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Volume parameters such as the volume of voids (VV), voids filled with asphalt (VFA), and voids in mineral aggregates (VMA) all have significant impact on asphalt mixtures. In this study, the vertical vibration compaction method (VVCM) was employed to produce a large-particle-size asphalt mixture (LSAM-50). The correlations between the mechanical strengths of VVCM specimens, static compression test (PCT) specimens, and in situ core samples were verified. Additionally, the influence of volumetric parameters on the mechanical properties of VVCM specimens was assessed. Based on the principle of optimal mechanical properties, volume parameter design standards for the LSAM-50 asphalt mixture were proposed. Results indicated that the mechanical properties correlation between VVCM specimens and in situ core samples was substantial, reaching over 90%. With increasing VV and VFA, the compressive strength, splitting strength, and dynamic stability of the LSAM-50 asphalt mixture initially increased and then decreased. The design standards for VV were proposed to be between 3.5% and 4.8%, and for VFA between 49.7% and 52.9%. There was no clear correlation between VMA and the mechanical properties of the mixture; hence, based on the standards, the minimum design value for VMA was set at 7.5%. [ABSTRACT FROM AUTHOR]

Polyamide 66 was extensively utilized in various applications contributed by its excellent mechanical performance and outstanding durability. However, its high crystallinity renders it to have low transparency, which seriously limits its application in optical devices. Herein, a highly transparent polyamide (PA) 66-based copolymer was reported using 4,4′-diaminodicyclohexylmethane (PACM), adipic acid, and polyamide 66 salt as the reaction monomers. Wide-angle X-ray diffraction (WAXD) analysis revealed that the crystal phase of the synthesized PA66/PACM6 displayed a clear transition from α to γ as the PACM6 increased accompanied by a decreased intensity in the diffraction peak of the copolymer, whose transmittance was successfully adjusted reaching as high as 92.5% (at 550 nm) when the PACM6 was 40 wt%. Moreover, the copolymer with a higher content of PACM6 exhibited larger toughness. On the other hand, the biaxially oriented films of PA66/PACM6 (20 wt%) were also prepared, and it was found that the transparency of the PA66/PACM6 copolymer could be further enhanced via adjusting the stretching ratio of the film. Furthermore, the mechanical strength of the biaxially oriented PA66/PACM6 was also improved with the increase in the orientation degree in the stretching process, indicating that the physical properties of the transparent PA66 were significantly influenced by its alicyclic structure, and the introduction of PACM into PA66 was capable of effectively improving the optical and crystalline characteristics of PA66, revealing that the synthetic strategy has great potential for guiding the design and development of transparent polyamide materials. [ABSTRACT FROM AUTHOR]

Peripheral blood lymphocytes (PBLs), which play a pivotal role in orchestrating the immune system, garner minimal attention in hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). The impact of primary liver cancers on PBLs remains unexplored. In this study, flow cytometry facilitated the quantification of cell populations, while transcriptome of PBLs was executed utilizing 10× single-cell sequencing technology. Additionally, pertinent cases were curated from the GEO database. Subsequent bioinformatics and statistical analyses were conducted utilizing R (4.2.1) software. Elevated counts of NK cells and CD8+ T cells were observed in both ICC and HCC when compared to benign liver disease (BLD). In the multivariate Cox model, NK cells and CD8+ T cells emerged as independent risk factors for recurrence-free survival. Single-cell sequencing of PBLs uncovered the downregulation of TGFβ signaling in tumor-derived CD8+ T cells. Pathway enrichment analysis, based on differential expression profiling, highlighted aberrations in selenium metabolism. Proteomic analysis of preoperative and postoperative peripheral blood samples from patients undergoing tumor resection revealed a significant upregulation of SELENBP1 and a significant downregulation of SEPP1. Primary liver cancer has a definite impact on PBLs, manifested by alterations in cellular quantities and selenoprotein metabolism. [ABSTRACT FROM AUTHOR]

Simple Summary: Beta-transducin repeat-containing proteins (β-TrCPs) are a component of the E3 ubiquitin ligase complex and function in many cellular processes to maintain protein homeostasis. Mounting evidence suggests that β-TrCPs are aberrantly upregulated in cancer tissues and are potential targets for cancer treatment. Although extensive studies have been performed to understand the mode of regulation of their substrates and its biological consequences, little attention has been paid to the mechanisms of the regulation of β-TrCPs themselves. The current review is focused on the modulation of β-TrCPs' activities and the implications for cancer treatment. Beta-transducin repeat-containing proteins (β-TrCPs) are E3-ubiquitin-ligase-recognizing substrates and regulate proteasomal degradation. The degradation of β-TrCPs' substrates is tightly controlled by various external and internal signaling and confers diverse cellular processes, including cell cycle progression, apoptosis, and DNA damage response. In addition, β-TrCPs function to regulate transcriptional activity and stabilize a set of substrates by distinct mechanisms. Despite the association of β-TrCPs with tumorigenesis and tumor progression, studies on the mechanisms of the regulation of β-TrCPs' activity have been limited. In this review, we studied publications on the regulation of β-TrCPs themselves and analyzed the knowledge gaps to understand and modulate β-TrCPs' activity in the future. [ABSTRACT FROM AUTHOR]

