Circulating tumor cells with metastasis-initiating competence survive fluid shear stress during hematogenous dissemination through CXCR4-PI3K/AKT signaling.

To seed lethal secondary lesions, circulating tumor cells (CTCs) must survive all rate-limiting factors during hematogenous dissemination, including fluid shear stress (FSS) that poses a grand challenge to their survival. We thus hypothesized that CTCs with the ability to survive FSS in vasculature might hold metastasis-initiating competence. This study reported that FSS of physiologic magnitude selected a small subpopulation of suspended tumor cells in vitro with the traits of metastasis-initiating cells, including stemness, migration/invasion potential, cellular plasticity, and biophysical properties. These shear-selected cells generated local and metastatic tumors at the primary and distal sites efficiently, implicating their metastasis competence. Mechanistically, FSS activated the mechanosensitive protein CXCR4 and the downstream PI3K/AKT signaling, which were essential in shear-mediated selection of metastasis-competent CTCs. In summary, these findings conclude that CTCs with metastasis-initiating competence survive FSS during hematogenous dissemination through CXCR4-PI3K/AKT signaling, which may provide new therapeutic targets for the early prevention of tumor metastasis.

Visible light to the second near-infrared light-harvesting donor-acceptor1-donor-acceptor2-type terpolymers for boosted photocatalytic hydrogen evolution via dual-sulfone-acceptor engineering.

Developing visible to near-infrared light-absorbing conjugated polymer photocatalysts is crucial for enhancing solar energy utilization efficiency, as most conjugated organic polymers only absorb light in the visible range. In this work, we firstly developed a novel thiophene S,S-dioxide (TDO) monomer with the stronger electron-withdrawing character, and then prepared a series of donor-acceptor1-donor-acceptor2-type (D-A1-D-A2-type) conjugated terpolymers (THTDB-1-THTDB-5) by statistically adjusting the molar ratio of two sulfone-based acceptor monomers, dibenzothiophene-S,S-dioxide (BTDO, A1) and TDO (A2). These terpolymers demonstrate a gradually expanding absorption range from visible light to the second near-infrared (Vis-to-NIR-II) region with the gradual increase of the TDO contents in the polymer skeleton, showcasing excellent absorption properties and efficient light-capturing capabilities. The optimized D-A1-D-A2 polymer photocatalyst THTDB-4 exhibits a high hydrogen evolution rate of 21.27 mmol g-1 h-1 under visible light without any co-catalyst. The dual-sulfone-acceptor engineering offers a viable approach for developing efficient the longer Vis-to-NIR-II light-harvesting polymer photocatalysts.

Regulation of Hot Electrons Transport Achieved through Controlled Electron-Phonon Coupling in Metallic Heterostructures.

The electron-phonon (e-ph) interactions are pivotal in shaping the electrical and thermal properties, and in particular, determining the carrier dynamics and transport behaviors in optoelectronic devices. By employing pump-probe spectroscopy and ultrafast microscopy, the consequential role of e-ph coupling strength in the spatiotemporal evolution of hot electrons is elucidated. Thermal transport across the metallic interface is controlled to regulate effective e-ph coupling factor Geff in Au and Au/Cr heterostructure, and their impact on nonequilibrium transport of hot electrons is examined. Via the modulation of buried Cr thickness, a strong correlation between Geff and the diffusive behavior of hot electrons is found. By enhancing Geff through the regulation of thermal transport across interface, there is a significant reduction in e-ph thermalization time, the maximum diffusion length of hot electrons, and lattice heated area which are extracted from the spatiotemporal evolution profiles. Therefore, the increased Geff significantly weakens the diffusion of hot electrons and promotes heat relaxation of electron subsystems in both time and space. These insights propose a robust framework for spatiotemporal investigations of G impact on hot electron diffusion, underscoring its significance in the rational design of advanced optoelectronic devices with high efficiency.

Cell mechanics regulate the migration and invasion of hepatocellular carcinoma cells via JNK signaling.

