Sialic Acid-Functionalized Pyroptosis Nanotuner for Epigenetic Regulation and Enhanced Cancer Immunotherapy.

The efficacy of immune checkpoint blockade (ICB) in promoting an immune response against tumors still encounters challenges such as low response rates and off-target effects. Pyroptosis, an immunogenic cell death (ICD) mechanism, holds the potential to overcome the limitations of ICB by activating and recruiting immune cells. However, the expression of the pyroptosis-related protein Gasdermin-E(GSDME) in some tumors is limited due to mRNA methylation. To overcome this obstacle, sialic acid-functionalized liposomes coloaded with decitabine, a demethylation drug, and triclabendazole, a pyroptosis-inducing drug are developed. This nanosystem primarily accumulates at tumor sites via sialic acid and the Siglec receptor, elevating liposome accumulation in tumors up to 3.84-fold at 24 h and leading to the upregulation of pyroptosis-related proteins and caspase-3/GSDME-dependent pyroptosis. Consequently, it facilitates the infiltration of CD8+ T cells into the tumor microenvironment and enhances the efficacy of ICB therapy. The tumor inhibition rate of the treatment group is 89.1% at 21 days. This study highlights the potential of sialic acid-functionalized pyroptosis nanotuners as a promising approach for improving the efficacy of ICB therapy in tumors with low GSDME expression through epigenetic alteration and ICD.

DNA methylation of IFI44L as a potential blood biomarker for childhood-onset systemic lupus erythematosus.

BACKGROUND: IFN-induced protein 44-like (IFI44L) promoter methylation has been demonstrated to serve as an effective blood diagnostic biomarker for adult-onset SLE. However, its utility as a diagnostic marker for childhood-onset SLE (cSLE) remains to be verified. METHODS: Initially, we conducted a differential analysis of gene methylation and mRNA expression patterns in cSLE whole blood samples obtained from the public GEO database to determine IFI44L gene expression and assess the methylation status at its CpG sites. Subsequently, we collected clinical whole blood samples from 49 cSLE patients and 12 healthy children, employing an HRM-qPCR-based IFI44L methylation detection technique to evaluate its diagnostic efficacy in pediatric clinical practice. RESULTS: A total of 26 hypomethylated, highly expressed genes in cSLE were identified by intersecting differentially expressed genes (DEGs) and differentially methylation genes (DMGs). GO enrichment analysis for these 26 genes indicated a robust association with type I IFN. Among the overlapping genes, IFI44L exhibited the most pronounced differential expression and methylation. In subsequent clinical validation experiments, IFI44L methylation was confirmed as an effective blood-based diagnostic biomarker for cSLE, achieving an AUC of 0.867, a sensitivity of 0.753, and a specificity of 1.000. CONCLUSIONS: IFI44L methylation is a promising blood biomarker for cSLE. IMPACT: IFI44L promoter methylation was reported to serve as a highly sensitive and specific diagnostic marker for adult-onset SLE. However, the diagnostic efficacy of IFI44L in childhood-onset SLE (cSLE) still remains to be confirmed. In this study, we utilized bioinformatics analysis and conducted clinical experiments to demonstrate that IFI44L methylation can also serve as a promising blood biomarker for cSLE. The findings of this study can facilitate the diagnosis of cSLE and broaden our understanding of its molecular mechanisms, with a particular focus on those related to type I interferons.

[Oblique Lumbar Interbody Fusion Combined With 4-Screw Fixation for Treating Two-Level Degenerative Lumbar Diseases:A Finite Element Study].

Objective To demonstrate the feasibility of oblique lumbar interbody fusion (OLIF) combined with 4-screw fixation for treating two-level lumbar degenerative diseases.Methods An intact finite element model of L3-S1 (M0) was constructed and validated.Then,we constructed the M1 model by simulating OLIF surgery at L3/4 and L4/5 segments on the M0 model.By attachment of posterior 4-screw or 6-screw fixation to the M1 model,three 4-screw fixation models (M2-M4) and one 6-screw fixation model (M5) were established.The segmental and overall range of motion (ROM) and the peak von Mises stresses of superior endplate,cage,and posterior screw-rod were investigated under each implanted condition.Results Under the motion modes of forward flexion,backward extension,bilateral (left and right) flexion,and left and right rotation,the L3/4 ROM of M2 model and L4/5 ROM of M3 model increased,while the L3/4 and L4/5 ROM of M4 and M5 models significantly decreased compared with those of M1 model.Under all motion modes,the L4 superior endplate in M2 model and the L5 superior endplate in M3 model showed the maximum peak von Mises stress,and the peak von Mises stresses of L4 and L5 superior endplates in M4 and M5 models were close.The L3/4 cage in M2 model and the L4/5 cage in M3 model showcased the largest peak von Mises stress,and the peak von Mises stresses of cages in M4 and M5 models were close.The peak stresses of internal fixation in M2-M5 models were close.Conclusion Four-screw fixation can replace 6-screw fixation in the OLIF surgery for treating two-level degenerative lumbar diseases.

