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The reaction of 1,3,5-[([.sup.i][Pr.sub.2]]PO).sub.3][C.sub.6]H3 with [Co.sub.2][(CO).sub.8] leads to the isolation of a POCOP-type mononuclear pincer complex {[K.sup.P],[K.sup.C],[K.sup.P]-2,4,6-[([.sup.i][Pr.sub.2]]PO).sub.3]C6[H.sub.2]}Co[(CO).sub.2] [(1) or a tetranuclear species {[K.sup.P]-{[K.sup.P],[K.sup.C],[K.sup.P]-2,4,6-[([.sup.i][Pr.sub.2]]PO).sub.3][C.sub.6][H.sub.2]}Co[(CO).sub.2]}.sub.2][Co.sub.2][(CO).sub.6] (2), depending on the ligand to cobalt ratio employed. The latter compound can be an impurity during the synthesis of {2,6-[([.sup.i][Pr.sub.2]]PO).sub.2]-4-[Me.sub.2]N-[C.sub.6][H.sub.2]}Co[(CO).sub.2], when the ligand precursor 5-(dimethylamino)resorcinol is contaminated with phloroglucinol due to incomplete monoamination. Similarly, the reaction of 1,3,5-[( [.sup.i][Pr.sub.2]]PO).sub.3]C6H3 with [NiCl.sub.2] in the presence of 4-dimethylaminopyridine provides {[K.sup.P],[K.sup.C],[K.sup.P]-2,4,6-[([.sup.i][Pr.sub.2]]PO).sub.3][C.sub.6][H.sub.2]}NiCl (3) bearing an appended phosphinite group. Structures 1-3 have been studied by X-ray crystallography. Key words: phosphinite, pincer complexes, C-H activation, appended functionality, catalyst immobilization. La reaction du 1,3,5-[([.sup.i][Pr.sub.2]PO).sub.3][C.sub.6][H.sub.3] avec le [Co.sub.2][(CO).sub.8] permet d'isoler le complexe de ligand pince mononucleaire de type POCOP{[K.sup.P],[K.sup.C],[K.sup.P]-2,4,6-[([.sup.i][Pr.sub.2]PO)3[C.sub.6][H.sub.2]}Co(CO).sub.2] [(1)oul'especetetranucleaire[{[K.sup.P]-{[K.sup.P],[K.sup.C],[K.sup.P]-2,4,6-([.sup.i][Pr.sub.2]PO)3[C.sub.6][H.sub.2]}Co(CO).sub.2]}.sub.2][Co.sub.2][(CO).sub.6](2), selon le rapport ligand-cobalt utilise. Cette derniere espece peut etre une impurete issue de la synthese du {2,6-[([.sup.i][Pr.sub.2]]PO).sub.2]-4-[Me.sub.2]N-[C.sub.6][H.sub.2]}Co[(CO).sub.2], lorsque le precurseur de ligand 5-(dimethylamino)resorcinol est contamine par du phloroglucinol en raison d'une monoamination incomplete. De maniere similaire, la reaction du 1,3,5-[([.sup.i][Pr.sub.2]PO).sub.3][C.sub.6][H.sub.3] avec le [NiCl.sub.2] en presence de 4-dimethylaminopyridine produit le {[K.sup.P],[K.sup.C],[K.sup.P]-2,4,6-([.sup.i][Pr.sub.2]PO)3[C.sub.6][H.sub.2]}NiCl (3) portant un groupe phosphinite attache. Nous avons etudie les structures 1-3 par radiocristallographie. [Traduit par la Redaction] Mots-cles : phosphinite, complexes de ligands pinces, activation de liaison C-H, groupe fonctionnel attache, immobilisation du catalyseur., Introduction Diphosphinite-derived POCOP-type pincer complexes have been studied extensively as homogeneous catalysts for a wide variety of organic transformations (.1-11) To facilitate catalyst-product separation and catalyst recycling, (12), (13) Lewis [...]