Hepatocellular carcinoma (HCC) cells, especially those with metastatic competence, show reduced stiffness compared to the non-malignant counterparts. However, it is still unclear whether and how the mechanics of HCC cells influence their migration and invasion. This study reports that HCC cells with enhanced motility show reduced mechanical stiffness and cytoskeleton, suggesting the inverse correlation between cellular stiffness and motility. Through pharmacologic and genetic approaches, inhibiting actomyosin activity reduces HCC cellular stiffness but promotes their migration and invasion, while activating it increases cell stiffness but impairs cell motility. Actomyosin regulates cell motility through the influence on cellular stiffness. Mechanistically, weakening/strengthening cells inhibits/promotes c-Jun N terminal kinase (JNK) phosphorylation, activation/inhibition of which rescues the effects of cell mechanics on their migration and invasion. Further, HCC cancer stem cells (CSCs) exhibit higher motility but lower stiffness than control cells. Increasing CSC stiffness weakens migration and invasion through the activation of JNK signaling. In conclusion, our findings unveil a new regulatory role of actomyosin-mediated cellular mechanics in tumor cell motility and present new evidence to support that tumor cell softening may be one driving force for HCC metastasis. STATEMENT OF SIGNIFICANCE: Tumor cells progressively become softened during metastasis and low cell stiffness is associated with high metastatic potential. However, it remains unclear whether tumor cell softening is a by-product of or a driving force for tumor progression. This work reports that the stiffness of hepatocellular carcinoma cells is linked to their migration and invasion. Importantly, tumor cell softening promotes migration and invasion, while cell stiffening impairs the mobility. Weakening/strengthening cells inhibits/promotes JNK phosphorylation, activation/inhibition of which rescues the effects of cell mechanics on their migration and invasion ability. Further, stiffening liver cancer stem cells attenuates their motility through activating JNK signaling. In summary, our study uncovers a previously unappreciated role of tumor cell mechanics in migration and invasion and implicates the therapeutic potential of cell mechanics in the mechanotargeting of metastasis.

Biophysics in tumor growth and progression: from single mechano-sensitive molecules to mechanomedicine.

Evidence from physical sciences in oncology increasingly suggests that the interplay between the biophysical tumor microenvironment and genetic regulation has significant impact on tumor progression. Especially, tumor cells and the associated stromal cells not only alter their own cytoskeleton and physical properties but also remodel the microenvironment with anomalous physical properties. Together, these altered mechano-omics of tumor tissues and their constituents fundamentally shift the mechanotransduction paradigms in tumorous and stromal cells and activate oncogenic signaling within the neoplastic niche to facilitate tumor progression. However, current findings on tumor biophysics are limited, scattered, and often contradictory in multiple contexts. Systematic understanding of how biophysical cues influence tumor pathophysiology is still lacking. This review discusses recent different schools of findings in tumor biophysics that have arisen from multi-scale mechanobiology and the cutting-edge technologies. These findings range from the molecular and cellular to the whole tissue level and feature functional crosstalk between mechanotransduction and oncogenic signaling. We highlight the potential of these anomalous physical alterations as new therapeutic targets for cancer mechanomedicine. This framework reconciles opposing opinions in the field, proposes new directions for future cancer research, and conceptualizes novel mechanomedicine landscape to overcome the inherent shortcomings of conventional cancer diagnosis and therapies.

Dual CNN cross-teaching semi-supervised segmentation network with multi-kernels and global contrastive loss in ACDC.

The cross-teaching based on Convolutional Neural Network (CNN) and Transformer has been successful in semi-supervised learning; however, the information interaction between local and global relations ignores the semantic features of the medium scale, and at the same time, the information in the process of feature coding is not fully utilized. To solve these problems, we proposed a new semi-supervised segmentation network. Based on the principle of complementary modeling information of different kernel convolutions, we design a dual CNN cross-supervised network with different kernel sizes under cross-teaching. We introduce global feature contrastive learning and generate contrast samples with the help of dual CNN architecture to make efficient use of coding features. We conducted plenty of experiments on the Automated Cardiac Diagnosis Challenge (ACDC) dataset to evaluate our approach. Our method achieves an average Dice Similarity Coefficient (DSC) of 87.2% and Hausdorff distance ([Formula: see text]) of 6.1 mm on 10% labeled data, which is significantly improved compared with many current popular models. Supervised learning is performed on the labeled data, and dual CNN cross-teaching supervised learning is performed on the unlabeled data. All data would be mapped by the two CNNs to generate features, which are used for contrastive learning to optimize the parameters.

