Enabling High Reversibility of Zn anode via Interfacial Engineering Induced by Amino acid Electrolyte Additive.

Despite possessing substantial benefits of enhanced safety and cost-effectiveness, the aqueous zinc ion batteries (AZIBs) still suffers with the critical challenges induced by inherent instability of Zn metal in aqueous electrolytes. Zn dendrites, surface passivation, and corrosion are some of the key challenges governed by water-driven side reactions in Zn anodes. Herein, a highly reversible Zn anode is demonstrated via interfacial engineering of Zn/electrolyte driven by amino acid D-Phenylalanine (DPA) additions. The preferential adsorption of DPA and the development of compact SEI on the Zn anode suppressed the side reactions, leading to controlled and uniform Zn deposition. As a result, DPA added aqueous electrolyte stabilized Zn anode under severe test environments of 20.0 mA cm-2 and 10.0 mAh cm-2 along with an average plating/stripping Coulombic efficiency of 99.37%. Under multiple testing conditions, the DPA-incorporated electrolyte outperforms the control group electrolyte, revealing the critical additive impact on Zn anode stability. This study advances interfacial engineering through versatile electrolyte additive(s) toward development of stable Zn anode, which may lead to its practical implementation in aqueous rechargeable zinc batteries.

Insight into the Storage Mechanism of Sandwich-Like Molybdenum Disulphide/Carbon Nanofibers Composite in Aluminum-Ion Batteries.

Aluminum-ion batteries (AIBs) have become a research hotspot in the field of energy storage due to their high energy density, safety, environmental friendliness, and low cost. However, the actual capacity of AIBs is much lower than the theoretical specific capacity, and their cycling stability is poor. The exploration of energy storage mechanisms may help in the design of stable electrode materials, thereby contributing to improving performance. In this work, molybdenum disulfide (MoS2) was selected as the host material for AIBs, and carbon nanofibers (CNFs) were used as the substrate to prepare a molybdenum disulfide/carbon nanofibers (MoS2/CNFs) electrode, exhibiting a residual reversible capacity of 53 mAh g-1 at 100 mA g-1 after 260 cycles. The energy storage mechanism was understood through a combination of electrochemical characterization and first-principles calculations. The purpose of this study is to investigate the diffusion behavior of ions in different channels in the host material and its potential energy storage mechanism. The computational analysis and experimental results indicate that the electrochemical behavior of the battery is determined by the ion transport mechanism between MoS2 layers. The insertion of ions leads to lattice distortion in the host material, significantly impacting its initial stability. CNFs, serving as a support material, not only reduce the agglomeration of MoS2 grown on its surface, but also effectively alleviate the volume expansion caused by the host material during charging and discharging cycles.

Rigid-flexible coupling network solid polymer electrolytes for all-solid-state lithium metal batteries.

Poor mechanical strength at working temperature and low ionic conductivity seriously hinder the application of poly(ethylene oxide) (PEO)-based solid polymer electrolytes (SPEs) in high performance all-solid-state lithium metal batteries (LMBs). Here, we design and prepare a series of rigid-flexible coupling network SPEs (RFN-SPEs) with soft poly(ethylene glycol) (PEG) chains and rigid crosslinkers containing the benzene structure. Compared with soft crosslinkers, rigid crosslinkers provide the same amount of active crosslinking points with smaller molecular weight, and meanwhile enhance the mechanical strength of the network. Therefore, based on the rigid crosslinkers, RFN-SPEs exhibit synchronously improved ionic conductivity and mechanical strength. With these RFN-SPEs, symmetrical cells can be cycled for over 2100 h at 0.5 mA cm-2. Meanwhile, stable cycling and high-rate capability could be achieved for LMBs, revealing that SPEs with the rigid-flexible coupling network are promising electrolyte systems for all-solid-state LMBs.

Zn-In Alloying Powder Solvent Free Electrode Toward High-Load Ampere-Hour Aqueous Zn-Mn Secondary Batteries.

