. Consequently, in this work, we systematically investigated the stability, electronic properties, photocatalytic properties, optical properties, and carrier mobility of SPtAZ2 (A = Si and Ge; Z = N, P, and As) monolayers using first-principles calculations. In the equilibrium state, we identified four stable structures that exhibited the properties of indirect band gap semiconductors using the HSE06 hybrid functional. Through the exploration of the photocatalytic and optical properties of these four stable structures, we observed that SPtSiN2, SPtSiP2, and SPtGeAs2 monolayers possess favorable band edge positions, high solar-to-hydrogen efficiency (up to 30.74%), and light absorption efficiency, thus endowing these three structures with commendable photocatalytic and light absorption performance. We additionally calculated the carrier mobility of these three structures and identified significant differences in electron and hole mobilities in the same direction, facilitating the effective separation of electrons and holes. Finally, we explored the effects of biaxial strain on the electronic properties, photocatalysis, and light absorption of stable SPtAZ2 monolayers. Our research results not only expand the 2D Janus material family, but also successfully predict a type of photocatalyst capable of utilizing visible light for overall water splitting.

Tunable polarization properties of charge, spin, and valley in Janus VSiGeZ4 (Z = N, P, As) monolayers.

Polarization, as an important characterization of the symmetry breaking systems, has attracted tremendous attention in two-dimensional (2D) materials. Due to their significant symmetry breaking, Janus 2D ferrovalley materials provide a desirable platform to investigate the charge, spin, and valley polarization, as well as their coupling effects. Herein, using first-principles calculations, the polarization properties of charge, spin, and valley in Janus VSiGeZ4 (Z = N, P, and As) monolayers are systematically studied. The mirror symmetry breaking leads to a non-zero dipole moment and surface work function difference, indicating the presence of out-of-plane charge polarization. Magnetic properties calculations demonstrate that VSiGeN4 is a 2D-XY magnet with a Berezinskii-Kosterlitz-Thouless temperature of 342 K, while VSiGeP4 and VSiGeAs4 have an out-of-plane magnetization with a Curie temperature below room temperature. The magnetization can be rotated by applying biaxial strain, allowing manipulation of the spin polarization via nonmagnetic means. The spontaneous valley polarization is predicted to be 46, 49, and 70 meV for VSiGeN4, VSiGeP4, and VSiGeAs4, respectively, whose physical origin can be elucidated by employing the model analysis. In particular, the biaxial strain can induce the valley polarization switching from the valence (conduction) band to conduction (valence) band, but it hardly changes the valley polarization strength. Meanwhile, the valley extremum is transformed from the K' (K) to K (K') points. The present work not only provides an underlying insight into the polarization properties of Janus VSiGeZ4 but also offers a class of promising materials for spintronic and valleytronic devices.

Structural characteristics of gut microbiota in longevity from Changshou town, Hubei, China.

The gut microbiota (GM) and its potential functions play a crucial role in maintaining host health and longevity. The aim of this study was to investigate the potential relationship between GM and longevity. We collected fecal samples from 92 healthy volunteers (middle-aged and elderly: 43-79 years old; longevity: ≥ 90 years old) from Changshou Town, Zhongxiang City, Hubei, China. In addition, we collected samples from 30 healthy middle-aged and elderly controls (aged 51-70 years) from Wuhan, Hubei. The 16S rDNA V3 + V4 region of the fecal samples was sequenced using high-throughput sequencing technology. Diversity analysis results showed that the elderly group with longevity and the elderly group with low body mass index (BMI) exhibited higher α diversity. However, no significant difference was observed in ß diversity. The results of the microbiome composition indicate that Firmicutes, Proteobacteria, and Bacteroidota are the core phyla in all groups. Compared to younger elderly individuals, Akkermansia and Lactobacillus are significantly enriched in the long-lived elderly group, while Megamonas is significantly reduced. In addition, a high abundance of Akkermansia is a significant characteristic of elderly populations with low BMI values. Furthermore, the functional prediction results showed that the elderly longevity group had higher abilities in short-chain fatty acid metabolism, amino acid metabolism, and xenobiotic biodegradation. Taken together, our study provides characteristic information on GM in the long-lived elderly population in Changshou Town. This study can serve as a valuable addition to the current research on age-related GM. KEY POINTS: • The gut microbiota of elderly individuals with longevity and low BMI exhibit higher alpha diversity • Gut microbiota diversity did not differ significantly between genders in the elderly population • Several potentially beneficial bacteria (e.g., Akkermansia and Lactobacillus) are enriched in long-lived individuals.