Evaluation of belimumab in treatment of Chinese childhood-onset systemic lupus erythematosus: a prospective analysis from multicenter study.

OBJECTIVE: The aim of this study is to identify whether low lupus disease activity status (LLDAS) and clinical remission (CR) of belimumab plus standard of care (SoC) therapy are achievable goals in childhood-onset SLE (cSLE). METHODS: This multicentre, one arm pre-post intervention study was conducted at 15 centers in China. The primary end point was to describe the proportion of patients who achieved LLDAS and CR after 3, 6, and 12 months after treatment with belimumab plus SoC therapy. A multiple regression model was used to impute missing data. A Poisson regression model was used to calculate the effect of belimumab treatment on the reduced risk of serious diseases and the incidence of new damage. RESULT: 193 (92.2% female) with active cSLE from 15 centers were included. At 3, 6 and 12 months, the proportion of LLDAS (CR) was 12.4% (1.0%), 25.6% (4.5%) and 70.3% (29.7%), respectively. The mean SELENA-SLEDAI score decreased from 11.0 at baseline to 3.7, 2.9 and 1.7 at 3, 6, and 12 months. At baseline, all patients received steroids at a mean (SD) prednisone equivalent dose of 31.0 (18.2) mg/day, which decreased to 19.4 (10.8) mg/day at month 3, 12.6 (7.2) mg/day at month 6 and 6.7 (5.3) mg/day at month 12. The symptoms and immunological indicators were also significantly improved. CONCLUSION: This is the first and largest sample size prospective clinical intervention study of cSLE patients treated with belimumab in China. LLDAS and CR were attainable treat-to-target of belimumab plus SoC therapy in cSLE.

Nanodrug Delivery Strategies to Signaling Pathways in Alopecia.

Over 50% of the global population suffers from hair loss. The mixed results in the treatment of hair loss reveal the limitations of conventional commercial topical drugs. One the one hand, the definite pathogenesis of hair loss is still an enigma. On the other hand, targeted drug carriers ensure the drug therapeutic effect and low side effects. This review highlights the organization and overview of nine crucial signaling pathways associated with hair loss, as well as the development of nanobased topical delivery systems loading the clinical drugs, which will fuel emerging hair loss treatment strategies.

Analysis of efficacy and safety of abatacept for rheumatoid arthritis: systematic review and meta-analysis.

OBJECTIVES: Abatacept (Orencia) is a drug used to treat patients with rheumatoid arthritis. The agent improves patients' pain and joint inflammation through modulation of a co-stimulatory signal necessary for T cell activation. We aimed to analyse the efficacy and safety of abatacept in the management of rheumatoid arthritis using the Cochrane systematic review. METHODS: We conducted a systematic search among PubMed, Cochrane central register of controlled trials, Web of Science, and Embase databases from the establishment of these databases to April 2022. The effectiveness and safety of abatacept in treating rheumatoid arthritis were assessed in terms of American College of Rheumatology (ACR) 20/50/70/90 responses, Disease Activity Score-28 for Rheumatoid Arthritis with C-reactive protein (DAS-28-CRP), and adverse events. The Relative Risks (RRs) of relative safety and efficacy and their corresponding 95 confidence intervals (CIs) were used to compute the pooled assessments of the outcomes. We used the review manager software version 5.4 to analyse our data, and the PRISMA checklist 2020 was used to ensure that our work conforms with the specification of meta-analysis. RESULTS: Our study included 13 randomised control trials with a total of 5978 adult patients from different geographic regions and races. Following the combined analysis of these enrolled studies, the RRs for ACR 20/50/70/90 responses were 1.57 [95%CI 1.27, 1.93], 1.84 [95%CI 1.38, 2.44], 2.36 [95%CI 1.60, 3.47], and 2.95 [95%CI 1.88, 4.63], respectively. Such findings suggest that abatacept-treated patients were 1.57, 1.84, 2.36, and 2.95 times more likely to achieve ACR 20/50/70/90 responses, respectively, than those treated with placebo, conventional synthetic disease-modifying antirheumatic drugs, and or other biologic disease-modifying anti-rheumatic drugs. An exclusive comparison of abatacept and other biologic/targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) indicated that participants who were treated with abatacept could achieve better ACR responses than those treated with other b/tsDMARDs. Adverse events were less seen in abatacept-treated patients than in those who were given other b/tsDMARDs. CONCLUSIONS: This meta-analysis concludes that in adult with rheumatoid arthritis, abatacept can achieve better health outcomes than other biologic drugs.