Aqueous Zn-ion batteries (ZIBs) are promising candidates for large-scale energy storage due to high safety, abundant reserves, low-cost, and high energy density. However, the reversibility of the metallic Zn anode in the mild electrolyte is still unsatisfactory, due to the Zn dendrite growth, hydrogen evolution, and corrosion passivation. Herein, a Zn-In alloying powder solvent free electrode is proposed to replace the Zn foil in ZIBs. The novel Zn anodes are constructed by a solvent-free manufacturing process with carbons, forming a 3D Zn deposition network and providing uniformly electric field distribution. The In on the Zn powder surface can increase the overpotential for hydrogen evolution and further improve the morphology of Zn deposition against dendrite growth. The Zn solvent-free electrodes enable the Zn-MnO2 batteries with high cathode loading mass of 10-20 mg cm-2 to achieve >380 stable cycles. Furthermore, the assembled soft package batteries of 2.4 Ah (52 Wh kg-2 ) is evaluated and the capacity retention is maintained at 80% after 200 cycles at a high areal capacity of 5 mAh cm-2 without gas evolution. This work offers a workable strategy to develop a durable Zn anode for the eventually commercial applications of aqueous Zn-Mn secondary batteries.

Revealing the Preventable Effects of Fu-Zheng-Qu-Xie Decoction against Recurrence and Metastasis of Postoperative Early-Stage Lung Adenocarcinoma Based on Network Pharmacology Coupled with Metabolomics Analysis.

Fu-Zheng-Qu-Xie (FZQX) decoction is a traditional Chinese herbal prescription for the treatment of lung cancer and exerts proapoptotic and immunomodulatory effects. It has been clinically suggested to be effective in improving the survival of postoperative early-stage lung adenocarcinoma (LUAD), but the mechanism remains unclear. In this study, we used network pharmacology coupled with metabolomics approaches to explore the pharmacological action and effective mechanism of FZQX against the recurrence and metastasis of postoperative early-stage LUAD. Network pharmacology analysis showed that FZQX could prevent the recurrence and metastasis of postoperative early-stage LUAD by regulating a series of targets involving vascular endothelial growth factor receptor 2, estrogen receptor 1, sarcoma gene, epidermal growth factor receptor, and protein kinase B and by influencing the Ras, PI3K-Akt, and mitogen-activated protein kinase signaling pathways. In liquid chromatography-mass spectrometry analysis, 11 differentially expressed metabolites, including PA(12:0/18:4(6Z,9Z,12Z,15Z)), PC(16:0/0:0)[U], LysoPC(18:1(11Z)), and LysoPC(18:0), were discovered in the FZQX-treated group compared to those in the model group before treatment or normal group. They were enriched in cancer metabolism-related signaling pathways such as central carbon metabolism in cancer, choline metabolism, and glycerol phospholipid metabolism. Collectively, our results suggest that the multicomponent and multitarget interaction network of FZQX inhibits the recurrence and metastasis of postoperative early-stage LUAD by activating the receptor signal transduction pathway to inhibit proliferation, induce cell apoptosis, inhibit aerobic glycolysis, and reprogram tumor lipid metabolism.

Elucidation of the anti-lung cancer mechanism of Juan-Liu-San-Jie prescription based on network pharmacology and experimental validation.

Lung cancer is a malignancy characterized by high morbidity and mortality, with lung adenocarcinoma being the most prevalent subtype. Our preliminary studies have demonstrated that the Juan-Liu-San-Jie (JLSJ) prescription, a Traditional Chinese Medicine prescription, possesses anti-lung adenocarcinoma cancer properties. However, the molecular mechanism underlying the therapeutic effects of the JLSJ prescription for lung adenocarcinoma remains incompletely elucidated. To address the knowledge gap, the present study employed network pharmacology to identify potential therapeutic targets. Specifically, the study utilized TCMSP, TCMID, and related references, as well as ChemMapper, to identify and predict the main active components and potential targets. Additionally, differentially expressed genes associated with the disease were obtained from the microarray dataset GSE19804 and GSE118370. The protein-protein Interaction network and Target-pathway network were then constructed. We also conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, and subsequently presented the top 20 enriched pathways. The results indicated that the anti-lung cancer effects of JLSJ prescription may be attributed to its ability to mediate apoptosis of tumor cells, potentially through the PI3K/Akt signaling pathway. Then, a series of in vitro and in vivo experiments were conducted to validate the molecular mechanism predicted by network pharmacology. The findings of the in vivo study suggested that the JLSJ prescription could inhibit the growth of xenograft tumors of lung adenocarcinoma with fewer adverse effects. Also, the in vitro experiments corroborated that the JLSJ prescription could induce apoptosis of A549 cells. Furthermore, the upregulation of pro-apoptosis-related proteins and mRNAs, coupled with the downregulation of anti-apoptotic-related proteins and mRNAs, was observed. In conclusion, inducing apoptosis by inhibiting the PI3K/Akt signaling pathway was one of the underlying mechanisms by which the JLSJ prescription exerted its anti-lung adenocarcinoma effect.