The Mechanics of Tumor Cells Dictate Malignancy via Cytoskeleton-Mediated APC/Wnt/ß-Catenin Signaling.

Tumor cells progressively remodel cytoskeletal structures and reduce cellular stiffness during tumor progression, implicating the correlation between cell mechanics and malignancy. However, the roles of tumor cell cytoskeleton and the mechanics in tumor progression remain incompletely understood. We report that softening/stiffening tumor cells by targeting actomyosin promotes/suppresses self-renewal in vitro and tumorigenic potential in vivo. Weakening/strengthening actin cytoskeleton impairs/reinforces the interaction between adenomatous polyposis coli (APC) and ß-catenin, which facilitates ß-catenin nuclear/cytoplasmic localization. Nuclear ß-catenin binds to the promoter of Oct4, which enhances its transcription that is crucial in sustaining self-renewal and malignancy. These results demonstrate that the mechanics of tumor cells dictate self-renewal through cytoskeleton-APC-Wnt/ß-catenin-Oct4 signaling, which are correlated with tumor differentiation and patient survival. This study unveils an uncovered regulatory role of cell mechanics in self-renewal and malignancy, and identifies tumor cell mechanics as a hallmark not only for cancer diagnosis but also for mechanotargeting.

Fluid shear stress enhances natural killer cell's cytotoxicity toward circulating tumor cells through NKG2D-mediated mechanosensing.

Tumor cells metastasize to distant organs mainly via hematogenous dissemination, in which circulating tumor cells (CTCs) are relatively vulnerable, and eliminating these cells has great potential to prevent metastasis. In vasculature, natural killer (NK) cells are the major effector lymphocytes for efficient killing of CTCs under fluid shear stress (FSS), which is an important mechanical cue in tumor metastasis. However, the influence of FSS on the cytotoxicity of NK cells against CTCs remains elusive. We report that the death rate of CTCs under both NK cells and FSS is much higher than the combined death induced by either NK cells or FSS, suggesting that FSS may enhance NK cell's cytotoxicity. This death increment is elicited by shear-induced NK activation and granzyme B entry into target cells rather than the death ligand TRAIL or secreted cytokines TNF-α and IFN-γ. When NK cells form conjugates with CTCs or adhere to MICA-coated substrates, NK cell activating receptor NKG2D can directly sense FSS to induce NK activation and degranulation. These findings reveal the promotive effect of FSS on NK cell's cytotoxicity toward CTCs, thus providing new insight into immune surveillance of CTCs within circulation.

Adhesion to the Brain Endothelium Selects Breast Cancer Cells with Brain Metastasis Potential.

Tumor cells metastasize from a primary lesion to distant organs mainly through hematogenous dissemination, in which tumor cell re-adhesion to the endothelium is essential before extravasating into the target site. We thus hypothesize that tumor cells with the ability to adhere to the endothelium of a specific organ exhibit enhanced metastatic tropism to this target organ. This study tested this hypothesis and developed an in vitro model to mimic the adhesion between tumor cells and brain endothelium under fluid shear stress, which selected a subpopulation of tumor cells with enhanced adhesion strength. The selected cells up-regulated the genes related to brain metastasis and exhibited an enhanced ability to transmigrate through the blood-brain barrier. In the soft microenvironments that mimicked brain tissue, these cells had elevated adhesion and survival ability. Further, tumor cells selected by brain endothelium adhesion expressed higher levels of MUC1, VCAM1, and VLA-4, which were relevant to breast cancer brain metastasis. In summary, this study provides the first piece of evidence to support that the adhesion of circulating tumor cells to the brain endothelium selects the cells with enhanced brain metastasis potential.

Five New Cantharidin Derivatives from the Insect Mylabris cichorii L. and Their Potential against Kidney Fibrosis In Vitro.

