The combination of methionine adenosyltransferase 2A inhibitor and methyltransferase like 3 inhibitor promotes apoptosis of non-small cell lung cancer cells and produces synergistic anti-tumor activity.

Methionine adenosyltransferase 2 A (MAT2A) mediates the synthesis of methyl donor S-Adenosylmethionine (SAM), providing raw materials for methylation reactions in cells. MAT2A inhibitors are currently used for the treatment of tumors with methylthioadenosine phosphorylase (MTAP) deficiency in clinical research. Methyltransferase like 3 (METTL3) catalyzes N6-methyladenosine (m6A) modification of mRNA in mammalian cells using SAM as the substrate which has been shown to affect the tumorigenesis of non-small cell lung cancer (NSCLC) from multiple perspectives. MAT2A-induced SAM depletion may have the potential to inhibit the methyl transfer function of METTL3. Therefore, in order to expand the applicability of inhibitors, improve anti-tumor effects and reduce toxicity, the combinational effect of MAT2A inhibitor AG-270 and METTL3 inhibitor STM2457 was evaluated in NSCLC. The results showed that this combination induced cell apoptosis rather than cell cycle arrest, which was non-tissue-specific and was independent of MTAP expression status, resulting in a significant synergistic anti-tumor effect. We further elucidated that the combination-induced enhanced apoptosis was associated with the decreased m6A level, leading to downregulation of PI3K/AKT protein, ultimately activating the apoptosis-related proteins. Unexpectedly, although combination therapy resulted in metabolic recombination, no significant change in methionine metabolic metabolites was found. More importantly, the combination also exerted synergistic effects in vivo. In summary, the combination of MAT2A inhibitor and METTL3 inhibitor showed synergistic effects both in vivo and in vitro, which laid a theoretical foundation for expanding the clinical application research of the two types of drugs.

Distribution characteristics of reactive silicon in six water bodies in the Yangtze River Basin in China.

Terrestrial silicon (Si) from biogeochemically weathered rocks and soils into oceans must pass through several water bodies, resulting in some Si immobilized. Hence, the knowledge on Si distribution characteristics in different water bodies at a basin scale is helpful to understand Si immobilization. A total of 65 surface sediments and corresponding overlying water samples were sampled from six water bodies (Dianchi Lake, DL; Dadu River, DR; Tuojiang River, TR; Honghu Lake, HL; Donghu Lake, DhL; Taihu Lake, TL) in the Yangtze River Basin of China, total dissolved Si (TDSi) in overlying water and exchangeable Si (Ex-Si), active non-biogenic Si (NBSi), and total acid dissolved Si (TADSi) in sediments were analyzed. Water chemical parameters (pH, EC, and TDP) and sediment components (LOI, TN, TP, and TADFe) showed that the water environment characteristics of six water bodies differed. TDSi differed among regions and between lakes and rivers, significantly higher in water bodies in the upper reaches and rivers than the middle or lower reaches and lakes (p < 0.05), respectively. Ex-Si in sediments in the upper reaches was significantly higher than in the middle or lower reaches (p < 0.05), except for DhL, whose Ex-Si was the highest. Mean TADSi and active NBSi were significantly higher in lakes than rivers (p < 0.05). Oxidation of sediments significantly increased TDSi in overlying water and active NBSi in sediments (p < 0.01). Si forms in six water bodies significantly depended on components of the sediments (e.g. active Ca2+, Mg2+, Fe, and Al3+) and water chemical parameters (p < 0.05). Our results suggest that immobilization of Si in water bodies in the Yangtze River Basin depends on the types of water bodies and sediments, lakes and Fe-Al dominated sediments have a high potential to immobilize Si, but anthropogenic interference should not be ignored.

Measurement of the distance between tumor micro-foci and gross tumor in rectal cancer pathological specimens: implication on margin distance of clinical target volume treated with high-dose radiotherapy for rectal cancer.

PURPOSE: To measure the micro-foci distance away from gross tumor and to provide reference to create the clinical target volume (CTV) margin for boost radiotherapy in rectal adenocarcinoma. METHODS: Twenty-eight rectal cancer surgical specimens of only total mesorectal excision were collected. The pathological specimens were retrospectively measured, and the nearest distance between the tumor micro-foci and gross tumor was microscopically measured. The "in vivo-in vitro" retraction factor was calculated as the ratio of the deepest thickness laterally and the vertical height superior/inferiorly of the rectal tumor measured in MRI and those measured in immediate pathological specimens. The retraction factor during pathological specimen processing was calculated as the distance ratio before and after dehydration in the lateral, superior, and inferior sides by the "knot marking method." The distances of tumor micro-foci were individually corrected with these two retraction factors. RESULTS: The mean "in vivo-in vitro" tumor retraction factors were 0.913 peripherally and 0.920 superior/inferiorly. The mean tumor specimen processing retraction factors were 0.804 peripherally, 0.815 inferiorly, and 0.789 superiorly. Of 28 patients, 14 cases (50.0%) had 24 lateral micro-foci, 8 cases (28.6%) had 13 inferior micro-foci, and 7 cases (25.0%) had 19 superior micro-foci. The 95th percentiles of the micro-foci distance for 28 patients were 6.44 mm (peripheral), 5.54 mm (inferior), and 5.42 mm (superior) after retraction correction. CONCLUSION: The micro-foci distances of 95% of rectal adenocarcinoma patients examined were within 6.44 mm peripherally, 5.54 mm inferiorly, and 5.42 mm superiorly. These findings provide reference to set the boost radiotherapy CTV margin for rectal cancer.