In order to adjust the properties of polyamide 6 (PA6) and expand its application, a new strategy of introducing an aromatic imide structure into the PA6 chain through the random copolymerization method is reported. The diimide diacid monomer was first synthesized by the dehydration and cyclization of pyromellitic dianhydride and 6-aminocaproic acid before it reacted with 1,6-hexamethylene diamine to form poly(amide imide) (PAI) salt, and finally synthesized PA6/PAI random copolymers containing an aromatic imide structure by the random copolymerization of ε-caprolactam and PAI salt. The introduction of an aromatic imide structural unit into the PA6 chain could have a great influence on its properties. As the content of PAI increases, the crystallinity (Xc) and melting temperature (Tm) of the PA6/PAI random copolymer gradually decrease, but its glass transition temperature (Tg) increases obviously. When the PAI content is 20 wt%, the copolymer PA6/PAI-20 has the best comprehensive performance and not only has high thermal stabilities but also excellent mechanical properties (high strength, high modulus, and good toughness) and dielectric properties (low dielectric constant and dielectric loss). Moreover, these properties are significantly superior to those of PA6. Such high-performance PA6 random copolymers can provide great promise for the wider applications of PA6 materials. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatocellular carcinoma has a clear male predominance, but gender-specific differences remain incompletely understood. Our findings look specifically at the Louisiana population, which has some of the highest rates of hepatitis, alcoholic liver disease, and metabolic syndrome—thus providing important data to better evaluate HCC trends. Our findings help illustrate specific gender differences in this disease, which remains one of the leading causes of cancer-related deaths worldwide. Hepatocellular carcinoma (HCC) is a male-dominated disease. Currently, gender differences remain incompletely defined. Data from the state tumor registry were used to investigate differences in demographics, comorbidities, treatment patterns, and cancer-specific survival (HSS) among HCC patients according to gender. Additional analyses were performed to evaluate racial differences among women with HCC. 2627 patients with HCC were included; 498 (19%) were women. Women were mostly white (58%) or African American (39%)—only 3.8% were of another or unknown race. Women were older (65.1 vs. 61.3 years), more obese (33.7% vs. 24.2%), and diagnosed at an earlier stage (31.7% vs. 28.4%) than men. Women had a lower incidence of liver associated comorbidities (36.1% vs. 43%), and more often underwent liver-directed surgery (LDS; 27.5% vs. 22%). When controlling for LDS, no survival differences were observed between genders. African American women had similar HSS rates compared to white women (HR 1.14 (0.91,1.41), p = 0.239) despite having different residential and treatment geographical distributions. African American race and age >65 were predictive for worse HSS in men, but not in women. Overall, women with HCC undergo more treatment options—likely because of the earlier stage of the cancer and/or less severe underlying liver disease. However, when controlling for similar stages and treatments, HCC treatment outcomes were similar between men and women. African American race did not appear to influence outcomes among women with HCC as it did in men. [ABSTRACT FROM AUTHOR]

As a result of their cell structures, elastomeric foams exhibit high compressibility and are frequently used as buffer cushions in energy absorption. Foam pads between two surfaces typically withstand uniaxial loads. In this paper, we considered the effects of porosity and cell size on the mechanical behavior of random elastomeric foams, and proposed a constitutive model based on an artificial neural network (ANN). Uniform cell size distribution was used to represent monodisperse foam. The constitutive relationship between Cauchy stress and the four input variables of axial stretch λU, lateral stretch λL, porosity φ, and cell size θ was given by con-ANN. The mechanical responses of 500 different foam structures (20% < φ < 60%, 0.1 mm < θ < 0.5 mm) under compression and tension loads (0.4 < λU < 3) were simulated, and a dataset containing 100,000 samples was constructed. We also introduced a pre-ANN to predict lateral stretch to address the issue of missing lateral strain data in practical applications. By combining physical experience, we chose appropriate input forms and activation functions to improve ANN's extrapolation capability. The results showed that pre-ANN and con-ANN could provide reasonable predictions for λU outside the dataset. We can obtain accurate lateral stretch and axial stress predictions from two ANNs. The porosity affects the stress and λL, while the cell size only affects the stress during foam compression. [ABSTRACT FROM AUTHOR]

Anticancer drug resistance is a significant impediment in current cancer treatment. Extracellular vesicles (EVs) derived from cancer cells were recently acknowledged as a critical mechanism of drug resistance, tumor progression, and metastasis. EVs are enveloped vesicles comprising a lipid bilayer that transfers various cargo, including proteins, nucleic acids, lipids, and metabolites, from an originating cell to a recipient cell. Investigating the mechanisms whereby EVs confer drug resistance is still in the early stages. In this review, I analyze the roles of EVs derived from triple-negative breast cancer cells (TNBC-EVs) in anticancer drug resistance and discuss strategies to overcome TNBC-EV-mediated drug resistance. [ABSTRACT FROM AUTHOR]

Although the pathogenesis of atopic dermatitis (AD) remains to be fully deciphered, skin barrier abnormality and immune dysregulation are known to be involved. Recently, the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) system has also been implicated in the pathogenesis of this multifactorial chronic inflammatory skin disorder. Previously, we showed that a novel tetrapeptide, N-acetyl-Arg-Leu-Tyr-Glu (Ac-RLYE), inhibits angiogenesis and vascular permeability effectively by selectively antagonizing VEGFR-2. The current study aimed to investigate the pharmacological effect of Ac-RLYE on AD in vitro and in vivo. The in vitro experiments demonstrated that Ac-RLYE inhibited VEGF-induced vascular permeability in endothelial cells. Moreover, in an in vivo animal model of AD, Ac-RLYE relieved AD-like symptoms such as ear thickness and dermatitis severity scores and infiltration of immune cells, including mast cells and eosinophils. Ac-RLYE inhibited IgE secretion, restored the skin barrier protein filaggrin level, and markedly downregulated gene expression of AD-related Th1, Th2, and Th17 cytokines. Collectively, these findings suggest that Ac-RLYE would be useful for the treatment of AD and associated inflammatory skin disorders. [ABSTRACT FROM AUTHOR]

