Hyperactivation of SREBP induces Pannexin-1-dependent lytic cell death.

Sterol-regulatory element binding proteins (SREBPs) are a conserved transcription factor family governing lipid metabolism. When cellular cholesterol level is low, SREBP2 is transported from the endoplasmic reticulum to the Golgi apparatus where it undergoes proteolytic activation to generate a soluble N-terminal fragment, which drives the expression of lipid biosynthetic genes. Malfunctional SREBP activation is associated with various metabolic abnormalities. In this study, we find that overexpression of the active nuclear form SREBP2 (nSREBP2) causes caspase-dependent lytic cell death in various types of cells. These cells display typical pyroptotic and necrotic signatures, including plasma membrane ballooning and release of cellular contents. However, this phenotype is independent of the gasdermin family proteins or mixed lineage kinase domain-like (MLKL). Transcriptomic analysis identifies that nSREBP2 induces expression of p73, which further activates caspases. Through whole-genome CRISPR-Cas9 screening, we find that Pannexin-1 (PANX1) acts downstream of caspases to promote membrane rupture. Caspase-3 or 7 cleaves PANX1 at the C-terminal tail and increases permeability. Inhibition of pore-forming activity of PANX1 alleviates lytic cell death. PANX1 can mediate gasdermins and MLKL-independent cell lysis during TNF-induced or chemotherapeutic reagents (doxorubicin or cisplatin)-induced cell death. Together, this study uncovers a noncanonical function of SREBPs as a potentiator of programmed cell death and suggests that PANX1 can directly promote lytic cell death independent of gasdermins and MLKL.

Case report: Pathological complete response induced by immunochemotherapy in a case of Pulmonary Sarcomatoid Carcinoma staged IIIA-N2.

Pulmonary sarcomatoid carcinoma (PSC) represents a rare and highly aggressive variant of lung cancer, characterized by its recalcitrance to conventional therapeutic modalities and the attendant dismal prognosis it confers. Recent breakthroughs in immunotherapy have presented novel prospects for PSC patients; nevertheless, the utility of neoadjuvant/conversional immunotherapy in the context of PSC remains ambiguous. In this report, we present a middle-aged male presenting with Stage III PSC, notable for its high expression of the programmed death-ligand 1 (PD-L1), initially deemed as non-resectable for sizeable tumor mass and multiple lymph nodes metastases. The patient underwent a transformation to a resectable state after a regimen of three cycles of platinum-based chemotherapy plus immunotherapy. Following definitive surgical resection, the individual realized a pathological complete response (pCR), culminating in a significant prolongation of event-free survival (EFS). This case underscores the viability of employing immunochemotherapy as a neoadjuvant/conversional strategy for chosen cases of PSC.

Photoinduced decatungstate-catalyzed C(sp3)-H thioetherification by sulfinate salts.

Thiols and thioesters play crucial roles in pharmaceuticals, biology, and material science as essential organosulfur compounds. Leveraging readily available and cost-effective inert alkanes through direct thioetherification holds promise for yielding high-value-added products. Herein, we present a photoinduced strategy for sulfur-containing modification of inert alkanes utilizing decatungstate as hydrogen atom transfer reagent, offering a straightforward and practical approach for synthesizing thioethers and thioesters.

A sterol analog inhibits hedgehog pathway by blocking cholesterylation of smoothened.

The hedgehog (Hh) signaling pathway has long been a hotspot for anti-cancer drug development due to its important role in cell proliferation and tumorigenesis. However, most clinically available Hh pathway inhibitors target the seven-transmembrane region (7TM) of smoothened (SMO), and the acquired drug resistance is an urgent problem in SMO inhibitory therapy. Here, we identify a sterol analog Q29 and show that it can inhibit the Hh pathway through binding to the cysteine-rich domain (CRD) of SMO and blocking its cholesterylation. Q29 suppresses Hh signaling-dependent cell proliferation and arrests Hh-dependent medulloblastoma growth. Q29 exhibits an additive inhibitory effect on medulloblastoma with vismodegib, a clinically used SMO-7TM inhibitor for treating basal cell carcinoma (BCC). Importantly, Q29 overcomes resistance caused by SMO mutants against SMO-7TM inhibitors and inhibits the activity of SMO oncogenic variants. Our work demonstrates that the SMO-CRD inhibitor can be a new way to treat Hh pathway-driven cancers.