Five new monoterpenoids including three 1-hydroxymethyl-2-methyl cantharimide-type derivatives (1, 2, and 5) and two 1,2-dimethyl cantharimide-type derivatives (3 and 4), together with three known compounds (6-8) were isolated from the insect Mylabris cichorii Linnaeus. The structures of these new compounds, including their absolute configurations, were characterized by detailed analysis of NMR, chemical derivatization, and quantum chemical ECD calculations. All of the compounds were tested for their biological activity against kidney fibrosis. The results revealed that compounds 2, 4, and 7 could inhibit kidney fibrosis in vitro at 40 µM by inhibiting the expression of fibronectin and collagen I in TGF-ß1-induced NRK-52e cells.

Biomechanics of cancer stem cells.

Cancer stem cells (CSCs) have been believed to be one driving force for tumor progression and drug resistance. Despite the significance of biochemical signaling in malignancy, highly malignant tumor cells or CSCs exhibit lower cellular stiffness than weakly malignant cells or non-CSCs, which are softer than their healthy counterparts, suggesting the inverse correlation between cell stiffness and malignancy. Recent years have witnessed the rapid accumulation of evidence illustrating the reciprocity between cell cytoskeleton/mechanics and CSC functions and the potential of cellular stiffness for specific targeting of CSCs. However, a systematic understanding of tumor cell mechanics and their role in CSCs and tumor progression is still lacking. The present review summarizes the recent progress in the alterations of tumor cell cytoskeleton and stiffness at different stages of tumor progression and recapitulates the relationship between cellular stiffness and CSC functions. The altered cell mechanics may mediate the mechanoadaptive responses that possibly empower CSCs to survive and thrive during metastasis. Furthermore, we highlight the possible impact of tumor cell mechanics on CSC malignancy, which may potentiate low cell stiffness as a mechanical marker for CSC targeting.

Unusual sesquilignans with anti-inflammatory activities from the resin of Ferula sinkiangensis.

Sinkianlignans A - D (1-4), four new sesquilignans with an unusual architectures was characterized with a rarely α-γ', ß-γ', and γ-γ' linkage pattern, and sinkianlignans E - F (5 and 6), two lignans, were isolated from the Ferula sinkiangensis. Hypothetic biosynthetic pathway of compound 3 contain a newly formed six-membered C-ring by Diels-Alder cycloaddition. The structures of isolates were established by spectroscopic techniques and computational methods. Biological evaluation of all the isolated compounds revealed that compounds 2a and 2b could inhibit IL-6 and TNF-α production in lipopolysaccharide (LPS) induced RAW264.7 cells in a dose-dependent manner.

Fluid shear stress regulates the survival of circulating tumor cells via nuclear expansion.

Distant metastasis mainly occurs through hematogenous dissemination, where suspended circulating tumor cells (CTCs) experience a considerable level of fluid shear stress. We recently reported that shear flow induced substantial apoptosis of CTCs, although a small subpopulation could still persist. However, how suspended tumor cells survive in shear flow remains poorly understood. This study finds that fluid shear stress eliminates the majority of suspended CTCs and increases nuclear size, whereas it has no effect on the viability of adherent tumor cells and decreases their nuclear size. Shear flow promotes histone acetylation in suspended tumor cells, the inhibition of which using one drug suppresses shear-induced nuclear expansion, suggesting that shear stress might increase nuclear size through histone acetylation. Suppressing histone acetylation-mediated nuclear expansion enhances shear-induced apoptosis of CTCs. These findings suggest that suspended tumor cells respond to shear stress through histone acetylation-mediated nuclear expansion, which protects CTCs from shear-induced destruction. Our study elucidates a unique mechanism underlying the mechanotransduction of suspended CTCs to shear flow, which might hold therapeutic promise for CTC eradication.

The toxicity of perfluorodecanoic acid is mainly manifested as a deflected immune function.

