Transition Metal Oxide Nanomaterials: New Weapons to Boost Anti-Tumor Immunity Cycle.

Semiconductor nanomaterials have emerged as a significant factor in the advancement of tumor immunotherapy. This review discusses the potential of transition metal oxide (TMO) nanomaterials in the realm of anti-tumor immune modulation. These binary inorganic semiconductor compounds possess high electron mobility, extended ductility, and strong stability. Apart from being primary thermistor materials, they also serve as potent agents in enhancing the anti-tumor immunity cycle. The diverse metal oxidation states of TMOs result in a range of electronic properties, from metallicity to wide-bandgap insulating behavior. Notably, titanium oxide, manganese oxide, iron oxide, zinc oxide, and copper oxide have garnered interest due to their presence in tumor tissues and potential therapeutic implications. These nanoparticles (NPs) kickstart the tumor immunity cycle by inducing immunogenic cell death (ICD), prompting the release of ICD and tumor-associated antigens (TAAs) and working in conjunction with various therapies to trigger dendritic cell (DC) maturation, T cell response, and infiltration. Furthermore, they can alter the tumor microenvironment (TME) by reprogramming immunosuppressive tumor-associated macrophages into an inflammatory state, thereby impeding tumor growth. This review aims to bring attention to the research community regarding the diversity and significance of TMOs in the tumor immunity cycle, while also underscoring the potential and challenges associated with using TMOs in tumor immunotherapy.

Quantum Dots as a Potential Multifunctional Material for the Enhancement of Clinical Diagnosis Strategies and Cancer Treatments.

Quantum dots (QDs) represent a class of nanoscale wide bandgap semiconductors, and are primarily composed of metals, lipids, or polymers. Their unique electronic and optical properties, which stem from their wide bandgap characteristics, offer significant advantages for early cancer detection and treatment. Metal QDs have already demonstrated therapeutic potential in early tumor imaging and therapy. However, biological toxicity has led to the development of various non-functionalized QDs, such as carbon QDs (CQDs), graphene QDs (GQDs), black phosphorus QDs (BPQDs) and perovskite quantum dots (PQDs). To meet the diverse needs of clinical cancer treatment, functionalized QDs with an array of modifications (lipid, protein, organic, and inorganic) have been further developed. These advancements combine the unique material properties of QDs with the targeted capabilities of biological therapy to effectively kill tumors through photodynamic therapy, chemotherapy, immunotherapy, and other means. In addition to tumor-specific therapy, the fluorescence quantum yield of QDs has gradually increased with technological progress, enabling their significant application in both in vivo and in vitro imaging. This review delves into the role of QDs in the development and improvement of clinical cancer treatments, emphasizing their wide bandgap semiconductor properties.

Effects of Soil Conditioner (Volcanic Ash) on Yield Quality and Rhizosphere Soil Characteristics of Melon.