Targeting ferroptosis has attracted exponential attention to eradicate cancer cells with high iron‐dependent growth. Increasing the level of intracellular labile iron pool via small molecules and iron‐containing nanomaterials is an effective approach to induce ferroptosis but often faces insufficient efficacy due to the fast drug metabolism and toxicity issues on normal tissues. Therefore, developing a long‐acting and selective approach to regulate ferroptosis is highly demanded in cancer treatment. Herein, a lysosome‐targeted magnetic nanotorquer (T7‐MNT) is proposed as the mechanical tool to dynamically induce the endogenous Fe2+ pool outbreak for ferroptosis of breast cancer. T7‐MNTs target lysosomes via the transferrin receptor‐mediated endocytosis in breast cancer cells. Under the programmed rotating magnetic field, T7‐MNTs generate torques to trigger endogenous Fe2+ release by disrupting the lysosomal membrane. This magneto‐mechanical manipulation can induce oxidative damage and antioxidant defense imbalance to boost frequency‐ and time‐dependent lipid peroxidization. Importantly, in vivo studies show that T7‐MNTs can efficiently trigger ferroptosis under the magnetic field and play as a long‐acting physical inducer to boost ferrotherapy efficacy in combination with RSL3. It is anticipated that this dynamic targeted strategy can be coupled with current ferroptosis inducers to achieve enhanced efficacy and inspire the design of mechanical‐based ferroptosis inducers for cancer treatment. [ABSTRACT FROM AUTHOR]

Lysosomes play a central role in biochemical signal transduction and oxidative stress in cells. Inducing lysosome membrane penetration (LMP) to cause lysosomal‐dependent cell death (LCD) in tumor cells is an effective strategy for cancer therapy. Chemical drugs can destroy the stability of lysosomes by neutralizing protons within the lysosomes or enhancing the fragility of the lysosomal membranes. However, there remain several unsolved problems of traditional drugs in LMP induction due to insufficient lysosomal targeting, fast metabolism, and toxicity in normal cells. With the development of nanotechnology, magnetic nanoparticles have been demonstrated to target lysosomes naturally, providing a versatile tool for lysosomal modulation. Combined with excellent tissue penetration and spatiotemporal manipulability of magnetic fields, magnetic modulation of lysosomes progresses rapidly in inducing LMP and LCD for cancer therapy. This review comprehensively discussed the strategies of magnetic modulation of lysosomes for cancer therapy. The intrinsic mechanisms of LMP‐induced LCD were first introduced. Then, the modulation of lysosomes by diverse physical outputs of magnetic fields was emphatically discussed. Looking forward, this review will shed the light on the prospect of magnetic modulation of lysosomes, inspiring future research of magnetic modulation strategy in cancer therapy. This article is categorized under:Therapeutic Approaches and Drug Discovery > Emerging TechnologiesTherapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic DiseaseNanotechnology Approaches to Biology > Nanoscale Systems in Biology [ABSTRACT FROM AUTHOR]

Hydration plays a crucial role in cement composites, but the traditional methods for measuring hydration heat face several limitations. In this study, we propose a machine learning-based approach to predict hydration heat at specific time points for three types of cement composites: ordinary Portland cement pastes, fly ash cement pastes, and fly ash–metakaolin cement composites. By adjusting the model architecture and analyzing the datasets, we demonstrate that the optimized artificial neural network model not only performs well during the learning process but also accurately predicts hydration heat for various cement composites from an extra dataset. This approach offers a more efficient way to measure hydration heat for cement composites, reducing the need for labor- and time-intensive sample preparation and testing. Furthermore, it opens up possibilities for applying similar machine learning approaches to predict other properties of cement composites, contributing to efficient cement research and production. [ABSTRACT FROM AUTHOR]