Identification of key genes involved in collagen hydrogel-induced chondrogenic differentiation of mesenchymal stem cells through transcriptome analysis: the role of m6A modification.

Collagen hydrogel has been shown promise as an inducer for chondrogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), contributing to the repair of cartilage defects. However, the precise molecular mechanism underlying this phenomenon remains poorly elucidated. Here, we induced chondrogenic differentiation of BMSCs using collagen hydrogel and identified 4451 differentially expressed genes (DEGs) through transcriptomic sequencing. Our analysis revealed that DEGs were enriched in the focal adhesion pathway, with a notable decrease in expression levels in the collagen hydrogel group compared to the control group. Protein-protein interaction network analysis suggested that actinin alpha 1 (ACTN1) and actinin alpha 4 (ACTN4), two proteins also involved in cytoskeletal recombination, may be crucial in collagen hydrogel-induced chondrogenic differentiation of BMSCs. Additionally, we found that N6-methyladenosine RNA methylation (m6A) modification was involved in collagen hydrogel-mediated chondrogenic differentiation, with fat mass and obesity-associated protein (FTO) implicated in regulating the expression of ACTN1 and ACTN4. These findings suggest that collagen hydrogel might regulate focal adhesion and actin cytoskeletal signaling pathways through down-regulation of ACTN1 and ACTN4 mRNA via FTO-mediated m6A modification, ultimately driving chondrogenic differentiation of BMSCs. In conclusion, our study provides valuable insights into the molecular mechanisms of collagen hydrogel-induced chondrogenic differentiation of BMSCs, which may aid in developing more effective strategies for cartilage regeneration.

Long-Term Coherent Integration Algorithm for High-Speed Target Detection.

Long-term coherent integration (CI) can effectively improve the radar detection capability for high-speed targets. However, the range walk (RW) effect caused by high-speed motion significantly degrades the detection performance. To improve detection performance, this study proposes an improved algorithm based on the modified Radon inverse Fourier transform (denoted as IMRIFT). The proposed algorithm uses parameter searching for velocity estimation, designs a compensation function based on the relationship between velocity and distance walk and Doppler ambiguity terms, and performs CI based on the compensated signal. IMRIFT can achieve RW correction, avoid the blind-speed sidelobe (BSSL) effect caused by velocity mismatch, and improve detection performance, while ensuring low computational complexity. In addition, considering the relationship between energy concentration regions and bandwidth in the 2D frequency domain, a fast method based on IMIRFT is proposed, which can balance computational cost and detection capacity. Finally, a series of comparative experiments are conducted to demonstrate the effectiveness of the proposed algorithm and the fast method.

Density Functional Study of Electrocatalytic Carbon Dioxide Reduction in Fourth-Period Transition Metal-Tetrahydroxyquinone Organic Framework.

This study investigates the utilisation of organometallic network frameworks composed of fourth-period transition metals and tetrahydroxyquinone (THQ) in electrocatalytic CO2 reduction. Density functional theory (DFT) calculations were employed in analysing binding energies, as well as the stabilities of metal atoms within the THQ frameworks, for transition metal TM-THQs ranging from Y to Cd. The findings demonstrate how metal atoms could be effectively dispersed and held within the THQ frameworks due to sufficiently high binding energies. Most TM-THQ frameworks exhibited favourable selectivity towards CO2 reduction, except for Tc and Ru, which experienced competition from hydrogen evolution reaction (HER) and required solution environments with pH values greater than 5.716 and 8.819, respectively, to exhibit CO2RR selectivity. Notably, the primary product of Y, Ag, and Cd was HCOOH; Mo produced HCHO; Pd yielded CO; and Zr, Nb, Tc, Ru, and Rh predominantly generated CH4. Among the studied frameworks, Zr-THQ displayed values of 1.212 V and 1.043 V, corresponding to the highest limiting potential and overpotential, respectively, while other metal-organic frameworks displayed relatively low ranges of overpotentials from 0.179 V to 0.949 V. Consequently, it is predicted that the TM-THQ framework constructed using a fourth-period transition metal and tetrahydroxyquinone exhibits robust electrocatalytic reduction of CO2 catalytic activity.