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Systemic lupus erythematosus (SLE) is an autoimmune disease that affects multiple organ systems, presenting a complex and diverse clinical manifestation. The heterogeneous treatment response and prognosis of SLE pose significant challenges to its diagnosis, classification, and homogeneous treatment. The emergence of new technologies and fields, such as synthetic biology, genomics, and proteomics, has contributed to a deeper exploration of the pathogenesis and biomarkers of SLE, facilitating precision diagnosis and treatment. This review summarizes the latest research data and achievements in SLE for the years 2021-2022, providing an overview and summary of relevant studies conducted in the past two years.

Decreased Resting-State Functional Complexity in Elderly with Subjective Cognitive Decline.

Individuals with subjective cognitive decline (SCD) are at high risk of developing preclinical or clinical state of Alzheimer's disease (AD). Resting state functional magnetic resonance imaging, which can indirectly reflect neuron activities by measuring the blood-oxygen-level-dependent (BOLD) signals, is promising in the early detection of SCD. This study aimed to explore whether the nonlinear complexity of BOLD signals can describe the subtle differences between SCD and normal aging, and uncover the underlying neuropsychological implications of these differences. In particular, we introduce amplitude-aware permutation entropy (AAPE) as the novel measure of brain entropy to characterize the complexity in BOLD signals in each brain region of the Brainnetome atlas. Our results demonstrate that AAPE can reflect the subtle differences between both groups, and the SCD group presented significantly decreased complexities in subregions of the superior temporal gyrus, the inferior parietal lobule, the postcentral gyrus, and the insular gyrus. Moreover, the results further reveal that lower complexity in SCD may correspond to poorer cognitive performance or even subtle cognitive impairment. Our findings demonstrated the effectiveness and sensitiveness of the novel brain entropy measured by AAPE, which may serve as the potential neuroimaging marker for exploring the subtle changes in SCD.

Rituximab treatment for lupus nephritis: A systematic review.

PURPOSE: We used the Cochrane systematic review to analyze the effectiveness and safety of rituximab for lupus nephritis. METHODS: Systematic search was performed among Cochrane clinical controlled trials database, MEDLINE, MEDLINE-IN-Process and Other Non-Indexed Citations, EMBASE, EBSCO CINAHL, CNKI, VIP and Wanfang database from the establishment of the database to February 2016. The effectiveness and safety were evaluated in terms of the complete remission rate, total remission rate, urinary protein, Systemic Lupus Erythematosus Disease Activity Index changes and adverse events rate. Data were analyzed by the Review Manager Software version 5.3. RESULTS: Five RCTs that met the inclusion criteria, including a total of 238 patients, were enrolled in our study. The results showed that the complete remission rate in rituximab group was a significantly higher than that of cyclophosphamide group. The difference between the two groups was statistically significant (OR=2.80, 95%CI(1.08,7.26), P=0.03). But there was no significant difference between the two groups in partial and total remission rate. The complete remission rate, partial remission rate and total remission rate in rituximab treatment group was similar compared with mycophenolate mofetil group and rituximab combined with cyclophosphamide group. The adverse reaction rate was also similar among the groups. CONCLUSION: The study systematically analyzed the effectiveness and safety of rituximab for lupus nephritis, which suggested that the complete remission rate of rituximab in the treatment of lupus nephritis was a significantly higher than that of cyclophosphamide group, while the effectiveness and safety was of no difference compared with cyclophosphamide and mycophenolate mofetil.

Podocytic infolding in Schimke immuno-osseous dysplasia with novel SMARCAL1 mutations: a case report.

