The roles and mechanisms of SREBP1 in cancer development and drug response.

Cancer occurrence and development are closely related to increased lipid production and glucose consumption. Lipids are the basic component of the cell membrane and play a significant role in cancer cell processes such as cell-to-cell recognition, signal transduction, and energy supply, which are vital for cancer cell rapid proliferation, invasion, and metastasis. Sterol regulatory element-binding transcription factor 1 (SREBP1) is a key transcription factor regulating the expression of genes related to cholesterol biosynthesis, lipid homeostasis, and fatty acid synthesis. In addition, SREBP1 and its upstream or downstream target genes are implicated in various metabolic diseases, particularly cancer. However, no review of SREBP1 in cancer biology has yet been published. Herein, we summarized the roles and mechanisms of SREBP1 biological processes in cancer cells, including SREBP1 modification, lipid metabolism and reprogramming, glucose and mitochondrial metabolism, immunity, and tumor microenvironment, epithelial-mesenchymal transition, cell cycle, apoptosis, and ferroptosis. Additionally, we discussed the potential role of SREBP1 in cancer prognosis, drug response such as drug sensitivity to chemotherapy and radiotherapy, and the potential drugs targeting SREBP1 and its corresponding pathway, elucidating the potential clinical application based on SREBP1 and its corresponding signal pathway.

Mitochondria-Specific Molecular Crosstalk between Ferroptosis and Apoptosis Revealed by In Situ Raman Spectroscopy.

Ferroptosis and apoptosis are two types of regulated cell death that are closely associated with the pathophysiological processes of many diseases. The significance of ferroptosis-apoptosis crosstalk in cell fate determination has been reported, but the underlying molecular mechanisms are poorly understood. Herein mitochondria-mediated molecular crosstalk is explored. Based on a comprehensive spectroscopic investigation and mass spectrometry, cytochrome c-involved Fenton-like reactions and lipid peroxidation are revealed. More importantly, cytochrome c is found to induce ROS-independent and cardiolipin-specific lipid peroxidation depending on its redox state. In situ Raman spectroscopy unveiled that erastin can interrupt membrane permeability, specifically through cardiolipin, facilitating cytochrome c release from the mitochondria. Details of the erastin-cardiolipin interaction are determined using molecular dynamics simulations. This study provides novel insights into how molecular crosstalk occurs around mitochondrial membranes to trigger ferroptosis and apoptosis, with significant implications for the rational design of mitochondria-targeted cell death reducers in cancer therapy.

A comprehensive study on the co-removal of Cr (VI) and ciprofloxacin via microbial-photocatalytic coupling: Mechanistic insights and performance evaluation.

The increasing contamination of water systems by antibiotics and heavy metals has become a growing concern. The intimately coupled photocatalysis and biodegradation (ICPB) approach offers a promising strategy for the effective removal of mixed pollutants. Despite some prior research on ICPB applications, the mechanism by which ICPB eliminates mixed pollutants remains unclear. In our current study, the ICPB approach achieved approximately 1.53 times the degradation rate of ciprofloxacin (CIP) and roughly 1.82 times the reduction rate of Cr (VI) compared to photocatalysis. Remarkably, after 30 days, the ICPB achieved a 96.1% CIP removal rate, and a 97.8% reduction in Cr (VI). Our investigation utilized three-dimensional fluorescence analysis and photo-electrochemical characterization to unveil the synergistic effects of photocatalysis and biodegradation in removal of CIP and Cr (VI). Incorporation of B-Bi3O4Cl (B-BOC) photocatalyst facilitated electron-hole separation, leading to production of ·O2-, ·OH, and h+ species which interacted with CIP, while electrons reduced Cr (VI). Subsequently, the photocatalytic products were biodegraded by a protective biofilm. Furthermore, we observed that CIP, acting as an electron donor, promoted the reduction of Cr (VI). The microbial communities revealed that the number of bacteria favoring pollutant removal increased during ICPB operation, leading to a significant enhancement in performance.

In Situ Raman Spectroscopy Reveals Cytochrome c Redox-Controlled Modulation of Mitochondrial Membrane Permeabilization That Triggers Apoptosis.