Lysine metabolism is a novel metabolic tumor suppressor pathway in breast cancer.

The International Agency for Research on Cancer determined that obesity is the primary preventable cause of breast cancer. The nuclear receptor peroxisome proliferator activated receptor γ (PPARγ) binds inflammatory mediators in obesity and its expression is reduced in human breast cancer. We created a new model to better understand how the obese microenvironment alters nuclear receptor function in breast cancer. The obesity related cancer phenotype was PPARγ dependent; deletion of PPARγ in mammary epithelium which is a tumor suppressor in lean mice unexpectedly increased tumor latency, reduced the luminal progenitor (LP) tumor cell fraction, and increased autophagic and senescent cells. Loss of PPARγ expression in mammary epithelium of obese mice increased expression of 2-aminoadipate semialdehyde synthase (AASS) which regulates lysine catabolism to acetoacetate. PPARγ-associated co-repressors and activators regulated AASS expression via a canonical response element. AASS expression was significantly reduced in human breast cancer, and AASS overexpression or acetoacetate treatment inhibited proliferation and induced autophagy and senescence in human breast cancer cell lines. Genetic or pharmacologic HDAC inhibition promoted autophagy and senescence in mammary tumor cells in vitro and in vivo. We concluded that lysine metabolism is a novel metabolic tumor suppressor pathway in breast cancer.

Rotation and separation of chiral active particles in a ring-shaped channel.

Transport of chiral active particles is numerically investigated in a two-dimensional ring-shaped channel. The ring-shaped channel is transversal asymmetric and can induce the directed transport (rotation) of chiral active particles. For the particles with small chirality, they slide along the outer boundary of the channel. For the particles with large chirality, the particles move along some small local circular orbits and can also exhibit directed rotation. Moreover, the rotation effect can be strongly enhanced by modifying the inner boundary geometry. Based on the study of particle rotation, we further study the separation of active particles with different chiralities. It is found that the particles with different chiralities may be distributed in different regions of the ring-shaped channel. Interestingly, these particles can be completely separated by shifting the channel's inner boundary or adding a blocking plate in the channel. Our results may be useful for understanding relevant experimental phenomena and provide a scheme for the separation of binary mixtures.

Comprehensive analysis of a novel signature incorporating lipid metabolism and immune-related genes for assessing prognosis and immune landscape in lung adenocarcinoma.

Background: As the crosstalk between metabolism and antitumor immunity continues to be unraveled, we aim to develop a prognostic gene signature that integrates lipid metabolism and immune features for patients with lung adenocarcinoma (LUAD). Methods: First, differentially expressed genes (DEGs) related to lipid metabolism in LUAD were detected, and subgroups of LUAD patients were identified via the unsupervised clustering method. Based on lipid metabolism and immune-related DEGs, variables were determined by the univariate Cox and LASSO regression, and a prognostic signature was established. The prognostic value of the signature was evaluated by the Kaplan-Meier method, time-dependent ROC, and univariate and multivariate analyses. Five independent GEO datasets were employed for external validation. Gene set enrichment analysis (GSEA), gene set variation analysis (GSVA), and immune infiltration analysis were performed to investigate the underlying mechanisms. The sensitivity to common chemotherapeutic drugs was estimated based on the GDSC database. Finally, we selected PSMC1 involved in the signature, which has not been reported in LUAD, for further experimental validation. Results: LUAD patients with different lipid metabolism patterns exhibited significant differences in overall survival and immune infiltration levels. The prognostic signature incorporated 10 genes and stratified patients into high- and low-risk groups by median value splitting. The areas under the ROC curves were 0.69 (1-year), 0.72 (3-year), 0.74 (5-year), and 0.74 (10-year). The Kaplan-Meier survival analysis revealed a significantly poorer overall survival in the high-risk group in the TCGA cohort (p < 0.001). In addition, both univariate and multivariate Cox regression analyses indicated that the prognostic model was the individual factor affecting the overall survival of LUAD patients. Through GSEA and GSVA, we found that tumor progression and inflammatory and immune-related pathways were enriched in the high-risk group. Additionally, patients with high-risk scores showed higher sensitivity to chemotherapeutic drugs. The in vitro experiments further confirmed that PSMC1 could promote the proliferation and migration of LUAD cells. Conclusions: We developed and validated a novel signature incorporating both lipid metabolism and immune-related genes for all-stage LUAD patients. This signature can be applied not only for survival prediction but also for guiding personalized chemotherapy and immunotherapy regimens.