In this study, the effects of soil conditioners on the growth and development of melons and the rhizosphere soil environment were explored. The optimal amount of added soil conditioner was screened to solve the practical production problems of high-quality and high-yield thin-skinned melon. The melon variety "Da Shetou" was used as the material. Under the conditions of conventional fertilization and cultivation technology management, different soil conditioners were set up for potted melons. The effects of Pastoral soil (CK), 95% Pastoral soil + 5% volcanic ash soil conditioner (KT1), 85% Pastoral soil + 15% volcanic ash soil conditioner (KT2), 75% Pastoral soil + 25% volcanic ash soil conditioner (KT3), 65% Pastoral soil + 35% volcanic ash soil conditioner (KT4), and 55% Pastoral soil + 45% volcanic ash soil conditioner (KT5) on melon yield, quality, and rhizosphere soil characteristics were investigated. The soil microbial community was analyzed using Illumina MiSeq technology. Compared to CK, KT1, KT3, KT4, and KT5, the KT2 treatment could improve the single fruit yield of melon, increasing it by 4.35%, 2.48%, 2.31%, 5.92%, and 2.92%. Meanwhile, the highest contents of soluble protein, soluble solid, and soluble sugar in the KT2 treatment were 1.89 mg·100 g-1, 16.35%, and 46.44 mg·g-1, which were significantly higher than those in the control treatment. The contents of organic matter, total nitrogen, alkali-soluble nitrogen, nitrate nitrogen, ammonium nitrogen, available potassium, and available phosphorus in melon rhizosphere soil were the highest in the KT2 treatment. Through Alpha diversity analysis, it was found that the Chao1 index, Shannon index, and ACE index were significantly higher in the KT1 treatment than in the control, while, among all groups, the Simpson index and coverage were not significantly different. The dominant bacteria in the six treated samples were mainly Actinobacteriota, Proteobacteria, Cyanobacteria, Chloroflexi, Acidobacteria, Bacteroidetes, Myxomycota, Firmicutes, Gemmatimonadota, Verrucomicrobia, and Planctomycetes, which accounted for 96.59~97.63% of the relative abundance of all bacterial groups. Through redundancy analysis (RDA), it was found that the organic matter, electrical conductivity, available phosphorus, and nitrate nitrogen of melon rhizosphere soil were the dominant factors of bacterial community change at the dominant genus level. In summary, 15% ash soil conditioner applied on melon was the selected treatment to provide a theoretical reference for the application of soil conditioner in facility cultivation.

Development of CDK12 as a Cancer Therapeutic Target and Related Inhibitors.

Cyclin-dependent Kinase 12 (CDK12) is a Cyclin-dependent Kinase (CDK) that plays a crucial role in various biological processes, including transcription, translation, mRNA splicing, cell cycle regulation, and DNA damage repair. Dysregulation of CDK12 has been implicated in tumorigenesis, and genetic alterations affecting CDK12 have been identified in multiple cancer types, including breast cancer, ovarian cancer, gastric cancer, and prostate cancer. Numerous studies have demonstrated that suppression of CDK12 expression effectively inhibits tumor growth and proliferation, underscoring its significance as a cancer biomarker and a potential therapeutic target in cancer treatment. A thorough comprehension of CDK12 is expected to significantly enhance the advancement of novel approaches for the treatment and prevention of cancer. In recent times, endeavors have been undertaken to formulate targeted inhibitors for CDK12, such as PROTAC and molecular gel degraders. Concurrently, investigations have been conducted on the combined utilization of CDK12 small molecule inhibitors and immunotherapy as a potential strategy. This paper examines the diverse functions of CDK12 in the modulation of gene expression and its implications in human tumors. Specifically, it explores the recently uncovered roles of CDK12 kinases in various cellular processes, emphasizing the potential of CDK12 as a viable therapeutic target for the management of human tumors. Furthermore, this review provides an up-to-- date account of the advancements made in utilizing CDK12 in tumor therapy.

Aerial signaling by plant-associated Streptomyces setonii WY228 regulates plant growth and enhances salt stress tolerance.

Plant-associated streptomycetes play important roles in plant growth and development. However, knowledge of volatile-mediated crosstalk between Streptomyces spp. and plants remains limited. In this study, we investigated the impact of volatiles from nine endophytic Streptomyces strains on the growth and development of plants. One versatile strain, Streptomyces setonii WY228, was found to significantly promote the growth of Arabidopsis thaliana and tomato seedlings, confer salt tolerance, and induce early flowering and increased fruit yield following volatile treatment. Analysis of plant growth-promoting traits revealed that S. setonii WY228 could produce indole-3-acetic acid, siderophores, ACC deaminase, fix nitrogen, and solubilize inorganic phosphate. These capabilities were further confirmed through genome sequencing and analysis. Volatilome analysis indicated that the volatile organic compounds emitted from ISP-2 medium predominantly comprised sesquiterpenes and 2-ethyl-5-methylpyrazine. Further investigations showed that 2-ethyl-5-methylpyrazine and sesquiterpenoid volatiles were the primary regulators promoting growth, as confirmed by experiments using the terpene synthesis inhibitor phosphomycin, pure compounds, and comparisons of volatile components. Transcriptome analysis, combined with mutant and inhibitor studies, demonstrated that WY228 volatiles promoted root growth by activating Arabidopsis auxin signaling and polar transport, and enhanced root hair development through ethylene signaling activation. Additionally, it was confirmed that volatiles can stimulate plant abscisic acid signaling and activate the MYB75 transcription factor, thereby promoting anthocyanin synthesis and enhancing plant salt stress tolerance. Our findings suggest that aerial signaling-mediated plant growth promotion and abiotic stress tolerance represent potentially overlooked mechanisms of Streptomyces-plant interactions. This study also provides an exciting strategy for the regulation of plant growth and the improvement of horticultural crop yields within sustainable agricultural practices.