Difference in muscle metabolism caused by metabolism disorder of rainbow trout liver exposed to ammonia stress.

Ammonia pollution is an important environmental stress factors in water eutrophication. The intrinsic effects of ammonia stress on liver toxicity and muscle quality of rainbow trout were still unclear. In this study, we focused on investigating difference in muscle metabolism caused by metabolism disorder of rainbow trout liver at exposure times of 0, 3, 6, 9 h at 30 mg/L concentrations. Liver transcriptomic analysis revealed that short-term (3 h) ammonia stress inhibited carbohydrate metabolism and glycerophospholipid production but long-term (9 h) ammonia stress inhibited the biosynthesis and degradation of fatty acids, activated pyrimidine metabolism and mismatch repair, lead to DNA strand breakage and cell death, and ultimately caused liver damage. Metabolomic analysis of muscle revealed that ammonia stress promoted the reaction of glutamic acid and ammonia to synthesize glutamine to alleviate ammonia toxicity, and long-term (9 h) ammonia stress inhibited urea cycle, hindering the alleviation of ammonia toxicity. Moreover, it accelerated the consumption of flavor amino acids such as arginine and aspartic acid, and increased the accumulation of bitter substances (xanthine) and odorous substances (histamine). These findings provide valuable insights into the potential risks and hazards of ammonia in eutrophic water bodies subject to rainbow trout.

Rapid classification of whole milk powder and skimmed milk powder by laser-induced breakdown spectroscopy combined with feature processing method and logistic regression.

Whole milk powder and skimmed milk powder are suitable for different groups of people due to their differences in composition. Therefore, a rapid classification method for whole milk powder and skimmed milk powder is urgently needed. In this paper, a novel strategy based on laser-induced breakdown spectroscopy (LIBS) and feature processing methods combined with logistic regression (LR) was constructed for the classification of milk powder. A LR classification model based on mini-batch gradient descent (MGD) was employed first. As indicated by the research results, the accuracy of the MGD-LR model for the milk powder samples in the test set is 96.33% and the modeling time is 33.07 s. The modeling efficiency is low and needs to be improved. Principal components analysis (PCA) and mutual information (MI) were used as feature processing methods to reduce the high dimensional LIBS data into fewer features for improving the modeling efficiency of the classification model. The research results indicate that the accuracy of the PCA-MGD-LR model and the MI-MGD-LR model for the test set of milk powder samples was 99.33% and 99.67%, respectively. Compared with MGD-LR model, the modeling efficiency of PCA-MGD-LR and MI-MGD-LR models has increased by 89.7% and 74.8%, respectively. The results fully demonstrate the feasibility of rapid milk powder classification based on LIBS and feature processing methods combined with LR, and it will provide a new technology for the identification and classification of milk powder.

Hierarchically decorated magnetic nanoparticles amplify the oxidative stress and promote the chemodynamic/magnetic hyperthermia/immune therapy.

Magnetic nanoparticles (MNPs) are promising in tumor treatments due to their capacity for magnetic hyperthermia therapy (MHT), chemodynamic therapy (CDT), and immuno-related therapies, but still suffer from unsatisfactory tumor inhibition in the clinic. Insufficient hydrogen peroxide supply, glutathione-induced resistance, and high-density extracellular matrix (ECM) are the barriers. Herein, we hierarchically decorated MNPs with disulfide bonds (S-S), dendritic L-arginine (R), and glucose oxidase (GOx) to form a nanosystem (MNPs-SS-R-GOx). Its outer GOx layer not only enhanced the H2O2 supply to produce .OH by Fenton reaction, but also generated stronger oxidants (ONOO-) together with the interfaced R layer. The inner S-S layer consumed glutathione to interdict its reaction with oxidants, thus enhancing CDT effects. Importantly, the generated ONOO- tripled the MMP-9 expression to induce ECM degradation, enabling much deeper penetration of MNPs and benefiting CDT, MHT, and immunotherapy. Finally, the MNPs-SS-R-GOx demonstrated a remarkable 91.7% tumor inhibition in vivo. STATEMENT OF SIGNIFICANCE: Magnetic nanoparticles (MNPs) are a promising tumor therapeutic agent but with limited effectiveness. Our hierarchical MNP design features disulfide bonds (S-S), dendritic L-arginine (R), and glucose oxidase (GOx), which boosts H2O2 supply for ·OH generation in Fenton reactions, produces potent ONOO-, and enhances chemodynamic therapy via glutathione consumption. Moreover, the ONOO- facilitates the upregulation of matrix metalloprotein expression beneficial for extracellular matrix degradation, which in turn enhances the penetration of MNPs and benefits the antitumor CDT/MHT/immuno-related therapy. In vivo experiments have demonstrated an impressive 91.7% inhibition of tumor growth. This hierarchical design offers groundbreaking insights for further advancements in MNP-based tumor therapy. Its implications extend to a broader audience, encompassing those interested in material science, biology, oncology, and beyond.

