Theranostics最新文献

Background: Gastric cancer (GC) ranks as the fifth leading cause of cancer mortality, with cancer stem cells (CSCs) playing a critical role in tumor progression and resistance to chemotherapy. Conventional chemotherapy often fails to effectively target these stem cells. BATF2, a tumor suppressor, is known for its role in gastric cancer, but its influence on cancer stem cell-like properties and chemotherapy response remains unclear. Methods: Single-cell RNA sequencing (scRNA-seq) analysis was performed on 9 gastric cancer samples to evaluate the expression and regulatory function of BATF2. In vitro experiments involving cell cultures, tumor cell spheroids, and organoids were conducted to assess BATF2's impact on 5-Fu sensitivity and its interaction with drug transporters and signaling pathways. In vivo studies, including subcutaneous tumor formation assays, immunohistochemistry, and immunoblotting, were used to validate findings. Results: BATF2 was confirmed as a tumor suppressor in gastric cancer through scRNA-seq analysis. Elevated BATF2 expression correlated with improved outcomes from postoperative chemotherapy in GC patients and increased sensitivity to 5-Fu. BATF2 enhanced 5-Fu responsiveness by inhibiting the ABCG2 drug transporter and promoting PTEN stability, which suppressed AKT phosphorylation. This led to reduced nuclear β-catenin levels and decreased expression of stem cell markers CD44, SOX2, and NANOG, ultimately reducing chemoresistance and stem-like properties in GC cells. Conclusions: BATF2 plays a pivotal role in regulating stem-like characteristics and chemoresistance in gastric cancer through the BATF2/PTEN/AKT/ABCG2 pathway. These findings suggest a novel therapeutic strategy targeting BATF2 to enhance chemotherapy effectiveness in gastric cancer treatment.

Rationale: Childhood nephrotic syndrome (NS) is a serious disease affecting the health and quality of life of children, which is characterized by a series of pathophysiological changes due to the increased permeability of the glomerular membrane to plasma proteins. Low renal drug distribution and inefficient cellular uptake, resulting from cellular dysfunctions of filtration and internalization, are the main barriers to drug treatment in childhood NS, leading to deterioration in nephropathy. However, efficient therapeutic methods against childhood NS are still lacking in clinic. Methods: This study found that γ-glutamyltransferase (GGT) was highly expressed in the glomeruli of childhood NS in juvenile rats. We proposed GGT as the receptor target of the kidney-targeted drug delivery system, and then designed a GGT enzyme-responsive dendrimer-drug conjugate (GSHPD) as a kidney-targeted drug delivery platform for treating childhood NS. This platform could overcome the physiological and cellular uptake barriers of the kidney through receptor-mediated transcytosis. Results: GSHPD was composed of glutathione-modified polyamidoamine dendrimers and conjugated with triptolide (TP). Once GSHPD was delivered to the glomerulus in nephropathy, the overexpressed GGT in the endothelial cells of the glomerular capillaries activated the γ-glutamyl transfer reactions of glutathione to generate positively charged primary amines. The resulting cationic conjugate rapidly underwent caveola-mediated endocytosis and exocytosis, augmenting its renal accumulation and cellular internalization. Active TP was gradually released by intracellular enzyme hydrolysis, enabling sustained therapeutic effects and resulting in significant recovery of renal physiological function (e.g., lowering the levels of urea nitrogen and serum creatinine, improving the levels of urinary creatinine and creatinine clearance rate, and inhibiting podocyte injury). Conclusion: The conjugate exhibited an excellent kidney-targeted distribution and a potent recovery of renal physiological function in NS of juvenile rats. This study presented a promising and active kidney-targeted drug delivery platform for efficient childhood nephropathy therapy.

