A cancer cell nanotherapy method based on GHz film bulk acoustic resonator and nanoscale CaO2.

Sonodynamic therapy (SDT) is an emerging cancer treatment method in recent years. However, the ultrasound signal utilized for SDT is usually located at a low-frequency spectrum (<2 MHz), and in the field of SDT research, few studies have focused on the exploration and development of ultrasound frequency. Studies have shown that the GHz-level ultrasound can increase cell membrane permeability and have a negligible effect on cell vitality. Herein, we reported the study of a GHz thin film bulk acoustic resonator as an ultrasound source for synergistic treatment with nanoscale calcium peroxide (CaO2). It was discovered that this ultrasound source ultimately achieved an efficient therapeutic outcome on mouse breast cancer cell line 4T1. Such GHz-level ultrasound application in SDT is of high significance to broaden the cognition and application scope of SDT.

Design, Synthesis, and Antitumor Activity Evaluation of Novel VISTA Small Molecule Inhibitors.

VISTA (V-domain Ig suppressor of T cell activation) is a novel immune checkpoint protein and represents a promising target for cancer immunotherapy. Here, we report the design, synthesis, and evaluation of a series of methoxy-pyrimidine-based VISTA small molecule inhibitors with potent antitumor activity. By employing molecular docking and microscale thermophoresis (MST) assay, we identified a lead compound A1 that binds to VISTA protein with high affinity and optimized its structure. A4 was then obtained, which exhibited the strongest binding ability to VISTA protein, with a KD value of 0.49 ± 0.20 µM. In vitro, A4 significantly activated peripheral blood mononuclear cells (PBMCs) induced the release of cytokines such as IFN-γ and enhanced the cytotoxicity of PBMCs against tumor cells. In vivo, A4 displayed potent antitumor activity and synergized with PD-L1 antibody to enhance the therapeutic effect against cancer. These results suggest that compound A4 is an effective VISTA small molecule inhibitor, providing a basis for the future development of VISTA-targeted drugs.

Bispecific antibodies in cancer therapy: Target selection and regulatory requirements.

In recent years, the development of bispecific antibodies (bsAbs) has been rapid, with many new structures and target combinations being created. The boom in bsAbs has led to the successive issuance of industry guidance for their development in the US and China. However, there is a high degree of similarity in target selection, which could affect the development of diversity in bsAbs. This review presents a classification of various bsAbs for cancer therapy based on structure and target selection and examines the advantages of bsAbs over monoclonal antibodies (mAbs). Through database research, we have identified the preferences of available bsAbs combinations, suggesting rational target selection options and warning of potential wastage of medical resources. We have also compared the US and Chinese guidelines for bsAbs in order to provide a reference for their development.

A Survival Model for Patients with Upper Tract Urothelial Carcinoma.

OBJECTIVES: We aimed to establish a survival model for patients with upper tract urothelial carcinoma (UTUC). METHODS: A total of 241 patients with UTUC treated from January 2010 to December 2018 were selected. Their general clinical data were collected, and urological indices were measured. They were followed up after discharge, and divided into a death group (n = 51) and a survival group (n = 190) to compare the clinical data. Multivariate logistic regression analysis was performed to analyze the independent risk factors for postoperative death, based on which a nomogram prediction model was established and then validated. RESULTS: The death group had significantly older age, larger tumor diameter, and higher tumor grade, pathological stage and proportion of no adjuvant chemotherapy than those of the control group (p < 0.01). The results of multivariate logistic analysis suggested that high tumor grade, tumor located in the ureter, large tumor diameter, high pathological stage, and lymph node metastasis were independent risk factors for postoperative death. A nomogram prediction model was established based on the prognostic independent risk factors. The area under the curve of receiver operating characteristic curve was 0.828 (95% confidence interval (CI): 0.801-0.845), so the model had good discrimination. The calibration curve showed that the model had high consistency. CONCLUSIONS: The established nomogram model can be used to predict the mortality risk of patients with UTUC and postoperative survival, and to develop individualized treatment plans for improving the prognosis and survival.