Strategy for reducing the effect of surface fluctuation in the classification of aluminum alloy via data transfer and laser-induced breakdown spectroscopy.

Laser-induced breakdown spectroscopy (LIBS) plays an increasingly important role in the classification and recycling of aluminum alloys owing to its outstanding elemental analysis performance. For LIBS measurements with sample surface fluctuations, consistently and exactly maintaining the laser and fiber focus points on the sample surface is difficult, and fluctuations in the focus severely affect the stability of the spectrum. In this study, a data transfer method is introduced to reduce the effect of spectral fluctuations on the model performance. During the experiment, a focal point is placed on the sample surface. Then, keeping experimental conditions unchanged, the three-dimensional platform is only moved up and down along the z-axis by 0.5 mm, 1 mm, 1.5 mm, 2 mm and 2.5 mm, respectively. Eleven spectral datasets at different heights are collected for analysis. The KNN model is used as the base classifier, and the accuracies of the 11 datasets, from the lowest to the highest, are 11.48%, 19.71%, 30.57%, 45.71%, 53.57%, 88.28%, 52.57%, 21.42%, 14.42%, 14.42%, and 14.42%. To improve predictive performance, the difference in data distribution between the spectra collected at the sample surface and those collected at other heights is reduced by data transfer. Feature selection is introduced and combined with data transfer, and the final accuracies are 78.14%, 82.28%, 80.14%, 89.71%, 91.85%, 98.42%, 94.28%, 92.42%, 82.14%, 78.57%, and 73.71%. It can be seen that the proposed method provides a new feasible and effective way for the classification of aluminum alloys in a real detection environment.

[Medication rules of Chinese herbal compound prescriptions for treating angina in national patent database based on multiple data mining].