The selective interaction of cytochrome c (Cyt c) with cardiolipin (CL) is involved in mitochondrial membrane permeabilization, an essential step for the release of apoptosis activators. The structural basis and modulatory mechanism are, however, poorly understood. Here, we report that Cyt c can induce CL peroxidation independent of reactive oxygen species, which is controlled by its redox states. The structural basis of the Cyt c-CL binding was unveiled by comprehensive spectroscopic investigation and mass spectrometry. The Cyt c-induced permeabilization and its effect on membrane collapse, pore formation, and budding are observed by confocal microscopy. Moreover, cytochrome c oxidase dysfunction is found to be associated with the initiation of Cyt c redox-controlled membrane permeabilization. These results verify the significance of a redox-dependent modulation mechanism at the early stage of apoptosis, which can be exploited for the design of cytochrome c oxidase-targeted apoptotic inducers in cancer therapy.

In Situ Monitoring of Membrane Protein Electron Transfer via Surface-Enhanced Resonance Raman Spectroscopy.

In situ analysis of membrane protein-ligand interactions under physiological conditions is of significance for both fundamental and applied science, but it is still a big challenge due to the limits in sensitivity and selectivity. Here, we demonstrate the potential of surface-enhanced resonance Raman spectroscopy (SERRS) for the investigation of membrane protein-protein interactions. Lipid biolayers are successfully coated on silver nanoparticles through electrostatic interactions, and a highly sensitive and biomimetic membrane platform is obtained in vitro. Self-assembly and immobilization of the reduced cytochrome b5 on the coated membrane are achieved and protein native biological functions are preserved. Owing to resonance effect, the Raman fingerprint of the immobilized cytochrome b5 redox center is selectively enhanced, allowing for in situ and real-time monitoring of the electron transfer process between cytochrome b5 and their partners, cytochrome c and myoglobin. This study provides a sensitive analytical approach for membrane proteins and paves the way for in situ exploration of their structural basis and functions.

Construction and preclinical evaluation of a zirconium-89 labelled monoclonal antibody targeting PD-L2 in lung cancer.

OBJECTIVES: The aim of this study was to design a novel tracer targeting programmed cell death-ligand 2 (PD-L2) to dynamically monitor PD-L2 expression and perform preclinical screening to identify patients who may benefit from immune checkpoint inhibitor therapy (ICI) therapy. METHODS: 89Zr labelling of DFO-conjugated PD-L2 antibody (ATL2) was carried out in Na2CO3 buffer at pH 7 (37 °C, 1 h). In vitro stability was analysed using radio-thin layer chromatography (radio-TLC). The affinity of [89Zr]Zr-DFO-ATL2 was evaluated by radio-ELISA. Cell uptake, pharmacokinetic, and biodistribution experiments were used to evaluate the biological properties. Micro-PET/CT imaging with [89Zr]Zr-DFO-ATL2 was conducted at different time points. Immunohistochemical and HE staining studies were carried out using tumour tissues from tumour-bearing mice. RESULTS: The radiochemical yield of [89Zr]Zr-DFO-ATL2 was 65.6 ± 3.9%, and the radiochemical purity (RCP) of the tracer was greater than 99%. The tracer maintained relatively high stability and had a high affinity for the PD-L2 protein (Kd = 31.85 nM, R2 = 0.94). The uptake of [89Zr]Zr-DFO-ATL2 in A549-PD-L2 cells was higher than that in A549 cells at each time point. Micro-PET/CT showed significant uptake in the tumour region of mice bearing tumours derived from A549-PD-L2 (SUVmax = 3.53 ± 0.09 at 96 h) and H2228 (SUVmax = 2.30 ± 0.12 at 48 h) cells. CONCLUSION: The high tumour uptake at early imaging time points demonstrates the feasibility of applying [89Zr]Zr-DFO-ATL2 to image PD-L2 expression in tumours and is encouraging for further clinical application in the screening of patients who may benefit from ICI therapy.

Super-small zwitterionic micelles enable the improvement of blood-brain barrier crossing for efficient orthotopic glioblastoma combinational therapy.

