Acidic/hypoxia dual-alleviated nanoregulators for enhanced treatment of tumor chemo-immunotherapy.

Chemotherapy plays a crucial role in triple-negative breast cancer (TNBC) treatment as it not only directly kills cancer cells but also induces immunogenic cell death. However, the chemotherapeutic efficacy was strongly restricted by the acidic and hypoxic tumor environment. Herein, we have successfully formulated PLGA-based nanoparticles concurrently loaded with doxorubicin (DOX), hemoglobin (Hb) and CaCO3 by a CaCO3-assisted emulsion method, aiming at the effective treatment of TNBC. We found that the obtained nanomedicine (DHCaNPs) exhibited effective drug encapsulation and pH-responsive drug release behavior. Moreover, DHCaNPs demonstrated robust capabilities in neutralizing protons and oxygen transport. Consequently, DHCaNPs could not only serve as oxygen nanoshuttles to attenuate tumor hypoxia but also neutralize the acidic tumor microenvironment (TME) by depleting lactic acid, thereby effectively overcoming the resistance to chemotherapy. Furthermore, DHCaNPs demonstrated a notable ability to enhance antitumor immune responses by increasing the frequency of tumor-infiltrating effector lymphocytes and reducing the frequency of various immune-suppressive cells, therefore exhibiting a superior efficacy in suppressing tumor growth and metastasis when combined with anti-PD-L1 (αPD-L1) immunotherapy. In summary, this study highlights that DHCaNPs could effectively attenuate the acidic and hypoxic TME, offering a promising strategy to figure out an enhanced chemo-immunotherapy to benefit TNBC patients.

Prediction of the Ki-67 expression level in head and neck squamous cell carcinoma with machine learning-based multiparametric MRI radiomics: a multicenter study.

BACKGROUND: This study aimed to develop and validate a machine learning (ML)-based fusion model to preoperatively predict Ki-67 expression levels in patients with head and neck squamous cell carcinoma (HNSCC) using multiparametric magnetic resonance imaging (MRI). METHODS: A total of 351 patients with pathologically proven HNSCC from two medical centers were retrospectively enrolled in the study and divided into training (n = 196), internal validation (n = 84), and external validation (n = 71) cohorts. Radiomics features were extracted from T2-weighted images and contrast-enhanced T1-weighted images and screened. Seven ML classifiers, including k-nearest neighbors (KNN), support vector machine (SVM), logistic regression (LR), random forest (RF), linear discriminant analysis (LDA), naive Bayes (NB), and eXtreme Gradient Boosting (XGBoost) were trained. The best classifier was used to calculate radiomics (Rad)-scores and combine clinical factors to construct a fusion model. Performance was evaluated based on calibration, discrimination, reclassification, and clinical utility. RESULTS: Thirteen features combining multiparametric MRI were finally selected. The SVM classifier showed the best performance, with the highest average area under the curve (AUC) of 0.851 in the validation cohorts. The fusion model incorporating SVM-based Rad-scores with clinical T stage and MR-reported lymph node status achieved encouraging predictive performance in the training (AUC = 0.916), internal validation (AUC = 0.903), and external validation (AUC = 0.885) cohorts. Furthermore, the fusion model showed better clinical benefit and higher classification accuracy than the clinical model. CONCLUSIONS: The ML-based fusion model based on multiparametric MRI exhibited promise for predicting Ki-67 expression levels in HNSCC patients, which might be helpful for prognosis evaluation and clinical decision-making.

Damage Detection in FRP-Reinforced Concrete Elements.

Fiber-Reinforced Polymer (FRP) composites have emerged as a promising alternative to conventional steel reinforcements in concrete structures owing to their benefits of corrosion resistance, higher strength-to-weight ratio, reduced maintenance cost, extended service life, and superior durability. However, there has been limited research on non-destructive testing (NDT) methods applicable for identifying damage in FRP-reinforced concrete (FRP-RC) elements. This knowledge gap has often limited its application in the construction industry. Engineers and owners often lack confidence in utilizing this relatively new construction material due to the challenge of assessing its condition. Thus, the main objective of this study is to determine the applicability of two of the most common NDT methods: the Ground-Penetrating Radar (GPR) and Phased Array Ultrasonic (PAU) methods for the detection of damage in FRP-RC elements. Three slab specimens with variations in FRP type (glass-, carbon- and basalt-FRP, i.e., GFRP, CFRP, and BFRP, respectively), bar diameter, bar depths, and defect types were investigated to determine the limitations and detection capabilities of these two NDT methods. The results show that GPR could detect damage in GFRP bars and CFRP strands, but PAU was limited to damage detection in CFRP strands. The findings of this study show the applicability of conventional NDT methods to FRP-RC and at the same time identify the areas with a need for further research.