Simple Summary: Triple-negative breast cancer (TNBC) is an aggressive and intractable malignancy. Although a high-level expression of epidermal growth factor receptor (EGFR) is a distinct feature of TNBC, targeting EGFR has not been successful yet. Here, we described a combination of the EGFR inhibitor gefitinib and IκB kinase (IKK) inhibitor IKK16 (Gefitinib+IKK16) as a potential therapeutic approach to treat TNBC. The combination of these drugs resulted in reduced cell viability and survival in TNBC cells in vitro. Mechanistically, several components of PI3K/AKT/mTOR pathway were further downregulated by drug combination compared with single-agent treatments. Gene expression analysis revealed that several NF-κB/RELA targets were suppressed, and a couple of tumor suppressor genes were induced by the drug combination. Taken together, targeting IKK may potentiate EGFR inhibition in TNBC. Triple-negative breast cancer (TNBC) remains as an intractable malignancy with limited therapeutic targets. High expression of epidermal growth factor receptor (EGFR) has been associated with a poor prognosis of TNBC; however, EGFR targeting has failed with unfavorable clinical outcomes. Here, we performed a combinatorial screening of fifty-five protein kinase inhibitors with the EGFR inhibitor gefitinib in the TNBC cell line MDA-MB-231 and identified the IκB kinase (IKK) inhibitor IKK16 as a sensitizer of gefitinib. Cell viability and clonogenic survival assays were performed to evaluate the antiproliferative effects of the gefitinib and IKK16 (Gefitinib + IKK16) combination in TNBC cell lines. Western blot analyses were also performed to reveal the potential mode of action of this combination. In addition, next-generation sequencing (NGS) analysis was performed in Gefitinib+IKK16-treated cells. The Gefitinib+IKK16 treatment synergistically reduced cell viability and colony formation of TNBC cell lines such as HS578T, MDA-MB-231, and MDA-MB-468. This combination downregulated p-STAT3, p-AKT, p-mTOR, p-GSK3β, and p-RPS6. In addition, p-NF-κB and the total NF-κB were also regulated by this combination. Furthermore, NGS analysis revealed that NF-κB/RELA targets including CCL2, CXCL8, EDN1, IL-1β, IL-6, and SERPINE1 were further reduced and several potential tumor suppressors, such as FABP3, FADS2, FDFT1, SEMA6A, and PCK2, were synergistically induced by the Gefitinib-+IKK16 treatment. Taken together, we identified the IKK/NF-κB pathway as a potential target in combination of EGFR inhibition for treating TNBC. [ABSTRACT FROM AUTHOR]

Phaeocystis globosa is a marine-bloom-forming haptophyte with a polymorphic life cycle alternating between free-living cells and a colonial morphotype, that produces high biomass and impacts ecological structure and function. The mechanisms of P. globosa bloom formation have been extensively studied, and various environmental factors are believed to trigger these events. However, little is known about the intrinsic biological processes that drive the bloom process, and the mechanisms underlying P. globosa bloom formation remain enigmatic. Here, we investigated a P. globosa bloom occurring along the Chinese coast and compared the proteomes of in situ P. globosa colonies from bloom and dissipation phases using a tandem mass tag (TMT)-based quantitative proteomic approach. Among the 5540 proteins identified, 191 and 109 proteins displayed higher abundances in the bloom and dissipation phases, respectively. The levels of proteins involved in photosynthesis, pigment metabolism, nitrogen metabolism, and matrix substrate biosynthesis were distinctly different between these two phases. Ambient nitrate is a key trigger of P. globosa bloom formation, while the enhanced light harvest and multiple inorganic carbon-concentrating mechanisms support the prosperousness of colonies in the bloom phase. Additionally, colonies in the bloom phase have greater carbon fixation potential, with more carbon and energy being fixed and flowing toward the colonial matrix biosynthesis. Our study revealed the key biological processes underlying P. globosa blooms and provides new insights into the mechanisms behind bloom formation. [ABSTRACT FROM AUTHOR]

In light of ignoring the effect of backlash on mesh stiffness in existing gear dynamic theory, a precise profile equation was established based on the generating processing principle. An improved potential energy method was proposed to calculate the mesh stiffness. The calculation result showed that when compared with the case of ignoring backlash, the mesh stiffness with backlash had an obvious decrease in a mesh cycle and the rate of decline had a trend of decreasing first and then increasing, so a stiffness coefficient was introduced to observe the effect of backlash. The Fourier series expansion was employed to fit the mesh stiffness rather than time-varying mesh stiffness, and the stiffness coefficient was fitted with the same method. The time-varying mesh stiffness was presented in terms of the piecewise function. The single degree of freedom model was employed, and the fourth order Runge–Kutta method was utilized to investigate the effect of backlash on the nonlinear dynamic characteristics with reference to the time history chart, phase diagram, Poincare map, and Fast Fourier Transformation (FFT) spectrogram. The numerical results revealed that the gear system primarily performs a non-harmonic-single-periodic motion. The partially enlarged views indicate that the system also exhibits small-amplitude and low-frequency motion. For different cases of backlash, the low-frequency motion sometimes shows excellent periodicity and stability and sometimes shows chaos. It is of practical guiding significance to know the mechanisms of some unusual noises as well as the design and manufacture of gear backlash. [ABSTRACT FROM AUTHOR]

(C-E) MIA PaCa-2 cells stably expressing shGFP, shp63-1 or shp63-2 were subjected to Western blot analyses (C) or transwell assay for cell motility (D,E). TGF- 1 Facilitates TAp63 Protein Lysosomal Degradation to Promote Pancreatic Cancer Cell Migration. (F-H) MIA PaCa-2 cells stably expressing a vector control (Vec) or TAp63 were subjected to Western blot analyses (F) or transwell assay for cell motility (G,H). [Extracted from the article]

This work was inspired by previous experiments which managed to establish an optimal template-dealloying route to prepare ultralow density metal foams. In this study, we propose a new analytical--numerical model of hollow-structured metal foams with structural hierarchy to predict its stiffness and strength. The two-level model comprises a main backbone and a secondary nanoporous structure. The main backbone is composed of hollow sphere-packing architecture, while the secondary one is constructed of a bicontinuous nanoporous network proposed to describe the nanoscale interactions in the shell. Firstly, two nanoporous models with different geometries are generated by Voronoi tessellation, then the scaling laws of the mechanical properties are determined as a function of relative density by finite volume simulation. Furthermore, the scaling laws are applied to identify the uniaxial compression behavior of metal foams. It is shown that the thickness and relative density highly influence the Young's modulus and yield strength, and vacancy defect determines the foams being self-supported. The present study provides not only new insights into the mechanical behaviors of both nanoporous metals and metal foams, but also a practical guide for their fabrication and application. [ABSTRACT FROM AUTHOR]