Advances in ovarian tumor stem cells and therapy.

Ovarian cancer is considered the most lethal among all gynecological malignancies due to its early metastatic dissemination, extensive spread, and malignant ascites. The current standard of care for advanced ovarian cancer involves a combination of cytoreductive surgery and chemotherapy utilizing platinum-based and taxane-based agents. Although initial treatment yields clinical remission in 70-80% of patients, the majority eventually develop treatment resistance and tumor recurrence. A growing body of evidence indicates the existence of cancer stem cells within diverse solid tumors, including ovarian cancer, which function as a subpopulation to propel tumor growth and disease advancement by means of drug resistance, recurrence, and metastasis. The presence of ovarian cancer stem cells is widely considered to be a significant contributor to the unfavorable clinical outcomes observed in patients with ovarian cancer, as they play a crucial role in mediating chemotherapy resistance, recurrence, and metastasis. Ovarian cancer stem cells possess the capacity to reassemble within the entirety of the tumor following conventional treatment, thereby instigating the recurrence of ovarian cancer and inducing resistance to treatment. Consequently, the creation of therapeutic approaches aimed at eliminating ovarian cancer stem cells holds great potential for the management of ovarian cancer. These cells are regarded as one of the most auspicious targets and mechanisms for the treatment of ovarian cancer. There is a pressing need for a comprehensive comprehension of the fundamental mechanisms of ovarian cancer's recurrence, metastasis, and drug resistance, alongside the development of effective strategies to overcome chemoresistance, metastasis, and recurrence. The implementation of cancer stem cell therapies may potentially augment the tumor cells' sensitivity to existing chemotherapy protocols, thereby mitigating the risks of tumor metastasis and recurrence, and ultimately improving the survival rates of ovarian cancer patients.

In Situ Collection and SERS Detection of Nitrite in Exhalations on Facemasks Based on Wettability Differences.

As one of the common carriers of biological information, along with human urine specimens and blood, exhaled breath condensate (EBC) carries reliable and rich information about the body's metabolism to track human physiological normal/abnormal states and environmental exposures. What is more, EBC has gained extensive attention because of the convenient and nondestructive sampling. Facemasks, which act as a physical filter barrier between human exhaled breath and inhaled substances from the external environment, are safe, noninvasive, and economic devices for direct sampling of human exhaled breath and inhaled substances. Inspired by the ability of fog collection of Namib desert beetle, a strategy for in situ collecting and detecting EBC with surface-enhanced Raman scattering is illustrated. Based on the intrinsic and unique wettability differences between the squares and the surrounding area of the pattern on facemasks, the hydrophilic squares can capture exhaled droplets and spontaneously enrich the analytes and silver nanocubes (AgNCs), resulting in good repeatability in situ detection. Using R6G as the probe molecule, the minimal detectable concentration can reach as low as 10-16 M, and the relative standard deviation is less than 7%. This proves that this strategy can achieve high detection sensitivity and high detection repeatability. Meanwhile, this strategy is applicable for portable nitrite analysis in EBC and may provide an inspiration for monitoring other biomarkers in EBC.

The emergence, isolation, and phylogenetic analysis of a closely related human strain of parainfluenza virus 5 from a case of porcine reproductive and respiratory syndrome in China.