Glioblastoma multiforme (GBM) remains incurable in clinical, nanotechnology-based drug delivery strategies show promising perspective in alleviating GBM, while limited blood-brain-barrier (BBB) permeation, short blood half-live accompanied by the poor tumor accumulation and penetration, significantly restrict the therapeutic outcomes. Herein, a versatile super-small zwitterionic nano-system (MCB(S)) based on carboxybetaine (CB) zwitterion functionalized hyperbranched polycarbonate (HPCB) is developed to overcome the brain delivery challenges. After grafting with amino-functionalized IR780 (free IR780), the ultimate paclitaxel (PTX)-encapsulated micelles (MCB(S)-IR@PTX) are precisely activated by near-infrared (NIR) for accelerated drug release and effective combinational GBM therapy. Importantly, MCB(S)-IR@PTX with the crosslinked structure and CB zwitterion prolongs blood-circulation, and CB-zwitterion further facilitates BBB-traversing through betaine/γ-aminobutyric acid (GABA) transporter-1 (BGT-1) pathway. Combined with the benefit of super small-size, MCB(S)-IR@PTX highly accumulates at tumor sites and penetrates deeply, thus efficiently inhibiting tumor growth and strikingly improving survival time in U87MG orthotopic GBM-bearing mouse model. The ingenious nanoplatform furnishes a versatile strategy for delivering therapeutics into the brain and realizing efficient brain cancer therapy.

The effect and mechanism of iodophors on the adhesion and virulence of Staphylococcus aureus biofilms attached to artificial joint materials.

BACKGROUND: Iodophors are known to be a treatment for biofilm-related periprosthetic joint infection. However, the efficacy and mechanism of eradicating biofilms from different artificial joint materials after iodophor treatment are unknown. This study was conducted to understand the effect and mechanism of iodophors with respect to the adhesion and virulence of Staphylococcus aureus biofilms attached to artificial joint materials. METHODS: Biofilms of Staphylococcus aureus strains were grown on titanium alloy, cobalt chromium molybdenum and polyethylene coupons, which are commonly used materials for artificial joints, for 24 h. Afterward, all coupons were divided into experimental and control groups: (1) exposed to a 0.5 ± 0.05% iodophor for 5 min and (2) exposed to phosphate-buffered saline for 5 min. To gauge the level of biofilm, colony forming units (CFU), live/dead staining confocal microscopy and crystal violet staining were used. Meanwhile, the expression of icaACDR and clfA, which are related to virulence and adhesion, was examined in both the experimental and control groups. RESULTS: A roughly three-log decrease in CFU/cm2 was seen in the viable plate count compared to the control group. Confocal imaging and crystal violet staining verified the CFU data. Moreover, the expression of icaACDR was reduced on three different orthopaedic implant materials, and the expression of clfA was also inhibited on titanium alloy coupons exposed to the iodophor. CONCLUSIONS: Our results indicated that exposure to an iodophor for 5 min could significantly eliminate biofilms. When Staphylococcus aureus that had adhered to these three materials, which were used for artificial joints, was treated with an iodophor for 5 min, the expression of icaACDR was significantly reduced. This provides strong evidence for clinically clearing periprosthetic joint infections without removing the artificial joints.

In Situ and Real-Time Monitoring of Mitochondria-Endoplasmic Reticulum Crosstalk in Apoptosis via Surface-Enhanced Resonance Raman Spectroscopy.

The crosstalk between mitochondria and endoplasmic reticula plays a crucial role in apoptotic pathways in which reactive oxygen species (ROS) produced by microsomal monooxygenase (MMO) are believed to accelerate cytochrome c release. Herein, we successfully demonstrate the potential of surface-enhanced resonance Raman spectroscopy (SERRS) for monitoring MMO-derived ROS formation and ROS-mediated cytochrome c release. Silver nanoparticles coated with nickel shells are used as both Raman signal enhancers and electron donors for cytochrome c. SERRS of cytochrome c is found to be sensitive to ROS, allowing for in situ probing of ROS formation with a cell death inducer. Label-free evaluation of ROS-induced apoptosis is achieved by SERRS-based monitoring of cytochrome c release in living cells. This study verifies the capability of SERRS for label-free, in situ, and real-time monitoring of the mitochondria-endoplasmic reticulum crosstalk in apoptosis and provides a novel strategy for the rational design and screening of ROS-inducing drugs for cancer treatment.