BACKGROUND: Schimke immuno-osseous dysplasia (SIOD) is a rare autosomal recessive disorder characterized by spondyloepiphyseal dysplasia, progressive renal insufficiency and defective cellular immunity. Podocytic infolding glomerulopathy (PIG) is a newly proposed disease entity characterized by microspheres or microtubular structures associated with podocytes infolding into the glomerular basement membrane (GBM) on electron microscopy (EM). CASE PRESENTATION: A 4-year-old boy was admitted to our ward due to proteinuria and edema lasting 1 month. He had a short trunk and demonstrated subtle dysmorphology, with a triangular shape, a broad nasal bridge and a bulbous nasal tip. The laboratory findings were as follows: lymphocytes, 0.5 × 109/L; urine protein, 3.67 g/d; albumin, 9.8 g/L; and cholesterol, 11.72 mmol/L. Skeletal X rays showed small iliac wings, small ossification centers of the capital femoral epiphyses, shallow dysplastic acetabular fossae and mildly flattened vertebrae. The specimen for light microscopy (LM) suggested focal segmental glomerulosclerosis (FSGS). EM revealed a focal thickness of the GBM with some cytoplasmic processes of podocyte infolding into the GBM. Gene sequencing showed novel compound heterozygous mutations in the SMARCAL1 gene (c.2141 + 5G > A; c.2528 + 1G > A) that were inherited from his parents. Finally, we established the diagnosis of SIOD and treated him with diuretics and angiotensin-converting enzyme inhibitors (ACEIs). CONCLUSION: The pathogenic mechanism of PIG has not been clarified. Further studies are required to understand whether gene mutations, especially those related to podocytes, contribute to the pathogenesis of podocytic infolding.

Robust Adaptive Beamforming with Optimal Covariance Matrix Estimation in the Presence of Gain-Phase Errors.

An adaptive beamformer is sensitive to model mismatch, especially when the desired signal exists in the training samples. Focusing on the problem, this paper proposed a novel adaptive beamformer based on the interference-plus-noise covariance (INC) matrix reconstruction method, which is robust with gain-phase errors for uniform or sparse linear array. In this beamformer, the INC matrix is reconstructed by the estimated steering vector (SV) and the corresponding individual powers of the interference signals, as well as noise power. Firstly, a gain-phase errors model of the sensors is deduced based on the first-order Taylor series expansion. Secondly, sensor gain-phase errors, the directions of the interferences, and the desired signal can be accurately estimated by using an alternating descent method. Thirdly, the interferences and noise powers are estimated by solving a quadratic optimization problem. To reduce the computational complexity, we derive the closed-form solutions of the second and third steps with compressive sensing and total least squares methods. Simulation results and measured data demonstrate that the performance of the proposed beamformer is always close to the optimum, and outperforms other tested methods in the case of gain-phase errors.

Design and DOF Analysis of a Novel Compliant Parallel Mechanism for Large Load.

The degree of freedom (DOF) and motion characteristics of a kind of compliant spherical joint were analyzed based on the screw theory, and a new design scheme for force-inversion of the compliant spherical joint was proposed in this paper. A novel type of six DOF compliant parallel mechanism (CPM) was designed based on this scheme to provide a large load capacity and achieve micrometer-level positioning accuracy. The compliance matrix of the new type of CPM was obtained through matrix transformation and was then decomposed into its generalized eigenvalues. Then, the DOF of the mechanism was numerically analyzed based on the symbolic formulation. The finite element analysis model of the compliant parallel mechanism was established. The static load analysis was used to verify the large load capacity of the mobile platform. By comparing the deformation obtained by the compliance matrix numerical method with the deformation obtained by the finite element method, the correctness of the compliance matrix and the number of the DOF of the CPM was verified.

Multi-material decomposition of spectral CT images via Fully Convolutional DenseNets.

BACKGROUND: Spectral computed tomography (CT) has the capability to resolve the energy levels of incident photons, which has the potential to distinguish different material compositions. Although material decomposition methods based on x-ray attenuation characteristics have good performance in dual-energy CT imaging, there are some limitations in terms of image contrast and noise levels. OBJECTIVE: This study focused on multi-material decomposition of spectral CT images based on a deep learning approach. METHODS: To classify and quantify different materials, we proposed a multi-material decomposition method via the improved Fully Convolutional DenseNets (FC-DenseNets). A mouse specimen was first scanned by spectral CT system based on a photon-counting detector with different energy ranges. We then constructed a training set from the reconstructed CT images for deep learning to decompose different materials. RESULTS: Experimental results demonstrated that the proposed multi-material decomposition method could more effectively identify bone, lung and soft tissue than the basis material decomposition based on post-reconstruction space in high noise levels. CONCLUSIONS: The new proposed approach yielded good performance on spectral CT material decomposition, which could establish guidelines for multi-material decomposition approaches based on the deep learning algorithm.