This study explored the medication rules of Chinese herbal compound prescriptions for the treatment of angina based on the Chinese herbal compound patents in the patent database of the China National Intellectual Property Administration. The data of eligible Chinese herbal compound patents for the treatment of angina were collected from the patent database of the China National Intellectual Property Administration from database inception to November 10, 2022, and subjected to data modeling, analysis of main syndromes, medication frequency analysis, cluster analysis, association rule analysis, and data visualization by using Excel 2021, IBM SPSS Statistics 26.0, IBM SPSS Modeler 18.0, Cytoscape 3.9.1, and Rstudio R 4.2.2.2 to explore the medication rules for angina. The study included 636 pieces of patent data for angina that met the inclusion criteria, involving 815 drugs, with a total frequency of 6 586. The most common main syndromes were blood stasis obstructing the heart syndrome(222, 34.91%) and Qi deficiency and blood stasis syndrome(112, 17.61%). The top 10 most frequently used drugs were Salviae Miltiorrhizae Radix et Rhizoma, Chuanxiong Rhizoma, Notoginseng Radix et Rhizoma, Astragali Radix, Angelicae Sinensis Radix, Carthami Flos, Glycyrrhizae Radix et Rhizoma, Ginseng Radix et Rhizoma, Borneolum Syntheticum, and Corydalis Rhizoma. High-frequency drugs included blood-activating and stasis-resolving drugs(1 197, 18.17%) and deficiency-tonifying drugs(809, 12.28%). Cluster analysis identified eight drug combinations, including five new prescriptions suitable for clinical use and new drug development, and three drug pairs. The core drug combination of Salviae Miltiorrhizae Radix et Rhizoma-Chuanxiong Rhizoma-Carthami Flos was identified through the complex co-occurrence network analysis of Chinese medicines. Association rule analysis yielded a total of 17 rules, including 13 drug pairs and 4 tripartite combinations. Common drug pairs included Salviae Miltiorrhizae Radix et Rhizoma-Chuanxiong Rhizoma(support degree 25.79%, confidence coefficient 69.49%, lift 1.30) and Salviae Miltiorrhizae Radix et Rhizoma-Notoginseng Radix et Rhizoma(support degree 22.01%, confidence coefficient 61.95%, lift 1.16). Common tripartite combinations included Salviae Miltiorrhizae Radix et Rhizoma-Chuanxiong Rhizoma-Astragali Radix(support degree 10.85%, confidence coefficient 73.40%, lift 1.37) and Salviae Miltiorrhizae Radix et Rhizoma-Chuanxiong Rhizoma-Notoginseng Radix et Rhizoma(support degree 10.69%, confidence coefficient 79.07%, lift 1.48). The results showed that the underlying pathogenesis of angina involved blood stasis obstructing the heart and Qi deficiency and blood stasis. The overall nature of the disease was characterized as asthenia in origin and sthenia in superficiality. In the prescription formulation, blood-activating and stasis-resolving drugs, such as Salviae Miltiorrhizae Radix et Rhizoma, Chuanxiong Rhizoma, and Carthami Flos were often used to resolve the excess manifestation, which were combined with tonifying drugs such as Astragali Radix, Angelicae Sinensis Radix, Glycyrrhizae Radix et Rhizoma, and Ginseng Radix et Rhizoma to reinforce the deficiency. The syndrome, pathogenesis, disease nature, and medication were consistent with clinical practice. Additionally, the new compound prescriptions and drug combinations derived from the multiple data mining in this study could provide references and insights for the clinical diagnosis and treatment of angina and the development of new drugs.

Application of Virtual Reality Technology in Post-Stroke Depression.

Post-stroke depression (PSD) is one of the most common complications of emotional disorders after stroke, and the recovery effect of clinical intervention using conventional means is limited. As an emerging technology, virtual reality technology provides a new idea for the clinical rehabilitation of patients with post-stroke depression. Through literature retrieval and review of domestic and foreign studies, this paper summarizes the development of virtual reality technology in psychotherapy. This paper expounds the application value of virtual reality technology in post-stroke depression, summarizes the common types of virtual reality technology combined with conventional intervention to treat post-stroke depression, and analyzes the influence of virtual reality technology on physical and mental rehabilitation of patients with post-stroke depression combined with empirical data. At the same time, the positive significance of virtual reality technology popularization and application is discussed. Finally, it is concluded that virtual reality technology can make up for the shortcomings of traditional treatment in the application of post-stroke depression, and can effectively improve the physical and mental state of patients. The application prospect is broad, but there is still room for development and improvement.

Lipid-anchored proteasomes control membrane protein homeostasis.

Protein degradation in eukaryotic cells is mainly carried out by the 26S proteasome, a macromolecular complex not only present in the cytosol and nucleus but also associated with various membranes. How proteasomes are anchored to the membrane and the biological meaning thereof have been largely unknown in higher organisms. Here, we show that N-myristoylation of the Rpt2 subunit is a general mechanism for proteasome-membrane interaction. Loss of this modification in the Rpt2-G2A mutant cells leads to profound changes in the membrane-associated proteome, perturbs the endomembrane system, and undermines critical cellular processes such as cell adhesion, endoplasmic reticulum-associated degradation and membrane protein trafficking. Rpt2G2A/G2A homozygous mutation is embryonic lethal in mice and is sufficient to abolish tumor growth in a nude mice xenograft model. These findings have defined an evolutionarily conserved mechanism for maintaining membrane protein homeostasis and underscored the significance of compartmentalized protein degradation by myristoyl-anchored proteasomes in health and disease.

Energy value measurement of milk powder using laser-induced breakdown spectroscopy (LIBS) combined with long short-term memory (LSTM).