Hypomethylation of Tumor necrosis factor-like cytokine 1A(TL1A) and its decoy receptor 3 expressive level increase has diagnostic value in HBV-associated cirrhosis.

For patients with cirrhosis, early diagnosis is the key to delaying the development of liver fibrosis and improving prognosis. This study aimed to investigate the clinical significance of TL1A, which is a susceptibility gene for hepatic fibrosis, and DR3 in the development of cirrhosis and fibrosis. We analyzed the expression of TL1A, DR3, and other inflammatory cytokines associated with liver fibrosis in serum and PBMCs in 200 patients.TL1A methylation level was lower in patients with HBV-associated LC than in the other groups. In addition, the mRNA level and serum of TL1A and DR3 expression levels were found to increase in the LC. Hypomethylation of the TL1A promoter is present in HBV-associated LC, and TL1A and DR3 are highly expressed in HBV-associated cirrhosis. These results indicate that TL1A and DR3 may play an important role in the pathogenesis of LC and TL1A methylation levels may serve as a noninvasive biomarker for early diagnosis and progression of LC.

Multimodal Image Fusion Offers Better Spatial Resolution for Mass Spectrometry Imaging.

High-resolution reconstruction has attracted increasing research interest in mass spectrometry imaging (MSI), but it remains a challenging ill-posed problem. In the present study, we proposed a deep learning model to fuse multimodal images to enhance the spatial resolution of MSI data, namely, DeepFERE. Hematoxylin and eosin (H&E) stain microscopy imaging was used to pose constraints in the process of high-resolution reconstruction to alleviate the ill-posedness. A novel model architecture was designed to achieve multi-task optimization by incorporating multi-modal image registration and fusion in a mutually reinforced framework. Experimental results demonstrated that the proposed DeepFERE model is able to produce high-resolution reconstruction images with rich chemical information and a detailed structure on both visual inspection and quantitative evaluation. In addition, our method was found to be able to improve the delimitation of the boundary between cancerous and para-cancerous regions in the MSI image. Furthermore, the reconstruction of low-resolution spatial transcriptomics data demonstrated that the developed DeepFERE model may find wider applications in biomedical fields.

The roles and mechanism of m6A RNA methylation regulators in cancer immunity.

N6-methyladenosine (m6A), the most common internal modification in RNA, can be regulated by three types of regulators, including methyltransferases (writers), demethylases (erasers), and m6A binding proteins (readers). Recently, immunotherapy represented by immune checkpoint blocking has increasingly become an effective cancer treatment, and increasing shreds of evidence show that m6A RNA methylation affects cancer immunity in various cancers. Until now, there have been few reviews about the role and mechanism of m6A modification in cancer immunity. Here, we first summarized the regulation of m6A regulators on the expression of target messenger RNAs (mRNA) and their corresponding roles in inflammation, immunity response, immune process and immunotherapy in various cancer cells. Meanwhile, we described the roles and mechanisms of m6A RNA modification in tumor microenvironment and immune response by affecting the stability of non-coding RNA (ncRNA). Moreover, we also discussed the m6A regulators or its target RNAs which might be used as predictor of cancer diagnosis and prognosis, and shed light on the potentiality of m6A methylation regulators as therapeutic targets in cancer immunity.

MRI characteristics of lumbosacral dural arteriovenous fistulas.

Background and purpose: Spinal dural arteriovenous fistulas located in the lumbosacral region are rare and present with nonspecific clinical signs. The purpose of this study was to find out the specific radiologic features of these fistulas. Methods: We retrospectively reviewed the clinical and radiological data of 38 patients diagnosed with lumbosacral spinal dural arteriovenous fistulas in our institution from September 2016 to September 2021. All patients underwent time-resolved contrast-enhanced three-dimensional MRA and DSA examinations, and were treated with either endovascular or neurosurgical strategies. Results: Most of the patients (89.5%) had motor or sensory disorders in both lower limbs as the first symptoms. On MRA, the dilated filum terminale vein or radicular vein was seen in 23/30 (76.7%) patients with lumbar spinal dural arteriovenous fistulas and 8/8 (100%) patients with sacral spinal dural arteriovenous fistulas. T2W intramedullary abnormally high signal intensity areas were found in all lumbosacral spinal dural arteriovenous fistula patients, with involvement of the conus present in 35/38 (92.1%) patients. The "missing piece sign" in the intramedullary enhancement area was seen in 29/38 (76.3%) patients. Conclusion: Dilatation of the filum terminale vein or radicular vein is powerful evidence for diagnosis of lumbosacral spinal dural arteriovenous fistulas, especially for sacral spinal dural arteriovenous fistulas. T2W intramedullary hyperintensity in the thoracic spinal cord and conus, and the missing-piece sign could be indicative of lumbosacral spinal dural arteriovenous fistula.