Reports of Parainfluenza virus 5 (PIV5) epidemics have been on a global upward trend, with an expanding host range across various animals. In 2020, we isolated a PIV5 strain from a PRRSV-positive serum sample. This strain was named GX2020. Genetic analysis revealed that GX2020 belongs to group A, represented by the AGS strain isolated from a human in the USA. Comparisons of amino acid identity in the coding regions showed that GX2020 had the highest amino acid identity (99.6%) with the AGS strain. The emergence of PIV5 strains genetically similar to human strains in pigs highlights its zoonotic potential and underscores the need for enhanced PIV5 surveillance in the future.

Preoperative prediction of histopathological grading in patients with chondrosarcoma using MRI-based radiomics with semantic features.

BACKGROUND: Distinguishing high-grade from low-grade chondrosarcoma is extremely vital not only for guiding the development of personalized surgical treatment but also for predicting the prognosis of patients. We aimed to establish and validate a magnetic resonance imaging (MRI)-based nomogram for predicting preoperative grading in patients with chondrosarcoma. METHODS: Approximately 114 patients (60 and 54 cases with high-grade and low-grade chondrosarcoma, respectively) were recruited for this retrospective study. All patients were treated via surgery and histopathologically proven, and they were randomly divided into training (n = 80) and validation (n = 34) sets at a ratio of 7:3. Next, radiomics features were extracted from two sequences using the least absolute shrinkage and selection operator (LASSO) algorithms. The rad-scores were calculated and then subjected to logistic regression to develop a radiomics model. A nomogram combining independent predictive semantic features with radiomic by using multivariate logistic regression was established. The performance of each model was assessed by the receiver operating characteristic (ROC) curve analysis and the area under the curve, while clinical efficacy was evaluated via decision curve analysis (DCA). RESULTS: Ultimately, six optimal radiomics signatures were extracted from T1-weighted imaging (T1WI) and T2-weighted imaging with fat suppression (T2WI-FS) sequences to develop the radiomics model. Tumour cartilage abundance, which emerged as an independent predictor, was significantly related to chondrosarcoma grading (p < 0.05). The AUC values of the radiomics model were 0.85 (95% CI, 0.76 to 0.95) in the training sets, and the corresponding AUC values in the validation sets were 0.82 (95% CI, 0.65 to 0.98), which were far superior to the clinical model AUC values of 0.68 (95% CI, 0.58 to 0.79) in the training sets and 0.72 (95% CI, 0.57 to 0.87) in the validation sets. The nomogram demonstrated good performance in the preoperative distinction of chondrosarcoma. The DCA analysis revealed that the nomogram model had a markedly higher clinical usefulness in predicting chondrosarcoma grading preoperatively than either the rad-score or clinical model alone. CONCLUSION: The nomogram based on MRI radiomics combined with optimal independent factors had better performance for the preoperative differentiation between low-grade and high-grade chondrosarcoma and has potential as a noninvasive preoperative tool for personalizing clinical plans.

Projection du fardeau du cancer au Canada en 2024.