Aluminum Nitride-Based Adjustable Effective Electromechanical Coupling Coefficient Film Bulk Acoustic Resonator.

The arrival of the 5G era has promoted the need for filters of different bandwidths. Thin-film bulk acoustic resonators have become the mainstream product for applications due to their excellent performance. The Keff2 of the FBAR greatly influences the bandwidth of the filter. In this paper, we designed an AlN-based adjustable Keff2 FBAR by designing parallel capacitors around the active area of the resonator. The parallel capacitance is introduced through the support column structure, which is compatible with conventional FBAR processes. The effects of different support column widths on Keff2 were verified by finite element simulation and experimental fabrication. The measured results show that the designed FBAR with support columns can achieve a Keff2 value that is 25.9% adjustable.

Lipid peroxide-derived short-chain aldehydes promote programmed cell death in wheat roots under aluminum stress.

Lipid peroxidation is a primary event in plant roots exposed to aluminum (Al) toxicity, which leads to the formation of reactive aldehydes. Current evidence demonstrates that the resultant aldehydes are integrated components of cellular damage in plants. Here, we investigated the roles of aldehydes in mediating Al-induced damage, particularly cell death, using two wheat genotypes with different Al resistances. Aluminum treatment significantly induced cell death, which was accompanied by decreased root activity and cell length. Al-induced cell death displayed granular nuclei and internucleosomal fragmentation of nuclear DNA, suggesting these cells underwent programmed cell death (PCD). During this process, caspase-3-like protease activity was extensively enhanced and showed a significant difference between these two wheat genotypes. Further experiments showed that Al-induced cell death was positively correlated with aldehydes levels. Al-induced representative diagnostic markers for PCD, such as TUNEL-positive nuclei and DNA fragmentation, were further enhanced by the aldehyde donor (E)-2-hexenal, but significantly suppressed by the aldehyde scavenger carnosine. As the crucial executioner of Al-induced PCD, the activity of caspase-3-like protease was further enhanced by (E)-2-hexenal but inhibited by carnosine in wheat roots. These results suggest that reactive aldehydes sourced from lipid peroxidation mediate Al-initiated PCD probably through activating caspase-3-like protease in wheat roots.

Novel Small-Molecule PD-L1 Inhibitor Induces PD-L1 Internalization and Optimizes the Immune Microenvironment.

Blocking the PD-1/PD-L1 interaction has become an important strategy for tumor therapy, which has shown outstanding therapeutic effects in clinical settings. However, unsatisfactory response rates and immune-related adverse effects limit the use of anti-PD1/PD-L1 antibodies. Here, we report the discovery and identification of S4-1, an innovative small-molecule inhibitor of PD-L1. In vitro, S4-1 effectively altered the PD-L1/PD-1 interaction, induced PD-L1 dimerization and internalization, improved its localization to endoplasmic reticulum, and thus enhanced the cytotoxicity of peripheral blood mononuclear cells toward tumor cells. In vivo, S4-1 significantly inhibited tumor growth in both lung and colorectal cancer models, particularly in colorectal cancer, where it led to complete clearance of a portion of the tumor cells. Furthermore, S4-1 induced T-cell activation and inversed the inhibitory tumor microenvironment, consistent with the PD-L1/PD-1 pathway blockade. These data support the continued evaluation of S4-1 as an alternative ICB therapeutic strategy.

Novel phthalimides regulating PD-1/PD-L1 interaction as potential immunotherapy agents.

Programmed cell death 1(PD-1)/programmed cell death ligand 1(PD-L1) have emerged as one of the most promising immune checkpoint targets for cancer immunotherapy. Despite the inherent advantages of small-molecule inhibitors over antibodies, the discovery of small-molecule inhibitors has fallen behind that of antibody drugs. Based on docking studies between small molecule inhibitor and PD-L1 protein, changing the chemical linker of inhibitor from a flexible chain to an aromatic ring may improve its binding capacity to PD-L1 protein, which was not reported before. A series of novel phthalimide derivatives from structure-based rational design was synthesized. P39 was identified as the best inhibitor with promising activity, which not only inhibited PD-1/PD-L1 interaction (IC50 = 8.9 nmol/L), but also enhanced killing efficacy of immune cells on cancer cells. Co-crystal data demonstrated that P39 induced the dimerization of PD-L1 proteins, thereby blocking the binding of PD-1/PD-L1. Moreover, P39 exhibited a favorable safety profile with a LD50 > 5000 mg/kg and showed significant in vivo antitumor activity through promoting CD8+ T cell activation. All these data suggest that P39 acts as a promising small chemical inhibitor against the PD-1/PD-L1 axis and has the potential to improve the immunotherapy efficacy of T-cells.