Exploring the CO2 Electrocatalysis Potential of 2D Metal-Organic Transition Metal-Hexahydroxytriquinoline Frameworks: A DFT Investigation.

Metal-organic frameworks have demonstrated great capacity in catalytic CO2 reduction due to their versatile pore structures, diverse active sites, and functionalization capabilities. In this study, a novel electrocatalytic framework for CO2 reduction was designed and implemented using 2D coordination network-type transition metal-hexahydroxytricyclic quinazoline (TM-HHTQ) materials. Density functional theory calculations were carried out to examine the binding energies between the HHTQ substrate and 10 single TM atoms, ranging from Sc to Zn, which revealed a stable distribution of metal atoms on the HHTQ substrate. The majority of the catalysts exhibited high selectivity for CO2 reduction, except for the Mn-HHTQ catalysts, which only exhibited selectivity at pH values above 4.183. Specifically, Ti and Cr primarily produced HCOOH, with corresponding 0.606 V and 0.236 V overpotentials. Vanadium produced CH4 as the main product with an overpotential of 0.675 V, while Fe formed HCHO with an overpotential of 0.342 V. Therefore, V, Cr, Fe, and Ti exhibit promising potential as electrocatalysts for carbon dioxide reduction due to their favorable product selectivity and low overpotential. Cu mainly produces CH3OH as the primary product, with an overpotential of 0.96 V. Zn primarily produces CO with a relatively high overpotential of 1.046 V. In contrast, catalysts such as Sc, Mn, Ni, and Co, among others, produce multiple products simultaneously at the same rate-limiting step and potential threshold.

Identification of hyperosmotic stress-responsive genes in Chinese hamster ovary cells via genome-wide virus-free CRISPR/Cas9 screening.

Chinese hamster ovary (CHO) cells are the preferred mammalian host cells for therapeutic protein production that have been extensively engineered to possess the desired attributes for high-yield protein production. However, empirical approaches for identifying novel engineering targets are laborious and time-consuming. Here, we established a genome-wide CRISPR/Cas9 screening platform for CHO-K1 cells with 111,651 guide RNAs (gRNAs) targeting 21,585 genes using a virus-free recombinase-mediated cassette exchange-based gRNA integration method. Using this platform, we performed a positive selection screening under hyperosmotic stress conditions and identified 180 genes whose perturbations conferred resistance to hyperosmotic stress in CHO cells. Functional enrichment analysis identified hyperosmotic stress responsive gene clusters, such as tRNA wobble uridine modification and signaling pathways associated with cell cycle arrest. Furthermore, we validated 32 top-scoring candidates and observed a high rate of hit confirmation, demonstrating the potential of the screening platform. Knockout of the novel target genes, Zfr and Pnp, in monoclonal antibody (mAb)-producing recombinant CHO (rCHO) cells and bispecific antibody (bsAb)-producing rCHO cells enhanced their resistance to hyperosmotic stress, thereby improving mAb and bsAb production. Overall, the collective findings demonstrate the value of the screening platform as a powerful tool to investigate the functions of genes associated with hyperosmotic stress and to discover novel targets for rational cell engineering on a genome-wide scale in CHO cells.

Effects of glutamine on plasma protein and inflammation in postoperative patients with colorectal cancer: a meta-analysis of randomized controlled trials.