Purpose: Fibroblast-like synoviocytes and angiogenesis play crucial roles in the advancement of rheumatoid arthritis (RA). This prospective study aimed to assess the efficacy of [¹⁸F]AlF-FAPI-RGD, a dual-targeting heterodimer tracer that focuses on fibroblast activation protein (FAP) and integrin α_vβ₃, through PET/CT imaging for evaluating disease activity and response to treatment in RA. Methods: Twenty-eight participants with active RA (12 males and 16 females; mean age, 55 ± 9 years) underwent clinical evaluation of disease activity and [¹⁸F]AlF-FAPI-RGD PET/CT imaging at enrollment. Subsequently, after a 3-month period, a follow-up scan and clinical assessments were conducted on these participants. Imaging parameters such as PET-positive joint count (PJC), PET-positive articular index (PAI), average SUV_max (aSUV_max), and highest SUV_max (hSUV_max) in affected joints were compared with clinical and laboratory findings, as well as traditional imaging modalities. Results: [¹⁸F]AlF-FAPI-RGD PET/CT imaging produced high-quality images, revealing notable tracer uptake in the synovium of affected joints. [¹⁸F]AlF-FAPI-RGD demonstrated a higher positivity rate in detecting affected joints compared to the tender or swollen joint counts during clinical assessment (82.4% [342 of 415] vs 68.4% [284 of 415], respectively). Additionally, this imaging method successfully identified lung lesions with atypical respiratory symptoms in participants with RA. Following treatment, PJC, PAI, aSUV_max, and hSUV_max values significantly decreased in responders (P < 0.001), while no significant changes were observed in non-responders (P > 0.05). Furthermore, a notable association was found between the percentage change in certain PET parameters and modifications in specific clinical parameters. Conclusion: [¹⁸F]AlF-FAPI-RGD PET/CT represents a promising tool for the objective assessment of disease activity and treatment response in patients with RA. Furthermore, it may offer a novel imaging method for the early detection of subclinical RA and interstitial lung disease present with atypical respiratory symptoms.

Background: As a critical member of the Coronin family, Coronin 1A (CORO1A) plays a crucial role in the progression of triple-negative breast cancer (TNBC). However, CORO1A is typically considered "undruggable" due to its smooth surface and complex protein-protein interactions (PPIs). Molecular glues have emerged as one of the most effective strategies to rapidly degrade such "undruggable" targets. Neddylation, an emerging approach, has shown promise in targeting pathogenic proteins for degradation through the NEDD8 pathway, making the degradation of CORO1A an attractive pharmacological strategy. Methods: A phenotypic drug screening strategy coupled with multi-omics approaches was utilized to rapidly identify a molecular glue degrader for CORO1A and to uncover the associated mechanisms. The Omics and Text-based Target Enrichment and Ranking (OTTER) tools, co-immunoprecipitation (Co-IP) assay, mass spectrometry, and the separation of phases-based protein interaction reporter (SPPIER) method were employed to explore the interaction between Aurovertin B (AB) and CORO1A via TRIM4. The pharmacological effects of AB were assessed using TNBC patient-derived organoids (PDOs) and 3D bioprinting models. Results: We identified AB as a previously undisclosed molecular glue that significantly promotes the neddylation and proteasomal degradation of CORO1A via TRIM4, an atypical E3 ligase. Notably, the degradation of CORO1A markedly inhibited various cellular processes and exerted robust antitumor effects in TNBC PDOs and 3D bioprinting models. Conclusions: Our findings underscore the critical role of CORO1A in TNBC and lay a crucial foundation for the development of innovative drugs based on molecular glue technology.

Rationale: While immunotherapy shows great promise in patients with triple negative breast cancer, many will not respond to treatment. Radiotherapy has the potential to prime the tumor-immune microenvironment for immunotherapy. However, predicting response is difficult due to tumor heterogeneity across patients, which necessitates personalized medicine strategies that incorporate tumor tracking into the therapeutic approach. Here, we investigated the use of ultrasound (US) imaging of the tumor vasculature to monitor the tumor response to treatment. Methods: We utilized ultrafast power doppler US to track the vascular response to radiotherapy over time. We used 4T1 (metastatic) and 67NR (non-metastatic) breast cancer models to determine if US measurements corroborate conventional immunostaining analysis of the tumor vasculature. To evaluate the effects of radiation, tumor volume and vascular index were calculated using US, and the correlation between vascular changes and immune cell infiltration was determined. Results: US tumor measurements and the quantified vascular response to radiation were confirmed with caliper measurements and immunostaining, respectively, demonstrating a proof-of-principle method for non-invasive vascular monitoring. Additionally, we found significant infiltration of CD8⁺ T cells into irradiated tumors 10 days after radiation, which followed a sustained decline in vascular index and an increase in splenic CD8⁺ T cells that was first observed 1 day post-radiation. Conclusions: Our findings reveal that ultrafast power doppler US can evaluate changes in tumor vasculature that are indicative of shifts in the tumor-immune microenvironment. This work may lead to improved patient outcomes through observing and predicting response to therapy.