Tunable High-Sensitivity Four-Frequency Refractive Index Sensor Based on Graphene Metamaterial.

As graphene-related technology advances, the benefits of graphene metamaterials become more apparent. In this study, a surface-isolated exciton-based absorber is built by running relevant simulations on graphene, which can achieve more than 98% perfect absorption at multiple frequencies in the MWIR (MediumWavelength Infra-Red (MWIR) band as compared to the typical absorber. The absorber consists of three layers: the bottom layer is gold, the middle layer is dielectric, and the top layer is patterned with graphene. Tunability was achieved by electrically altering graphene's Fermi energy, hence the position of the absorption peak. The influence of graphene's relaxation time on the sensor is discussed. Due to the symmetry of its structure, different angles of light source incidence have little effect on the absorption rate, leading to polarization insensitivity, especially for TE waves, and this absorber has polarization insensitivity at ultra-wide-angle degrees. The sensor is characterized by its tunability, polarisation insensitivity, and high sensitivity, with a sensitivity of up to 21.60 THz/refractive index unit (RIU). This paper demonstrates the feasibility of the multi-frequency sensor and provides a theoretical basis for the realization of the multi-frequency sensor. This makes it possible to apply it to high-sensitivity sensors.

Case report: A lung squamous cell carcinoma patient with a rare EGFR G719X mutation and high PD-L1 expression showed a good response to anti-PD1 therapy.

Lung cancer treatment has transitioned fully into the era of immunotherapy, yielding substantial improvements in survival rate for patients with advanced non-small cell lung cancer (NSCLC). In this report, we present a case featuring a rare epidermal growth factor receptor (EGFR) mutation accompanied by high programmed death-ligand 1 (PD-L1) expression, demonstrating remarkable therapeutic efficacy through a combination of immunotherapy and chemotherapy. A 77-year-old male with no family history of cancer suffered from upper abdominal pain for more than half months in August 2020 and was diagnosed with stage IV (cT3N3M1c) lung squamous cell carcinoma (LUSC) harboring both a rare EGFR p.G719C mutation and high expression of PD-L1 (tumor proportion score [TPS] = 90%). Treatment with the second-generation targeted therapy drug Afatinib was initiated on September 25, 2020. However, resistance ensued after 1.5 months of treatment. On November 17, 2020, immunotherapy was combined with chemotherapy (Sintilimab + Albumin-bound paclitaxel + Cisplatin), and a CT scan conducted three months later revealed significant tumor regression with a favorable therapeutic effect. Subsequently, the patient received one year of maintenance therapy with Sintilimab, with follow-up CT scans demonstrating subtle tumor shrinkage (stable disease). This case provides evidence for the feasibility and efficacy of immunotherapy combined with chemotherapy in the treatment of EGFR-mutated and PD-L1 highly expressed LUSC.

[Biological Effect of Microplastics with Different Functional Groups on the Bacterial Communities and Metabolic Functions of Zebrafish (Danio rerio) Embryos].

To investigate the influences of functional groups on the biological effects caused by microplastics, the accumulation of three polystyrene microplastics (PS, PS-NH2, and PS-COOH) in zebrafish (Danio rerio) embryos were analyzed, and then the responses of metabolic functions and microbial communities in zebrafish larvae were revealed using the combination of the microbiome and metabolome methods. The results showed that all microplastics could accumulate in zebrafish with concentrations ranging from 143 to 175 µg·g-1, and there were no significant differences in the accumulation potentials among different PS treatments. Exposure to plain PS significantly affected the metabolic capacity of aminoglycosides in zebrafish larvae, whereas the metabolic processes of amino acids were affected by PS-NH2. In the PS-COOH treatment, the metabolic pathways of the tricarboxylic acid cycle, amino acids, and glycolysis in zebrafish were markedly altered. The metabolic functions of zebrafish larvae were changed by all PS microplastics, resulting in toxic effects on zebrafish, and the functional group modification of microplastics may have further enhanced these toxicities. Compared to that in the control, exposure to PS-NH2 significantly reduced the diversity of microbial communities in zebrafish larvae and increased the proportion of Proteobacteria in the composition, leading to an imbalance of the bacterial community in zebrafish and thus disrupting the metabolic functions in the fish. Therefore, the functional modifications of microplastics may significantly alter the related stresses on aquatic organisms, leading to unpredictable ecological risks.