Open in new tab Download slide OBJECTIVES Limited data exist on the characteristics of atypical epidermal growth factor receptor (EGFR) mutations in early-stage lung cancer. Our goal was to elucidate the associations with outcomes and recurrence patterns in resected stage I lung adenocarcinoma harbouring atypical EGFR mutations. METHODS Eligible patients between 2014 and 2019 were retrospectively identified and grouped into exon20 insertion mutations and major atypical mutations, which included G719X, L861Q and S768I. Disease-free survival (DFS) was evaluated in the entire cohort and stratified by radiologic characteristics. Recurrence patterns were investigated and compared between groups. A competing risk model was used to estimate the cumulative incidence of recurrence. RESULTS A total of 710 patients were finally included. Among them, 289 (40.7%) patients had exon 20 insertion mutations and 421 (59.3%) patients had major atypical mutations. There was no significant difference regarding DFS (P  = 0.142) between groups in the entire cohort. The interaction between mutation subtype and the presence of ground-glass opacities was significant (hazard ratio 2.00, 95% confidence interval 1.59–2.51, P  < 0.001), indicating DFS between exon 20 insertion mutations and major atypical mutations may be different among subsolid and solid tumours. Survival analysis consistently revealed no significant difference in subsolid tumours (P  = 0.680), but favourable DFS of exon 20 insertion mutations in solid tumours (P  = 0.037). Furthermore, patients with exon 20 insertion mutations had a lower risk of developing bone metastases did those with radiologic solid tumours (Gray's test, P  = 0.012). CONCLUSIONS Exon 20 insertion mutations were correlated with favourable DFS and lower incidence of bone metastases in radiologic solid lung adenocarcinomas harbouring atypical EGFR mutations. [ABSTRACT FROM AUTHOR]

Heart failure is a serious and life-threatening disease worldwide. Cadherin-11 (Cad-11) is highly expressed in the heart and closely associated with inflammation. There is currently limited understanding on how Cad-11 contributes to cardiac remodeling and its underline molecular mechanism. We found an increased expression of Cad-11 in biopsy heart samples from heart failure patients, suggesting a link between Cad-11 and heart failure. To determine the role of Cad-11 in cardiac remodeling, Cad-11-deficient mice were used in a well-established mouse transverse aortic constriction (TAC) model. Loss of Cad11 greatly improved pressure overload-induced LV structural and electrical remodeling. IL (interleukin)-6 production was increased following TAC in WT mice and this increase was inhibited in cadherin-11−/− mice. We further tested the effect of IL-6 on myocyte hypertrophy and fibrosis in a primary culture system. The addition of hCad-11-Fc to cultured cardiac fibroblasts increased IL-6 production and fibroblast cell activation, whereas neutralizing IL-6 with an IL-6 antibody resulted in alleviating the fibroblast activation induced by hCad-11-Fc. On the other hand, cardiomyocytes were promoted to cardiomyocyte hypertrophy when cultured in condition media collected from cardiac fibroblasts stimulated by hCad-11-Fc.Similarly, neutralizing IL-6 prevented cardiomyocyte hypertrophy. Finally, we found that MAPKs and CaMKII–STAT3 pathways were activated in both hCad-11-Fc stimulated fibroblasts and cardiomyocytes treated with hCad-11-Fc stimulated fibroblast condition medium. IL-6 neutralization inhibited such MAPK and CaMKII-STAT3 signaling activation. These data demonstrate that Cad-11 functions in pressure overload-induced ventricular remodeling through inducing IL-6 secretion from cardiac fibroblasts to modulate the pathophysiology of neighboring cardiomyocytes. [ABSTRACT FROM AUTHOR]