Milk powder can provide the necessary nutrients for the growth of infants, and the level of its energy value is an important factor in the measurement of its nutritional value. Therefore, the measurement of the energy value in milk powder is of great significance for the nutritional health of infants. In this study, samples of 32 different brands of milk powder were selected for spectral analysis, and laser-induced breakdown spectroscopy (LIBS) combined with deep belief network (DBN), back propagation (BP) neural network, and long short-term memory (LSTM) models was used to achieve quantitative analysis of the energy value of the milk powder. The experimental results revealed that the LSTM model outperformed the DBN and BP models in terms of accuracy, with a mean relative error (MREP) of 1.0029%, which was 73.03% lower than that of DBN (3.7186%) and 69.53% lower than that of BP (3.2914%). Moreover, the determination coefficient (RP2) value improved significantly from 0.9341 for DBN and 0.9766 for BP to 0.9984. In addition, the root mean square error (RMSEP) decreased to 0.2140 from 0.7042 for DBN and 0.9051 for BP. These results demonstrate that the LSTM model has superior predictive performance compared to the other models. Therefore, the combination of LIBS and LSTM can accurately measure the energy value of milk powder and provide an effective and feasible means for its commercial measurement.

Rapid Generation of Recombinant Flaviviruses Using Circular Polymerase Extension Reaction.

The genus Flavivirus is a group of arthropod-borne single-stranded RNA viruses, which includes important human and animal pathogens such as Japanese encephalitis virus (JEV), Zika virus (ZIKV), Dengue virus (DENV), yellow fever virus (YFV), West Nile virus (WNV), and Tick-borne encephalitis virus (TBEV). Reverse genetics has been a useful tool for understanding biological properties and the pathogenesis of flaviviruses. However, the conventional construction of full-length infectious clones for flavivirus is time-consuming and difficult due to the toxicity of the flavivirus genome to E. coli. Herein, we applied a simple, rapid, and bacterium-free circular polymerase extension reaction (CPER) method to synthesize recombinant flaviviruses in vertebrate cells as well as insect cells. We started with the de novo synthesis of the JEV vaccine strain SA-14-14-2 in Vero cells using CPER, and then modified the CPER method to recover insect-specific flaviviruses (ISFs) in mosquito C6/36 cells. Chimeric Zika virus (ChinZIKV) based on the Chaoyang virus (CYV) backbone and the Culex flavivirus reporter virus expressing green fluorescent protein (CxFV-GFP) were subsequently rescued in C6/36 cells. CPER is a simple method for the rapid generation of flaviviruses and other potential RNA viruses. A CPER-based recovery system for flaviviruses of different host ranges was established, which would facilitate the development of countermeasures against flavivirus outbreaks in the future.

Delivery of low-density lipoprotein from endocytic carriers to mitochondria supports steroidogenesis.

The low-density lipoprotein (LDL) is a major cholesterol carrier in circulation and is internalized into cells through LDL receptor (LDLR)-mediated endocytosis. The LDLR protein is highly expressed in the steroidogenic organs and LDL cholesterol is an important source for steroidogenesis. Cholesterol must be transported into the mitochondria, where steroid hormone biosynthesis initiates. However, how LDL cholesterol is conveyed to the mitochondria is poorly defined. Here, through genome-wide small hairpin RNA screening, we find that the outer mitochondrial membrane protein phospholipase D6 (PLD6), which hydrolyses cardiolipin to phosphatidic acid, accelerates LDLR degradation. PLD6 promotes the entrance of LDL and LDLR into the mitochondria, where LDLR is degraded by mitochondrial proteases and LDL-carried cholesterol is used for steroid hormone biosynthesis. Mechanistically, the outer mitochondrial membrane protein CISD2 binds to the cytosolic tail of LDLR and tethers LDLR+ vesicles to the mitochondria. The fusogenic lipid phosphatidic acid generated by PLD6 facilitates the membrane fusion of LDLR+ vesicles with the mitochondria. This intracellular transport pathway of LDL-LDLR bypasses the lysosomes and delivers cholesterol to the mitochondria for steroidogenesis.

Lipid-anchored Proteasomes Control Membrane Protein Homeostasis.