Improvement of both human and animal memory by synergy between fructooligosaccharide and L-theanine function establishing a safe and effective food supplement.

Aging is classically associated with a decline of cognitive abilities, especially in relation to memory. While the development of potential treatments for neurodegenerative diseases has been in sharp focus, mild cognitive impairment (MCI), a form of age-related memory loss, in the absence of severe functional impairment, a condition experienced by many healthy adults, has received relatively little attention. Advances in this space would make significant contributions to the goal of healthy aging and may also help promote cognitive performance across the wider population. The individual action of either fructooligosaccharide (FOS) or L-theanine, both natural plant-derived molecules, has been tentatively linked with improvements in cognition, but our understanding remains far from complete. We therefore determined the effect of different dose combinations of FOS and L-theanine (termed MT-01/GBL-Memory1) in mice against FOS and L-theanine monotherapy. FOS and L-theanine were found to synergistically enhance murine memory in our animal tests at a dose of 100 mg/kg (coefficient of drug interaction (CDI) < 1). In a subsequent human trial, we demonstrated that MT-01 improved the memory of healthy adults after 1 month of consumption. Our results suggest that a combination of FOS and L-theanine synergistically enhances murine memory within a specific dose range. We show that this plant natural product regimen also improves human memory in a population of healthy adults. MT-01 therefore represents a novel, safe, and effective dietary supplement to promote human memory and cognition.

Identification of YCH2823 as a novel USP7 inhibitor for cancer therapy.

Inhibition of the human ubiquitin-specific protease 7 (USP7), the key deubiquitylating enzyme in regulating p53 protein levels, has been considered an attractive anticancer strategy. In order to enhance the cellular activity of FT671, scaffold hopping strategy was employed. This endeavor resulted in the discovery of YCH2823, a novel and potent USP7 inhibitor.YCH2823 demonstrated remarkable efficacy in inhibiting the growth of a specific subset of TP53 wild-type, -mutant, and MYCN-amplified cell lines, surpassing the potency of FT671 by approximately 5-fold. The mechanism of action of YCH2823 involves direct interaction with the catalytic domain of USP7, thereby impeding the cleavage of ubiquitinated substrates. An increase in the expression of p53 and p21, accompanied by G1 phase arrest and apoptosis, was observed upon treatment with YCH2823. Subsequently, the knockdown of p53 or p21 in CHP-212 cells exhibited a substantial reduction in sensitivity to YCH2823, as evidenced by a considerable increase in IC50 values up to 690-fold. Furthermore, YCH2823 treatment specifically enhanced the transcriptional and protein levels of BCL6 in sensitive cells. Moreover, a synergistic effect between USP7 inhibitors and mTOR inhibitors was observed, suggesting the possibility of novel therapeutic strategies for cancer treatment. In conclusion, YCH2823 exhibits potential as an anticancer agent for the treatment of both TP53 wild-type and -mutant tumors.

Co-inhibition of BET and NAE enhances BIM-dependent apoptosis with augmented cancer therapeutic efficacy.

Agents that inhibit bromodomain and extra-terminal domain (BET) proteins have been actively tested in the clinic as potential anticancer drugs. NEDD8-activating enzyme (NAE) inhibitors, represented by MLN4924, target the only activation enzyme in the neddylation pathway that has been identified as an attractive target for cancer therapy. In this study, we focus on the combination of BET inhibitors (BETis) and NAE inhibitors (NAEis) as a cancer therapeutic strategy and investigate its underlying mechanisms to explore and expand the application scope of both types of drugs. The results showed that this combination synergistically inhibited the proliferative activity of tumor cells from different tissues. Compared to a single drug, combination therapy had a weak effect on cycle arrest but significantly enhanced cell apoptosis. Furthermore, the growth of NCI-H1975 xenografts in nude mice was significantly inhibited by the combination without obvious body weight loss. Research on the synergistic mechanism demonstrated that combination therapy significantly increased the mRNA and protein levels of the proapoptotic gene BIM. The inhibition and knockout of BIM significantly attenuated the apoptosis induced by the combination, whereas the re-expression of BIM restored the synergistic effects, indicating that BIM induction plays a critical role in mediating the enhanced apoptosis induced by the co-inhibition of BET and NAE. Together, the enhanced transcription mediated by miR-17-92 cluster inhibition and reduced degradation promoted the increase in BIM levels, resulting in a synergistic effect. Collectively, these findings highlight the need for further clinical investigation into the combination of BETi and NAEi as a promising strategy for cancer therapy.