Sanguinarine Regulates Tumor-Associated Macrophages to Prevent Lung Cancer Angiogenesis Through the WNT/ß-Catenin Pathway.

Tumor-associated macrophage (TAM)-mediated angiogenesis in the tumor microenvironment is a prerequisite for lung cancer growth and metastasis. Therefore, targeting TAMs, which block angiogenesis, is expected to be a breakthrough in controlling the growth and metastasis of lung cancer. In this study, we found that Sanguinarine (Sang) inhibits tumor growth and tumor angiogenesis of subcutaneously transplanted tumors in Lewis lung cancer mice. Furthermore, Sanguinarine inhibited the proliferation, migration, and lumen formation of HUVECs and the expression of CD31 and VEGF by regulating the polarization of M2 macrophages in vitro. However, the inhibitory effect of Sanguinarine on angiogenesis remained in vivo despite the clearance of macrophages using small molecule drugs. Further high-throughput sequencing suggested that WNT/ß-Catenin signaling might represent the underlying mechanism of the beneficial effects of Sanguinarine. Finally, the ß-Catenin activator SKL2001 antagonized the effect of Sanguinarine, indicating that Sanguinarine can regulate M2-mediated angiogenesis through the WNT/ß-Catenin pathway. In conclusion, this study presents the first findings that Sanguinarine can function as a novel regulator of the WNT/ß-Catenin pathway to modulate the M2 macrophage polarization and inhibit angiogenesis, which has potential application value in immunotherapy and antiangiogenic therapy for lung cancer.

Integrating Network Pharmacology, Molecular Docking, and Experimental Validation to Investigate the Mechanism of (-)-Guaiol Against Lung Adenocarcinoma.

BACKGROUND Lung adenocarcinoma (LUAD) is the most common type of lung cancer, which poses a serious threat to human life and health. -(-)Guaiol, an effective ingredient of many medicinal herbs, has been shown to have a high potential for tumor interference and suppression. However, knowledge of pharmacological mechanisms is still lacking adequate identification or interpretation. MATERIAL AND METHODS The genes of LUAD patients collected from TCGA were analyzed using limma and WGCNA. In addition, targets of (-)-Guaiol treating LUAD were selected through a prediction network. Venn analysis was then used to visualize the overlapping genes, which were further condensed using the PPI network. GO and KEGG analyses were performed sequentially, and the essential targets were evaluated and validated using molecular docking. In addition, cell-based verification, including the CCK-8 assay, cell death assessment, apoptosis analysis, and western blot, was performed to determine the mechanism of action of (-)-Guaiol. RESULTS The genes included 959 differentially-expressed genes, 6075 highly-correlated genes, and 480 drug-target genes. Through multivariate analysis, 23 hub genes were identified and functional enrichment analyses revealed that the PI3K/Akt signaling pathway was the most significant. Experiment results showed that -(-)Guaiol can inhibit LUAD cell growth and induce apoptosis. Additional evidence suggested that the PI3K/Akt signaling pathway established an inseparable role in the antitumor processes of -(-)Guaiol, which is consistent with network pharmacology results. CONCLUSIONS Our results show that the effect of (-)-Guaiol in LUAD treatment involves the PI3K/Akt signaling pathway, providing a useful reference and medicinal value in the treatment of LUAD.

Solasonine Causes Redox Imbalance and Mitochondrial Oxidative Stress of Ferroptosis in Lung Adenocarcinoma.

