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In this study, we design a specific geometry of plasma particles and further translate it into mathematical form, i.e., formulated time-fractional semi relativistic Vlasov Maxwell system. This extended version of model is very significant and ground-breaking because it has ability to study the behavior of plasma particles at macroscopic and microscopic time-evaluation scales, which is not studied yet. This model is further tackled with numerical strategy, projected in accordance with spectral and finite difference approximations. The numerical results demonstrate that there are certain variations of the plasma particles that were out of sight at fractional scale and dynamically, we have entered into the real profundity of the problem. Numerical convergence of the projected technique is also inspected. These designed tools, such as the plasma and numerical methods, are very significant and can say that it is a remarkable contribution in this field. In addition, the established numerical structure can utilize to scrutinize the required numerical solution of highly non-linear and fractional problems.

With the historical review, it can determine that plasma scientists devolved many numerical schemes in literature to solve the kinetic plasma models such as Vlasov- Maxwell system, but the fatal problem is that most of the designed algorithms violate the conservation laws. This issue is significant and cannot disregard because the Vlasov Maxwell system is connected with conservations properties and can evaluate after performing some effective mathematical operations. In this prospective, we formulated the Atangana-Baleanu fractional derivative with Caputo concepts based fractional-order plasma model to study the fractional performance of the plasma particles and further suggested a higher-order conservative numerical algorithm that follows the conservation laws, based on operational matrices theory which is evaluated by using the concepts of Shifted Gegenbauer estimations. The numerical convergence of the designed algorithm is also inspected to validate the competency and compatibility. The comprehensive analysis of the fractional performance of the plasma particles is also part of the study. Moreover, this concept can extend to the variable order and multi-dimensional problems for Vlasov and Boltzmann system.

The historical analysis demonstrates that plasma scientists produced a variety of numerical methods for solving “kinetic” models, i.e., the Vlasov-Maxwell (VM) system. Still, on the other hand, a significant fact or drawback of most algorithms is that they do not preserve conservation philosophies. This is a crucial fact that cannot be disregarded since the Vlasov Maxwell system is associated with conservation rules and is capable of assessing after the accomplishment of certain helpful mathematical actions. To examine the fractional-order routine of charged particles, we constructed a fractional-order plasma model and proposed a higher-order conservative numerical approach based on operational matrices theory and Shifted Gegenbauer estimations. Numerical convergence is investigated to confirm its competence and compatibility. This concept may be used in problems involving variable order and multidimensionality, such as those involving Vlasov and Boltzmann systems.

The “Vlasov-Maxwell system” is a groundbreaking differential procedure to visualize, model, simulate and further analyze the vigorous performance of plasma (collisionless) in the presence of the different fields (electromagnetic). In this frame of reference, the analysis of “Vlasov-Maxwell system” with the deep conceptions of (time-fractional) calculus is a novel benchmark and also the key intentions of this study. For this purpose, (1D + 1P) dimensional semi-relativistic time-fractional Vlasov-Maxwell system is formulated with the physical significances of the geometry. Furthermore, to fabricate the numerical consequences, we suggest (and also implement) an innovative algorithm which based on spectral and finite-difference estimations. The spatial and temporal variables are handled by using sifted Gegenbauer polynomials and finite-difference calculations respectively. Numerous simulations are executed to validate the reliability and accuracy of anticipated method. Error bound convergence and stability of the method is inspected numerically. Moreover, the established technique can be used conveniently to observe the numerical result of other multi-dimensional fraction (variable) order problems of physical nature.

Abstract Triple-negative breast cancer (TNBC) is the most malignant molecular subtype of breast cancer and is characterized by aggressiveness, high mortality, significant heterogeneity, and poor prognosis. AMPK plays a critical role in maintaining the cellular energy balance, and its inactivation is associated with malignant breast cancer. Here, we identified the pharmacological mechanism of the 1,4-naphthoquinone derivative ZSW-4B. MTT, colony formation, and nude mouse xenograft tumour models demonstrated that ZSW-4B selectively inhibits the proliferation of TNBC cells both in vitro and in vivo. Flow cytometry and Western blot analysis revealed that ZSW-4B induces apoptosis in TNBC cells. Phosphoproteomic analysis revealed activation of the AMPK signalling pathway by ZSW-4B. Additionally, the application of the CRISPR-Cas9 system to genetically knockout AMPK in TNBC cell lines was demonstrated to reverse the antitumour effects elicited by ZSW-4B both in vitro and in vivo. In summary, ZSW-4B inhibits TNBC by inducing cellular apoptosis through the activation of AMPK.

