Probing Selenium-Deficient Chicken Spleen Th1/Th17 Differentiation Based on Selenoprotein W Targeting of PKM2/HIF1α.

Selenium regulates the differentiation and function of immune cells mainly through selenoproteins. Selenoprotein W (SelW) has been shown to mitigate inflammatory bowel disease in mice by modulating the differentiation of helper T (CD4+ T) cell. Previous studies by our team have underscored SelW's critical role in safeguarding chicken spleens and splenic lymphocytes against inflammatory injury. However, research examining SelW's involvement in regulating CD4+ T cell differentiation in avian spleens remains scarce. Therefore, the selenium-deficient chicken model was constructed in this study. It was found that the spleen of selenium-deficient chickens showed significant inflammatory damage, accompanied by decreased SelW expression, diminished antioxidant capacity, heightened glycolysis, and an elevated count of Th1/Th17 cells. To elucidate the specific mechanism of SelW regulating Th1/Th17 cell differentiation, this study used molecular docking technology, fluorescence colocalization, and co-immunoprecipitation and initially confirmed the targeting relationship between SelW and pyruvate kinase M2 (PKM2). Subsequently, an in vitro model of SelW overexpression, knockdown, and TEPP-46 (PKM2 tetramer activator) cotreatment of chicken primary splenic lymphocytes was replicated. Our findings revealed that selenium deficiency triggers oxidative stress and promotes PKM2 nuclear translocation via SelW downregulation, which stabilizes HIF1α transcription in the nucleus, enhancing glycolysis and skewing chicken splenic CD4+ T cells toward the Th1/Th17 phenotype. Our study, for the first time, demonstrates the existence of an interaction between SelW and PKM2 in poultry, emphasizing SelW's paramount significance in CD4+ T cell differentiation, providing fresh perspectives on the contributions of selenoproteins to T cell biology and immune processes.

Double Enzyme Active Hydrogel Program Regulates the Microenvironment of Staphylococcus aureus-Infected Pressure Ulcers.

The treatment of infected pressure ulcers (IUPs) requires addressing diverse microenvironments. A pressing challenge is to effectively enhance the regenerative microenvironment at different stages of the healing process, tailoring interventions as needed. Here, a dual enzyme mimetic and bacterial responsive self-activating antimicrobial hydrogel designed to enhance IPUs healing is introduced. This hydrogel incorporates pH-responsive dual enzyme-active nanoplatforms (HNTs-Fe-Ag) encapsulated within a methacrylate-modified silk fibroin (SFMA) and dopamine methacrylamide (DMA) matrix. This composite hydrogel exhibits adaptive microenvironment regulation capabilities. Under the low pH microenvironment of bacterial infection, it has excellent antimicrobial activity by self-activating the •OH generation in conjunction with photothermal effects. Under the neutral and alkaline microenvironment of chronic inflammation, it catalyzes the decomposition of hydrogen peroxide (H2O2) to produce oxygen (O2), thereby alleviating hypoxia and scavenging reactive oxygen species (ROS), which in turn remodulates the phenotype of macrophages. The composite hydrogel demonstrates on-demand therapeutic effects in the microenvironment of infected wounds, significantly enhancing the regenerative microenvironment of IUPs by promoting wound closure, inflammation regulation, and collagen deposition through self-activated antimicrobial action during infection and adaptive hypoxia relief during recovery. This approach offers a novel strategy for developing smart wound dressings.

A near-infrared triggered multi-functional indocyanine green nanocomposite with NO gas release function inducing improved photothermal therapy.

The integration of photothermal and near-infrared (NIR) imaging capabilities of indocyanine green (ICG) small molecules has attracted considerable attention in tumor diagnosis and treatment. However, the abnormal upregulation of cellular heat shock proteins (HSPs) induced by photothermal therapy (PTT) enhances cellular heat resistance, thereby severely affecting the efficacy of PTT. In this study, to address the impact of HSPs on the efficacy of PTT while obtaining high-quality NIR fluorescence imaging in the NIR region, we designed a targeted peptide@ICG nanofluorescent probe encapsulated in liposomes. The introduced cRGD targeting peptide not only possesses tumor-targeting capabilities but also features LA as the last amino acid in the targeting peptide, which can generate nitric oxide (NO) under reactive oxygen species (ROS) triggering. It can happen under 808 nm single-light source NIR light, and the guanidine group in the peptide decomposes and combines with singlet oxygen molecules to generate NO gas molecules, thereby exerting an elevated photothermal effect by inhibiting the expression of HSP70. In addition, the nanoprobes enable deep imaging and treatment of glioma in situ and can be combined with a laser speckle contrast imaging (LSCI) system for multimodal imaging. This composite probe demonstrates synergistic tumor therapeutic effects of photodynamic therapy (PDT), PTT, and gas therapy, offering a promising strategy for cancer treatment.

Selenium deficiency modulates necroptosis-mediated intestinal inflammation in broiler through the lncRNAWSF27/miRNA1696/GPX3 axis.