Ferroptosis, a type of iron-dependent oxidative cell death caused by excessive lipid peroxidation, is emerging as a promising cancer therapeutic strategy. Solasonine has been reported as a potential compound in tumor suppression, which is closely linked to ferroptosis. However, ferroptosis caused by solasonine is insufficiently identified and elaborated in lung adenocarcinoma, a fatal disease with high morbidity and mortality rates. First, the biochemical and morphological changes in Calu-1 and A549 cells exposed to solasonine are observed using a cell death assay and a microscope. The cell viability assay is performed after determining the executive concentration of solasonine to assess the effects of solasonine on tumor growth in Calu-1 and A549 cells. The ferroptosis is then identified by using ferroptosis-related reagents on CCK-8, lipid peroxidation assessment, Fe2+, and ROS detection. Furthermore, the antioxidant system, which includes GSH, Cys, GPx4, SLC7A11, and mitochondrial function, is measured to identify the potential pathways. According to the results, solasonine precisely exerts antitumor ability in lung adenocarcinoma cells. Ferroptosis is involved in the solasonine-induced cell death, as well as the accumulation of lipid peroxide, Fe2+, and ROS. Moreover, the failures of antioxidant defense and mitochondrial damage are considered to make a significant contribution to the occurrence of ferroptosis caused by solasonine. The study describes the potential process of ferroptosis caused by solasonine when dealing with lung adenocarcinoma. This encouraging evidence suggests that solasonine may be useful in the treatment of lung cancer.

Role of sanguinarine in regulating immunosuppression in a Lewis lung cancer mouse model.

Myeloid-derived suppressor cells (MDSCs) play an important role in the tumor-induced immunosuppressive microenvironment and have been linked with tumor development, proliferation, and resistance to treatment. Therefore, therapies that target MDSCs, such as sanguinarine (SNG), are now being considered potential treatments for lung cancer. However, the role of SNG in regulating the immune response in lung cancer is still not clear. In view of this, we evaluated the mechanism involved in the antitumor and immunoregulatory response to SNG therapy in a Lewis lung cancer (LLC) mouse model. The tumor mass and volume in the SNG treated LLC mouse model were significantly lower when compared with the control group (p < 0.05), indicating a good response to SNG. SNG also reduced the damage to the spleen, decreased the proportion of MDSCs, and increased the production of T helper 1 (Th1), T helper 2 (Th2), cytotoxic T-lymphocyte (CTL), macrophages, dendritic cells (DC) within the spleen. However, it did not affect the proportion of T helper 17 (Th17) and regulatory T cells (Treg). SNG also down-regulated the proportion of MDSCs in vitro and promoted their apoptosis, differentiation, and maturation. SNG was found to induce the differentiation of MDSCs into macrophages and DC through the nuclear factor kappa-B (NF-κB) pathway in vitro, while it also decreased the expression of arginase-1 (Arg-1) anti-inducible nitric oxide synthase (iNOS) and reactive oxygen species (ROS) in MDSCs.SNG also reduced the inhibitory effect on the proliferation of CD8+T cells. SNG may reduce the immunosuppressive state induced by lung cancer by promoting cell differentiation and by inhibiting the immunosuppressive activity of MDSCs.

A validated nomogram integrating baseline peripheral T-lymphocyte subsets and NK cells for predicting survival in stage I-IIIA non-small cell lung cancer after resection.

Background: Accurately predicting the risk of recurrence in stage I-IIIA non-small cell lung cancer (NSCLC) after resection is critical in the treatment process. This study aimed to establish a novel nomogram to identify patients with a risk of disease progression in stage I-IIIA lung cancer based on clinical characteristics, peripheral T-lymphocyte subsets, and CD16+56 natural killer (NK) cells. Methods: A total of 306 NSCLC patients from Shanghai Municipal Hospital of Traditional Chinese Medicine between 2010 and 2020 who met the inclusion and exclusion criteria between January 2011 and December 2020 were retrospectively reviewed. Patients were randomly assigned to the training cohort (206 patients) and the validation cohort (100 patients). A nomogram model was developed based on the results of multivariate Cox regression in the training cohort. The optimal cut-off values were determined by X-tile software. The bootstrap method was used to validate the nomogram. Receiver operating characteristics curves (ROC) and the area under the ROC curve (AUC) were used to compare prognostic factors. The concordance index (C-index) was calculated to determine the accuracy of the nomogram in predicting disease-free survival (DFS). Results: Gender, drinking history, TNM stage, and CD4+T/CD8+T were independent factors for DFS and were integrated into the model, while CD16+56 NK cells were not proven to be significant independent factors for DFS. The calibration curves for probability of 3- and 5-year DFS showed excellent agreement between predicted and actual survival. The C-index for the nomogram to predict DFS was 0.839 in the training cohort. The nomogram showed an excellent predictive performance in the training cohort (3-/5-year AUC: 0.860/0.847) and in the validation cohort (3-/5-year AUC: 0.726/0.748). Conclusions: We developed a prognostic model which provided individual prediction of DFS for stage I-IIIA NSCLC patients after resection. This practical prognostic tool may help oncologists in clinical treatment planning.