Prostate cancer (PCa) is the most common non-cutaneous cancer in men and a major cause of cancer-related deaths. Whereas localized PCa can be cured by surgery and radiotherapy, metastatic disease can be treated, but is not curable. Inhibition of androgen signaling remains the main therapeutic intervention for treatment of metastatic PCa, in addition to chemotherapy, radionuclide therapy and emerging targeted therapies. Although initial responses are favorable, resistance to these therapies invariably arise with development of castration resistant PCa (CRPC) and lethal phenotypes. Recent findings have implicated the crosstalk between PCa cells and the tumor microenvironment (TME) as a key factor for disease progression and metastasis, and the immune system is becoming an increasingly attractive target for therapy. Given the striking success of immune checkpoint inhibitors (ICIs) in various cancer types, preclinical and clinical studies have begun to explore their potential in PCa. It has become clear that the PCa TME is largely immunosuppressive, and ICI therapy does not have efficacy for PCa. Intense effort is therefore being made in the field to understand the mechanisms of suppression and to turn the immunosuppressive TME into an immune active one that would enable ICI efficacy. Herein we examine this recent body of knowledge and how the mutational landscape of PCa integrates with an immunosuppressive TME to circumvent ICI-mediated T-cell activity and tumor killing. We then review the emerging potential success of combinatorial ICI approaches, utility of careful patient selection, and potential novel strategies to improve the efficacy of ICI for PCa therapy.

Cardiorenal syndrome (CRS) involves bidirectional crosstalk between the failing heart and the kidneys. Depending on the primum movens (primary cardiac or renal injury), systems-based interactions in the secondary affected organ may include pro-fibrotic signaling, overzealous inflammation, impaired nerve integrity or overactivity of specific renal transporters mediating glucose absorption. Those pathophysiological pillars can be investigated by molecular imaging using SPECT or PET agents. Targeted whole-body molecular imaging may allow for a) systems-based analysis along the heart-kidney axis, b) may provide prognostic information on longitudinal organ-based functional decline or c) may be used for guidance of reparative intervention based on peak activation identified on PET (paradigm of cardiorenal theranostics). We will discuss the current state of translational molecular imaging for CRS, along with future clinical aspects in the field.

Saliva contains a diverse array of biomarkers indicative of various diseases. Saliva testing has been a major advancement towards non-invasive point-of-care diagnosis with clinical significance. However, there are challenges associated with salivary diagnosis from sample treatment and standardization. This review highlights the biomarkers in saliva and their role in identifying relevant diseases. It provides an overview and discussion about the current practice of saliva collection and processing, and advancements in saliva detection systems from in vitro methods to wearable oral devices. The review also addresses challenges in saliva diagnostics and proposes solutions, aiming to offer a comprehensive understanding and practical guidance for improving saliva-based detection in clinical diagnosis. Saliva diagnosis provides a rapid, effective, and safe alternative to traditional blood and urine tests for screening large populations and enhancing infectious disease diagnosis and surveillance. It meets the needs of various fields such as disease management, drug screening, and personalized healthcare with advances in saliva detection systems offering high sensitivity, fast response times, portability, and automation. Standardization of saliva collection, treatment, biomarker discovery, and detection between different laboratories needs to be implemented to obtain reliable salivary diagnosis in clinical practice.