OBJECTIVE: To evaluate the effects of glutamine on the plasma protein and inflammatory responses in colorectal cancer (CRC) patients following radical surgery. METHODS: We thoroughly retrieved online databases (EMBASE, MEDLINE, PubMed, and others) and selected the randomized controlled trials (RCTs) with glutamine vs. conventional nutrition or blank treatment up until March 2023. The plasma protein associated markers indicators (consisting of albumin (ALB), prealbumin (PA), nitrogen balance (NB), total protein (TP)), inflammatory indicators (including TNF-α, CRP, infectious complications (ICs)), and matching 95% confidence intervals (CIs) were evaluated utilizing the pooled analysis. Subsequently, meta-regression analysis, contour-enhanced funnel plot, Egger's test, and sensitivity analysis were carried out. RESULTS: We discovered 26 RCTs, included an aggregate of 1678 patients, out of which 844 were classified into the glutamine group whereas 834 were classified into the control group. The findings recorded from pooled analysis illustrated that glutamine substantially enhanced the plasma protein markers (ALB [SMD[random-effect] = 0.79, 95% CI: 0.55 to 1.03, I2 = 79.4%], PA [SMD[random-effect] = 0.94, 95% CI: 0.69 to 1.20, I2 = 75.1%], NB [SMD[random-effect] = 1.11, 95% CI: 0.46 to 1.75, I2 = 86.9%). However, the content of TP was subjected to comparison across the 2 groups, and no statistical significance was found (SMD[random-effect] = - 0.02, 95% CI: - 0.60 to 0.57, P = 0.959, I2 = 89.7%). Meanwhile, the inflammatory indicators (including TNF-α [SMD[random-effect] = - 1.86, 95% CI: - 2.21 to - 1.59, I2 = 56.7%], CRP [SMD[random-effect] = - 1.94, 95% CI: - 2.41 to - 1.48, I2 = 79.9%], ICs [RR[fixed-effect] = 0.31, 95% CI: 0.21 to 0.46, I2 = 0.00%]) were decreased significantly followed by the treatment of glutamine. CONCLUSIONS: The current study's findings illustrated that glutamine was an effective pharmaco-nutrient agent in treating CRC patients following a radical surgical operation. PROSPERO registration number: CRD42021243327.

Efficacy and safety of total neoadjuvant therapy in locally advanced rectal cancer: a meta-analysis.

PURPOSE: The standard of care for locally advanced rectal cancer (LARC) has changed from a single radical surgical treatment to the current multimodality treatment (standard chemoradiotherapy (CRT) and total neoadjuvant therapy (TNT)). The efficacy and safety of both TNT and standard CRT are evaluated in randomized controlled trials (RCTs). METHODS: RCTs were comprehensively searched in Chinese and English electronic databases. The experimental and control groups were TNT and the standard CRT, respectively, included in this meta-analysis. The outcomes were assessed through a fixed-effect or random-effect model of pooled odds (OR) or hazard ratios (HR). RESULTS: Eleven RCTs, involving 3,101 patients were included in the final analysis. TNT showed increase in the pathological complete response (pCR) (OR = 1.95, 95% confidence interval (CI): 1.57-2.41; P < 0.05) and the R0 resection (OR = 1.19, 95% CI: 0.99-1.43; P = 0.062). There was no significant difference in local recurrence-free survival (LRFS) (HR = 0.97, P = 0.803), but TNT had better 3-year disease-free survival (DFS) (HR = 0.82, 95% CI: 0.72-0.93, P < 0.05), overall survival (OS) (HR = 0.87, 95% CI: 0.74-1.02, P = 0.08) and distant metastasis-free survival (DMFS) (HR = 0.79, 95% CI: 0.67-0.93, P < 0.05) than standard CRT. CONCLUSIONS: TNT was safe and feasible as it improved pCR and survival outcomes, and reduced the risk of distant metastasis compared with standard CRT. TNT may be a superior strategy for LARC, but more RCTs are needed to prove it. REGISTRATION AND PROTOCOL: PROSPERO CRD42022327697. We added the Chinese database after registration because of the inclusion of fewer RCTs www.crd.york.ac.uk/PROSPERO/ .