Abstract Argininosuccinate synthase (ASS1), a critical enzyme in the urea cycle, acts as a tumor suppressor in many cancers. To date, the anticancer mechanism of ASS1 has not been fully elucidated. Here, we found that phosphoglycerate dehydrogenase (PHGDH), a key rate-limiting enzyme in serine synthesis, is a pivotal protein that interacts with ASS1. Our results showed that ASS1 directly binds to PHGDH and promotes its ubiquitination-mediated degradation to inhibit serine synthesis, consequently suppressing tumorigenesis. Importantly, the tumor suppressive effects of ASS1 were strongly abrogated by PHGDH knockout. In addition, ASS1 knockout and knockdown partially rescued cell proliferation when serine and glycine were depleted, while the inhibitory effect of ASS1 overexpression on cell proliferation was restored by the addition of serine and glycine. These findings unveil a novel role of ASS1 and suggest that the ASS1/PHGDH serine synthesis pathway is a promising target for cancer therapy.

Abstract Background Head and neck squamous cell carcinoma (HNSCC) remains an unmet medical challenge. Metabolic reprogramming is a hallmark of diverse cancers, including HNSCC. Methods We investigated the metabolic profile in HNSCC by using The Cancer Genome Atlas (TCGA) (n = 481) and Gene Expression Omnibus (GEO) (n = 97) databases. The metabolic stratification of HNSCC samples was identified by using unsupervised k-means clustering. We analyzed the correlations of the metabolic subtypes in HNSCC with featured genomic alterations and known HNSCC subtypes. We further validated the metabolism-related subtypes based on features of ENO1, PFKFB3, NSDHL and SQLE expression in HNSCC by Immunohistochemistry. In addition, genomic characteristics of tumor metabolism that varied among different cancer types were confirmed. Results Based on the median expression of coexpressed cholesterogenic and glycolytic genes, HNSCC subtypes were identified, including glycolytic, cholesterogenic, quiescent and mixed subtypes. The quiescent subtype was associated with the longest survival and was distributed in stage I and G1 HNSCC. Mutation analysis of HNSCC genes indicated that TP53 has the highest mutation frequency. The CDKN2A mutation frequency has the most significant differences amongst these four subtypes. There is good overlap between our metabolic subtypes and the HNSCC subtype. Conclusion The four metabolic subtypes were successfully determined in HNSCC. Compared to the quiescent subtype, glycolytic, cholesterogenic and mixed subtypes had significantly worse outcome, which might offer guidelines for developing a novel treatment strategy for HNSCC.

Arginine addiction induced by argininosuccinate synthase (ASSN1) deficiency has been exploited to treat ASS1-deficient cancers. Here, the authors show an alternative therapeutic approach where ASS1 activity is increased by the pesticide spinosyn A and is shown to inhibit breast cancer cell proliferation.

Background: Head and neck squamous cell carcinoma’s tumor immune microenvironment (TIME) plays an important role in tumorigenesis and progression, but its clinical significance remains unclear. Therefore, the TIME needs to be better understood in order to improve the response of diagnosis and therapy.Methods: The gene expression and clinical data of 569 HNSCC patients were obtained from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO). Immune-related genes (IRGs) from the ImmPort database were used for immunotyping of HNSCC patients, and independent GEO datasets were used for subtype verification and comprehensive molecular identification.Results: The patients were divided into three subtypes (C1, C2, and C3) related to different gene expression profiles. The three subtypes showed widely different patterns in tumor genetic distortion, immune cell composition, cytokine profile, and so on, verifying that the immune-enhanced C2 subtype was associated with better prognosis. In addition, the stroma-deficient C1 subtype may be more efficient for the immune response than the C3 subtype. Furthermore, using WGCNA on the IRGs of those three subtypes, we found two C2-positive gene modules closely related to infection- and immune-associated pathways in the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database, and the two modules had 22 common pathways.Conclusion: This study improves the power for prognosis prediction and develops new therapeutic strategies to stratify HNSCC patients into clinically significant groups through TIME-related prognostic signature.