Sodium butyrate alleviates free fatty acid-induced steatosis in primary chicken hepatocytes via the AMPK/PPARα pathway.

Fatty liver hemorrhagic syndrome (FLHS) is a prevalent metabolic disorder observed in egg-laying hens, characterized by fatty deposits and cellular steatosis in the liver. Our preliminary investigations have revealed a marked decrease in the concentration of butyric acid in the FLHS strain of laying hens. It has been established that sodium butyrate (NaB) protects against metabolic disorders. However, the underlying mechanism by which butyrate modulates hepato-lipid metabolism to a great extent remains unexplored. In this study, we constructed an isolated in vitro model of chicken primary hepatocytes to induce hepatic steatosis by free fatty acids (FFA). Our results demonstrate that treatment with NaB effectively mitigated FFA-induced hepatic steatosis in chicken hepatocytes by inhibiting lipid accumulation, downregulating the mRNA expression of lipo-synthesis-related genes (sterol regulatory element binding transcription factor 1 (SREBF1), acetyl-CoA carboxylase 1(ACC1), fatty acid synthase (FASN), stearoyl-CoA desaturase 1 (SCD1), liver X receptor α (LXRα), 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR)) (P < 0.05), and upregulating the mRNA and protein expression of AMP-activated protein kinase α1 (AMPKα1), peroxisome proliferator-activated receptor α (PPARα), and carnitine palmitoyl-transferase 1A (CPT1A) (P < 0.05). Moreover, AMPK and PPARα inhibitors (Compound C (Comp C) and GW6471, respectively) reversed the protective effects of NaB against FFA-induced hepatic steatosis by blocking the AMPK/PPARα pathway, leading to lipid droplet accumulation and triglyceride (TG) contents in chicken primary hepatocytes. With these findings, NaB can alleviate hepatocyte lipoatrophy injury by activating the AMPK/PPARα pathway, promoting fatty acid oxidation, and reducing lipid synthesis in chicken hepatocytes, potentially being able to provide new ideas for the treatment of FLHS.

Biomarker Changes during 20 Years Preceding Alzheimer's Disease.

BACKGROUND: Biomarker changes that occur in the period between normal cognition and the diagnosis of sporadic Alzheimer's disease have not been extensively investigated in longitudinal studies. METHODS: We conducted a multicenter, nested case-control study of Alzheimer's disease biomarkers in cognitively normal participants who were enrolled in the China Cognition and Aging Study from January 2000 through December 2020. A subgroup of these participants underwent testing of cerebrospinal fluid (CSF), cognitive assessments, and brain imaging at 2-year-to-3-year intervals. A total of 648 participants in whom Alzheimer's disease developed were matched with 648 participants who had normal cognition, and the temporal trajectories of CSF biochemical marker concentrations, cognitive testing, and imaging were analyzed in the two groups. RESULTS: The median follow-up was 19.9 years (interquartile range, 19.5 to 20.2). CSF and imaging biomarkers in the Alzheimer's disease group diverged from those in the cognitively normal group at the following estimated number of years before diagnosis: amyloid-beta (Aß)42, 18 years; the ratio of Aß42 to Aß40, 14 years; phosphorylated tau 181, 11 years; total tau, 10 years; neurofilament light chain, 9 years; hippocampal volume, 8 years; and cognitive decline, 6 years. As cognitive impairment progressed, the changes in CSF biomarker levels in the Alzheimer's disease group initially accelerated and then slowed. CONCLUSIONS: In this study involving Chinese participants during the 20 years preceding clinical diagnosis of sporadic Alzheimer's disease, we observed the time courses of CSF biomarkers, the times before diagnosis at which they diverged from the biomarkers from a matched group of participants who remained cognitively normal, and the temporal order in which the biomarkers became abnormal. (Funded by the Key Project of the National Natural Science Foundation of China and others; ClinicalTrials.gov number, NCT03653156.).