A Novel Predictive Model Incorporating Ferroptosis-Related Gene Signatures for Overall Survival in Patients with Lung Adenocarcinoma.

BACKGROUND Lung adenocarcinoma (LUAD) is the predominant histological type of lung cancer with high morbidity and mortality. Ferroptosis is regarded as a new pattern of programmed cell death concerned with the progression of lung cancer characterized by lipid peroxidation. Nevertheless, the prognostic role of ferroptosis-related genes for LUAD warrant to be explored. MATERIAL AND METHODS RNA sequencing and relevant clinical patient data were obtained from public-access databanks. A prognostic model was constructed through the LASSO Cox regression in the cancer genome atlas cohort. The diagnostic value of the prognostic model was further evaluated in the gene expression omnibus cohort. RESULTS Most of the ferroptosis-related genes (69.9%) were differentially expressed between tumor and adjacent non-cancerous tissues. 43 differentially expressed genes showed a close association with the prognosis of LUAD patients (adjusted p-value <0.05). An 18-gene signature was built and applied to assign patients into high vs low-risk groups. Compared with the high-risk group, patients defined as the low-risk group suffered significantly prolonged OS. Both uni- and multivariate analyses demonstrated that the signature-based score served as a crucial role in influencing the OS of LUAD patients (hazard ratio >1, p<0.001). The immunity-related signaling pathway was enriched in the functional analysis and the infiltration of the immune cells showed a great difference between groups. CONCLUSIONS The predictive model could be applied for prognostic prediction for LUAD. Targeting ferroptosis could be a possible curative strategy against LUAD, and immunomodulation may be one of the potential mechanisms.

Sanguinarine Represses the Growth and Metastasis of Non-small Cell Lung Cancer by Facilitating Ferroptosis.

OBJECTIVE: Ethnopharmacological relevance: Sanguinarine (SAG), a natural benzophenanthridine alkaloid derived from the root of Sanguinaria canadensis Linn. (Bloodroot), possesses a potential anticancer activity. Lung carcinoma is the chief cause of malignancy-related mortality in China. Non-small cell lung carcinoma (NSCLC) is the main subtype of lung carcinoma and accounts for about eighty-five percent of this disease. Current treatment in controlling and curing NSCLC remains deficient. AIM: The role and underlying mechanism of SAG in repressing the growth and metastasis of NSCLC were explored. MATERIALS AND METHODS: The role of SAG in regulating the proliferation and invasion of NSCLC cells was evaluated in vitro and in a xenograft model. After treatment with SAG, Fe2+ concentration, reactive oxygen species (ROS) levels, malondialdehyde (MDA), and glutathione (GSH) content in NSCLC cells were assessed to evaluate the effect of SAG on facilitating ferroptosis. RESULTS: SAG exhibited a dose- and time-dependent cytotoxicity in A549 and H3122 cells. SAG treatment effectively repressed the growth and metastasis of NSCLC in a xenograft model. We, for the first time, verified that SAG triggered ferroptosis of NSCLC cells, as evidenced by increased Fe2+ concentration, ROS level, and MDA content, and decreased GSH content. Mechanistically, SAG decreased the protein stability of glutathione peroxide 4 (GPX4) through E3 ligase STUB1-mediated ubiquitination and degradation of endogenous GPX4. GPX4 overexpression restored the proliferation and invasion of NSCLC cells treated with SAG through inhibiting ferroptosis. CONCLUSION: SAG inhibits the growth and metastasis of NSCLC by regulating STUB1/GPX4-dependent ferroptosis.

Absolute negative mobility of active polymer chains in steady laminar flows.

We investigate the transport of active polymer chains in steady laminar flows in the presence of thermal noise and an external constant force. In the model, the polymer chain is worm-like and is propelled by active forces along its tangent vectors. Compared with inertial Brownian particles, active polymer chains in steady laminar flows exhibit richer movement patterns due to their specific spatial structures. The simulation results show that the velocity-force relation is strongly dependent on the system parameters such as the chain length, bending rigidity, active force and so on. The polymer chain may move in some preferential movement directions and exhibits absolute negative mobility within appropriate parameter regimes, i.e., the polymer chain can move in a direction opposite to the external constant force. In particular, we can observe giant negative mobility in a broad range of parameter regimes.

