Target Response Research Articles

Sex-dimorphic effects of glucose transporter-2 gene knockdown on hypothalamic primary astrocyte phosphoinositide-3-kinase (PI3K)/protein kinase B (PKB/Akt)/mammalian target of rapamycin (mTOR) cascade protein expression and phosphorylation

Glucose transporter-2 (GLUT2), a unique high capacity/low affinity, highly efficient membrane transporter and sensor, regulates hypothalamic astrocyte glucose phosphorylation and glycogen metabolism. The phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway participates in glucose homeostasis, but its sensitivity to glucose-sensory cues is unknown. Current research used a hypothalamic astrocyte primary culture model to investigate whether glucoprivation causes PI3K/Akt/mTOR pathway activation in one or both sexes by GLUT2-dependent mechanisms. Glucoprivation did not alter astrocyte PI3K levels, yet up-regulated both phosphorylated derivatives in female and down-regulated male p60 phosphoprotein expression. GLUT2 siRNA pretreatment diminished glucoprivic patterns of PI3K and phospho-PI3K expression in each sex. Astrocyte Akt and phospho-Akt/Thr308 proteins exhibited divergent, sex-contingent responses to GLUT2 gene knockdown or glucoprivation. GLUT2 siRNA pretreatment exacerbated glucoprivic-associated Akt diminution in the female, and either amplified (male) or reversed (female) glucoprivic regulation of phospho-Akt/Thr308 expression. GLUT2 gene silencing down- (male) or up-(female) regulated mTOR protein, and phospho-mTOR protein in male. Male astrocyte mTOR and phospho-mTOR profile were refractory to glucoprivation, but glucose-deprived females showed GLUT2-independent mTOR inhibition and GLUT2-dependent phospho-mTOR up-augmentation. Results identify a larger number of glucoprivic-sensitive PI3K/Akt/mTOR pathway proteins in female versus male astrocytes, and document divergent responses of common glucose-sensitive targets. GLUT2 stimulates phosphoPI3K protein expression in each sex, but imposes differential control of PI3K, Akt, phospho-Akt/Thr308, mTOR, and phospho-mTOR profiles in male versus female. Data implicate GLUT2 as a driver of distinctive pathway protein responses to glucoprivation in female, but not male.

Multi-targeting optimization of cladding process parameters based on NSGA-II algorithm and entropy weight method

Abstract Laser cladding is a new technology that can be used in the field of manufacturing and surface modification. The parameters of cladding 316L powder on 45 steel are studied by designing orthogonal experiments. Three optimal variables including laser power, scanning speed and cladding height are established. The mathematical model of target response with coating width, height and cladding area as indexes is constructed. Based on the Pareto set of NSGA-II, the optimal process parameters are found. The optimal solution on the Pareto front is obtained by the entropy weight method and data normalization. According to the results, when the laser power is 1607.0079 W, the scanning speed is 6.0033 mm/min, and the cladding height is 11.9961 mm, the optimized predicted cladding width is 1.3776 mm, the cladding height is 0.1847 mm, and the cladding area is 2.2907 mm2.

Precision Nanovaccines for Potent Vaccination.

Compared with traditional vaccines, nanoparticulate vaccines are especially suitable for delivering antigens of proteins, peptides, and nucleic acids and facilitating lymph node targeting. Moreover, apart from improving pharmacokinetics and safety, nanoparticulate vaccines assist antigens and molecular adjuvants in crossing biological barriers, targeting immune organs and antigen-presenting cells (APC), controlled release, and cross-presentation. However, the process that stimulates and orchestrates the immune response is complicated, involving spatiotemporal interactions of multiple cell types, including APCs, B cells, T cells, and macrophages. The performance of nanoparticulate vaccines also depends on the microenvironments of the target organs or tissues in different populations. Therefore, it is necessary to develop precise nanoparticulate vaccines that accurately regulate vaccine immune response beyond simply improving pharmacokinetics. This Perspective summarizes and highlights the role of nanoparticulate vaccines with precise size, shape, surface charge, and spatial management of antigen or adjuvant for a precision vaccination in regulating the distribution, targeting, and immune response. It also discusses the importance of the rational design of nanoparticulate vaccines based on the anatomical and immunological microstructure of the target tissues. Moreover, the target delivery and controlled release of nanovaccines should be taken into consideration in designing vaccines for achieving precise immune responses. Additionally, it shows that the nanovaccines remodel the suppressed tumor environment and modulate various immune cell responses which are also essential.