Background: Resistance to sorafenib remains a major challenge in the systemic therapy of liver cancer. However, the involvement of lipid metabolism-related lncRNAs in this process remains unclear. Methods: Different expression levels of lipid metabolism-related lncRNAs in HCC were compared by analysis of Gene Expression Omnibus and The Cancer Genome Atlas databases. The influence of HNF4A-AS1 on sorafenib response was evaluated through analysis of public biobanks, cell cytotoxicity and colony formation assays. The effect of HNF4A-AS1 on sorafenib-induced ferroptosis was measured using lipid peroxidation, glutathione, malondialdehyde, and ROS levels. Furthermore, bioinformatic analyses and lipidomic profiling were conducted to study HNF4A-AS1 involvement in lipid metabolic reprogramming. Mechanistic experiments, including the luciferase reporter assay, RNA pulldown, RNA immunoprecipitation (RIP), methylated RNA immunoprecipitation (MeRIP), and RNA remaining assays, were employed to uncover the downstream targets and regulatory mechanisms of HNF4A-AS1 in sorafenib resistance in HCC. Xenograft and organoid experiments were carried out to assess the impact of HNF4A-AS1 on sorafenib response. Results: Bioinformatics analysis revealed that HNF4A-AS1, a lipid metabolism-related lncRNA, is specifically high-expressed in the normal liver and associated with sorafenib resistance in HCC. We further confirmed that HNF4A-AS1 was downregulated in HCC cells and organoids that resistant to sorafenib. Moreover, both in vitro and in vivo studies demonstrated that HNF4A-AS1 overexpression reversed sorafenib resistance in HCC cells, which was further enhanced by polyunsaturated fatty acids (PUFA) supplementation. Mechanistically, HNF4A-AS1 interacted with METTL3, leading to m6A modification of DECR1 mRNA, which subsequently decreased DECR1 expression via YTHDF3-dependent mRNA degradation. Consequently, decreased HNF4A-AS1 levels caused DECR1 overexpression, leading to decreased intracellular PUFA content and promoting resistance to sorafenib-induced ferroptosis in HCC. Conclusions: Our results indicated the pivotal role of lipid metabolism-related and liver-specific HNF4A-AS1 in inhibiting sorafenib resistance by promoting ferroptosis and suggesting that HNF4A-AS1 might be a potential target for HCC.

Rationale: Ferroptosis in lung epithelium and endothelium contributes to the pathogenesis of acute respiratory distress syndrome (ARDS), a critical and often fatal condition marked by acute inflammation and elevated pulmonary vascular permeability. Despite this, there are currently no FDA-approved therapeutics specifically targeting ferroptosis for ARDS management. Methods: A screening of 259 FDA-approved drugs was conducted to identify an effective ferroptosis inhibitor in pulmonary epithelial and endothelial cells. The anti-ferroptotic and therapeutic efficacy of this screened drug was rigorously evaluated using two distinct ARDS mouse models (LPS-induced acute lung injury and CLP-induced sepsis) and human airway organoids (hAOs). The regulatory mechanism of this drug on ferroptosis inhibition was investigated via RNA-sequencing, qRT-PCR, western blotting, IF, luciferase reporter assay, chromatin immunoprecipitation assay, limited proteolysis-mass spectrometry assay, cellular thermal shift assay, and drug affinity responsive target stability assay. Furthermore, a proof-of-concept clinical trial was conducted, wherein ARDS patients were administered with the drug as adjunctive therapy. Results: Dipyridamole (DIPY) was identified as a potent inhibitor of ferroptosis in pulmonary epithelial and endothelial cells. DIPY effectively mitigated ferroptosis and pulmonary damage in both mouse models and hAOs, primarily by downregulating heme oxygenase 1 (HMOX1). The transcription factor cAMP responsive element binding protein 1 (CREB1) was identified as a key transactivator of HMOX1, which DIPY effectively downregulated. Mechanistically, DIPY binds to and activates superoxide dismutase 1 (SOD1), which in turn inhibits the CREB1/HMOX1 pathway, thereby suppressing ferroptosis. Notably, the clinical trial further corroborated the therapeutic potential of DIPY in ARDS patients, demonstrating improved outcomes with DIPY adjunctive therapy. Conclusions: These findings provide compelling evidence that DIPY inhibits ferroptosis in pulmonary epithelial and endothelial cells by modulating the SOD1/CREB1/HMOX1 signaling axis and suggest DIPY as a promising therapeutic strategy for ARDS treatment.