Aluminum scandium nitride thin-film bulk acoustic resonators for 5G wideband applications.

Bulk acoustic wave (BAW) filters have been extensively used in consumer products for mobile communication systems due to their high performance and standard complementary metal-oxide-semiconductor (CMOS) compatible integration process. However, it is challenging for a traditional aluminum nitride (AlN)-based BAW filter to meet several allocated 5G bands with more than a 5% fractional bandwidth via an acoustic-only approach. In this work, we propose an Al0.8Sc0.2N-based film bulk acoustic wave resonator (FBAR) for the design of radio frequency (RF) filters. By taking advantage of a high-quality Al0.8Sc0.2N thin film, the fabricated resonators demonstrate a large K eff 2 of 14.5% and an excellent figure of merit (FOM) up to 62. The temperature coefficient of frequency (TCF) of the proposed resonator is measured to be -19.2 ppm/°C, indicating excellent temperature stability. The fabricated filter has a center frequency of 4.24 GHz, a -3 dB bandwidth of 215 MHz, a small insertion loss (IL) of 1.881 dB, and a rejection >32 dB. This work paves the way for the realization of wideband acoustic filters operating in the 5G band.

Discovery of Novel Phosphoinositide-3-Kinase α Inhibitors with High Selectivity, Excellent Bioavailability, and Long-Acting Efficacy for Gastric Cancer.

Phosphoinositide-3-kinase (PI3K) overexpressed in many tumors is a promising target for cancer therapy. However, due to toxicity from the ubiquitous expression of PI3K in many tissues, the development of PI3K inhibitors with high selectivity and low toxicity has become an urgent need for tumor treatment. Herein, based on the HipHop, we designed and synthesized a series of 6-(4,6-dimorpholino-1,3,5-triazin-2-yl)benzo[d]oxazol-2-amine derivatives as potent, selective, and long-acting PI3Kα inhibitors. Compound 27 was determined with potent PI3Kα inhibitory activity (IC50 = 4.4 nM), which exhibited excellent selectivity for homologous PI3K enzymes and a 370 kinome panel. Meanwhile, 27 featured favorable stability (T1/2 > 10 h) and high bioavailability (130%). Importantly, compound 27 exerted great antigastric cancer activity in vivo when combined with taxol. Collectively, these characteristics suggested 27 to be a promising PI3K agent for cancer treatment.

Development and clinical advancement of small molecules for ex vivo expansion of hematopoietic stem cell.

Hematopoietic stem cell (HSC) transplantation is the only curative therapy for many diseases. HSCs from umbilical cord blood (UCB) source have many advantages over from bone marrow. However, limited HSC dose in a single CB unit restrict its widespread use. Over the past two decades, ex vivo HSC expansion with small molecules has been an effective approach for obtaining adequate HSCs. Till now, several small-molecule compounds have entered the phase I/II trials, showing safe and favorable pharmacological profiles. As HSC expansion has become a hot topic over recent years, many newly identified small molecules along with novel biological mechanisms for HSC expansion would help solve this challenging issue. Here, we will give an overview of HSC biology, discovery and medicinal chemistry development of small molecules, natural products targeting for HSC expansion, and their recent clinical progresses, as well as potential protein targets for HSC expansion.

Targeting dual-specificity tyrosine phosphorylation-regulated kinase 2 with a highly selective inhibitor for the treatment of prostate cancer.