PARP5B is required for nonhomologous end joining during tumorigenesis in vivo.

Poly(ADP-ribose) polymerases (PARP) act as DNA damage sensors that produce poly(ADP-ribose) (PAR) chains at double-strand breaks, facilitating the recruitment of repair factors. Cancers with homologous recombination defects are sensitive to small molecule PARP inhibitors. Despite PARP5B gene copy number changes in many cancers, the effects of this genetic alteration on tumor phenotype are largely unknown. To better understand this clinical finding, we characterized a PARP5B null mutation in a carcinogen-induced in vivo head and neck squamous cell carcinoma (SCC) model. Reduced PARP5B expression inhibited tumor growth, induced primary tumor differentiation and apoptosis, and inhibited cell proliferation and metastasis. Loss of PARP5B expression-induced ataxia telangiectasia and Rad3 related (ATR) activation and depleted the cancer stem cell fraction. PARP5B null tumor cells lacked 53BP1+ double-strand break foci, ATM activation, and p53 induction compared to PARP5B+/+ cancers. PARP5B null SCC expresses a multiprotein complex containing PML, pRPA, Rad50, Rad51, XRCC1, proliferating cell nuclear antigen (PCNA), and Mcm2, suggesting an HR-mediated repair mechanism at DNA replication foci. Low doses of etoposide combined with the PARP5B inhibitor XAV939 induced senescence and apoptosis in human SCC lines. NBS1 overexpression in these cells inhibited the effects of low-dose etoposide/XAV939 treatment. Our results indicate that PARP5B inhibition is new targeted cancer therapy.

Downregulation of KIF15 inhibits the tumorigenesis of non-small-cell lung cancer via inactivating Raf/MEK/ERK signaling.

BACKGROUND: Lung cancer is one of the most common causes of cancer-associated mortality worldwide. Upregulation of kinesin family member 15 (KIF15) expression has been observed in non-small cell lung cancer (NSCLC), and high expression levels of KIF15 are associated with a poor prognosis in patients with NSCLC. However, to the best of our knowledge, the mechanisms by which KIF15 regulates apoptosis, migration and invasion in NSCLC remain unclear. METHODS: Cell Counting Kit-8, flow cytometry and Transwell assays were performed to determine the proliferation, apoptosis and invasion of NSCLC cells, respectively. In addition, western blotting was used to detect the levels of phosphorylated (p-)c-Raf, p-ERK and p-MEK in NSCLC cells. RESULTS: Downregulation of KIF15 expression markedly inhibited the proliferation, migration and invasion of NSCLC cells through mediation of MMP2 and MMP9. In addition, downregulation of KIF15 markedly induced apoptosis and cell cycle arrest in NSCLC cells through regulation of active caspase 3, p27 Kip1 and cyclin D1. Furthermore, KIF15 knockdown notably decreased the levels of activating transcription factor 2, p-c-Raf, p-ERK and p-MEK in A549 and NCI-H460 cells. Finally, KIF15 knockdown notably inhibited the tumor growth of NSCLC in vivo. CONCLUSION: In conclusion, the present study indicated that downregulation of KIF15 expression was able to inhibit the tumorigenesis of NSCLC by inactivating Raf/MEK/ERK signaling. These findings may help improve the diagnosis and treatment of NSCLC.

DNA Double-strand Break Signaling Is a Therapeutic Target in Head and Neck Cancer.

BACKGROUND: Head and neck cancer (HNC) is common worldwide. Given poor outcomes for patients with HNC, research into targeted therapies is needed. Ataxia telangiectasia mutated (ATM) is a DNA damage kinase which is activated by double-strand DNA breaks. We tested the effects of a novel ATM inhibitor on HNC cell lines and xenografts. MATERIALS AND METHODS: p53-Binding protein 1 and phosphorylated ATM were localized in cultured cells by immunofluorescence microscopy. Protein expression was determined by western blot. Tumor xenografts were established by injecting HNC lines into immunocompromised mice. Tumor sections were characterized by immunohistochemistry. Apoptotic cells were determined by terminal transferase-mediated dUTP nick-end labeling assay. RESULTS: ATM inhibition increased double-strand DNA breaks at replication foci in HNC cell lines. ATM inhibition affected cell-cycle regulatory protein expression, blocked cell-cycle progression at the G2/M phase and resulted in apoptosis. CONCLUSION: ATM inhibition may be therapeutically useful in treating HNC.