Mapping of individual sensory nerve axons from digits to spinal cord with the transparent embedding solvent system.

Achieving uniform optical resolution for a large tissue sample is a major challenge for deep imaging. For conventional tissue clearing methods, loss of resolution and quality in deep regions is inevitable due to limited transparency. Here we describe the Transparent Embedding Solvent System (TESOS) method, which combines tissue clearing, transparent embedding, sectioning and block-face imaging. We used TESOS to acquire volumetric images of uniform resolution for an adult mouse whole-body sample. The TESOS method is highly versatile and can be combined with different microscopy systems to achieve uniformly high resolution. With a light sheet microscope, we imaged the whole body of an adult mouse, including skin, at a uniform 0.8 × 0.8 × 3.5 µm3 voxel resolution within 120 h. With a confocal microscope and a 40×/1.3 numerical aperture objective, we achieved a uniform sub-micron resolution in the whole sample to reveal a complete projection of individual nerve axons within the central or peripheral nervous system. Furthermore, TESOS allowed the first mesoscale connectome mapping of individual sensory neuron axons spanning 5 cm from adult mouse digits to the spinal cord at a uniform sub-micron resolution.

A Golgi-Targeted Platinum Complex Plays a Dual Role in Autophagy Regulation for Highly Efficient Cancer Therapy.

Regulating autophagy to control the homeostatic recycling process of cancer cells is a promising anticancer strategy. Golgi apparatus is a substrate of autophagy but the Golgi-autophagy (Golgiphagy) mediated antitumor pathway is rarely reported. Herein, we have developed a novel Golgi-targeted platinum (II) complex Pt3, which is ca. 20 times more cytotoxic to lung carcinoma than cisplatin and can completely eliminate tumors after intratumoral administration in vivo. Its nano-encapsulated system for tail vein administration also features a good anti-tumor effect. Mechanism studies indicate that Pt3 induces substantial Golgi stress, indicated by the fragmentation of Golgi structure, down-regulation of Golgi proteins (GM130, GRASP65/55), loss of Golgi-dependent transport and glycosylation. This triggers Golgiphagy but blocks the subsequent fusion of autophagosomes with lysosomes, that is a dual role in autophagy regulation, resulting in loss of proteostasis and apoptotic cell death. As far as we know, Pt3 is the first Golgi-targeted Pt complex that can trigger Golgi stress-mediated dual-regulation of autophagic flux and autophagy-apoptosis crosstalk for highly efficient cancer therapy.

Mesenchymal stem cell-derived extracellular vesicles in skin wound healing: roles, opportunities and challenges.

Skin wounds are characterized by injury to the skin due to trauma, tearing, cuts, or contusions. As such injuries are common to all human groups, they may at times represent a serious socioeconomic burden. Currently, increasing numbers of studies have focused on the role of mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) in skin wound repair. As a cell-free therapy, MSC-derived EVs have shown significant application potential in the field of wound repair as a more stable and safer option than conventional cell therapy. Treatment based on MSC-derived EVs can significantly promote the repair of damaged substructures, including the regeneration of vessels, nerves, and hair follicles. In addition, MSC-derived EVs can inhibit scar formation by affecting angiogenesis-related and antifibrotic pathways in promoting macrophage polarization, wound angiogenesis, cell proliferation, and cell migration, and by inhibiting excessive extracellular matrix production. Additionally, these structures can serve as a scaffold for components used in wound repair, and they can be developed into bioengineered EVs to support trauma repair. Through the formulation of standardized culture, isolation, purification, and drug delivery strategies, exploration of the detailed mechanism of EVs will allow them to be used as clinical treatments for wound repair. In conclusion, MSC-derived EVs-based therapies have important application prospects in wound repair. Here we provide a comprehensive overview of their current status, application potential, and associated drawbacks.

Biomaterials evolution: from inert to instructive.