Combatting Antibiotic-Resistant Staphylococcus aureus: Discovery of TST1N-224, a Potent Inhibitor Targeting Response Regulator VraRC, through Pharmacophore-Based Screening and Molecular Characterizations.

Staphylococcus aureus (S. aureus) is a major global health concern, causing various infections and presenting challenges due to antibiotic resistance. In particular, methicillin-resistant S. aureus, vancomycin-intermediate S. aureus (VISA), and vancomycin-resistant S. aureus pose significant obstacles in treating S. aureus infections. Therefore, the critical need for novel drugs to counter these resistant forms is pressing. Two-component systems (TCSs), integral to bacterial regulation, offer promising targets for disruption. In this study, a comprehensive approach, involving pharmacophore-based inhibitor screening, along with biochemical and biophysical analyses were conducted to identify, characterize, and validate potential inhibitors targeting the response regulator VraRC of S. aureus. The constructed pharmacophore model, Phar-VRPR-N3, demonstrated effectiveness in identifying a potent inhibitor, TST1N-224 (IC50 = 60.2 ± 4.0 μM), against the formation of the VraRC-DNA complex. Notably, TST1N-224 exhibited strong binding to VraRC (KD = 23.4 ± 1.2 μM) using a fast-on-fast-off binding mechanism. Additionally, NMR-based molecular modeling revealed that TST1N-224 predominantly interacts with the α9- and α10-helixes of the DNA-binding domain of VraR, where the interactive and functionally essential residues (N165, K180, S184, and R195) act as hotspots for structure-based inhibitor optimization. Furthermore, TST1N-224 evidently enhanced the susceptibility of VISA to both vancomycin and methicillin. Importantly, TST1N-224 distinguished by 1,2,5,6-tetrathiocane with the 3 and 8 positions modified with ethanesulfonates holds significant potential as a lead compound for the development of new antimicrobial agents.

Imaging-guided companion diagnostics in radiotherapy by monitoring APE1 activity with afterglow and MRI imaging

Companion diagnostics using biomarkers have gained prominence in guiding radiotherapy. However, biopsy-based techniques fail to account for real-time variations in target response and tumor heterogeneity. Herein, we design an activated afterglow/MRI probe as a companion diagnostics tool for dynamically assessing biomarker apurinic/apyrimidinic endonuclease 1(APE1) during radiotherapy in vivo. We employ ultrabright afterglow nanoparticles and ultrasmall FeMnOx nanoparticles as dual contrast agents, significantly broadening signal change range and enhancing the sensitivity of APE1 imaging (limit of detection: 0.0092 U/mL in afterglow imaging and 0.16 U/mL in MRI). We devise longitudinally and transversely subtraction-enhanced imaging (L&T-SEI) strategy to markedly enhance MRI contrast and signal-to-noise ratio between tumor and normal tissue of living female mice. The combined afterglow and MRI facilitate both anatomical and functional imaging of APE1 activity. This probe enables correlation of afterglow and MRI signals with APE1 expression, radiation dosage, intratumor ROS, and DNA damage, enabling early prediction of radiotherapy outcomes (as early as 3 h), significantly preceding tumor size reduction (6 days). By monitoring APE1 levels, this probe allows for early and sensitive detection of liver organ injury, outperforming histopathological analysis. Furthermore, MRI evaluates APE1 expression in radiation-induced abscopal effects provides insights into underlying mechanisms, and supports the development of treatment protocols.