CONTEXTE: Les données de surveillance du cancer sont essentielles pour mieux comprendre les lacunes et les progrès réalisés dans la lutte contre le cancer. Nous avons cherché à résumer les répercussions prévues du cancer au Canada en 2024, en effectuant des projections sur les nouveaux cas de cancer et les décès par cancer, par sexe et par province ou territoire, pour tous les âges confondus. MÉTHODES: Nous avons obtenu les données sur les nouveaux cas de cancer (c.-à-d., l'incidence, 1984­2019) et les décès par cancer (c.-à-d., la mortalité, 1984­2020) du Registre canadien du cancer et de la Base canadienne de données de l'état civil ­ Décès, respectivement. Nous avons projeté les chiffres et les taux d'incidence du cancer et de mortalité jusqu'en 2024 pour 23 types de cancer, par sexe et par province ou territoire. Nous avons calculé des taux normalisés selon l'âge au moyen de données de la population type canadienne de 2011. RÉSULTATS: En 2024, les nombres de nouveaux cas de cancer et de décès causés par le cancer devraient atteindre 247 100 et 88 100, respectivement. Le taux d'incidence normalisé selon l'âge (TINA) et le taux de mortalité normalisé selon l'âge (TMNA) devraient diminuer légèrement par rapport aux années précédentes, tant chez les hommes que chez les femmes, avec des taux plus élevés chez les hommes (TINA de 562,2 pour 100 000, et TMNA de 209,6 pour 100 000 chez les hommes; TINA de 495,9 pour 100 000 et TMNA de 152,8 pour 100 000 chez les femmes). Les TINA et les TMNA de plusieurs cancers courants devraient continuer à diminuer (p. ex., cancer du poumon, cancer colorectal et cancer de la prostate), tandis que ceux de plusieurs autres cancers devraient augmenter (p. ex., cancer du foie et des voies biliaires intrahépatiques, cancer du rein, mélanome et lymphome non hodgkinien). INTERPRÉTATION: Bien que l'incidence globale du cancer et la mortalité connexe sont en déclin, il devrait y avoir une augmentation des nouveaux cas et des décès au Canada en 2024, en grande partie en raison de la croissance et du vieillissement de la population. Les efforts en matière de prévention, de dépistage et de traitement ont atténué les répercussions de certains cancers, mais ces projections à court terme soulignent l'effet potentiel du cancer sur les gens et les systèmes de soins de santé au Canada.

2 × 4†kW near-single-mode laser output assisted by an optimized bidirectional oscillating-amplifying integrated fiber laser configuration.

Bidirectional output oscillating-amplifying integrated fiber laser (B-OAIFL) can achieve the two-ports laser amplification based on a single cavity, showcasing a promising prospect. In order to improve both the laser power and beam quality, we first simulate and optimize the stimulated Raman scattering (SRS) effect in the B-OAIFL. The simulation results show the SRS effect can be suppressed by optimizing the diameter as well as the length of the active fiber at different locations. With the guidance of theoretical and experimental analysis for the combined suppression of SRS and transverse mode instability (TMI), a near-single-mode B-OAIFL with 2 × 4 kW was demonstrated. Based on this foundation, we further devoted ourselves to the pursuit of the optimization of the structure and performance. The necessity of the configuration of side pump, which was initially introduced for its exceptional performance in stabilizing temporal chaos, was reevaluated in detail. With its negative impacts on efficiency improvement and SRS suppression were analyzed and verified, we removed this configuration and finally demonstrated a more simplified design with superior performance. A total bidirectional output of 8105 W was achieved, with an O-O efficiency of 79.6% and a near-single-mode beam quality of M A 2∼1.36,M B 2∼1.63. No signs of TMI were observed, and the signal-to-SRS suppression ratio was over 38 dB. The results still demonstrate a promising potential for power scaling based on this configuration and parameters.

Machine learning-based nomogram: integrating MRI radiomics and clinical indicators for prognostic assessment in acute ischemic stroke.

Background: Acute Ischemic Stroke (AIS) remains a leading cause of mortality and disability worldwide. Rapid and precise prognostication of AIS is crucial for optimizing treatment strategies and improving patient outcomes. This study explores the integration of machine learning-derived radiomics signatures from multi-parametric MRI with clinical factors to forecast AIS prognosis. Objective: To develop and validate a nomogram that combines a multi-MRI radiomics signature with clinical factors for predicting the prognosis of AIS. Methods: This retrospective study involved 506 AIS patients from two centers, divided into training (n = 277) and validation (n = 229) cohorts. 4,682 radiomic features were extracted from T1-weighted, T2-weighted, and diffusion-weighted imaging. Logistic regression analysis identified significant clinical risk factors, which, alongside radiomics features, were used to construct a predictive clinical-radiomics nomogram. The model's predictive accuracy was evaluated using calibration and ROC curves, focusing on distinguishing between favorable (mRS ≤ 2) and unfavorable (mRS > 2) outcomes. Results: Key findings highlight coronary heart disease, platelet-to-lymphocyte ratio, uric acid, glucose levels, homocysteine, and radiomics features as independent predictors of AIS outcomes. The clinical-radiomics model achieved a ROC-AUC of 0.940 (95% CI: 0.912-0.969) in the training set and 0.854 (95% CI: 0.781-0.926) in the validation set, underscoring its predictive reliability and clinical utility. Conclusion: The study underscores the efficacy of the clinical-radiomics model in forecasting AIS prognosis, showcasing the pivotal role of artificial intelligence in fostering personalized treatment plans and enhancing patient care. This innovative approach promises to revolutionize AIS management, offering a significant leap toward more individualized and effective healthcare solutions.