Prostate cancer (PCa) is one of the most prevalent cancers in men worldwide, and hormonal therapy plays a key role in the treatment of PCa. However, the drug resistance of hormonal therapy makes it urgent and necessary to identify novel targets for PCa treatment. Herein, dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) is found and confirmed to be highly expressed in the PCa tissues and cells, and knock-down of DYRK2 remarkably reduces PCa burden in vitro and in vivo. On the base of DYRK2 acting as a promising target, we further discover a highly selective DYRK2 inhibitor YK-2-69, which specifically interacts with Lys-231 and Lys-234 in the co-crystal structure. Especially, YK-2-69 exhibits more potent anti-PCa efficacy than the first-line drug enzalutamide in vivo. Meanwhile, YK-2-69 displays favorable safety properties with a maximal tolerable dose of more than 10,000 mg/kg and pharmacokinetic profiles with 56% bioavailability. In summary, we identify DYRK2 as a potential drug target and verify its critical roles in PCa. Meanwhile, we discover a highly selective DYRK2 inhibitor with favorable druggability for the treatment of PCa.

Short-chain aldehydes increase aluminum retention and sensitivity by enhancing cell wall polysaccharide contents and pectin demethylation in wheat seedlings.

Upon environmental stimuli, aldehydes are generated downstream of reactive oxygen species and thereby contribute to severe cell damage. In this study, using two wheat genotypes differing in aluminum (Al) tolerance, we investigated the effects of lipid peroxidation-derived aldehydes on cell wall composition and subsequent Al-binding capacities. The spatial accumulation of Al along wheat roots was found to the generation of reactive aldehydes, which are highly localized to the apical regions of roots. Elimination of aldehydes by carnosine significantly reduced Al contents in root tips, with a concomitant alleviation of root growth inhibition. In contrast, root growth and Al accumulation were exacerbated by application of the short-chain aldehyde (E)-2-hexenal. We further confirmed that cell wall binding capacity, rather than malate efflux or pH alteration strategies, is associated with the aldehyde-induced accumulation of Al. Scavenging of lipid-derived aldehydes reduced Al accumulation in the pectin and hemicellulose 1 (HC1) fractions of root cell walls, whereas exposure to (E)-2-hexenal promoted a further accumulation of Al, particularly in the cell wall HC1 fraction of the Al-sensitive genotype. Different strategies were introduced by pectin and HC1 to accumulate Al in response to aldehydes in wheat roots. Accumulation in pectin is based on a reduction of methylation levels in response to elevated pectin methylesterase activity and gene expression, whereas that in HC1 is associated with an increase in polysaccharide contents. These findings indicate that aldehydes exacerbate Al phytotoxicity by enhancing Al retention in cell wall polysaccharides.

Metabolic disturbance in lettuce (Lactuca sativa) plants triggered by imidacloprid and fenvalerate.

Intensive and indiscriminate use of insecticides in agroecosystems causes phytotoxic disturbances in non-target crops. However, the mechanisms by which plants reprogram cellular metabolites to resist and tolerate such agrochemicals remain unclear. Here, the interaction between lettuce plants with imidacloprid and fenvalerate was investigated by the complementary use of physiological and metabolomic analyses. Neither imidacloprid nor fenvalerate induced overt phytotoxicity in lettuce seedlings. The plant biomass, chlorophyll fluorescence, lipid peroxidation, and membrane integrity were not significantly affected by the selected insecticides. Flavonoid content decreased by 25% in lettuce leaves under fenvalerate exposure, whereas polyphenol and flavonoid contents were not significantly altered by imidacloprid. Although the content of most of the nutrient element in the leaves remained the same following pesticide treatment, iron content decreased by 28.1% under imidacloprid exposure but increased by 22.8% under fenvalerate exposure. Metabolomic analysis revealed that the selected insecticides induced extensive metabolic reprogramming in lettuce roots and shoots. Imidacloprid dramatically increased the metabolism of several amino acids (arginine, cysteine, homoserine, and 4-hydroxyisoleucine), whereas markedly decreased the metabolism of various carbohydrates (glucose, raffinose, maltotetraose, maltopentaose, and stachyose). Fenvalerate did not significantly alter amino acid metabolism but decreased carbohydrate metabolism. Additionally, the relative abundance of most organic acids and polyphenolic compounds decreased significantly after pesticide exposure. These results suggest that plants might program their primary and secondary metabolism to resist and tolerate insecticides. The findings of this study provide important information on how neonicotinoid and pyrethroid insecticides affect the health and physiological state of plants, which are ultimately associated with crop yield and quality.