Silica aerogels are highly porous 3D nanostructures and have exhibited excellent physio-chemical properties. Although silica aerogels have broad potential in many fields, the poor mechanical properties greatly limit further applications. In this study, we have applied the finite volume method (FVM) method to calculate the mechanical properties of silica aerogels with different geometric properties such as particle size, pore size, ligament diameter, etc. The FVM simulation results show that a power law correlation existing between relative density and mechanical properties (elastic modulus and yield stress) of silica aerogels, which are consistent with experimental and literature studies. In addition, depending on the relative densities, different strategies are proposed in order to synthesize silica aerogels with better mechanical performance by adjusting the distribution of pore size and ligament diameter of aerogels. Finally, the results suggest that it is possible to synthesize silica aerogels with ultra-low density as well as high strength and stiffness as long as the textural features are well controlled. It is believed that the FVM simulation methodology could be a valuable tool to study mechanical performance of silica aerogel based materials in the future. [ABSTRACT FROM AUTHOR]

Ribosomal protein S6 (RPS6) is a component of the 40S small ribosomal subunit and participates in the control of mRNA translation. Additionally, phospho (p)-RPS6 has been recognized as a surrogate marker for the activated PI3K/AKT/mTORC1 pathway, which occurs in many cancer types. However, downstream mechanisms regulated by RPS6 or p-RPS remains elusive, and the therapeutic implication of RPS6 is underappreciated despite an approximately half a century history of research on this protein. In addition, substantial evidence from RPS6 knockdown experiments suggests the potential role of RPS6 in maintaining cancer cell proliferation. This motivates us to investigate the current knowledge of RPS6 functions in cancer. In this review article, we reviewed the current information about the transcriptional regulation, upstream regulators, and extra-ribosomal roles of RPS6, with a focus on its involvement in cancer. We also discussed the therapeutic potential of RPS6 in cancer. [ABSTRACT FROM AUTHOR]

Acyclovir (ACV) is an effective and selective antiviral drug, and the study of its toxicology and the use of appropriate detection techniques to control its toxicity at safe levels are extremely important for medicine efforts and human health. This review discusses the mechanism driving ACV's ability to inhibit viral coding, starting from its development and pharmacology. A comprehensive summary of the existing preparation methods and synthetic materials, such as 5-aminoimidazole-4-carboxamide, guanine and its derivatives, and other purine derivatives, is presented to elucidate the preparation of ACV in detail. In addition, it presents valuable analytical procedures for the toxicological studies of ACV, which are essential for human use and dosing. Analytical methods, including spectrophotometry, high performance liquid chromatography (HPLC), liquid chromatography/tandem mass spectrometry (LC-MS/MS), electrochemical sensors, molecularly imprinted polymers (MIPs), and flow injection–chemiluminescence (FI-CL) are also highlighted. A brief description of the characteristics of each of these methods is also presented. Finally, insight is provided for the development of ACV to drive further innovation of ACV in pharmaceutical applications. This review provides a comprehensive summary of the past life and future challenges of ACV. [ABSTRACT FROM AUTHOR]

Simple Summary: Numerous studies demonstrate that the activation of transforming growth factor-β (TGF-β) signaling is a critical driving force for promoting cancer cell migration and tumor metastasis. Our recent study indicates that TGF-β1 promotes FBXO3-mediated ΔNp63α protein degradation to facilitate cancer metastasis. In this study, we show that TGF-β1 can inhibit TAp63α protein stability in a lysosome-dependent, but canonical Smad pathway-independent manner, which leads to upregulation of p53-R248W expression, and consequently results in increased pancreatic cancer cell migration. TGF-β signaling plays a pivotal role in promoting tumor cell migration and cancer metastasis. ΔNp63α and TAp63α are two major isoforms of p53-related p63 protein. Our recent study has shown that TGF-β1 promotes ΔNp63α protein degradation to facilitate cancer metastasis. However, whether TAp63α is involved in TGF-β1-induced cancer metastasis remains unclear. In this study, we show that, in human pancreatic cancer MIA PaCa-2 cells harboring p53-R248W allele, TGF-β1 can significantly inhibit TAp63α protein stability in a Smad pathway-independent manner. Lysosome inhibitor, chloroquine, but not proteasome inhibitor MG132, can rescue TGF-β1-induced downregulation of TAp63α protein. In addition, we show that either TGF-β1 treatment or silencing of TAp63α can dramatically increase migration of MIA PaCa-2 cells. Importantly, the restored expression of TAp63α can effectively block TGF-β1-induced migration of MIA PaCa-2 cells. Mechanistically, we show that TGF-β1 promotes TAp63α protein degradation, leading to upregulation of p53-R248W protein expression, and consequently resulting in elevated MIA PaCa-2 cell migration. Together, this study indicates that lysosomal degradation is an important way for regulating TAp63α protein fate and highlights that TGF-β1-TAp63α-mutant p53 axis is critically important in pancreatic cancer metastasis. [ABSTRACT FROM AUTHOR]

Herein, the effects of the contents of emulsified asphalt, waterborne epoxy resin emulsion, and curing agent on the permeability, bond shear strength, water stability, and aging resistance of epoxy-emulsified asphalt were studied. A formulation of epoxy-emulsified asphalt as a fog-sealing adhesive material was recommended, and a comparison between the fabricated adhesive material and a traditional Chinese fog-sealing adhesive material was conducted to verify the technical performance of the new material. In addition, the strength formation mechanism of the epoxy-emulsified asphalt was revealed via microcosmic analysis. Results show that the curing agent content mainly affects the permeability of epoxy-emulsified asphalt, and the emulsified asphalt content significantly affects the bond shear strength, water stability, and aging resistance. Moreover, the ratio of waterborne epoxy resin emulsion to the curing agent (epoxy ratio) has a certain effect on the bond shear strength. In the recommended formulation (a high-permeability and high-bonding fog-sealing adhesive material, which can be referred to simply as HPBFA), emulsified asphalt accounts for 80% of the total mass of the mixture, and the epoxy ratio is 2:1–3:1. It can improve air permeability, bond shear strength, water stability and aging resistance. The HPBFA-cured material exhibits a continuous three-dimensional network structure, hydrophobic surface, and large contact angle. Furthermore, the initial thermal weight loss temperature of the HPBFA-cured material is significantly higher than the environmental aging temperature. Additionally, the maximum temperature decomposition range is 0–160 °C, indicating improved strength, wear resistance, permeability, and aging resistance of the material. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is a subset of breast cancer with aggressive characteristics and few therapeutic options. The lack of an appropriate therapeutic target is a challenging issue in treating TNBC. Although a high level expression of epidermal growth factor receptor (EGFR) has been associated with a poor prognosis among patients with TNBC, targeted anti-EGFR therapies have demonstrated limited efficacy for TNBC treatment in both clinical and preclinical settings. However, with the advantage of a number of clinically approved EGFR inhibitors (EGFRis), combination strategies have been explored as a promising approach to overcome the intrinsic resistance of TNBC to EGFRis. In this review, we analyzed the literature on the combination of EGFRis with other molecularly targeted therapeutics or conventional chemotherapeutics to understand the current knowledge and to provide potential therapeutic options for TNBC treatment. [ABSTRACT FROM AUTHOR]