The field of biomaterials has experienced substantial evolution in recent years, driven by advancements in materials science and engineering. This has led to an expansion of the biomaterials definition to include biocompatibility, bioactivity, bioderived materials, and biological tissues. Consequently, the intended performance of biomaterials has shifted from a passive role wherein a biomaterial is merely accepted by the body to an active role wherein a biomaterial instructs its biological environment. In the future, the integration of bioinspired designs and dynamic behavior into fabrication technologies will revolutionize the field of biomaterials. This perspective presents the recent advances in the evolution of biomaterials in fabrication technologies and provides a brief insight into smart biomaterials.

Mitochondrial mass of circulating NK cells as a novel biomarker in severe SARS-CoV-2 infection.

BACKGROUND: Severe SARS-CoV-2 infection results in lymphopenia and impaired function of T, B, and NK (TBNK-dominant) lymphocytes. Mitochondria are essential targets of SARS-CoV-2 and the efficacy of lymphocyte mitochondrial function for immunosurveillance in COVID-19 patients has not been evaluated. METHODS: Multi-parametric flow cytometry was used to characterize mitochondrial function, including mitochondrial mass (MM) and low mitochondrial membrane potential (MMPlow), in TBNK-dominant lymphocytes from severe (n = 93) and moderate (n = 77) hospitalized COVID-19 patients. We compared the role of novel lymphocyte mitochondrial indicators and routine infection biomarkers as early predictors of severity and death in COVID-19 patients. We then developed a mortality decision tree prediction model based on immunosurveillance indicators through machine learning. RESULTS: At admission, the MM of circulating NK cells (NK-MM) was the best discriminator of severe/moderate disease (AUC = 0.8067) compared with the routine infection biomarkers. The NK cell count and NK-MM displayed superior diagnostic effects to distinguish patients with non-fatal or fatal outcomes. Interestingly, NK-MM was significantly polarized in non-survivors, with some patients showing a decrease and others showing an abnormal increase. Kaplan-Meier analysis showed that NK-MM had the optimal predictive efficacy (hazard ratio = 11.66). The decision tree model has the highest proportion of importance for NK-MM, which is superior to the single diagnostic effect of the above indicators (AUC = 0.8900). CONCLUSION: NK-MM was not only associated with disease severity, its abnormal increases or decreases also predicted mortality risk. The resulting decision tree prediction model is the first to focus on immune monitoring indicators to provide decision-making clues for COVID-19 clinical management.

Tertiary lymphoid structures and cytokines interconnections: The implication in cancer immunotherapy.

Tertiary lymphoid structures (TLSs) are organized aggregates of lymphocytes and antigen-presenting cells that develop in non-lymphoid tissues during chronic inflammation, resembling the structure and features of secondary lymphoid organs. Numerous studies have shown that TLSs may be an important source of antitumor immunity within solid tumors, facilitating T cell and B cell differentiation and the subsequent production of antitumor antibodies, which are beneficial for cancer prognosis and responses to immunotherapy. The formation of TLSs relies on the cytokine signaling network between heterogeneous cell populations, such as stromal cells, lymphocytes and cancer cells. The coordinated action of various cytokines drives the complex process of TLSs development. In this review, we will comprehensively describe the mechanisms by which various cytokines regulate TLS formation and function, and the recent advancements and therapeutic potential of exploiting these mechanisms to induce intratumoral TLSs as an emerging immunotherapeutic approach or to enhance existing immunotherapy.

MEX3A determines in vivo hepatocellular carcinoma progression and induces resistance to sorafenib in a Hippo-dependent way.