A self-powered photoelectrochemical aptasensor based on target response and Ag-CdIn2S4 photosensitive material for ultrasensitive detection of prostate-specific antigen

In this study, Ag-CdIn2S4 was selected as a photosensitive material and combined with the zeolite imidazole frame-90 encapsulated methylene blue (ZIF-90@MB) to establish a controlled release system. On that basis, a self-powered photoelectrochemical (PEC) aptasensor was constructed based on target responses to realize the highly sensitive detection of prostate-specific antigen (PSA). The self-powered sensing method was employed to effectively avoid interference from other oxidizing/reducing substances in the system and improve the accuracy of the detection method. The band gap of CdIn2S4 was adjusted by Ag doping, and the visible light absorption capacity and photoelectric conversion efficiency of the material were improved by the local surface plasmon resonance (LSPR) effect of metal Ag. The ZIF-90 porous material was used as a carrier, the MB photosensitizer as a signal molecule was loaded in the ZIF-90 pore channel. The PSA aptamer (PApt) was attached to the ZIF-90@MB surface to form a simple biological gate. In the presence of the PSA, the recognition interaction between PApt and PSA made the biological gate open, then many MB molecules were released from ZIF-90 and enhanced the photocurrent signal. Under the optimal experimental conditions, the linear range of the sensor was 0.005 ∼ 50 ng mL−1, and the detection limit was 2.35 pg mL−1. The accurate determination of PSA in human serum was achieved, which provided a novel sensing strategy for the early diagnosis of clinical biomarkers.

Application of opposing coils transient electromagnetic method in urban area with metal interference

Opposing coils transient electromagnetic method (OCTEM) adopts small and weak-coupling transmitting-receiving coils configuration, which helps to reduce side effect and improve the detection resolution. With such advantages, it has been widely used for shallow sub-surface target detection. However, when the method is used in urban area, measured data may be distorted by electromagnetic (EM) interference from nearby metal objects. In practical application, it is necessary to perform modelling to provide guidance for measuring data analysis. Two OCTEM application cases in detecting shallow sub-surface karst caves in urban area with metal objects nearby are presented in this paper. Corresponding modelling are carried out to study the interference effect of the nearby metal objects. The first application case is about the EM interference of a vertical steel tower, of which the influence distance reaches up to 9 m by modelling. The second application case is about the EM interference of a thin aluminum fence, of which the influence distance reaches up to 6 m by modelling. Only when the observation is outside the influence zone, the metal influence can be ignored. When the measurement is inside the influence zone, the metal influence cannot be ignored. However, as the nearby metal objects mainly affects the early data, the subsurface target may also be detected in condition that the target response is stronger than the metal interference, or the target response time window is wider than that of the metal interference.

Color class and structure-related observable fluorescence response in arctic macroalgae as coastal underwater lidar substrates

In the context of underwater marine biological remote sensing surveys, we consider the fluorescence response of macroalgal and kelp targets to underwater fluorescence laser serial and lidar imaging applications. An investigation of absorption and fluorescence emission via excitation–emission (EEM) spectra of Arctic macroalgal substrates is presented via naturally and artificially generated structural scenarios. Fluorescence was found to increase with algal structure thickness for the kelp Alaria esculenta, both when its output is tested with or without structural modification (increase thickness) of the kelp thallus. Several trials involving other species of all three color classes showed fluorescence output decreased after a thickness increase via layering or structure reconfiguration: a process we suggest is due to fluorescence re-absorption sometimes occurring within and between the rearranged algal structures.