PhoPQ Regulates Quinolone and Cephalosporin Resistance Formation in Salmonella Enteritidis at the Transcriptional Level.

The two-component system (TCS) PhoPQ has been demonstrated to be crucial for the formation of resistance to quinolones and cephalosporins in Salmonella Enteritidis (S. Enteritidis). However, the mechanism underlying PhoPQ-mediated antibiotic resistance formation remains poorly understood. Here, it was shown that PhoP transcriptionally regulated an assortment of genes associated with envelope homeostasis, the osmotic stress response, and the redox balance to confer resistance to quinolones and cephalosporins in S. Enteritidis. Specifically, cells lacking the PhoP regulator, under nalidixic acid and ceftazidime stress, bore a severely compromised membrane on the aspects of integrity, fluidity, and permeability, with deficiency to withstand osmolarity stress, an increased accumulation of intracellular reactive oxygen species, and dysregulated redox homeostasis, which are unfavorable for bacterial survival. The phosphorylated PhoP elicited transcriptional alterations of resistance-associated genes, including the outer membrane porin ompF and the aconitate hydratase acnA, by directly binding to their promoters, leading to a limited influx of antibiotics and a well-maintained intracellular metabolism. Importantly, it was demonstrated that the cavity of the PhoQ sensor domain bound to and sensed quinolones/cephalosporins via the crucial surrounding residues, as their mutations abrogated the binding and PhoQ autophosphorylation. This recognition mode promoted signal transduction that activated PhoP, thereby modulating the transcription of downstream genes to accommodate cells to antibiotic stress. These findings have revealed how bacteria employ a specific TCS to sense antibiotics and combat them, suggesting PhoPQ as a potential drug target with which to surmount S. Enteritidis. IMPORTANCE The prevalence of quinolone and cephalosporin-resistant S. Enteritidis is of increasing clinical concern. Thus, it is imperative to identify novel therapeutic targets with which to treat S. Enteritidis-associated infections. The PhoPQ two-component system is conserved across a variety of Gram-negative pathogens, by which bacteria adapt to a range of environmental stimuli. Our earlier work has demonstrated the importance of PhoPQ in the resistance formation in S. Enteritidis to quinolones and cephalosporins. In the current work, we identified a global profile of genes that are regulated by PhoP under antibiotic stresses, with a focus on how PhoP regulated downstream genes, either positively or negatively. Additionally, we established that PhoQ sensed quinolones and cephalosporins in a manner of directly binding to them. These identified genes and pathways that are mediated by PhoPQ represent promising targets for the development of a drug potentiator with which to neutralize antibiotic resistance in S. Enteritidis.

TACE responser NDRG1 acts as a guardian against ferroptosis to drive tumorgenesis and metastasis in HCC.