It has been shown previously that a novel tetrapeptide, Arg-Leu-Tyr-Glu (RLYE), derived from human plasminogen inhibits vascular endothelial growth factor (VEGF)-induced angiogenesis, suppresses choroidal neovascularization in mice by an inhibition of VEGF receptor-2 (VEGFR-2) specific signaling pathway. In this study, we report that a modified tetrapeptide (Ac-RLYE) showed improved anti-choroidal neovascularization (CNV) efficacy in a number of animal models of neovascular age-related macular degeneration (AMD) which include rat, rabbit, and minipig. The preventive and therapeutic in vivo efficacy of Ac-RLYE via following intravitreal administration was determined to be either similar or superior to that of ranibizumab and aflibercept. Assessment of the intraocular pharmacokinetic and toxicokinetic properties of Ac-RLYE in rabbits demonstrated that it rapidly reached the retina with minimal systemic exposure after a single intravitreal dose, and it did not accumulate in plasma during repetitive dosing (bi-weekly for 14 weeks). Our results suggested that Ac-RLYE has a great potential for an alternative therapeutics for neovascular (wet) AMD. Since the amino acids in human VEGFR-2 targeted by Ac-RLYE are conserved among the animals employed in this study, the therapeutic efficacies of Ac-RLYE evaluated in those animals are predicted to be observed in human patients suffering from retinal degenerative diseases. [ABSTRACT FROM AUTHOR]

Simple Summary: Triple-negative breast cancer (TNBC) is an intractable subset of breast cancer without an efficient therapeutic strategy due to the lack of tractable targets, such as the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Activation and/or amplification of epidermal growth factor receptor (EGFR), phosphoinositide 3-kinase (PI3K)/v-akt murine thymoma viral oncogene homolog (AKT), and MAPK/ERK kinase (MEK)/ extracellular signal-regulated kinase (ERK) pathways is known in TNBC; however, interventions for these targets have not been successful to date. To explore a combinatorial strategy with existing clinical/preclinical protein kinase inhibitors (PKIs) in TNBC cells, we performed a series of cytotoxicity (cell viability) screenings with various PKIs in the presence figure of an EGFR inhibitor, gefitinib. The dual inhibition of AKT and MEK with gefitinib reduced the proliferation and colony formation of TNBC cells by inducing apoptosis. Our finding suggests a new approach for treating TNBC with a multiplex combination of PKIs. There is an unmet medical need for the development of new targeted therapeutic strategies for triple-negative breast cancer (TNBC). With drug combination screenings, we found that the triple combination of the protein kinase inhibitors (PKIs) of the epidermal growth factor receptor (EGFR), v-akt murine thymoma viral oncogene homolog (AKT), and MAPK/ERK kinase (MEK) is effective in inducing apoptosis in TNBC cells. A set of PKIs were first screened in combination with gefitinib in the TNBC cell line, MDA-MB-231. The AKT inhibitor, AT7867, was identified and further analyzed in two mesenchymal stem-like (MSL) subtype TNBC cells, MDA-MB-231 and HS578T. A combination of gefitinib and AT7867 reduced the proliferation and long-term survival of MSL TNBC cells. However, gefitinib and AT7867 induced the activation of the rat sarcoma (RAS)/ v-raf-1 murine leukemia viral oncogene homolog (RAF)/MEK/ extracellular signal-regulated kinase (ERK) pathway. To inhibit this pathway, MEK/ERK inhibitors were further screened in MDA-MB-231 cells in the presence of gefitinib and AT7867. As a result, we identified that the MEK inhibitor, PD-0325901, further enhanced the anti-proliferative and anti-clonogenic effects of gefitinib and AT7867 by inducing apoptosis. Our results suggest that the dual inhibition of the AKT and MEK pathways is a novel potential therapeutic strategy for targeting EGFR in TNBC cells. [ABSTRACT FROM AUTHOR]

In order to simulate the on-site compaction conditions of a Stone Matrix Asphalt (SMA) mixture, The Vertical Vibration Testing Method (VVTM), Superpave Gyratory Compactor (SGC), and Marshall method are used to test the SMA-13 mixture, and the physical and mechanical properties of the asphalt mixture designed by these three methods are tested. Subsequently, the influences of the molding method on the mechanical properties are compared. The influence of vibration compaction time on the volume parameters of the SMA mixture is studied. Following the heavy traffic compaction standards, the vibration compaction time of the SMA mixture is determined. The results show that the densities of the heavy Marshall specimen, VVTM specimen, and SGC specimen are 1.018 times, 1.019 times, and 1.015 times greater than that of the standard Marshall specimen, respectively. The passing rate of the 4.75 mm aggregate of the standard Marshall specimen is 29.9%, and that of the VVTM specimen and SGC specimen is 31.1% and 30.5%, respectively, while that of the heavy Marshall specimen is 34.5%. The mechanical strength of the specimen can be greatly improved as the density increases. On the other hand, by the same compaction work, the mechanical strength of the VVTM specimens can be increased by at least 7% compared with the heavy Marshall specimen. The mechanical strength of the VVTM specimen is increased by at least 22% compared with the standard Marshall specimen. The results also show that under the optimal asphalt-aggregate ratio and the same compaction work, the compressive strength and shear strength of the VVTM specimens are increased by at least 6% and 9%, respectively, compared with the Marshall specimens. In summary, the performance of the asphalt mixture designed by the VVTM is superior, providing a wider choice for future asphalt mixture design. [ABSTRACT FROM AUTHOR]