Inverse design of functionally graded porous structures with target dynamic responses

Although functionally graded porous structures (FGPS) have been studied comprehensively due to their excellent mechanical and functional properties, the design process of FGPS with target stress response still dependent on continuous trial and error, which is not only time-consuming but also heavily relies on experience and intuition. This study proposes a novel inverse design framework of 2D FGPS with targeted dynamic stress-strain responses via a combination of conditional diffusion model and a residual neural network. Unlike traditional binary pixel representations, this approach utilizes nuclei position maps and color mapping technique to represent the structure configurations and cell wall thicknesses to improve the efficiency and performance of the model. Firstly, various functionally graded porous structures were constructed by employing Voronoi diagram techniques, and finite element simulations were conducted to calculate the nonlinear responses subjected to dynamic loadings. A dataset comprising 2100 FGPS and corresponding nonlinear stress-strain responses was established. Then, an inverse design framework is formulated by integrating a generator that uses a diffusion model to synthesize structures conditioned on specific target responses, with a predictor that employs a residual neural network to assess the responses of these structures. Finally, to demonstrate the effectiveness of the approach, the performance of the predictor and generator was thoroughly investigated. Structures with various target stress-strain responses were generated through the proposed method, and validated by finite element analysis. A detailed impact experiment was also carried out to verify the effectiveness of the proposed methods. The result shows that the framework can effectively generate new structures with objective nonlinear responses. This work offers a fast and efficient way to design FGPS that meet specific performance objectives.

Un análisis del estímulo discriminativo durante el debate en contextos clínicos

The Socratic debate has traditionally been described as a procedure through which the therapist attempts to change the irrational beliefs of their client through questioning and dialogue. From an analytical-functional research perspective, it has been defined as a verbal shaping procedure in which the therapist differentially reinforces protherapeutic utterances. The objective of the present study was to analyze the relationship between the discriminative stimuli emitted by the therapist with and without prompts and the responses emitted by the client based on their approach to the therapeutic goal. Sixty debate recordings from 18 cases, which were classified according to their level of effectiveness, were analyzed. The analyses showed no statistically significant differences in the rate per minute of each type of discriminative stimulus according to the level of debate effectiveness. There was also a strong association of the discriminative category with response options and of discriminative with the description of contingencies with the verbalizations approaching the therapeutic goal. It is concluded that some prompts to the discriminative stimulus may make it more likely to evoke target responses, and thus, clients may more efficiently access the verbal reinforcers presented by therapists, facilitating the verbal shaping procedure.

Intratumoral Injection of Immunotherapeutics: State of the Art and Future Directions.

Systemic immunotherapies have led to tremendous progress across the cancer landscape. However, several challenges exist, potentially limiting their efficacy in the treatment of solid tumors. Direct intratumoral injection can increase the therapeutic index of immunotherapies while overcoming many of the barriers associated with systemic administration, including limited bioavailability to tumors and potential systemic safety concerns. However, challenges remain, including the lack of standardized approaches for administration, issues relating to effective drug delivery, logistical hurdles, and safety concerns specific to this mode of administration. This article reviews the biologic rationale for the localized injection of immunotherapeutic agents into tumors. It also addresses the existing limitations and practical considerations for safe and effective implementation and provide recommendations for optimizing logistics and treatment workflows. It also highlights the critical role that radiologists, interventional radiologists, and medical physicists play in intratumoral immunotherapy with respect to target selection, image-guided administration, and response assessment.

Energy absorption and impact response of ballistic resistance laminate

Abstract High-speed impact performance has significantly expanded over the past few decades. The target response based on the impact conditions has been more difficult to visualise and evaluate. In this article, Ansys model analysis has been used to measure, visualise, and predict the projectile and target responses of Kevlar® (K) and Ramie® textile-reinforced unsaturated polyester resin (UP) matrix. The laminate thickness threshold was detected experimentally based on the highest stress intensity factor and energy release rates. Furthermore, tensile strength and bending of the laminate were found. The impact conditions have a significant impact on the target response; thus, an explicit dynamic analysis was used to visualise the impact response based on the number of target fixed supports (FSs). Two FS (2 FS) target absorbs 11% more energy than four FS (4 FS) target. Additionally, the target size has a major effect on the projectile and laminate responses, and a successful arrest of the projectile was detected in both cases. The smallest targets with 2 FS have the highest and wider response, where a successful change in the projectile trajectory was obtained.