Cardiac fibrosis is an important pathological process in many diseases. Wdr5 catalyzes the trimethylation of lysine K4 on histone H3. The effects of Wdr5 on the cardiac fibrosis phenotype and the activation or transformation of cardiac fibroblasts were investigated by Ang-II-infused mice by osmotic mini-pump and isolated primary neonatal rat cardiac fibroblasts. We found that the Wdr5 expression and histone H3K4me3 modification were significantly increased in Ang-II-infused mice. By stimulating primary neonatal rat cardiac fibroblasts with Ang II, we detected that the expression of Wdr5 and H3K4me3 modification were also significantly increased. Two Wdr5-specific inhibitors, and the lentivirus that transfected Sh-Wdr5, were used to treat primary mouse cardiac fibroblasts, which not only inhibited the histone methylation by Wdr5 but also significantly reduced the activation and migration ability of Ang-II-treated fibroblasts. To explore its mechanism, we found that the inhibition of Wdr5 increased the expression of P53, P21. Cut&Tag-qPCR showed that the inhibition of Wdr5 significantly reduced the enrichment of H3K4me3 in the Mdm2 promoter region. For in vivo experiments, we finally proved that the Wdr5 inhibitor OICR9429 significantly reduced Ang-II-induced cardiac fibrosis and increased the expression of P21 in cardiac fibroblasts. Inhibition of Wdr5 may mediate cardiac fibroblast cycle arrest through the Mdm2/P53/P21 pathway and alleviate cardiac fibrosis. [ABSTRACT FROM AUTHOR]

Background: Non-small-cell lung cancer (NSCLC) with additional nodule(s) located in the same lobe or ipsilateral different lobe were designated as T3 and T4, respectively, which was merely defined by anatomical location of additional nodule(s), regardless of other prognostic factors. Methods: A total of 4711 patients with T1-4, N0-2, M0 NSCLC undergoing complete resection were identified between 2009 and 2014, including 145 patients with additional nodule(s) in the same lobe (T3-Add) and 174 patients with additional tumor nodule(s) in ipsilateral different lobe (T4-Add). Overall survival (OS) was compared using multivariable Cox regression models and propensity score matching analysis (PSM). Results: T3-Add patients [T3-Add versus T3, hazard ratio (HR), 0.695; 95% confidence interval (CI), 0.528–0.915; p = 0.009] and comparable OS with T2b patients through multivariable Cox analysis, and further validated by PSM. T4-Add patients carried a wide spectrum of prognosis, and the largest diameter of single tumor was screened out as the most effective indicator for distinguishing prognosis. T4-Add (⩽3 cm) patients had better OS than T4 patients [T4-Add (⩽3 cm) versus T4, HR, 0.629; 95% CI, 0.455–0.869; p = 0.005] and comparable OS with T3 patients. And T4-Add (>3 cm) patients had comparable OS with T4 patients. Conclusion: NSCLC patients with additional nodule(s) in the same lobe and ipsilateral different lobe (maximum tumor diameter ⩽ 3 cm) should be further validated and considered restaging as T2b and T3 in the forthcoming 9th tumor, node, and metastasis staging system. [ABSTRACT FROM AUTHOR]

Background: In most cell types, replicative senescence (RS) is supposed to be a principle causative factor for aging. Atrial fibrosis, pathologically characterized by proliferation of atrial fibroblasts (AFs) and excessive accumulation of extracellular matrix proteins, is the most common substrate of atrial fibrillation (Afib) in the elderly. However, whether AFs' RS develops in the aged and fibrotic left atrium (LA) and, if yes, what is the key regulator for the pathogenesis of AFs' RS remain largely unknown. Methods: We obtained the left atrial tissues from young (6– 8 weeks old) and aged (24 months old) C57BL/6 male mice. Screening and validation of differential genes were performed using comparative analysis of RNA-seq results. Replicative senescence was examined in primary AFs after cell passage. Further gain-of-function and loss-of-function experiments were performed to explore the regulation of the AFs' RS progression. Results: In the present study, we demonstrated that there was a considerable extent of AFs' RS in the aged and fibrotic LA. Transcriptome screening showed that Ezh2 (Enhancer of zeste homolog 2) was significantly downregulated in the LA tissue of aged mice. Ezh2 is a histone methyltransferase that catalyzes H3K27me3 and mediates transcriptional silencing. We confirmed that Ezh2 was downregulated in the isolated pure senescent AFs. Knockdown of Ezh2 by siRNA or inhibition of Ezh2ʹs methyltransferase activities by GSK-126 and GSK-343 accelerated RS in the early passage of AFs, while its overexpression deaccelerated RS in the late passage of AFs. Mechanistically, Ezh2 suppressed CDKN2a (p16, p19) and Timp4 gene transcription by forming canonical H3K27me3 modifications in their promoter regions. Furthermore, the functional balance between Timp4 and MMP8 in AFs could be collapsed by changes in Ezh2 expression. Conclusion: These results thus indicate that Ezh2 is a key regulator of AFs' RS and this work may provide a basis for future treatments for atrial fibrosis in the elderly. Graphical [ABSTRACT FROM AUTHOR]