Protein degradation in eukaryotic cells is mainly carried out by the 26S proteasome, a macromolecular complex not only present in the cytosol and nucleus but also associated with various membranes. How proteasomes are anchored to the membrane and the biological meaning thereof have been largely unknown in higher organisms. Here we show that N-myristoylation of the Rpt2 subunit is a general mechanism for proteasome-membrane interaction. Loss of this modification in the Rpt2-G2A mutant cells leads to profound changes in the membrane-associated proteome, perturbs the endomembrane system and undermines critical cellular processes such as cell adhesion, endoplasmic reticulum-associated degradation (ERAD) and membrane protein trafficking. Rpt2 G2A/G2A homozygous mutation is embryonic lethal in mice and is sufficient to abolish tumor growth in a nude mice xenograft model. These findings have defined an evolutionarily conserved mechanism for maintaining membrane protein homeostasis and underscored the significance of compartmentalized protein degradation by m yristoyl- a nchored p roteasomes (MAPs) in health and disease.

Optimal utilization of ecological economic resources and low-carbon economic analysis from the perspective of Public Health.

Introduction: China's urbanization process continues to deepen with social development, but the optimal utilization of ecological, economic resources and Public Health (PH) problems are becoming increasingly severe. Methods: This paper analyses the optimal use of urban resources based on PH. Here, the public space of urban settlements is selected as the research object. Firstly, the connotation and essence of the ecological economy and Low-Carbon Economy (LCE) are analyzed. Secondly, the characteristics of public space in urban settlements are studied based on PH. The public space satisfaction evaluation model in urban settlements is constructed with five first-level and 12 second-level indicators. Finally, a questionnaire is designed to analyze urban households' outdoor activities and evaluate public space in settlements. Results: The influencing factors of residents' satisfaction with public space in settlements are obtained through regression analysis. The results show that residents' satisfaction with the public space of the settlement is mainly evaluated from three aspects: the accessibility of public space, the integrity of public space, and the pleasure of public space. The influence coefficients are 0.355, 0.346, and 0.223, respectively, indicating that the influence degree of the three principal factors decreases in turn. Conclusion: We can optimize the utilization of urban residential public space resources from the aspects of accessibility, integrity and pleasure, so as to promote residents to go to public spaces for outdoor activities and physical exercise, which is more conducive to the public health of residents.

Iron-Catalyzed C(Sp3)-H Borylation, Thiolation, and Sulfinylation Enabled by Photoinduced Ligand-to-Metal Charge Transfer.

Catalytic C(sp3)-H functionalization has provided enormous opportunities to construct organic molecules, facilitating the derivatization of complex pharmaceutical compounds. Within this framework, direct hydrogen atom transfer (HAT) photocatalysis becomes an appealing approach to this goal. However, the viable substrates utilized in these protocols are limited, and the site selectivity shows preference to activated and thermodynamically favored C(sp3)-H bonds. Herein, we describe the development of undirected iron-catalyzed C(sp3)-H borylation, thiolation, and sulfinylation reactions enabled by the photoinduced ligand-to-metal charge transfer (LMCT) process. These reactions exhibit remarkably broad substrate scope (>150 examples in total), and most importantly, all of these three reactions show unconventional regioselectivity, with the occurrence of C(sp3)-H borylation, thiolation, and sulfinylation preferentially at the distal methyl position. The procedures are operationally simple and readily scalable and provide access to high-value products from simple hydrocarbons in one step. Mechanistic studies and control experiments indicate that the afforded site selectivity is not only relevant to the HAT species but also largely affected by the use of boron- and sulfone-based radical acceptors.

Controlled intracellular aggregation of magnetic particles improves permeation and retention for magnetic hyperthermia promotion and immune activation.