A neuromorphic device mimicking synaptic plasticity under different body fluid K+ homeostasis for artificial reflex path construction and pattern recognition.

The ionic environment of body fluids influences nervous functions for maintaining homeostasis in organisms and ensures normal perceptual abilities and reflex activities. Neural reflex activities, such as limb movements, are closely associated with potassium ions (K+). In this study, we developed artificial synaptic devices based on ion concentration-adjustable gels for emulating various synaptic plasticities under different K+ concentrations in body fluids. In addition to performing essential synaptic functions, potential applications in information processing and associative learning using short- and long-term plasticity realized using ion concentration-adjustable gels are presented. Artificial synaptic devices can be used for constructing an artificial neural pathway that controls artificial muscle reflex activities and can be used for image pattern recognition. All tests show a strong relationship with ion homeostasis. These devices could be applied to neuromorphic robots and human-machine interfaces.

Fine particulate matter components associated with exacerbated depressive symptoms among middle-aged and older adults in China.

Growing awareness acknowledges ambient fine particulate matter (PM2.5) as an environmental risk factor for mental disorders, especially among older people. However, there remains limited evidence regarding which specific chemical components of PM2.5 may be more detrimental. This nationwide prospective cohort study included 22,126 middle-aged and older adult participants of the China Health and Retirement Longitudinal Study (CHARLS, 2011-2016), to explore the individual and joint associations between long-term exposure to various PM2.5 components (sulfate, nitrate, ammonium, organic matter, and black carbon) and depressive symptoms. The depressive symptoms were assessed using the 10-item Center for Epidemiological Studies-Depression Scale (CES-D-10). Using the novel quantile-based g-computation for multi-pollutant mixture analysis, we found that exposure to the mixture of major PM2.5 components was significantly associated with aggravating depressive symptoms, with the exposure-response curve exhibiting consistent linear or supra-linear shape without a lower threshold. The estimated weight index indicated that, among major PM2.5 components, only nitrate, sulfate, and black carbon significantly contributed to the exacerbation of depressive symptoms. Given the expanding aging population, stricter regulation on the emissions of particularly toxic PM2.5 components may mitigate the escalating disease burden of depression.

Lipidomics Study of Type 1 Diabetic Rats Using Online Phase Transition Trapping-Supercritical Fluid Extraction-Chromatography Coupled with Quadrupole Time-of-Flight Tandem Mass Spectrometry.

Chromatography-mass spectrometry-based lipidomics represents an essential tool for elucidating lipid dysfunction mechanisms and is extensively employed in investigating disease mechanisms and identifying biomarkers. However, the detection of low-abundance lipids in biological matrices, along with cumbersome operational procedures, complicates comprehensive lipidomic analyses, necessitating the development of highly sensitive, environmentally friendly, and automated methods. In this study, an online phase transition trapping-supercritical fluid extraction-chromatography-mass spectrometry (PTT-SFEC-MS/MS) method was developed and successfully applied to plasma lipidomics analysis in Type 1 diabetes (T1D) rats. The PTT strategy captured entire extracts at the column head by converting CO2 from a supercritical state to a gaseous state, thereby preventing peak spreading, enhancing peak shape for precise quantification, and boosting sensitivity without any sample loss. This method utilized only 5 µL of plasma and accomplished sample extraction, separation, and detection within 27 min. Ultimately, 77 differential lipids were identified, including glycerophospholipids, sphingolipids, and glycerolipids, in T1D rat plasma. The results indicated that the progression of the disease might be linked to alterations in glycerophospholipid and sphingolipid metabolism. Our findings demonstrated a green, highly efficient, and automated method for the lipidomics analysis of biological samples, providing a scientific foundation for understanding the pathogenesis and diagnosis of T1D.