BACKGROUND: Perfluorodecanoic acid (PFDA) is a type of perfluoroalkyl acid (PFAA). PFDA has toxicity similar to dioxin; its effect on the body is not through a single target or a single pathway. However, the mechanism at the global level is still unclear. METHODS AND RESULTS: We treated mice with PFDA and characterized the global changes in gene expression in the liver using microarray analyses. The enriched KEGG pathways and GO analyses revealed that PFDA greatly affected the immune response, which was different from the response of gastric cells previously studied. As a proof of principle, the expressions of IL-1ß and IL-18 were both decreased after PFDA treatment, and qRT-PCR and ELISAs verified the reduction of IL-1ß and IL-18 in liver tissues. Mechanistic investigations indicated that PFDA inhibited caspase-1 activation, and decreased the mRNA levels of NLRP1, NLRP3, and NLRC4; thus, suggesting that inflammasome assemblies were suppressed. Further microarray data revealed that cIAP2 and its binding proteins, which are critical for regulating inflammasome assembly, were also repressed by PFDA. In addition, flow cytometry results revealed a significant inhibition of Th1 cell differentiation in the livers of PFDA-treated mice. CONCLUSIONS: The results of this study suggested that one of the main toxic effects of PFDA on livers was the inhibition of immune response.

The Relationship between MALAT1 Polymorphism rs3200401 C > T and the Risk of Overall Cancer: A Meta-Analysis.

Background and Objectives: At present, the association between the long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) polymorphism rs3200401 C > T and cancer risk remain controversial. The aim of this meta-analysis was to assess the association between rs3200401 C > T and cancer susceptibility. Materials and Methods: The databases of PubMed, EMBASE and Web of Science were searched for literature published in English until 1 September 2021. The odd ratios (ORs) and 95% confidence intervals (CIs) were applied to evaluate the strength of association in five genetic models. Heterogeneity was assessed using the Q-test and I2 test. Begg's funnel plot and Egger's linear regression test were conducted to assess publication bias. Meta-regression analysis was used to explore potential sources of heterogeneity. Trial sequential analysis (TSA) was performed to validate the reliability of the results. Results: A total of 10 case-control studies involving 6630 cases and 7457 controls were included in this study. The pooled ORs showed no significant association between MALAT1 rs3200401 C > T and cancer risk in five genetic models. Similarly, the association was not found in the subgroups of control source, ethnicity and study quality. In the cancer type subgroup, the results demonstrated that the T allele increased the risk of colorectal cancer (CRC) compared with the C allele. (C vs. T: OR, 1.16; 95% CI, 1.01-1.33). Conclusion: In the current meta-analysis, we found no significant association between MALAT1 polymorphism rs3200401 C > T and overall cancer risk. However, the rs3200401 C > T may be linked to a higher risk of CRC, which needs more studies to be further confirmed.

Structural Optimization and Improving Antitumor Potential of Moreollic Acid from Gamboge.

Moreollic acid, a caged-tetraprenylated xanthone from Gamboge, has been indicated as a potent antitumor molecule. In the present study, a series of moreollic acid derivatives with novel structures were designed and synthesized, and their antitumor activities were determined in multifarious cell lines. The preliminary screening results showed that all synthesized compounds selectively inhibited human colon cancer cell proliferation. TH12-10, with an IC50 of 0.83, 1.10, and 0.79 µM against HCT116, DLD1, and SW620, respectively, was selected for further antitumor mechanism studies. Results revealed that TH12-10 effectively inhibited cell proliferation by blocking cell-cycle progression from G1 to S. Besides, the apparent structure-activity relationships of target compounds were discussed. To summarize, a series of moreollic acid derivatives were discovered to possess satisfactory antitumor potentials. Among them, TH12-10 displays the highest antitumor activities against human colon cancer cells, in which the IC50 values in DLD1 and SW620 are lower than that of 5-fluorouracil.

Diagnostic value of RNA for hepatocellular carcinoma: a network meta-analysis.

Aim: The aim of this study was to evaluate the capacity of RNA in the diagnosis of hepatocellular carcinoma (HCC). Methods: A systematic review was conducted from PubMed, Cochrane Library, EMBASE and Web of Science databases via well-designed retrieval strategy. Subsequently, the network meta-analysis was performed by the STATA software. Results: Through statistical analysis, the three hypotheses of the network meta-analysis were established. In view of these hypotheses, the diagnostic efficacy of the three markers in HCC (HCC vs healthy people) may be consistent, and the cumulative ranking results showed such a trend: circular RNA >long noncoding RNA >microRNA. Conclusion: Circular RNA may be most effective for diagnosing HCC across the three types of RNA.