Rationale: Magnetic nanoparticles (MNPs) are the most used inorganic nanoparticles in clinics with therapeutic and imaging functions, but the inefficient magneto-thermal conversion efficiency, fast leakage, and uneven distribution impair their imaging sensitivity and therapeutic efficacy in tumors. Methods: Herein, we rationally designed a system containing pH-controllable charge-reversible MNPs (M20@DPA/HA) and negatively charged MMPs with different sizes (M5 and M20), which could induce intracellular aggregation. The dynamic hydrazone bonds with pH controllability were formed by the surface hydrazides on MNPs and aldehydes of hyaluronic acid (HA). Under the acidic pH, intracellular aggregation of the complex composed by M20@DPA/HA and M5 (M5&20), or M20@DPA/HA and M20 (M20&20) were investigated. In addition, the magnetic hyperthermia therapy (MHT) efficiency of tumor cells, tumor-associated macrophages polarization, giant cells formation and immune activation of tumor microenvironment were explored via a series of cell and animal model experiments. Results: Through physical and chemical characterization, the aggregation system (M20&20) exhibited a remarkable 20-fold increase in magnetothermal conversion efficiency compared to individual MNPs, together with enhanced penetration and retention inside the tumor tissues. In addition, it could promote immune activation, including repolarization of tumor-associated macrophages, as well as the formation of giant cells for T cell recruitment. As a result, the M20&20 aggregation system achieved a high degree of inhibition in 4T1 mouse mammary tumor model, with little tumor growth and metastasis after magnetic hyperthermia therapy. Conclusions: A controlled intracellular aggregation system was herein developed, which displayed an aggregation behavior under the acidic tumor microenvironment. The system significantly enhanced MHT effect on tumor cells as well as induced M1 polarization and multinucleated giant cells (MGC) formation of TAM for immune activation. This controlled aggregation system achieved barely tumor growth and metastasis, showing a promising strategy to improve MNPs based MHT on deteriorate cancers.

Development and validation of a radiomics-based nomogram for predicting a major pathological response to neoadjuvant immunochemotherapy for patients with potentially resectable non-small cell lung cancer.

Introduction: The treatment response to neoadjuvant immunochemotherapy varies among patients with potentially resectable non-small cell lung cancers (NSCLC) and may have severe immune-related adverse effects. We are currently unable to accurately predict therapeutic response. We aimed to develop a radiomics-based nomogram to predict a major pathological response (MPR) of potentially resectable NSCLC to neoadjuvant immunochemotherapy using pretreatment computed tomography (CT) images and clinical characteristics. Methods: A total of 89 eligible participants were included and randomly divided into training (N=64) and validation (N=25) sets. Radiomic features were extracted from tumor volumes of interest in pretreatment CT images. Following data dimension reduction, feature selection, and radiomic signature building, a radiomics-clinical combined nomogram was developed using logistic regression analysis. Results: The radiomics-clinical combined model achieved excellent discriminative performance, with AUCs of 0.84 (95% CI, 0.74-0.93) and 0.81(95% CI, 0.63-0.98) and accuracies of 80% and 80% in the training and validation sets, respectively. Decision curves analysis (DCA) indicated that the radiomics-clinical combined nomogram was clinically valuable. Discussion: The constructed nomogram was able to predict MPR to neoadjuvant immunochemotherapy with a high degree of accuracy and robustness, suggesting that it is a convenient tool for assisting with the individualized management of patients with potentially resectable NSCLC.

Serine-arginine protein kinase 1 (SRPK1) promotes EGFR-TKI resistance by enhancing GSK3ß Ser9 autophosphorylation independent of its kinase activity in non-small-cell lung cancer.

Resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is a major challenge for clinicians and patients with non-small cell lung cancer (NSCLC). Serine-arginine protein kinase 1 (SRPK1) is a key oncoprotein in the EGFR/AKT pathway that participates in tumorigenesis. We found that high SRPK1 expression was significantly associated with poor progression-free survival (PFS) in patients with advanced NSCLC undergoing gefitinib treatment. Both in vitro and in vivo assays suggested that SRPK1 reduced the ability of gefitinib to induce apoptosis in sensitive NSCLC cells independently of its kinase activity. Moreover, SRPK1 facilitated binding between LEF1, ß-catenin and the EGFR promoter region to increase EGFR expression and promote the accumulation and phosphorylation of membrane EGFR. Furthermore, we verified that the SRPK1 spacer domain bound to GSK3ß and enhanced its autophosphorylation at Ser9 to activate the Wnt pathway, thereby promoting the expression of Wnt target genes such as Bcl-X. The correlation between SRPK1 and EGFR expression was confirmed in patients. In brief, our research suggested that the SRPK1/GSK3ß axis promotes gefitinib resistance by activating the Wnt pathway and may serve as a potential therapeutic target for overcoming gefitinib resistance in NSCLC.