[Clinical and genetic characteristics of a young child with combined pituitary hormone deficiency type I caused by POU1F1 gene variation].

This paper reports the clinical and genetic characteristics of a case of combined pituitary hormone deficiency type I (CPHD1) caused by POU domain, class 1, transcription factor 1 (POU1F1) gene variation. A 2 years and 3 months old girl mainly presented with short stature, special facial features of prominent forehead, enophthalmos, and short mandible, loose skin, central hypothyroidism, complete growth hormone deficiency, and anterior pituitary hypoplasia. Gene analysis identified a novel heterozygous mutation, c.889C>T (p.R297W), in POU1F1 gene, and this locus of her parents was wild-type. This mutation was analyzed as a possible pathogenic variant according to the guidelines of the American College of Medical Genetics and Genomics, which has not been previously reported in the literature and conforms to the autosomal dominant inheritance. This child was diagnosed with CPHD1. Her height increased by 19.8 cm and showed a catch-up growth trend after one year of combined treatment with growth hormone and euthyrox. This study enriches the mutation spectrum of POU1F1 gene and has important significance for the diagnosis and classification of combined pituitary hormone deficiency.

The small animal material discrimination study based on equivalent monochromatic energy projection decomposition method with dual-energy CT system.

Material discrimination is an important application of dual-energy computed tomography (CT) techniques. Projection decomposition is a key problem for pre-reconstruction material discrimination. In this study, we focused on the pre-reconstruction space based on the photoelectric and Compton effect decomposition model to characterize different material components, and proposed an efficient method to calculate the projection decomposition coefficient. We converted the complex projection integral into a linear equation by calculating the equivalent monochromatic energy from the high and low energy spectrum. Meanwhile, we constructed a dual-energy CT system based on a photon-counting detector to take small animal scan and material discrimination analysis. Finally, the results of simulation and experimental study demonstrated the feasibility of our proposed new method, and explained the characteristics of photoelectric absorption and Compton scattering reconstruction images.

[Investigation into Feasibility of Congestive Heart Failure Diagnosis Based on Analysis of Very Short-term Heart Rate Variability].

The analysis parameters for the characterization of heart rate variability(HRV)within a very short time(< 1min)usually exhibit complicate variation patterns over time,which may easily interfere the judgment to the status of the cardiovascular system.In this study,long-term HRV sequence of 41 cases of healthy people(control group)and 25 cases of congestive heart failure(CHF)patients(experimental group)was divided into multiple segments of very short time series.The variation coefficient of the same HRV parameter under multiple segments of very short time series and the testing proportion with statistically significant differences under multiple interclass t-test were calculated.On this account,part of HRV analysis parameters under very short time were discussed to reveal the stability of difference of the cardiovascular system function under different status.Furthermore,with analyzing the receiver operating characteristic(ROC)curve and modeling the artificial neural network(ANN),the classification effects of these parameters between the control group and the experimental group were assessed.The results demonstrated that1 the indices of entropy of degree distribution based on the complex network analysis had a lowest variation coefficient and was sensitive to the pathological status(in 79.75% cases,there has statistically significant differences between the control group and experimental group),which can be served as an auxiliary index for clinical doctor to diagnose for CHF patient;2after conducting ellipse fitting to Poincare plot,in 98.5% cases,there had statistically significant differences for the ratio of ellipse short-long axis(SDratio)between the control group and the experimental group;when modeling the ANN and solely adopting SDratio,the classification accuracy to the control group and experimental group was 71.87%,which demonstrated that SDratio might be acted as the intelligent diagnosis index for CHF patients;3 however,more sensitive and robust indices were still needed to find out for the very-short HRV analysis and for the diagnosis of CHF patients as well.

[Recognizing pediatric acute kidney injury].

Acute kidney injury (AKI) is characterized by a reversible increase in blood concentration of creatinine and nitrogenous waste products and by the inability of the kidney to regulate fluid and electrolyte homeostasis appropriately. AKI in hospitalized patients is independently associated with increased morbidity and mortality in pediatric and adult populations. Continued reliance on serum creatinine and urine output for the diagnosis of AKI has resulted in an inability to provide successful therapeutic and supportive interventions to prevent and mitigate AKI. Research efforts over the last decade have foused on the discovery and validation of novel biomarkers to detect AKI prior to a change in kidney function and to make a differential diagnosis of AKI.