BACKGROUND: Hepatocellular carcinoma (HCC) is most common malignant tumor worldwide, and one of the most lethal malignancies. MEX3A, RNA-binding protein, is profoundly implicated in tumor initiation and progression. But its role and potential mechanism in HCC remains fully unclear. METHODS: The expression of MEX3A in HCC was analysis using the data derived from the Cancer Genome Atlas (TCGA) dataset and further confirmed by HCC samples and cells lines. The roles of MEX3A in the proliferation, migration and sorafenib resistance were detected both in vitro and vivo. In addition, the underline mechanism was investigated. RESULTS: In this study, MEX3A expression was upregulated in HCC tissue and cell lines. Knockdown or overexpression of MEX3A disturbed the proliferation, migration and apoptosis of HCC cells by modulating the activation of Hippo signaling pathway. The expression of MEX3A was negatively associated with sorafenib sensitivity and upregulated in sorafenib resistant HCC cells. MEX3A knockdown facilitated the expression of WWC1, a negative modulator of Hippo signaling pathway, and led to increase of the phosphorylation of LATS1 and YAP1. Pharmacological inhibition of LATS1 or WWC1 overexpression alleviated the proliferative and migrated suppression and increased sorafenib sensitivity, whereas WWC1 inhibition using genetic interference strategy showed opposite trend in MEX3A knockdown HCC cells. Importantly, MEX3A knockdown led to growth and lung metastasis inhibition using xenograft model established by means of subcutaneous or tail vein injection. In addition, a combination of MEX3A knockdown and WWC1 overexpression dramatically enhances the growth inhibition of sorafenib in vivo. CONCLUSION: MEX3A may facilitate HCC progression and hinder sorafenib sensitivity via inactivating Hippo signaling. The present study suggested that targeting MEX3A can be served as a novel therapeutic strategy for HCC.

Machine Learning Classifier for Preoperative Prediction of Early Recurrence After Bronchial Arterial Chemoembolization Treatment in Lung Cancer Patients.

RATIONALE AND OBJECTIVES: Bronchial arterial chemoembolization (BACE) was deemed as an effective and safe approach for advanced standard treatment-ineligible/rejected lung cancer patients. However, the therapeutic outcome of BACE varies greatly and there is no reliable prognostic tool in clinical practice. This study aimed to investigate the effectiveness of radiomics features in predicting tumor recurrence after BACE treatment in lung cancer patients. MATERIALS AND METHODS: A total of 116 patients with pathologically confirmed lung cancer who received BACE treatment were retrospectively recruited. All patients underwent contrast-enhanced CT within 2 weeks before BACE treatment and were followed up for more than 6 months. We conducted a machine learning-based characterization of each lesion on the preoperative contrast-enhanced CT images. In the training cohort, recurrence-related radiomics features were screened by least absolute shrinkage and selection operator (LASSO) regression. Three predictive radiomics signatures were built with linear discriminant analysis (LDA), support vector machine (SVM) and logistic regression (LR) algorithms, respectively. Univariate and multivariate LR analyses were performed to select the independent clinical predictors for recurrence. The radiomics signature with best predictive performance was integrated with the clinical predictors to form a combined model, which was visualized as a nomogram. The performance of the combined model was assessed by receiver operating characteristic curve (ROC), calibration curve, and decision curve analysis (DCA). RESULTS: Nine recurrence-related radiomics features were screened out, and three radiomics signatures (RadscoreLDA, RadscoreSVM and RadscoreLR) were built based on these features. Patients were classified into the low-risk and high-risk groups based on the optimal threshold of three signatures. Progression-free survival (PFS) analysis showed that patients of low-risk group achieved longer PFS than patients of high-risk group (P < 0.05). The combined model including RadscoreLDA and independent clinical predictors (tumor size, carcinoembryonic antigen and pro-gastrin releasing peptide) achieved the best predictive performance for recurrence after BACE treatment. It yields AUCs of 0.865 and 0.867 in the training and validation cohorts, with accuracy (ACC) of 0.804 and 0.750, respectively. Calibration curves indicated that the probability of recurrence predicted by the model fits well with the actual recurrence probability. DCA showed that the radiomics nomogram was clinically useful. CONCLUSION: The radiomics and clinical predictors-based nomogram can predict tumor recurrence after BACE treatment effectively, which allowing oncologists to identify potential recurrence and enable better patient management and clinical decision-making.

Cannabidiol Alleviates Perfluorooctanesulfonic Acid-Induced Cardiomyocyte Apoptosis by Maintaining Mitochondrial Dynamic Balance and Energy Metabolic Homeostasis.