The performance of a skid resistance fog seal is studied to develop a high bond performance road skid resistance fog seal. Accordingly, a fog seal is developed based on the bond strength, permeability, and aging resistance. To develop the skid resistance fog seal herein, the skid resistance particle types and dosages are optimized according to the skid and wear resistance properties. The fog seal performance is then verified. Furthermore, the road performance of the skid resistance fog seal is studied, and the optimal amount of the skid resistance fog seal is proposed. Finally, the influence of the construction process on the skid and wear resistance is investigated. The results show that the self-made skid resistance fog seal has better bond strength, permeability, and aging resistance. The 0.6 kg/m2 skid resistance fog seal exhibits the best skid and wear resistance and water penetration performance, while the skid resistance fog seal constructed by the premix process has the best skid and wear resistance properties. [ABSTRACT FROM AUTHOR]

Cement-modified loess has been used in the recent construction of an intercity high-speed railway in Xi'an, China. This paper studies the mechanical strength of cement-modified loess (CML) compacted by the vertical vibration compaction method (VVCM). First, the reliability of VVCM in compacting CML is evaluated, and then the effects of cement content, compaction coefficient, and curing time on the mechanical strength of CML are analyzed, establishing a strength prediction model. The results show that the correlation of mechanical strength between the CML specimens prepared by VVCM in the laboratory and the core specimens collected on site is as high as 83.8%. The mechanical strength of CML initially show linear growth with increasing cement content and compaction coefficient. The initial growth in CML mechanical strength is followed by a later period, with mechanical strength growth slowing after 28 days. The mechanical strength growth properties of the CML can be accurately predicted via established strength growth equations. The results of this study can guide the design and construction of CML subgrade. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is a fatal medical episode caused by sudden kidney damage or failure, leading to the death of patients within a few hours or days. Previous studies demonstrated that exosomes derived from various mesenchymal stem/stromal cells (MSC-exosomes) have positive effects on renal injuries in multiple experimental animal models of kidney diseases including AKI. However, the mass production of exosomes is a challenge not only in preclinical studies with large animals but also for successful clinical applications. In this respect, tangential flow filtration (TFF) is suitable for good manufacturing practice (GMP)-compliant large-scale production of high-quality exosomes. Until now, no studies have been reported on the use of TFF, but rather ultracentrifugation has been almost exclusively used, to isolate exosomes for AKI therapeutic application in preclinical studies. Here, we demonstrated the reproducible large-scale production of exosomes derived from adipose tissue-derived MSC (ASC-exosomes) using TFF and the lifesaving effect of the ASC-exosomes in a lethal model of cisplatin-induced rat AKI. Our results suggest the possibility of large-scale stable production of ASC-exosomes without loss of function and their successful application in life-threatening diseases. [ABSTRACT FROM AUTHOR]

Lung cancer stem cells (CSCs) play a pivotal role in tumor development, drug resistance, metastasis and recurrence of lung cancer. Thus, it is of great importance to study the mechanism by which CSCs are regulated. In this study, we demonstrate that the deubiquitinase USP4 is critically important in promoting lung cancer stemness. Silencing of USP4 leads to reduction of Oct4 and Sox2 expression, decreased CD133+ cell population and inhibition of tumorsphere formation. Conversely, ectopic expression of USP4 significantly enhances lung cancer cell stemness, which is effectively rescued by simultaneous silencing of Twist1. Mechanistically, we identified USP4 as a novel deubiquitinase of Twist1. USP4 binds to, deubiquitinates and stabilizes Twist1 protein. Furthermore, we show that USP4 expression is elevated in human lung cancer specimens and is positively correlated with Twist1 expression. High expression of USP4/Twist1 is associated with poor clinical outcomes of lung cancer patients. Together, this study highlights an important role for USP4 in lung cancer stemness and suggests USP4 as a potential target for lung cancer diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Exosomes are nano-sized vesicles that serve as mediators for cell-to-cell communication. With their unique nucleic acids, proteins, and lipids cargo compositions that reflect the characteristics of producer cells, exosomes can be utilized as cell-free therapeutics. Among exosomes derived from various cellular origins, mesenchymal stem cell-derived exosomes (MSC-exosomes) have gained great attention due to their immunomodulatory and regenerative functions. Indeed, many studies have shown anti-inflammatory, anti-aging and wound healing effects of MSC-exosomes in various in vitro and in vivo models. In addition, recent advances in the field of exosome biology have enabled development of specific guidelines and quality control methods, which will ultimately lead to clinical application of exosomes. This review highlights recent studies that investigate therapeutic potential of MSC-exosomes and relevant mode of actions for skin diseases, as well as quality control measures required for development of exosome-derived therapeutics. [ABSTRACT FROM AUTHOR]