Nanoparticle-mediated specific elimination of soft cancer stem cells by targeting low cell stiffness.

As the driving force of tumor progression, cancer stem cells (CSCs) hold much lower cellular stiffness than bulk tumor cells across many cancer types. However, it remains unclear whether low cell stiffness can be harnessed in nanoparticle-based therapeutics for CSC targeting. We report that breast CSCs exhibit much lower stiffness but considerably higher uptake of nitrogen-doped graphene quantum dots (N-GQDs) than bulk tumor cells. Softening/stiffening cells enhances/suppresses nanoparticle uptake through activating/inhibiting clathrin- and caveolae-mediated endocytosis, suggesting that low cell stiffness mediates the elevated uptake in soft CSCs that may lead to the specific elimination. Further, soft CSCs enhance drug release, cellular retention, and nuclear accumulation of drug-loaded N-GQDs by reducing intracellular pH and exocytosis. Remarkably, drug-loaded N-GQDs specifically eliminate soft CSCs both in vitro and in vivo, inhibit tumor but not animal growth, and reduce the tumorigenicity of xenograft cells. Our findings unveil a new mechanism by which low cellular stiffness can be harnessed in nanoparticle-based strategies for specific CSC elimination, opening a new paradigm of cancer mechanomedicine. STATEMENT OF SIGNIFICANCE: Low cell stiffness is associated with high malignancy of tumor cells and thus serves as a mechanical hallmark of CSCs. However, it remains unclear whether cellular stiffness can be exploited for specific targeting of soft CSCs. This work reports that soft CSCs exhibit high N-GQD uptake compared to stiff tumor cells, which is regulated by cellular stiffness. Further, soft CSCs have enhanced drug release, cellular retention, and nuclear accumulation of drug-loaded N-GQDs, which enable the specific elimination of malignant CSCs both in vitro and in vivo with minimal side effect. In summary, our study demonstrates that CSC's low stiffness can be harnessed as a mechanical target for specific eradication, which provides a new paradigm of cancer mechanomedicine.

MiR-448-5p/VEGFA Axis Protects Cardiomyocytes from Hypoxia Through Regulating the FAS/FAS-L Signaling Pathway.

Bioinformatics analysis showed that miR-448-5p expression in the myocardial tissue of rats with myocardial infarction significantly increased, suggesting that it may participate in myocardial cell apoptosis in myocardial infarction. This study aimed to explore the protective effects of miR-448-5p on hypoxic myocardial cells.H9C2 cells were cultured and subjected to anoxia for 2, 4, and 8 hours to establish a hypoxia model. MiR-448-5p mimic and inhibitor were transfected into the cells; then, a dual-luciferase experiment was conducted to verify the targeting relationship between miR-448-5p and VEGFA. Cell viability and apoptosis was detected by cell counting kit-8 and flow cytometry, respectively. The expressions of apoptosis-related proteins, miR-448-5p, FAS, and FAS-L were measured using western blotting and quantitative reverse transcription-polymerase chain reaction (qRT-PCR).Hypoxia-reduced H9C2 cell viability and promoted apoptosis. MiR-448-5p expression was increased after H9C2 cell hypoxia. MiR-448-5p mimic significantly inhibited the viability and promoted the apoptosis of hypoxia-induced model cells. Hypoxia promoted the expression of apoptosis-related protein B-cell lymphoma-2 (Bcl-2) and inhibited the expressions of Bcl-2-associated x protein (Bax), cleaved caspase-3, and caspase-3, whereas the effect of inhibitor on hypoxia-reduced H9C2 cell and apoptotic protein expression were opposite to miR-448-5p mimic. MiR-448-5p targeted VEGFA and regulated its expression. Silenced VEGFA expression significantly inhibited inhibitor effect on increasing cell viability and promoted apoptosis. In addition, miR-448-5p mimic inhibited the effect of hypoxia on promoting the expressions of FAS and FAS-L of H9C2 cells. Inhibitors had the opposite effect on cell hypoxia model.The miR-448-5p/VEGFA axis could protect cardiomyocytes from hypoxia through inhibiting the FAS/FAS-L signaling pathway.