Row Transmission for High Volume-Rate Ultrasound Imaging With a Matrix Array.

The widely used Vermon 1024-element matrix array for 3-D ultrasound imaging has three blank rows in the elevational direction, which breaks the elevation periodicity, thus degrading volumetric image quality. To bypass the blank rows in elevation while maintaining the steering capability in azimuth, we proposed a row-transmission (RT) scheme to improve 3-D spatial resolution. Specifically, we divided the full array into four apertures, each with multiple rows along the elevation. Each multirow aperture (MRA) was further divided into subapertures to transmit diverging waves (DWs) sequentially. Coherent DW compounding (CDWC) was realized in azimuth, while the elevation was multielement synthetic aperture (M-SA) imaging by regarding each row as an array of dashed line elements. An in-house spatiotemporal coding strategy, cascaded synthetic aperture (CaSA), was incorporated into the RT scheme as RT-CaSA to increase the signal-to-noise ratio (SNR). We compared the proposed RT with conventional bank-by-bank transmission-reception (Bank) and sparse-random-aperture compounding (SRAC) in a wire phantom and the in vivo human abdominal aorta (AA) to assess the performance of anatomical imaging and aortic wall motion estimation. Phantom results demonstrated superior lateral resolution achieved by our RT scheme (+19.52% and +16.88% versus Bank, +15.32% and +19.72% versus SRAC, in the azimuth-depth and elevation-depth planes, respectively). Our RT-CaSA showed excellent contrast ratios (CRs) (+8.19 and +8.08 dB versus Bank, +6.81 and +5.85 dB versus SRAC, +0.99 and +0.90 dB versus RT) and the highest in vivo aortic wall motion estimation accuracy. The RT scheme was demonstrated to have potential for various matrix array-based 3-D imaging research.

Computer-assisted discovery and evaluation of potential ribosomal protein S6 kinase beta 2 inhibitors.

S6K2 is an important protein in mTOR signaling pathway and cancer. To identify potential S6K2 inhibitors for mTOR pathway treatment, a virtual screening of 1,575,957 active molecules was performed using PLANET, AutoDock GPU, and AutoDock Vina, with their classification abilities compared. The MM/PB(GB)SA method was used to identify four compounds with the strongest binding energies. These compounds were further investigated using molecular dynamics (MD) simulations to understand the properties of the S6K2/ligand complex. Due to a lack of available 3D structures of S6K2, OmegaFold served as a reliable 3D predictive model with higher evaluation scores in SAVES v6.0 than AlphaFold, AlphaFold2, and RoseTTAFold2. The 150 ns MD simulation revealed that the S6K2 structure in aqueous solvation experienced compression during conformational relaxation and encountered potential energy traps of about 19.6 kJ mol-1. The virtual screening results indicated that Lys75 and Lys99 in S6K2 are key binding sites in the binding cavity. Additionally, MD simulations revealed that the ligands remained attached to the activation cavity of S6K2. Among the compounds, compound 1 induced restrictive dissociation of S6K2 in the presence of a flexible region, compound 8 achieved strong stability through hydrogen bonding with Lys99, compound 9 caused S6K2 tightening, and the binding of compound 16 was heavily influenced by hydrophobic interactions. This study suggests that these four potential inhibitors with different mechanisms of action could provide potential therapeutic options.

Self-Illuminating Nanoagonist Simultaneously Induces Dual Cell Death Pathways via Death Receptor Clustering for Cancer Therapy.

Inducing death receptor 5 (DR5) clustering holds particular promise in tumor-specific therapeutics because it could trigger an apoptotic cascade in cancerous cells. Herein, we present a tumor microenvironment H2O2-responsive self-illuminating nanoagonist, which could induce dual tumor cell death pathways through enhancing DR5 clustering. By conjugating DR5 ligand peptides onto the surfaces of self-illuminating nanoparticles with cross-linking capacity, this strategy not only provides scaffolds for ligands to bind receptors but also cross-links them through photo-cross-linking. This strategy allows for efficient activation of DR5 downstream signaling, initiating the extrinsic apoptosis pathway and immunogenic cell death of tumor cells, and contributes to improved tumor-specific immune responses, resulting in enhanced antitumor efficacy and minimized systemic adverse effects.