Influence of epidural anesthesia and general anesthesia on thromboembolism in patients undergoing total knee arthroplasty.

OBJECTIVE: This study aimed to explore the application value of epidural and general anesthesia in total knee arthroplasty (TKA). METHODS: We first retrospectively analyzed 156 patients who underwent total knee arthroplasty in our hospital from January 2019 to January 2020 as subjects. The control group (CG) included 86 subject who were treated with general anesthesia. The remaining 70 subjects with epidural anesthesia were divided to a research group (RG). The recovery and adverse reactions after surgery were compared. The coagulation function before and after surgery was analyzed. The incidence of deep vein thrombosis (DVT) after surgery was observed. The expression of inflammatory factors and the improvement of cognitive function were assessed before surgery, followed by 6 and 12 h after surgery. The pain degree of patients was compared at 6 and 12 h after surgery. RESULTS: Compared with the CG, the recovery condition after surgery in the RG were dramatically lower, the concentrations of PLT, PT, and APTT in the RG were higher, while FBG was markedly lower. The incidence of postoperative venous thrombosis in the RG was lower. The TNF-α, IL-6 levels, and VAS scores in the RG were remarkably lower at 6 and 12 h after surgery. MMSE score was significantly higher than CG score. The total incidence of adverse reactions in the RG was markedly lower. CONCLUSION: Epidural anesthesia can improve blood coagulation and cognitive function in patients undergoing TKA and reduce the incidence of DVT and the degree of postoperative pain.

Design, Synthesis, and Biological Evaluation of Icaritin Derivatives as Novel Putative DEPTOR Inhibitors for Multiple Myeloma Treatment.

Icaritin is an active ingredient in Epimedium, which has a variety of pharmacological activities. However, the low activity of Icaritin and the unclear target greatly limit its application. Therefore, based on the structure of Icaritin, we adopted the strategy of replacing toxic groups and introducing active groups to design and synthesize a series of new analogues. The top compound C3 exhibited better antimultiple myeloma activity with an IC50 of 1.09 µM for RPMI 8226 cells, induced RPMI 8226 apoptosis, and blocked the cell cycle in the S phase. Importantly, transcriptome analysis, cellular thermal shift assay, and microscale thermophoresis assay confirmed that DEPTOR was the target of C3. Moreover, we explored its binding mode with C3. Especially, C3 displayed satisfactory inhibition of tumor growth in RPMI 8226 xenografts without obvious side effects. In summary, C3 was discovered as a novel putative inhibitor of DEPTOR for the treatment of multiple myeloma.

Lipid Peroxide-Derived Short-Chain Aldehydes are Involved in Aluminum Toxicity of Wheat (Triticum aestivum) Roots.

Lipid peroxidation is a common event during aluminum (Al) toxicity in plants, and it generates an array of aldehyde fragments. The present study investigated and compared the profile and physiological functions of lipid peroxide-derived aldehydes under Al stress in two wheat genotypes that differed in Al resistance. Under Al stress, the sensitive genotype Yangmai-5 suffered more severe plasma membrane damage and accumulated higher levels of aldehydes in roots than the Al-tolerant genotype Jian-864. The complementary use of high-resolution mass spectrometry and standard compounds allowed the identification and quantification of 13 kinds of short-chain aldehydes sourced from lipids in wheat roots. Among these aldehydes, acetaldehyde, isovaldehyde, valeraldehyde, (E)-2-hexenal (HE), heptaldehyde, and nonyl aldehyde were the predominant species. Moreover, it was found that HE in the sensitive genotype was over 2.63 times higher than that in the tolerant genotype after Al treatment. Elimination of aldehydes using carnosine rescued root growth inhibition by 19.59 and 11.63% in Jian-864 and Yangmai-5, respectively, and alleviated Al-induced membrane damage and protein oxidation. Exogenous aldehyde application further inhibited root elongation and exacerbated oxidative injury. The tolerant genotype Jian-864 showed elevated aldehyde detoxifying enzyme activity and transcript levels. These results suggest that lipid peroxide-derived short-chain aldehydes are involved in Al toxicity, and a higher aldehyde-detoxifying capacity may be responsible for Al tolerance.