Perfluorooctanesulfonic acid (PFOS), a fluorine-containing organic compound, can be widely detected in the environment and living organisms. Accumulating evidence has shown that PFOS breaks through different biological barriers resulting in cardiac toxicity, but the underlying molecular mechanisms remain unclear. Cannabidiol (CBD) is a nonpsychoactive cannabinoid without potential adverse cardiotoxicity and has antioxidant and anti-inflammatory properties that reduce multiorgan damage and dysfunction. For these reasons, the aim of this study was to research how PFOS caused heart injury and whether CBD could attenuate PFOS-induced heart injury. Mice were fed PFOS (5 mg/kg) and/or CBD (10 mg/kg) in vivo. In vitro, H9C2 cells were intervened with PFOS (200 µM) and/or CBD (10 µM). After PFOS exposure, oxidative stress levels and the mRNA and protein expression of apoptosis-related markers increased distinctly, accompanied by mitochondrial dynamic imbalance and energy metabolism disorders in mouse heart and H9C2 cells. Moreover, terminal deoxynucleotidyl transferase dUTP nick end labeling staining, acridine orange/ethidium bromide staining and Hoechst 33258 staining signaled that the number of apoptotic cells increased after exposure to PFOS. Noteworthy, CBD simultaneous treatment alleviated a series of damages caused by PFOS-mediated oxidative stress. Our results demonstrated that CBD could alleviate PFOS-induced mitochondrial dynamics imbalance and energy metabolism disorder causing cardiomyocyte apoptosis by improving the antioxidant capacity, suggesting that CBD may represent a novel cardioprotective strategy against PFOS-induced cardiotoxicity. Our findings facilitate the understanding of the cardiotoxic effects of PFOS and the important role of CBD in protecting cardiac health.

The role of metabolic reprogramming of oxygen-induced macrophages in the dynamic changes of atherosclerotic plaques.

Atherosclerosis (As) is a chronic vascular inflammatory disease. Macrophages are the most important immune cells in atherosclerotic plaques, and the phenotype of plaque macrophages shifts dynamically to adapt to changes in the plaque microenvironment. The aerobic microenvironment of early atherosclerotic plaques promotes the transformation of M2/alternatively activated macrophages mainly through oxidative phosphorylation; the anoxic microenvironment of advanced atherosclerotic plaques mainly promotes the formation of M1/classically activated macrophages through anaerobic glycolysis; and the adventitia angiogenesis of aged atherosclerotic plaques leads to an increase in the proportion of M2/M1 macrophages. Therefore, this review deeply elucidates the dynamic change mechanism of plaque macrophages and the regulation of plaque oxygen content and immune metabolism to find new targets for the treatment of As.

Monodisperse CaCO3-loaded gelatin microspheres for reversing lactic acid-induced chemotherapy resistance during TACE treatment.

Transarterial chemoembolization (TACE) is an important approach for the treatment of unresectable hepatocellular carcinoma (HCC). However, the lactic acid-induced acidic tumor microenvironment (TME) may reduce the therapeutic outcome of TACE. Herein, monodispersed gelatin microspheres loaded with calcium carbonate nanoparticles (CaNPs@Gel-MS) as novel embolic agents were prepared by a simplified microfluidic device. It was found that the particle size and homogeneity of as-prepared CaNPs@Gel-MS were strongly dependent on the flow rates of continuous and dispersed phases, and the inner diameter of syringe needle. The introduction of CaNPs provided the gelatin microspheres with an enhanced ability to encapsulate the chemotherapeutic drug of DOX, as well as a pH-responsive sustained drug release behavior. In vitro results revealed that CaNPs@Gel-MS could largely increase the cellular uptake and chemotoxicity of DOX by neutralizing the lactic acid in the culture medium. In addition, CaNPs@Gel-MS exhibited an excellent and persistent embolic efficiency in a rabbit renal model. Finally, we found that TACE treatment with DOX-loaded CaNPs@Gel-MS (DOX/CaNPs@Gel-MS) had a much stronger ability to inhibit tumor growth than the DOX-loaded gelatin microspheres without CaNPs (DOX@Gel-MS). Overall, CaNPs@Gel-MS could be a promising embolic microsphere that can significantly improve anti-HCC ability by reversing lactic acid-induced chemotherapy resistance during TACE treatment.

Inactivation of KDM5A suppresses growth and enhances chemosensitivity in liver cancer by modulating ROCK1/PTEN/AKT pathway.