The role of α7nAchR and PD-L1 in neuroimmune regulation of keloid treatment.

Keloid formation, characterized by aberrant fibroproliferation and immune dysregulation, remains a challenging clinical concern. This study aims to elucidate the neuroimmune mechanisms underlying keloid pathogenesis and explores the efficacy of a combined treatment approach involving modulation of the α7 nicotinic acetylcholine receptor (α7nAchR), a key player in neural transmission, and programmed death ligand 1 (PD-L1), an immune checkpoint molecule, for keloid intervention. A key innovation lies in the identification of signal peptide-CUB-EGF-like domain-containing protein 3 (SCUBE3) as a potential target gene influenced by this dual treatment. We elucidate the underlying mechanism, wherein the hypoxic keloid microenvironment fosters an upsurge in SCUBE3 secretion. Subsequently, SCUBE3 forms complexes with TGF-ß, initiating the activation of the PI3K/AKT/NF-κB signaling pathway. Notably, SCUBE3 is secreted in the form of exosomes, thereby exerting a profound influence on the differentiation of T cells and macrophages within the keloid milieu. This research not only provides a comprehensive understanding of the molecular mechanisms involved but also offers a promising avenue for the development of targeted therapies to address keloid-associated fibrosis and immune dysregulation. In conclusion, the combined inhibition of α7nAchR and PD-L1 represents a promising therapeutic strategy with SCUBE3 as a pivotal molecular target in the complex landscape of keloid pathophysiology.

Advanced Design, Synthesis, and Evaluation of Highly Selective Wee1 Inhibitors: Enhancing Pharmacokinetics and Antitumor Efficacy.

Wee1 is a kinase that regulates cell cycle arrest in response to DNA damage. Wee1 inhibition is a potential strategy to suppress the growth of tumors with defective p53 or DNA repair pathways. However, the development of Wee1 inhibitors faces some challenges. AZD1775, the first-in-class Wee1 inhibitor, has poor kinase selectivity and dose-limiting toxicity. Here, we report the discovery of 12h, a highly selective and potent Wee1 inhibitor with a favorable pharmacokinetic profile. 12h showed strong antiproliferative effects against Lovo cells, a colorectal cancer cell line, both in vitro and in vivo. Moreover, 12h showed a clean kinase profile and effectively induced cell apoptosis. Our results suggest that 12h is a promising drug candidate for further development as a novel anticancer agent.

[Molecular modification of cyclodextrin glucosyltransferase and its application in the synthesis of α-arbutin].

α-arbutin has important applications in cosmetics and medicine. However, the extraction yield from plant tissues is relatively low, which restricts its application value. In this study, we investigated the synthesis of α-arbutin using maltodextrin as the donor and hydroquinone as the acceptor, using a cyclodextrin glucosyltransferase (CGTase) from Anaerobranca gottschalkii. We performed site-saturated and site-directed mutagenesis on AgCGTase. The activity of the variant AgCGTase-F235G-N166H was 3.48 times higher than that of the wild type. Moreover, we achieved a conversion rate of 63% by optimizing the reaction pH, temperature, and hydroquinone addition amount. Overall, this study successfully constructed a strain with improved conversion rate for the synthetic production of α-arbutin and hydroquinone. These findings have significant implications for reducing the industrial production cost of α-arbutin and enhancing the conversion rate of the product.