Abstract Background Breast cancer (BC) is a common malignant tumor with poor prognosis. Angiogenesis is related to the growth and progression of solid tumors and associated with prognosis. ZLM-7, SP1, VEGFA and miR-212-3p were associated with BC angiogenesis and proliferation, however the detailed mechanism was not clear. This study aimed to reveal the regulatory mechanism of angiogenesis of BC. Methods BC cell lines were treated with 10 nM ZLM-7 for 8 h. We detected protein expression level by western blot and RNA expression level by qRT-PCR. Overexpression or inhibition of miR-212-3p is performed using miR-212-3p mimics or miR-212-3p inhibitor, Sp1 overexpression using pcDNA3.1 vector. Angiogenesis was analyzed by co-culturing BC cell lines and HUVEC cells. To evaluate regulatory relationship between miR-212-3p and Sp1, dual luciferase assay was performed. Besides, the direct interaction between Sp1 and VEGFA was analyzed by ChIP. Migration and invasion were analyzed by transwell assay and proliferation was detected by clone formation assay. In mice xenograft model developed using BC cells, we also detected angiogenesis marker CD31 through immunohistochemistry. Results ZLM-7 up-regulated miR-212-3p and inhibited invasion, migration, proliferation and angiogenesis of BC, while miR-212-3p inhibitor antagonized such effects. Binding sequence was revealed between miR-212-3p and Sp1, and expression of Sp1 was inhibited by miR-212-3p on both protein and mRNA level. Sp1 could interact with VEGFA and promoted its expression. Overexpression of miR-212-3p inhibited migration, invasion, proliferation and angiogenesis of BC cell lines, while Sp1 overexpression showed the opposite effect and could antagonize these effects of miR-212-3p overexpression. ZLM-7 decreased VEGFA expression, which was rescued by co-transfection with miR-212-3p inhibitor. Similar, ZLM-7 could inhibit tumor growth and angiogenesis through the miR-212-3p/Sp1/VEGFA axis in vivo. Conclusions ZLM-7 could directly up-regulate miR-212-3p in BC. MiR-212-3p could inhibit VEGFA expression through Sp1, thereby inhibiting angiogenesis and progression of BC.

Breast cancer is one of the most prevalent malignancies with poor prognosis. Inhibition of angiogenesis is becoming a valid and evident therapeutic strategy to treat cancer. Recent studies uncovered the antiangiogenic activity of ZLM-7 (a combretastain A-4 derivative), but the regulatory mechanism is unclear. ZLM-7 treatment was applied in estrogen receptor-positive cell MCF-7, triple-negative breast cancer cell MDA-MB-231 and xenograft models. Transfections were conducted to overexpress or knockdown targeted genes. The gene and protein expressions were measured by qPCR and Western blotting assay, respectively. Cell proliferation and apoptosis were evaluated using the CCK8 method, clone formation assay and flow cytometry. We found that ZLM-7 upregulated 14-3-3 sigma expression but downregulated MDM2 expression in breast cancer cells. ZLM-7 delayed cell proliferation, promoted apoptosis and blocked cell-cycle progression in human breast cancer cells in vitro, while those effects were abolished by 14-3-3 sigma knockdown; overexpression of 14-3-3 sigma reproduced the actions of ZLM-7 on the cell cycle, which could be reversed by MDM2 overexpression. In xenograft models, ZLM-7 treatment significantly inhibited tumor growth while the inhibition was attenuated when 14-3-3 sigma was silenced. Collectively, ZLM-7 could inhibit MDM2 via upregulating 14-3-3 sigma expression, thereby blocking the breast cancer progression.