Optimization of column-in-column system based on non-conventional TMD concept

Previous studies showed that the non-conventional tuned mass damper (TMD) with large mass ratio outperforms the traditional one in respect to the structural vibration control efficiency and robustness. The authors recently proposed a novel control system based on the non-conventional TMD concept, namely the column-in-column (CIC) system, which was composed of a primary column, a secondary column and a series of interconnected springs/dashpots. In this novel system, the secondary column connected to the primary one with springs/dashpots could act as a large TMD to attenuate adverse vibration of the primary structure, and its control effectiveness was preliminarily verified through numerical investigations. However, the control robustness was found not sufficient based on the existing optimal formulae in the literature for CIC optimization. This paper presents a new design method for optimizing the CIC system for better harnessing its control effectiveness and robustness in reducing structural response. The CIC system consists of two columns with distributed mass and uniform flexural rigidity, connected by springs along the column height. The effective modal mass and modal stiffness of a specific vibration mode of the system can be straightforwardly calculated by using the Euler-Bernoulli beam theory. Considering the fundamental vibration mode of the system as the target response mode for vibration control, the multiple degree-of-freedom (DOF) CIC is simplified into a two DOF with three springs (2DOF3S) structural model, the design parameters, i.e., the optimal tuning frequency ratio and damping ratio of this system are derived to minimize the displacement response of the primary structure. To demonstrate the proposed design method, the effectiveness and robustness of the CIC system in controlling seismic induced structural vibrations are assessed in both the frequency and time domains. Results show that the derived optimum formulae are applicable for optimizing the TMD system with consideration of the distributed mass and deformation of the mass damper, i.e., a column in this study. The optimized CIC system has good control robustness even if the CIC is mistuned with its design parameters deviate from the optimal values by ±50 %. The conventional TMD system with lumped mass as the mass damper is a special case of the proposed CIC system. The optimized CIC system has favorable control efficiency in mitigating the seismic responses of structures with reduction ratios averagely varying within the range of 15 % ∼ 55 % with a probability of 92.67 %. It is concluded that the proposed method is reliable and can be used for the optimum design and control of the CIC system.

Efficient and Rapid Modeling of Radar Echo Responses for Complex Targets under Arbitrary Wideband Excitation

Efficient and Rapid Modeling of Radar Echo Responses for Complex Targets under Arbitrary Wideband Excitation

Environmentally adaptive fast object detection in UAV images

Detecting objects in aerial images poses a challenging task due to the presence of numerous small objects and complex environmental information. To address these problems, we propose an efficient detector specifically designed for aerial images, named EAF-YOLOv8, based on YOLOv8-S. In this paper, we introduce a novel backbone network called EAFNet, specifically designed for small object detection. EAFNet consists of the Rapidly Merging Receptive Fields Aggregation Module (RMRFAM) and Multi-Scale Channel Attention (MSCA). The RMRFAM utilizes dilated convolution (DConv) and partial convolution (PConv) to acquire richer receptive fields, capturing more extensive contextual information at higher levels while reducing redundancy in channel information, thereby accelerating inference speed. Furthermore, inspired by denoising tasks, we focus on the feature information surrounding the target background and propose MSCA. MSCA integrates channel attention with an embedded self-attention feature pyramid, extending the feature learning scope to the surrounding environment of the target, beyond the target itself. This approach utilizes enhanced background features to elicit a higher response for small targets, reducing false positives. Experimental results demonstrate that in UAVDT and VisDrone2019, the proposed EAF-YOLOv8 achieves mAP50 scores of 34.3% and 49.7%, respectively. Additionally, EAF-YOLOv8 exhibits high real-time inference speeds of 77.60 FPS and 55.56 FPS, showcasing competitive detection performance.