Gemcitabine is clinically used to treat certain types of cancers, including pancreatic and biliary cancer. We investigated the signal transduction pathways underlying the local antitumor effects of gemcitabine-eluting membranes (GEMs) implanted in pancreatic/biliary tumor-bearing nude mice. Here, we report that GEMs increased the E3 ubiquitin ligase c-CBL protein level, leading to degradation of epidermal growth factor receptor (EGFR) in SCK and PANC-1 cells. GEMs decreased the RAS and PI3K protein levels, leading to a reduction in the protein levels of active forms of downstream signaling molecules, including PDK, AKT, and GSK3β. GEM reduced proliferation of cancer cells by upregulating cell cycle arrest proteins, particularly p53 and p21, and downregulating cyclin D1 and cyclin B. Moreover, GEMs reduced the levels of proangiogenic factors, including VEGF, VEGFR2, CD31, and HIF-1α, and inhibited tumor cell migration and invasion by inducing the expression of E-cadherin and reducing that of N-cadherin, snail, and vimentin. We demonstrated that local delivery of gemcitabine using GEM implants inhibited tumor cell growth by promoting c-CBL-mediated degradation of EGFR and inhibiting the proliferation, angiogenesis, and epithelial–mesenchymal transition of pancreatic/biliary tumors. Use of gemcitabine-eluting stents can improve stent patency by inhibiting the ingrowth of malignant biliary obstructions. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a multifactorial, heterogeneous disease associated with epidermal barrier disruption and intense systemic inflammation. Previously, we showed that exosomes derived from human adipose tissue-derived mesenchymal stem cells (ASC-exosomes) attenuate AD-like symptoms by reducing multiple inflammatory cytokine levels. Here, we investigated ASC-exosomes' effects on skin barrier restoration by analyzing protein and lipid contents. We found that subcutaneous injection of ASC-exosomes in an oxazolone-induced dermatitis model remarkably reduced trans-epidermal water loss, while enhancing stratum corneum (SC) hydration and markedly decreasing the levels of inflammatory cytokines such as IL-4, IL-5, IL-13, TNF-α, IFN-γ, IL-17, and TSLP, all in a dose-dependent manner. Interestingly, ASC-exosomes induced the production of ceramides and dihydroceramides. Electron microscopic analysis revealed enhanced epidermal lamellar bodies and formation of lamellar layer at the interface of the SC and stratum granulosum with ASC-exosomes treatment. Deep RNA sequencing analysis of skin lesions demonstrated that ASC-exosomes restores the expression of genes involved in skin barrier, lipid metabolism, cell cycle, and inflammatory response in the diseased area. Collectively, our results suggest that ASC-exosomes effectively restore epidermal barrier functions in AD by facilitating the de novo synthesis of ceramides, resulting in a promising cell-free therapeutic option for treating AD. [ABSTRACT FROM AUTHOR]

Heat-reflective coatings, used to reduce the asphalt pavement temperature and urban heat island effect, have a good cooling effect; coating development, however, generally focuses on cooling. This study aims to design a heat-reflective coating with both durability and cooling effect by considering the functions of each component, improving the coating bond strength and abrasion resistance, and conducting laboratory tests and test section verification. The coating developed exhibits bond strength and abrasion resistance 20% and 49%, respectively, higher than those of ordinary coatings. The experiments reveal a cooling effect of red coating up to 10.2 °C, a bond strength of up to 1.20 MPa at 25 °C, and an abrasion rate of up to 25% after 60 min; the cooling effect is basically the same as that for traditional heat-reflective coatings, but the bond strength and abrasion resistance significantly improved. In the analysis of the test section, the cooling effect reaches 7.0 °C, the performance of anti-skid decreases little, and the coating is still usable normally after 4 months. [ABSTRACT FROM AUTHOR]

Cell–cell adhesion plays an important role in regulation of cell proliferation, migration, survival, and drug sensitivity. Metformin, a first line drug for type 2 diabetes, has been shown to possess anti-cancer activities. However, whether cell–cell adhesion affects metformin anti-cancer activity is unknown. In this study, Microscopic and FACS analyses showed that metformin induced cancer cell–cell adhesion exemplified by cell aggregation and anoikis under glucose restriction. Furthermore, western blot and QPCR analyses revealed that metformin dramatically upregulated integrin β1 expression. Silencing of integrin β1 significantly disrupted cell aggregation and reduced anoikis induced by metformin. Moreover, we showed that p53 family member ΔNp63α transcriptionally suppressed integrin β1 expression and is responsible for metformin-mediated upregulation of integrin β1. In summary, this study reveals a novel mechanism for metformin anticancer activity and demonstrates that cell–cell adhesion mediated by integrin β1 plays a critical role in metformin-induced anoikis. [ABSTRACT FROM AUTHOR]

In the present work, three NiTiNb alloys with nominal compositions of Ni50–x/2Ti50–x/2Nbx (x = 18, 20 and 22, at.%) were prepared. The microstructure, thermal-induced phase transformation, and phase components of NiTiNb hypoeutectic, eutectic, and hypereutectic alloys were investigated by scanning electron microscopy coupled with energy dispersive spectrometer (SEM/EDS), differential scanning calorimetry (DSC), and X-ray diffraction (XRD), respectively. Two peaks occurred in the DSC curves of Ni41Ti41Nb18 solution at 750 and 850 °C. The different microstructures of NiTiNb hypoeutectic, eutectic and hypereutectic alloys, the occurrence of two peaks in the DSC curves, and the characteristic of martensite transformation temperature were analyzed and discussed. The results show that different Nb content leads to different microstructures of Ni50–x/2Ti50–x/2-Nbx alloys. Moreover, the difference of Ni/Ti ratio between the primary NiTi matrix and NiTi in eutectic structure strongly influenced the phase transformation behavior that the DSC curves of Ni41Ti41Nb18 alloy show two peaks. Furthermore, under the same solution treatment, the Ni40Ti40Nb20 alloy has a lower Ms than the other two alloys. The Ms has a tendency to decrease with an increase in solution temperature. [ABSTRACT FROM AUTHOR]

Nanoporous metals with considerable specific surface areas and hierarchical pore structures exhibit promising applications in the field of hydrogen storage, electrocatalysis, and fuel cells. In this manuscript, a facile method is demonstrated for fabricating nanoporous Ni with a high surface area by using SiO2 aerogel as a template, i.e., electroless plating of Ni into an SiO2 aerogel template followed by removal of the template at moderate conditions. The effects of the prepared conditions, including the electroless plating time, temperature of the structure, and the magnetism of nanoporous Ni are investigated in detail. The resultant optimum nanoporous Ni with a special 3D flower-like structure exhibited a high specific surface area of about 120.5 m2/g. The special nanoporous Ni exhibited a promising prospect in the field of hydrogen storage, with a hydrogen capacity of 0.45 wt % on 4.5 MPa at room temperature. [ABSTRACT FROM AUTHOR]

To improve combustion efficiency and anti-oxidation property of aluminum nanoparticles (ANs), surface nitridation of ANs was performed in a pipe furnace under the protection of nitrogen gas in a glove-operation hermetic box via an off-line nitridation process. The product was characterized by transmission electron microscopy (TEM), X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS) analysis. A core-shell nanostructure with an aluminum nitride (AlN) coating on the ANs core was observed. The empirical kinetic triplets (Ea, A, and f(α)) for the nitridation of ANs, for the first time, were calculated and analyzed using five types of iso-conversional methods and a differentiation method. The effects of the kinetics of the reaction were investigated by simultaneous differential scanning calorimetry–thermogravimetry (DSC-TG) and thermal analysis using linear programmed temperature at different heating rates. [ABSTRACT FROM AUTHOR]