Deficiency of selenium (Se), an important trace element, causes diarrhea and even death in broilers, thereby affecting the economic development of poultry production. Adding Se is one way to relieve this situation; however, it has not fundamentally resolved intestinal inflammation. Therefore, we sought a new strategy to alleviate intestinal inflammation by studying the specific mechanisms of Se deficiency. By replicating the Se-deficient broiler model and establishing a chicken small intestinal epithelial cell (CSIEC) model, we determined that Se deficiency caused intestinal oxidative stress and necroptotic intestinal inflammation in broilers by decreasing glutathione peroxidase (GPX) 3 expression. Simultaneously, the expression of long non-coding RNA (lncRNA)WSF27 decreased and that of miR-1696 increased in Se-deficient intestines. Recently discovered competing endogenous RNAs (ceRNAs) form novel regulatory networks, which were found that selenoproteins involved in ceRNA regulation. However, the mechanism of action of the non-coding RNA/GPX3 axis in Se-deficient broiler intestinal inflammation remains unclear. This study aimed to explore the mechanism through which Se deficiency regulates intestinal inflammation in broilers through the lncRNAWSF27/miR-1696/GPX3 axis. Our previous studies showed that lncRNAWSF27, miR-1696, and GPX3 have ceRNA-regulatory relationships. To further determine the role of the lncRNAWSF27/miR-1696/GPX3 axis in Se-deficient broiler intestinal inflammation, CSIEC models with GPX3 knockdown/overexpression, lncRNAWSF27 knockdown, or miR-1696 knockdown/overexpression were established to simulate intestinal injury. GPX3 knockdown, as well as lncRNAWSF27 and miR-1696 overexpression, aggravated cell damage. On the contrary, it can alleviate this situation. Our results reveal that mechanism of lncRNAWSF27/miR-1696/GPX3 regulated Se-deficient broiler intestinal inflammation. This conclusion enriches our understanding of the mechanism of intestinal injury caused by Se deficiency, and contributes to the diagnosis of Se-deficient intestinal inflammation and relevant drug development.

The biological applications of near-infrared optical nanomaterials in atherosclerosis.

PURPOSE OF REVIEW: Atherosclerosis, a highly pathogenic and lethal disease, is difficult to locate accurately via conventional imaging because of its scattered and deep lesions. However, second near-infrared (NIR-II) nanomaterials show great application potential in the tracing of atherosclerotic plaques due to their excellent penetration and angiographic capabilities. RECENT FINDINGS: With the development of nanotechnology, among many nanomaterials available for the visual diagnosis and treatment of cardiovascular diseases, optical nanomaterials provide strong support for various biomedical applications because of their advantages, such as noninvasive, nondestructive and molecular component imaging. Among optical nanomaterials of different wavelengths, NIR-II-range (900 ~ 1700 nm) nanomaterials have been gradually applied in the visual diagnosis and treatment of atherosclerosis and other vascular diseases because of their deep biological tissue penetration and limited background interference. This review explored in detail the prospects and challenges of the biological imaging and clinical application of NIR-II nanomaterials in treating atherosclerosis.

Co-exposure of bisphenol A and selenium deficiency induces pyroptosis via ROS/NLRP3 pathway in chicken spleen.

Bisphenol A (BPA) is widely applied in plastic products, which will produce immunotoxicity to organisms after spilling in the environment, and become a kind of endocrine disruptor. Selenium (Se) is an essential trace element and plays an important role in maintaining redox homeostasis and immune function. BPA exposure and Se deficiency often occur together in livestock and poultry farming, however, studies on the effects of joint exposure on chicken immunotoxins have not been reported. Therefore, this study established a chicken spleen and MDCC-MSB1 cell model under the combined effects of BPA exposure or/and Se deficiency. Transcriptomic analysis showed that BPA exposure and/or Se deficiency induced differential enrichment of positive regulatory pathways such as NLRP3 inflammatory complex assembly, inflammatory response and cellular oxidative stress response. In the -Se+BPA group, pathological damage was significantly increased, Se content decreased, BPA accumulation, oxidative stress and pyroptosis. Meanwhile, the roles and mechanisms of oxidative stress and pyroptosis in BPA exposure or/and Se deficiency-induced splenic tissue injury were investigated by using IF and qRT-PCR methods. The results showed that joint BPA exposure with Se deficiency resulted in more significant changes in the above outcomes than 1 of them. The oxidative stress inhibitor NAC effectually reduced Se deficiency and BPA-induced oxidative stress and pyroptosis, further suggests that oxidative stress mediated Se deficiency or/and BPA-induced pyroptosis. This study revealed that BPA exposure and Se deficiency induced spleen pyroptosis in chickens via the ROS/NLRP3 pathway. These results provide the theoretical basis for the toxicity of BPA in poultry and enrich the toxicological mechanism of combined exposure of Se deficiency and environmental toxins.

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.

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.

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.

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.