Identifying barriers and interagency solutions to meeting the needs of families experiencing intimate partner violence (IPV): Home visiting and IPV agency perspectives

BackgroundAddressing intimate partner violence (IPV) among expectant families and caregivers with young children requires that multi-professional systems work collaboratively towards a common goal. IPV services and maternal and infant home visiting programs are two important perspectives to consider in designing interagency strategies. The purpose of this study was to identify shared priorities among home visiting and IPV professionals on IPV-related challenges and interagency solutions to support families with young children. MethodsHome visiting and IPV service providers (n=22) separately completed a structured brainstorming activity during four virtual focus groups using nominal group technique (NGT) to generate, rank, and reach consensus on prioritized barriers and solutions for the service population. The multi-professional study team (including home visiting and IPV partners) grouped and organized the top three prioritized barriers and solutions identified across groups using a pile sort activity. As a reliance measure, NGT discussion transcripts were coded to the final pile sort categories to ensure our presentation of the data was contextualized and supported by original participant responses. ResultsTwenty-four items were sorted into seven piles (three barriers and four solutions). The need to address families’ concrete needs was consistently prioritized across groups and matched with solutions that provide families with immediate financial support. Participants prioritized barriers resulting from client involvement in multiple, complex systems and named interagency process solutions (e.g., cross-systems training, enhanced referral processes) as the corresponding solution. The impact of individual and collective trauma was discussed as a barrier and matched with community-facing development (e.g., healthy relationship education). Policy, advocacy, and funding-oriented solutions were discussed as cross-cutting across all barriers. ConclusionEffective cross-system efforts are warranted to meet the interrelated needs of families impacted by IPV. The study highlights a shared view on prioritized challenges and actionable solutions to inform interagency collaboration among IPV agencies and early childhood home visiting programs. Our findings shed light on the importance of an organized public health approach to target IPV prevention and response.

Punishment-induced resurgence

The phenomenon of extinction-induced resurgence is well established, but there is comparatively little experimental evidence for punishment-induced resurgence. Punishment-induced resurgence can by tested by contingent shocks following the alternative response. The purpose of Experiment 1 was to test whether low-intensity shocks, that do not decrease rate of reinforcement, result in resurgence. Four rats served as subjects. Rats were exposed to three sequential conditions: (a) variable-interval (VI) 30-s food delivery for a lever press (target response); (b) VI 30-s food delivery for a nose poke (alternative response) and extinction of the lever press; (c) VI 30-s reinforcement for a nose poke with superimposed VI 60-s shock delivery. In the final condition, shocks increased gradually from 0.1 to 0.5 mA. Experiment 2 evaluated whether an abrupt introduction of a high-intensity shock would result in resurgence. Three rats served as subjects and were exposed to three sequential conditions: (a) VI 30-s food delivery for a lever press; (b) VI 30-s food delivery for a nose poke and extinction of the lever press; (c) continued VI 30-s reinforcement for a nose poke with superimposed VI 60-s 0.6 mA shock delivery. Resurgence was observed in all subjects, including in situations in which rate of responding, but not rate of reinforcement, decreased. The present study provides additional evidence for punishment-induced resurgence, but future studies are warranted to determine the extent to which punishment can produce resurgence with or without decreases in rates of reinforcement.

A guided network estimation approach using multi-omic information

IntoductionIn systems biology, an organism is viewed as a system of interconnected molecular entities. To understand the functioning of organisms it is essential to integrate information about the variations in the concentrations of those molecular entities. This information can be structured as a set of networks with interconnections and with some hierarchical relations between them. Few methods exist for the reconstruction of integrative networks.ObjectiveIn this work, we propose an integrative network reconstruction method in which the network organization for a particular type of omics data is guided by the network structure of a related type of omics data upstream in the omic cascade. The structure of these guiding data can be either already known or be estimated from the guiding data themselves.MethodsThe method consists of three steps. First a network structure for the guiding data should be provided. Next, responses in the target set are regressed on the full set of predictors in the guiding data with a Lasso penalty to reduce the number of predictors and an L2 penalty on the differences between coefficients for predictors that share edges in the network for the guiding data. Finally, a network is reconstructed on the fitted target responses as functions of the predictors in the guiding data. This way we condition the target network on the network of the guiding data.ConclusionsWe illustrate our approach on two examples in Arabidopsis. The method detects groups of metabolites that have a similar genetic or transcriptomic basis.