BACKGROUND: The treatment efficacy of transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) varies widely between individuals. The aim of this study was to identify subtype landscapes and responser related to TACE, and further clarify the regulatory effect and corresponding mechanism of NDRG1 on HCC tumorgenesis and metastasis. METHODS: The principal component analysis (PCA) algorithm was used to construct a TACE response scoring (TRscore) system. The random forest algorithm was applied to identify the TACE response-related core gene NDRG1 of HCC, and its role in the prognosis of HCC was explored. The role of NDRG1 in the progression and metastasis of HCC and functional mechanism were confirmed using several experimental methods. RESULTS: Based on the GSE14520 and GSE104580 cohorts, we identified 2 TACE response-related molecular subtypes for HCC with significant differences in clinical features, and the TACE prognosis of Cluster A was significantly better than that of Cluster B (p < 0.0001). We then established the TRscore system and found that the low TRscore group showed a higher probability of survival and a lower rate of recurrence than the high TRscore group (p < 0.05) in both the HCC and TACE-treated HCC cohorts within the GSE14520 cohort. NDRG1 was determined to be the the hub gene associated with the TACE response of HCC and its high expression suggested a poor prognosis. Furthermore, The suppression of NDRG1 konckdown in tumorgenesis and metastasis of HCC was clarified in both vivo and vitro, which was importantly achieved through inducing ferroptosis in HCC cells, especially contributing to RLS3-induced ferroptosis. CONCLUSION: The constructed TACE response-related molecular subtypes and TRscores can specifically and accurately predict TACE prognosis for HCC. In addition, the TACE response-related hub gene NDRG1 may act as a guardian against ferroptosis to drive tumorgenesis and metastasis in HCC, which laid a new foundation for the development of new potential targeted therapy strategies to improve disease prognosis in HCC patients.

Melanocyte stem cells and hair graying.

OBJECTIVES: To explore the relationship between melanocyte stem cells in the hair follicle bulge and hair graying so as to fully understand their key role in the pathogenesis of hair graying. METHODS: The published articles about "hair graying, hair color, pigmentation disorders" and "melanocyte stem cells, melanocyte" were searched and analyzed in PubMed to explore their relationship. RESULTS: Melanocytes in hair bulb are involved in the pathogenesis of hair graying as well as the melanocyte stem cells in hair follicle bulge also play important roles in the formation of hair graying through some ways. CONCLUSION: Loss of melanocyte stem cells in hair follicle bulge is one of the main reasons of hair graying, and more researches are needed to explain the underlying mechanisms of ectopic differentiation of melanocyte stem cells in different individual.

Superoxide dismutase 2 as a predictor in patients with hepatitis B virus-associated acute-on-chronic liver failure.

The prognosis of hepatitis B virus-associated acute-on-chronic liver failure (HBV-ACLF) is critical in clinical management. We aimed to assess the prognostic efficacy of superoxide dismutase 2 (SOD2) for 90-day mortality in HBV-ACLF patients. The expression patterns of SOD2 in peripheral blood mononuclear cells (PBMCs) were examined in a derivation set (n = 82) by quantitative real-time polymerase chain reaction (RT-qPCR). The results were further validated in a validation set (n = 35). The expression levels of SOD2 were significantly decreased in the derivation set compared to those with chronic hepatitis B (CHB) or the healthy controls (HCs) (P < 0.001). In HBV-ACLF patients, SOD2 levels were negatively correlated with serum total bilirubin (TBIL) (rs = - 0.43, P < 0.001) and model for end-stage liver disease (MELD) scores (rs = - 0.22, P = 0.047), but positively correlated with alkaline phosphatase (AKP) (rs = 0.23, P = 0.034). SOD2 was identified as an independent risk factor for 90-day mortality in HBV-ACLF patients (hazard ratio: 0.124, 95% confidence interval: 0.059-0.261, P < 0.001). SOD2 yielded a larger area under the receiver operating characteristic curve (AUROC) than the MELD score in predicting 90-day mortality (0.914 vs. 0.712, P < 0.001). Kaplan-Meier analysis revealed a favorable overall survival (OS) for the SOD2 high expression group compared with the SOD2 low expression group in both the derivation and validation sets (P < 0.001). SOD2 has promising potential as a predictor of 90-day mortality in patients with HBV-ACLF.

Chondroblastoma: clinicopathological analyses of 307 cases from a single institution in China and the diagnostic value of the H3F3 K36M mutant antibody.