Hyaluronic Acid-Modified Spherical MgO2/Pd Nanocomposites Exhibit Superior Antitumor Effect through Tumor Microenvironment-Responsive Ferroptosis Induction and Photothermal Therapy.

Metal peroxide nanomaterials as efficient hydrogen peroxide (H2O2) self-supplying agents have attracted the attention of researchers for antitumor treatment. However, relying solely on metal peroxides to provide H2O2 is undoubtedly insufficient to achieve optimal antitumor effects. Herein, we construct novel hyaluronic acid (HA)-modified nanocomposites (MgO2/Pd@HA NCs) formed by decorating palladium nanoparticles (Pd NPs) onto the surfaces of a magnesium peroxide (MgO2) nanoflower as a highly effective nanoplatform for the tumor microenvironment (TME)-responsive induction of ferroptosis in tumor cells and tumor photothermal therapy (PTT). MgO2/Pd@HA NC could be well endocytosed into tumor cells with CD44 expression depending on the specific recognition of HA with CD44, and then, the nanocomposites can be rapidly decomposed in mild acid and hyaluronidase overexpressed TME, and plenty of H2O2 was released. Simultaneously, Pd NPs catalyze self-supplied H2O2 to generate abundant hydroxyl radicals (•OH) and catalyze glutathione (GSH) into glutathione disulfide owing to its peroxidase and glutathione oxidase mimic enzyme activities, while the abundant •OH could also consume GSH in tumor cells and disturb the defense pathways of ferroptosis leading to the accumulation of lipid peroxidation and resulting in the occurrence of ferroptosis. Additionally, the superior photothermal conversion performance of Pd NPs in near-infrared II could also be used for PTT, synergistically cooperating with nanocomposite-induced ferroptosis for tumor inhibition. Consequently, the successfully prepared TME-responsive MgO2/Pd@HA NCs exhibited marked antitumor effect without obvious biotoxicity, contributing to thoroughly explore the nanocomposites as a novel and promising treatment for tumor therapy.

Exposure of pregnant women to neonicotinoids in Wenzhou City, East China: A biomonitoring study.

BACKGROUND: China produces and consumes a large amount of neonicotinoids. A non-negligible exposure to neonicotinoids might occur for Chinese pregnant women, but relevant data remain limited. OBJECTIVE: To investigate the exposure to neonicotinoids by urinary biomonitoring in pregnant women from Wenzhou City, East China. METHODS: We selected 432 pregnant women in Wenzhou City in 2022. A total of eight parent neonicotinoids and four metabolites were determined in single spot urine by liquid chromatography coupled to mass spectrometry. Basic characteristics, physical activity, pre-pregnant body mass index, and intake of drinking water and food were investigated by the questionnaire. Health risk was assessed by hazard quotient (HQ) and hazard index (HI) based on human safety thresholds derived from different health endpoints. RESULTS: Neonicotinoids and their metabolites in urine had a detection frequency between 0 % and 80.1 %. At least one neonicotinoid or metabolite was detected in 93.5 % of urine samples. Except for clothianidin (51.2 %) and N-desmethyl-acetamiprid (80.1 %), the detection frequencies of other neonicotinoids and metabolites ranged from 0 % to 43.8 %. The summed concentrations of all neonicotinoids and their metabolites ranged from < LOD to 222.83 µg/g creatinine with the median concentration of 2.58 µg/g creatinine. Maternal age, educational level, occupation, household income, screen time, and pre-pregnant body mass index were associated with detection frequencies or concentrations of neonicotinoids and their metabolites. Pregnant women with higher consumption frequencies of wheat, fresh vegetable, shellfish, fresh milk, and powdered milk had higher detection frequencies of neonicotinoids and their metabolites. Both HQ and HI were less than one. CONCLUSIONS: Overall, pregnant women in Wenzhou City showed a notable frequency of exposure to at least one neonicotinoid, although the exposure frequency for each specific neonicotinoid was generally low. Several food items derived from plants and animals were potential exposure sources. A low health risk was found based on current safety thresholds.