XCR1: A promising prognostic marker that pinpoints targeted and immune-based therapy in hepatocellular carcinoma

ObjectivesThe lymphotactin receptor X–C motif chemokine receptor 1 (XCR1) is an essential member of the chemokine receptor family and is related to tumor development and progression. Nevertheless, further investigation is required to explore its expression patterns, prognostic values, and functions related to target or immune therapies in patients with hepatocellular carcinoma (HCC). Materials and methodsThe differential expression patterns of XCR1 and its prognostic influences were performed through The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases. Subsequently, immunohistochemistry (IHC) staining and univariate and multivariate Cox regressions were performed to validate the prognostic values in different subgroups. Furthermore, the potential roles of XCR1 in predicting target and immune therapeutic responses were also investigated. ResultsIncreased expression level of XCR1 was associated with favorable overall survival (OS) and recurrence-free survival (RFS). Subgroup analysis revealed that a high expression level of XCR1 or positive immune cell proportion score (iCPS) were associated with favorable OS in the HCC patients with favorable tumor characteristics. In addition, the enhanced XCR1 expression was associated with the tumor environment scores, immune cell infiltration levels, and the expression levels of immune checkpoint genes. Further analysis revealed that improved expression of XCR1 was linked to better OS and RFS in HCC patients who received sorafenib. ConclusionThis study identified that XCR1 is a valuable prognostic biomarker in the HCC population, especially in those with favorable tumor characteristics. The combination of iCPS status and BCLC status has a synergistic effect on stratifying patients' OS and RFS. Further analyses showed that XCR1 has the potential ability to predict treatment responses to sorafenib and immune-based therapies.

Improved Immunotherapy Outcomes via Cuproptosis Upregulation of HLA-DRA Expression: Promoting the Aggregation of CD4+ and CD8+T Lymphocytes in Clear Cell Renal Cell Carcinoma.

Immunotherapy has shown promising clinical results in clear cell renal cell carcinoma (ccRCC), but low clinical target response rates due to dysfunction of the major histocompatibility complex (MHC) and an inhibitory tumor immune microenvironment (TIME) have largely limited the associated clinical benefits. In the present study, we explored the feasibility of enhancing tumor-specific-MHC-II-HLA-DRA expression, counteracting the TIME's suppressive effects, thereby improving the sensitivity of immune checkpoint inhibitor (ICI) therapy from the standpoint of cuproptosis. Immunohistochemical staining and in vitro experiments validated the expression of HLA-DRA in ccRCC and its positive impact on ICI therapy. Subsequently, we observed that cuproptosis upregulated HLA-DRA expression in a dose-dependent manner, further confirming the link between cuproptosis and HLA-DRA. In vivo experiments showed that cuproptosis increased the sensitivity to ICI treatment, and implementing cuproptosis alongside anti-PD-1 treatment curtailed tumor growth. Mechanistically, cuproptosis upregulates HLA-DRA expression at the transcriptional level in a dose-dependent manner by inducing the production of reactive oxygen species; high levels of HLA-DRA promote the expression of chemokines CCL5, CXCL9, and CXCL10 in the TIME, inhibiting the development of a pro-tumor microenvironment by promoting the infiltration of CD4+T and CD8+T cells, thereby synergizing ICI therapy and exerting anti-tumor effects. Taken together, this work highlights the role of cuproptosis in mediating TIME remodeling and synergistic immunotherapy, providing new evidence that cuproptosis can evoke effective anti-tumor immune responses.