AIMS: To elucidate the clinicopathological features and the diagnostic value of mutation specific antibody H3F3 K36M of chondroblastoma (CB) in China. METHODS: Clinicopathological profiles were retrieved, and immunohistochemistry was performed on 185 CB specimens and the control group. RESULTS: Our series included 307 patients with a mean age of 22.1 years. Long tubular bones (63.8%, 196/307) were most commonly involved, followed by short bones of the hands and feet (22.1%, 68/307), sesamoid bones (8.1%, 25/307), flat bones and irregular bones (5.9%, 18/307). The most commonly involved site was the proximal femur, followed by distal femur, proximal humerus and calcaneus. The average age in the long bones group (20.3 years) was significantly younger than the short bones group (24.9 years) (p<0.001), sesamoid bones group (24.4 years) (p=0.02) and flat bones and irregular bones group (29.1 years) (p<0.001). Microscopically, aneurysmal bone cyst-like change (63.6%, 117/184), necrosis (43.5%, 80/184) and chicken-wire calcification (26.1%, 48/184) were variably noted. In rare cases, cortical destruction, soft tissue and lymphovascular invasion were identified. Positive immunoreaction with H3F3 K36M was examined in all non-decalcified, all EDTA decalcified, 87.1% hydrochloric acid (HCl) decalcified CB samples and the high-grade sarcoma secondary to CB, but not the control group. CONCLUSIONS: CB usually involves the long tubular bones in younger age group. H3F3 K36M can identify K36M mutation with 100% specificity and 100% sensitivity in non-decalcified and EDTA decalcified samples, more than 80% sensitivity in HCl decalcified samples. Virtually, all CBs harbour an H3K36M mutation.

Targeted xCT-mediated Ferroptosis and Protumoral Polarization of Macrophages Is Effective against HCC and Enhances the Efficacy of the Anti-PD-1/L1 Response.

Tumor-associated macrophages (TAMs) play an essential role in tumor progression, metastasis, and antitumor immunity. Ferroptosis has attracted extensive attention for its lethal effect on tumor cells, but the role of ferroptosis in TAMs and its impact on tumor progression have not been clearly defined. Using transgenic mouse models, this study determines that xCT-specific knockout in macrophages is sufficient to limit tumorigenicity and metastasis in the mouse HCC models, achieved by reducing TAM recruitment and infiltration, inhibiting M2-type polarization, and activating and enhancing ferroptosis activity within TAMs. The SOCS3-STAT6-PPAR-γ signaling may be a crucial pathway in macrophage phenotypic shifting, and activation of intracellular ferroptosis is associated with GPX4/RRM2 signaling regulation. Furthermore, that xCT-mediated macrophage ferroptosis significantly increases PD-L1 expression in macrophages and improves the antitumor efficacy of anti-PD-L1 therapy is unveiled. The constructed Man@pSiNPs-erastin specifically targets macrophage ferroptosis and protumoral polarization and combining this treatment with anti-PD-L1 exerts substantial antitumor efficacy. xCT expression in tumor tissues, especially in CD68+ macrophages, can serve as a reliable factor to predict the prognosis of HCC patients. These findings provide further insight into targeting ferroptosis activation in TAMs and regulating TAM infiltration and functional expression to achieve precise tumor prevention and improve therapeutic efficacy.

Macrophage xCT deficiency drives immune activation and boosts responses to immune checkpoint blockade in lung cancer.

Tumor-associated macrophages (TAMs) play an important role in remodeling the tumor microenvironment (TME), which promotes tumor growth, immunosuppression and angiogenesis. Because of the high plasticity of macrophages and the extremely complex tumor microenvironment, the mechanism of TAMs in cancer progression is still largely unknown. In this study, we found that xCT (SLC7A11) was overexpressed in lung cancer-associated macrophages. Higher xCT in TAMs was associated with poor prognosis and was an independent predictive factor in lung cancer. In addition, lung cancer growth and progression was inhibited in xCT knockout mice, especially macrophage-specific xCT knockout mice. We also found that the deletion of macrophage xCT inhibited AKT/STAT6 signaling activation and reduced M2-type polarization of TAMs. Macrophage xCT deletion recruited more CD8+ T cells and activated the lung cancer cell-mediated and IFN-γ-induced JAK/STAT1 axis and increased the expression of its target genes, including CXCL10 and CD274. The combination of macrophage xCT deletion and anti-PDL1 antibody achieved better tumor inhibition. Finally, combining the xCT inhibitor erastin with an anti-PDL1 antibody was more potent in inhibiting lung cancer progression. Therefore, suppression of xCT may overcome resistance to cancer immunotherapy.