Lung cancer is the leading cause of cancer-related death worldwide. Cancer immunotherapy has shown great success in treating advanced-stage lung cancer but has yet been used to treat early-stage lung cancer, mostly due to lack of understanding of the tumor immune microenvironment in early-stage lung cancer. The immune system could both constrain and promote tumorigenesis in a process termed immune editing that can be divided into three phases, namely, elimination, equilibrium, and escape. Current understanding of the immune response toward tumor is mainly on the "escape" phase when the tumor is clinically detectable. The detailed mechanism by which tumor progenitor lesions was modulated by the immune system during early stage of lung cancer development remains elusive. The advent of single-cell sequencing technology enables tumor immunologists to address those fundamental questions. In this perspective, we will summarize our current understanding and big gaps about the immune response during early lung tumorigenesis. We will then present the state of the art of single-cell technology and then envision how single-cell technology could be used to address those questions. Advances in the understanding of the immune response and its dynamics during malignant transformation of pre-malignant lesion will shed light on how malignant cells interact with the immune system and evolve under immune selection. Such knowledge could then contribute to the development of precision and early intervention strategies toward lung malignancy. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) is the most common cardiac arrhythmia nowadays. The occurrence of AF is closely associated with obesity. Cadherin‐11 (Cad‐11), as a member of the cadherin family, can make a contribution to diet‐induced obesity and it will be informative to know whether Cad‐11 exerts its effects on atrial remodeling and AF vulnerability in a diet‐induced obesity model. In this study, we demonstrated that the expression of Cad‐11 was significantly upregulated in the left atrium of AF patients with obesity and mice following 16 weeks of high‐fat diet (HFD) feeding. Further confirmed that Cad‐11 could regulate the activity of atrial fibroblasts by participating in inducing proinflammatory cytokines production. At animal levels, we found that although there was a lack of statistical difference in body weight, Cad‐11−/− mice could markedly improve impaired glucose tolerance and hyperlipidemia. Adverse atrial structural remodeling, including atrial enlargement, inflammation, and fibrosis provoked by HFD feeding were mitigated in Cad‐11−/− mice. Mechanistically, Cad‐11 activated mitogen‐activated protein kinases and nuclear factor‐κB for interleukin‐6 production in atrial fibroblasts that may contribute to the atrial fibrosis process in obesity‐related AF, suggesting Cad‐11 might be a new therapeutic target for obesity‐related AF. [ABSTRACT FROM AUTHOR]

Background: Atrial fibrosis serves as a disease initiating mechanism in the development of atrial fibrillation. Angiotensin II (Ang-II), a key mediator for atrial fibrosis, aberrantly activates atrial fibroblasts (AFs) into myofibroblasts, resulting in subsequent excessive synthesis and deposition of extracellular matrix (ECM). Cadherin-11 (CDH11) is essential in the development of non-cardiac fibrotic diseases. In this study, we investigated its role in the pathogenesis and underlying mechanism of atrial fibrillation. Methods: We obtained left atrial tissues from either patients with atrial fibrillation or Ang-II-induced atrial fibrosis mice. We utilized a global CDH11 knockout mouse (CDH11−/-) model to determine the effect of CDH11 on AF cell proliferation, migration, ECM synthesis/deposition. RNA-Seq of isolated AFs from CDH11−/- or normal mice was performed and differential expressed genes were analyzed. The mouse susceptibility to atrial fibrillation was examined by cardiac electrophysiology. Results: We found that cadherin-11 was significantly up-regulated in fibrotic atrial tissue from patients with atrial fibrillation and Ang-II-induced mice. Both normal and CDH11−/- mice did not develop atrial fibrosis at resting state. However, after Ang-II infusion, unlike severe atrial fibrosis occurred in normal mice, CDH11−/- mice displayed a reduced atrial fibrosis. Atrial fibroblasts with CDH11 deletion from CDH11−/- mice showed reduction in Ang-II-induced cell proliferation, migration and ECM synthesis/deposition, indicating the involvement of CDH11 in atrial fibrosis. Consistently, RNA-Seq of CDH11-null AFs uncovered significant decrease in pro-fibrotic gene expression. In addition, we identified reduction of transcripts associated with Smad2/3, ERK1/2 and JNK pathways. Further, CDH11−/- mice showed a significantly attenuated Ang-II-induced susceptibility to atrial fibrillation. Conclusion: Our results indicate that CDH11 potentiates Ang-II-induced activation of AFs. The pathogenesis of atrial fibrosis is through CDH11 mediated stimulation of Smad2/3, ERK1/2 and JNK pathways. Thus, CDH11 might serve as a novel therapeutic target for ameliorating the development of atrial fibrillation. [ABSTRACT FROM AUTHOR]