Heat shock induces cross adaptation to aluminum stress through enhancing ascorbate-glutathione cycle in wheat seedlings.

Aluminum (Al), a neurotoxin agent, is universal in the earth crust, but its bioavailability and toxicity are manifested under acidic conditions. Up to 60% of the acid soils are distributed in tropical and subtropical regions, where crops simultaneously experience heat-shock stress. Here, we investigated the effects of heat shock-priming on Al tolerance in two different wheat genotypes. Conditioning of wheat seedlings with short period high temperature significantly alleviated Al-induced root growth inhibition, but did not significantly affect Al accumulation. However, we observed that heat shock-primed roots maintained lower levels of lipid peroxidation and higher cell viability. These priming-triggered effects were associated with reactive oxygen species (ROS) homeostasis. Furthermore, conditioning of plants with high temperature increased the contents of reduced ascorbate and glutathione, and ratios of reduced to oxidized forms of these molecules in wheat roots. However, ascorbate or glutathione biosynthesis inhibitors markedly prevented heat shock priming-induced ROS reduction accompanied by aggravated root elongation. Moreover, heat shock-priming enhanced the metabolic intensity of ascorbate-glutathione cycle, as activities of the cycle-allied enzymes were significantly increased. These results suggest that heat-shock induces cross adaptation to Al toxicity through sustaining efficient ascorbate-glutathione cycle operation in wheat plants.

Molecular functions of nitric oxide and its potential applications in horticultural crops.

Nitric oxide (NO) regulates plant growth, enhances nutrient uptake, and activates disease and stress tolerance mechanisms in most plants, making NO a potential tool for use in improving the yield and quality of horticultural crop species. Although the use of NO in horticulture is still in its infancy, research on NO in model plant species has provided an abundance of valuable information on horticultural crop species. Emerging evidence implies that the bioactivity of NO can occur through many potential mechanisms but occurs mainly through S-nitrosation, the covalent and reversible attachment of NO to cysteine thiol. In this context, NO signaling specifically affects crop development, immunity, and environmental interactions. Moreover, NO can act as a fumigant against a wide range of postharvest diseases and pests. However, for effective use of NO in horticulture, both understanding and exploring the biological significance and potential mechanisms of NO in horticultural crop species are critical. This review provides a picture of our current understanding of how NO is synthesized and transduced in plants, and particular attention is given to the significance of NO in breaking seed dormancy, balancing root growth and development, enhancing nutrient acquisition, mediating stress responses, and guaranteeing food safety for horticultural production.

Enalapril inhibits inflammatory osteolysis induced by wear debris in a mouse model.

OBJECTIVE: Aseptic loosening, the most frequent complication after total joint replacement, is probably caused by an inflammatory response to the shedding of wear debris from the implant. The only effective treatment is surgical revision. Using a mouse model, we investigated whether enalapril inhibits wear debris-induced inflammatory osteolysis. METHODS: Titanium (Ti) alloy particles were introduced, and calvarial bone from syngeneic mice was implanted into air pouches established in BALB/c mice. Histological and molecular analyses were performed with inflammatory tissue samples obtained from mice treated with and without enalapril. RESULTS: Enalapril inhibited tissue inflammation and inflammatory osteolysis induced by Ti particles, reducing pouch membrane thickness and decreasing inflammatory cell infiltration. In addition, enalapril inhibited the expression of the inflammatory cytokines vascular endothelial growth factor and tumor necrosis factor-α. CONCLUSIONS: Our study provides evidence that enalapril inhibits Ti particle-induced inflammatory osteolysis, and it may be a potentially useful treatment for aseptic loosening.