To study the mechanical properties of cement-graded crushed stone for use in the transition sections of intercity railways, the growth laws governing unconfined compressive strength, splitting strength and resilience modulus of cement-graded crushed stone and their influencing factors were studied by the vertical vibration compaction method (VVCM). The strength growth equations of cement-graded crushed stone are proposed, and strength prediction equations are established. The research shows the unconfined compressive strength, splitting strength and resilience modulus of cement-graded crushed stone with a strong interlocked skeleton density type (VGM-30) are significantly enhanced to 20, 20 and 17% higher, respectively, than those of standard cement-graded crushed stone. The growth law of mechanical properties of cement-graded crushed stone is similar, with the fastest growth occurring before 14 days, and the rate decreasing after 28 days. The strength growth tended to be stable after 90 days, increasing with the increase in curing time, compaction coefficient and cement dosage. The correlation coefficients (R 2 ) of the strength growth prediction models were found to be 0.99, 0.97, and 0.99, respectively. These values can be used to accurately predict the strength growth curve. This paper verifies the superiority of VGM-30 gradation through laboratory tests, providing a reference for gradation selection in the construction of intercity railway transition sections.

Ribosomal protein S6 (RPS6) is a component of the 40S small ribosomal subunit and participates in the control of mRNA translation. Additionally, phospho (p)-RPS6 has been recognized as a surrogate marker for the activated PI3K/AKT/mTORC1 pathway, which occurs in many cancer types. However, downstream mechanisms regulated by RPS6 or p-RPS remains elusive, and the therapeutic implication of RPS6 is underappreciated despite an approximately half a century history of research on this protein. In addition, substantial evidence from RPS6 knockdown experiments suggests the potential role of RPS6 in maintaining cancer cell proliferation. This motivates us to investigate the current knowledge of RPS6 functions in cancer. In this review article, we reviewed the current information about the transcriptional regulation, upstream regulators, and extra-ribosomal roles of RPS6, with a focus on its involvement in cancer. We also discussed the therapeutic potential of RPS6 in cancer.

Exosomes are nano-sized membranous vesicles produced by nearly all types of cells. Since exosome-like vesicles are produced in an evolutionarily conserved manner for information and function transfer from the originating cells to recipient cells, an increasing number of studies have focused on their application as therapeutic agents, drug delivery vehicles, and diagnostic targets. Analysis of the in vivo distribution of exosomes is a prerequisite for the development of exosome-based therapeutics and drug delivery vehicles with accurate prediction of therapeutic dose and potential side effects. Various attempts to evaluate the biodistribution of exosomes obtained from different sources have been reported. In this review, we examined the current trends and the advantages and disadvantages of the methods used to determine the biodistribution of exosomes by molecular imaging. We also reviewed 29 publications to compare the methods employed to isolate, analyze, and label exosomes as well as to determine the biodistribution of labeled exosomes., Competing Interests: Y.W.Y. and B.S.C. are founders and stockholders of ExoCoBio Inc. Y.W.Y., J.H.L., D.H.H., S.R.P., J.Y., and B.S.C. are employees of ExoCoBio Inc.

Cell⁻cell adhesion plays an important role in regulation of cell proliferation, migration, survival, and drug sensitivity. Metformin, a first line drug for type 2 diabetes, has been shown to possess anti-cancer activities. However, whether cell⁻cell adhesion affects metformin anti-cancer activity is unknown. In this study, Microscopic and FACS analyses showed that metformin induced cancer cell⁻cell adhesion exemplified by cell aggregation and anoikis under glucose restriction. Furthermore, western blot and QPCR analyses revealed that metformin dramatically upregulated integrin β1 expression. Silencing of integrin β1 significantly disrupted cell aggregation and reduced anoikis induced by metformin. Moreover, we showed that p53 family member ΔNp63α transcriptionally suppressed integrin β1 expression and is responsible for metformin-mediated upregulation of integrin β1. In summary, this study reveals a novel mechanism for metformin anticancer activity and demonstrates that cell⁻cell adhesion mediated by integrin β1 plays a critical role in metformin-induced anoikis.

In this work, a two-step extraction methodology of ionic liquid-based ultrasonic-assisted extraction (IL-UAE) and ionic liquid-based aqueous two-phase system (IL-ATPS) was developed for the extraction and purification of secoisolariciresinol diglucoside (SDG) from flaxseed. In the IL-UAE step, several kinds of ILs were investigated as the extractants, to identify the IL that affords the optimum extraction yield. The extraction conditions such as IL concentration, ultrasonic irradiation time, and liquid-solid ratio were optimized using response surface methodology (RSM). In the IL-ATPS step, ATPS formed by adding kosmotropic salts to the IL extract was used for further separation and purification of SDG. The most influential parameters (type and concentration of salt, temperature, and pH) were investigated to obtain the optimum extraction efficiency. The maximum extraction efficiency was 93.35% under the optimal conditions of 45.86% (w/w) IL and 8.27% (w/w) Na₂SO₄ at 22 °C and pH 11.0. Thus, the combination of IL-UAE and IL-ATPS makes up a simple and effective methodology for the extraction and purification of SDG. This process is also expected to be highly useful for the extraction and purification of bioactive compounds from other important medicinal plants.

The breast cancer susceptibility gene 1 (BRCA1) has been well established as a tumor suppressor and functions primarily by maintaining genome integrity. Genome stability is compromised when cells are exposed to oxidative stress. Increasing evidence suggests that BRCA1 regulates oxidative stress and this may be another mechanism in preventing carcinogenesis in normal cells. Oxidative stress caused by reactive oxygen species (ROS) is implicated in carcinogenesis and is used strategically to treat human cancer. Thus, it is essential to understand the function of BRCA1 in oxidative stress regulation. In this review, we briefly summarize BRCA1's many binding partners and mechanisms, and discuss data supporting the function of BRCA1 in oxidative stress regulation. Finally, we consider its significance in prevention and/or treatment of BRCA1-related cancers.