Open in new tab Download slide Open in new tab Download slide OBJECTIVES To investigate the impact of lung window (LW) and mediastinal window (MW) settings on the clinical T classifications and prognostic prediction of patients with subsolid nodules. METHODS Seven hundred and nineteen surgically resected subsolid nodules were reviewed, grouping into pure ground-glass nodules (n  = 179) or part-solid nodules (n  = 540) using LW. Interobserver agreement on nodule classifications was assessed via kappa-value, and predictive performance of the solid portion measurement in LW and MW for pathological invasiveness and malignancy were compared using receiver-operating characteristic analysis. Cox regression was used to identify prognostic factors. Prognostic significance of T classifications based on LW (c[l]T) and MW (c[m]T) was evaluated by Kaplan–Meier method after propensity score matching. The performance of c(m)T for discrimination survival was estimated via the concordance index (C-index), net reclassification improvement and integrated-discrimination improvement. RESULTS By adopting MW, 124 part-solid nodules were reclassified as pure ground-glass nodules, and interobserver agreement improved to 0.917 (95% confidence interval 0.888–0.946). The solid portion size under MW more strongly predicted pathological invasiveness (P  =   0.030), but did not better predict pathological malignancy. For remaining 416 part-solid nodules, c(l)T and c(m)T were both independent risk factors. c(m)T led to T classifications shifts in 321 nodules (14 upstaged and 307 downstaged) with no significant prognostic difference existing between the shifted c(m)T and matching c(l)T group after propensity score matching. The corrected C-index was improved to 0.695 (0.620–1.000) when adopting c(m)T with no significant difference in net reclassification improvement (P  =   0.098) and integrated-discrimination improvement (P  =   0.13) analysis. CONCLUSIONS As there is no significant benefit provided by MW in evaluating clinical T classification and prognosis, the current usage of LW is appropriate for assessing subsolid nodules. [ABSTRACT FROM AUTHOR]

Reactive oxygen species (ROS), a group of oxygen derived radicals and derivatives, can induce cancer cell death via elevated oxidative stress. A spatiotemporal approach with safe and deep‐tissue penetration capabilities to elevate the intracellular ROS level is highly desirable for precise cancer treatment. Here, a mechanical‐thermal induction therapy (MTIT) strategy is developed for a programmable increase of ROS levels in cancer cells via assembly of magnetic nanocubes integrated with alternating magnetic fields. The magneto‐based mechanical and thermal stimuli can disrupt the lysosomes, which sequentially induce the dysfunction of mitochondria. Importantly, intracellular ROS concentrations are responsive to the magneto‐triggers and play a key role for synergistic cancer treatment. In vivo experiments reveal the effectiveness of MTIT for efficient eradication of glioma and breast cancer. By remote control of the force and heat using magnetic nanocubes, MTIT is a promising physical approach to trigger the biochemical responses for precise cancer treatment. [ABSTRACT FROM AUTHOR]