Two-dimensional SPdAZ2 (A = Si, Ge; Z = N, P, As) monolayers with an intrinsic electric field for high-performance photocatalysis.

Two-dimensional materials exhibiting exceptional photocatalytic properties and a low carrier recombination rate have garnered significant attention. However, such attributes are relatively scarce among conventional two-dimensional materials. Two-dimensional Janus materials, owing to their intrinsic electric field, hold substantial promise in the realm of photocatalysis. In this study, we conducted a comprehensive investigation of the electronic, optical and photocatalytic properties, as well as the carrier mobility of SPdAZ2 (A = Si, Ge; Z = N, P, As) monolayers employing first-principles calculations. Employing the HSE06 hybrid density functional, we discovered that all six structures exhibit semiconductor characteristics with indirect band gaps under equilibrium conditions. Notably, SPdSiP2, SPdSiAs2, and SPdGeP2 monolayers displayed advantageous band edge positions, facilitating effective photocatalytic water decomposition. Furthermore, we computed the carrier mobility of SPdAZ2 monolayers, revealing significant variations in the electron and hole mobility along the same direction, which enhances the effective separation of electrons and holes. Finally, we explored the impact of biaxial strain and an applied electric field on the electronic properties, photocatalysis, and light absorption of SPdAZ2 monolayers. These compelling features underscore the broad potential applications of SPdAZ2 (A = Si, Ge; Z = N, P, As) monolayers in the realm of photocatalytic water decomposition.

Tuning of the electronic and photocatalytic properties of Janus WSiGeZ4 (Z = N, P, and As) monolayers via strain engineering.

Recently, MA2Z4 materials have received tremendous attention due to their amazing electronic, spintronic, and optoelectronic properties. In this work, we propose a class of 2D Janus materials WSiGeZ4 (Z = N, P, and As). It was found that their electronic and photocatalytic properties are sensitive to the change of the Z element. Biaxial strain results in an indirect-direct band gap transition in WSiGeN4 and a semiconductor-metal transition in WSiGeP4 and WSiGeAs4. Comprehensive studies demonstrate that these transitions as well as valley-contrasting physics are closely related to the crystal field induced orbital distribution. By taking into account several features of the excellent photocatalysts reported for water splitting, we predict three promising photocatalytic materials WSi2N4, WGe2N4, and WSiGeN4. Their optical and photocatalytic properties can be well modulated by applying biaxial strain. Our work not only provides a class of potential electronic and optoelectronic materials but also enriches the study of Janus MA2Z4 materials.

Sevoflurane Confers Protection Against the Malignant Phenotypes of Lung Cancer Cells via the microRNA-153-3p/HIF1α/KDM2B Axis.

Sevoflurane is shown to curtail lung cancer (LC) development. Herein, this research sought to investigate the underlying mechanism of sevoflurane in regard to its repressive effects on LC. Expression levels of microRNA (miR)-153-3p, HIF1α, and KDM2B in LC tissues and cells were determined with qRT-PCR. Following sevoflurane pretreatment and/or ectopic expression and knockdown experiments, the malignant phenotypes, and levels of miR-153-3p, HIF1α, and KDM2B in LC A549 cells were detected using Transwell, scratch, EdU, CCK-8, Western blot, and qRT-PCR assays. Relationship between HIF1α and miR-153-3p was verified with a dual-luciferase reporter assay. The interaction between HIF1α and KDM2B was verified with a ChIP assay. LC tissues and cells presented low miR-153-3p expression and high HIF1α and KDM2B expression. Sevoflurane pretreatment, miR-153-3p upregulation, HIF1α downregulation, or KDM2B downregulation impeded the malignant phenotypes of A549 cells. Sevoflurane pretreatment augmented miR-153-3p expression, while miR-153-3p negatively targeted HIF1α. HIF1α bound to the KDM2B promoter to upregulate KDM2B. HIF1α or KDM2B overexpression counteracted the inhibitory effects of sevoflurane pretreatment on A549 cell malignant behaviors. Sevoflurane decreased HIF1α expression through upregulation of miR-153-3p, thereby reducing KDM2B transcription to restrict the malignant phenotypes of LC A549 cells.