Liver cancer is a kind of malignant tumor with poor sensitivity to chemotherapy. It is urgent to investigate approaches to improve the outcome of chemotherapy. KDM5A has been reported to be an oncogene in various cancers and is associated with drug resistance. However, the functions of KDM5A in chemotherapeutic sensitivity of liver cancer not been well illustrated. In this study, we found that KDM5A was upregulated in liver cancer tissue and cell lines. KDM5A knockdown using a gene interference strategy suppressed the growth of liver cancer in vitro and in vivo. CPI-455, a pharmacological inactivation of KDM5A enhanced the cytotoxicity of cisplatin (CDDP) in liver cells. CPI-455 and CDDP cotreatment resulted in apoptosis and mitochondrial dysfunction. We also found that knockdown or inactivation of KDM5A resulted in the downregulation of ROCK1, an oncogene regulating the activation of the PTEN/AKT signaling pathway. In particular, overexpression of ROCK1 or SF1670, a pharmacological inhibitor of PTEN, alleviated the cytotoxicity of CPI-455 and CDDP cotreatment. In HCCLM3 xenografts, CPI-455 and CDDP cotreatment dramatically inhibited the growth of xenograft tumor compared to CPI-455 or CDDP treatment alone. In conclusion, this study suggested that targeting the inactivation of KDM5A is an efficient strategy to enhance the chemosensitivity of liver cancer cells to CDDP by modulating the ROCK1/PTEN/AKT signaling pathway.

Exosome-Mediated Immunosuppression in Tumor Microenvironments.

Exosomes are membranous structures secreted by nearly all cell types. As critical messengers for intercellular communication, exosomes deliver bioactive cargoes to recipient cells and are involved in multiple physiopathological processes, including immunoregulation. Our pioneering study revealed that cancer cells release programmed death-ligand 1-positive exosomes into the circulation to counter antitumor immunity systemically via T cells. Tumor cell-derived exosomes (TDEs) also play an immunosuppressive role in other immunocytes, including dendritic cells (DCs), macrophages, natural killer (NK) cells, and myeloid-derived suppressor cells (MDSCs). Moreover, exosomes secreted by nontumor cells in the tumor microenvironments (TMEs) also exert immunosuppressive effects. This review systematically provides a summary of the immunosuppression induced by exosomes in tumor microenvironments, which modulates tumor growth, invasion, metastasis, and immunotherapeutic resistance. Additionally, therapeutic strategies targeting the molecular mechanism of exosome-mediated tumor development, which may help overcome several obstacles, such as immune tolerance in oncotherapy, are also discussed. Detailed knowledge of the specific functions of exosomes in antitumor immunity may contribute to the development of innovative treatments.

xCT contributes to colorectal cancer tumorigenesis through upregulation of the MELK oncogene and activation of the AKT/mTOR cascade.

Colorectal cancer (CRC) is one of the most commonly diagnosed and deadly malignant tumors globally, and its occurrence and progression are closely related to the poor histological features and complex molecular characteristics among patients. It is urgent to identify specific biomarkers for effective treatment of CRC. In this study, we performed comprehensive experiments to validate the role of xCT expression in CRC tumorigenesis and stemness and confirmed xCT knockdown significantly suppressed the proliferation, migration, and stemness of CRC cells in vitro and effectively inhibited CRC tumorigenesis and metastasis in vivo. In addition, bioinformatic analysis and luciferase assays were used to identify E2F1 as a critical upstream transcription factor of SLC7A11 (the gene encoding for xCT) that facilitated CRC progression and cell stemness. Subsequent RNA sequencing, western blotting, rescue assay, and immunofluorescence assays revealed MELK directly co-expressed with xCT in CRC cells, and its upregulation significantly attenuated E2F1/xCT-mediated tumorigenesis and stemness in CRC. Further molecular mechanism exploration confirmed that xCT knockdown may exert an antitumor effect by controlling the activation of MELK-mediated Akt/mTOR signaling. Erastin, a specific inhibitor of xCT, was also proven to effectively inhibit CRC tumorigenesis and cell stemness. Altogether, our study showed that E2F1/xCT is a promising therapeutic target of CRC that promotes tumorigenesis and cell stemness. Erastin is also an effective antitumoral agent for CRC.