Photodecaging of a Mitochondria-Localized Iridium(III) Endoperoxide Complex for Two-Photon Photoactivated Therapy under Hypoxia.

Despite the clinical success of photodynamic therapy (PDT), the application of this medical technique is intrinsically limited by the low oxygen concentrations found in cancer tumors, hampering the production of therapeutically necessary singlet oxygen (1O2). To overcome this limitation, we report on a novel mitochondria-localized iridium(III) endoperoxide prodrug (2-O-IrAn), which, upon two-photon irradiation in NIR, synergistically releases a highly cytotoxic iridium(III) complex (2-IrAn), singlet oxygen, and an alkoxy radical. 2-O-IrAn was found to be highly (photo-)toxic in hypoxic tumor cells and multicellular tumor spheroids (MCTS) in the nanomolar range. To provide cancer selectivity and improve the pharmacological properties of 2-O-IrAn, it was encapsulated into a biotin-functionalized polymer. The generated nanoparticles were found to nearly fully eradicate the tumor inside a mouse model within a single treatment. This study presents, to the best of our knowledge, the first example of an iridium(III)-based endoperoxide prodrug for synergistic photodynamic therapy/photoactivated chemotherapy, opening up new avenues for the treatment of hypoxic tumors.

Review of arginase as a promising biocatalyst: characteristics, preparation, applications and future challenges.

As a committed step in the urea cycle, arginase cleaves l-arginine to form l-ornithine and urea. l-Ornithine is essential to: cell proliferation, collagen formation and other physiological functions, while the urea cycle itself converts highly toxic ammonia to urea for excretion. Recently, arginase was exploited as an efficient catalyst for the environmentally friendly synthesis of l-ornithine, an abundant nonprotein amino acid that is widely employed as a food supplement and nutrition product. It was also proposed as an arginine-reducing agent in order to treat arginase deficiency and to be a means of depleting arginine to treat arginine auxotrophic tumors. Targeting arginase inhibitors of the arginase/ornithine pathway offers great promise as a therapy for: cardiovascular, central nervous system diseases and cancers with high arginase expression. In this review, recent advances in the characteristics, structure, catalytic mechanism and preparation of arginase were summarized, with a focus being placed on the biotechnical and medical applications of arginase. In particular, perspectives have been presented on the challenges and opportunities for the environmentally friendly utilization of arginase during l-ornithine production and in therapies.

Autonomous Navigation of Unmanned Aircraft Using Space Target LOS Measurements and QLEKF.

An autonomous navigation method based on the fusion of INS (inertial navigation system) measurements with the line-of-sight (LOS) observations of space targets is presented for unmanned aircrafts. INS/GNSS (global navigation satellite system) integration is the conventional approach to achieving the long-term and high-precision navigation of unmanned aircrafts. However, the performance of INS/GNSS integrated navigation may be degraded gradually in a GNSS-denied environment. INS/CNS (celestial navigation system) integrated navigation has been developed as a supplement to the GNSS. A limitation of traditional INS/CNS integrated navigation is that the CNS is not efficient in suppressing the position error of the INS. To solve the abovementioned problems, we studied a novel integrated navigation method, where the position, velocity and attitude errors of the INS were corrected using a star camera mounted on the aircraft in order to observe the space targets whose absolute positions were available. Additionally, a QLEKF (Q-learning extended Kalman filter) is designed for the performance enhancement of the integrated navigation system. The effectiveness of the presented autonomous navigation method based on the star camera and the IMU (inertial measurement unit) is demonstrated via CRLB (Cramer-Rao lower bounds) analysis and numerical simulations.

Chiral RuII -PtII Complexes Inducing Telomere Dysfunction against Cisplatin-Resistant Cancer Cells.

The application of G-quadruplex stabilizers presents a promising anticancer strategy. However, the molecular crowding conditions within cells diminish the potency of current G-quadruplex stabilizers. Herein, chiral RuII -PtII dinuclear complexes were developed as highly potent G-quadruplex stabilizers even under challenging molecular crowding conditions. The compounds were encapsulated with biotin-functionalized DNA cages to enhance sub-cellular localization and provide cancer selectivity. The nanoparticles were able to efficiently inhibit the endogenous activities of telomerase in cisplatin-resistant cancer cells and cause cell death by apoptosis. The nanomaterials demonstrated high antitumor activity towards cisplatin-resistant tumor cells as well as tumor-bearing mice. To the best of our knowledge, this study presents the first example of a RuII -PtII dinuclear complex as a G-quadruplex stabilizer with an anti-cancer effect towards drug-resistant tumors inside an animal model.

A CTL/M2 macrophage-related four-gene signature predicting metastasis-free survival in triple-negative breast cancer treated with adjuvant radiotherapy.

PURPOSE: This study aimed to develop and validate a prognostic model for metastasis-free survival (MFS) based on genes that may functionally interact with cytotoxic T lymphocytes (CTLs) and M2 macrophages in patients with triple-negative breast cancer (TNBC) who underwent adjuvant radiotherapy. METHODS: The transcriptional and phenotypic profiles of TNBC and other breast cancer subtypes were downloaded from gene expression omnibus (GEO). The abundance of infiltrated immune cells was evaluated through CIBERSORTx or MCP-counter. A weighted linear model, the score for MFS (SMFS), was developed using the least absolute shrinkage and selection operator (LASSO) in GSE58812 and validated in GSE2034 and GSE12276. The biological implication of the SMFS was explored by evaluating its associations with TNBC molecular subtypes and other radiosensitivity- or immune-related signatures. RESULTS: A model consisting of the PCDH12/ELP3, PCDH12/MSRA, and FAM160B2/MSRA gene expression ratios with non-zero coefficients finally selected by LASSO was developed using GSE58812. In GSE2034 (treatment with adjuvant radiotherapy), the SMFS was significantly associated with MFS in TNBC patients (hazard ratio (HR) = 8.767, 95% confidence interval (CI) 1.856-41.408, P = 0.006) and, to a lesser extent, in non-TNBC patients (HR = 2.888, 95% CI 1.076-7.750, P = 0.035). However, the interaction of subtype (TNBC vs non-TNBC) and the SMFS tended to be significant (Pinteraction = 0.081). In contrast, the SMFS was not significantly associated with MFS in either TNBC patients (P = 0.499) or non-TNBC patients (P = 0.536) in GSE12276 (treatment without radiotherapy). Among the four TNBC molecular subtypes, the c1 and c4 subtypes exhibited higher CTL infiltration and lower SMFS values than the c2 and c3 subtypes. In addition, the SMFS was positively correlated with the abundance of endothelial cells (r = 0.413, P < 0.001). CONCLUSION: The proposed model has the potential to predict MFS in TNBC patients after adjuvant radiotherapy, and the SMFS may represent a measurement of tumor immune suppression.

An ER-Targeting Iridium(III) Complex That Induces Immunogenic Cell Death in Non-Small-Cell Lung Cancer.

Immunogenic cell death (ICD) is a vital component of therapeutically induced anti-tumor immunity. An iridium(III) complex (Ir1), containing an N,N-bis(2-chloroethyl)-azane derivate, as an endoplasmic reticulum-localized ICD inducer for non-small cell lung cancer (NSCLC) is reported. The characteristic discharge of damage-associated molecular patterns (DAMPs), that is, cell surface exposure of calreticulin (CRT), extracellular exclusion of high mobility group box 1 (HMGB1), and ATP, were generated by Ir1 in A549 lung cancer cells, accompanied by an increase in endoplasmic reticulum stress and reactive oxygen species (ROS). The vaccination of immunocompetent mice with Ir1-treated dying cells elicited an antitumor CD8+ T cell response and Foxp3+ T cell depletion, which eventually resulted in long-acting anti-tumor immunity by the activation of ICD in lung cancer cells. Ir1 is the first Ir-based complex that is capable of developing an immunomodulatory response by immunogenic cell death.