Enhancing head and neck tumor management with artificial intelligence: Integration and perspectives.

Head and neck tumors (HNTs) constitute a multifaceted ensemble of pathologies that primarily involve regions such as the oral cavity, pharynx, and nasal cavity. The intricate anatomical structure of these regions poses considerable challenges to efficacious treatment strategies. Despite the availability of myriad treatment modalities, the overall therapeutic efficacy for HNTs continues to remain subdued. In recent years, the deployment of artificial intelligence (AI) in healthcare practices has garnered noteworthy attention. AI modalities, inclusive of machine learning (ML), neural networks (NNs), and deep learning (DL), when amalgamated into the holistic management of HNTs, promise to augment the precision, safety, and efficacy of treatment regimens. The integration of AI within HNT management is intricately intertwined with domains such as medical imaging, bioinformatics, and medical robotics. This article intends to scrutinize the cutting-edge advancements and prospective applications of AI in the realm of HNTs, elucidating AI's indispensable role in prevention, diagnosis, treatment, prognostication, research, and inter-sectoral integration. The overarching objective is to stimulate scholarly discourse and invigorate insights among medical practitioners and researchers to propel further exploration, thereby facilitating superior therapeutic alternatives for patients.

Simultaneously blocking ANGPTL3 and CD47 prevents the progression of atherosclerosis through regulating lipid metabolism, macrophagic efferocytosis and lipid peroxidation.

Atherosclerosis (AS) ultimately cause major adverse cardiovascular events (MACEs). While traditional strategies by lipid-reducing have reduced MACEs, many patients continue to face significant risks. It might attribute to the upregulation of CD47 expression in AS lesions, that mediated anti-efferocytosis of macrophages. Therefore, we propose simultaneously blocking ANGPTL3, a vital regulator of lipid metabolism, and CD47 might be a potential approach for AS therapy. Firstly, we investigate the role of a novel anti-ANGPTL3 nanobody-Fc (FD03) in AS. We found that FD03 treatment significantly decreased circulating lipids, plaque size, and lipid deposition in apoE-/- mice compared to control Ab, but there was a twofold increase in plaque formation in comparison to baseline. However, immunofluorescence indicated the upregulation of CD47 expression in the plaques even after FD03 treatment compared to normal vascular tissue. Next, a bifunctional protein containing signal regulatory protein alpha (SIRPα) and FD03 (SIRPαD1-FD03) was constructed to block CD47 and ANGPTL3 concurrently, which had high purity, robust stability, and high affinity to CD47 and ANGPTL3 with biological activity in vitro. Furthermore, SIRPαD1-FD03 fusion protein exhibited the enhanced therapeutic effect on AS compared with SIRPαD1-Fc or FD03, regressing plaque contents and the necrotic core equal to baseline. Mechanistically, SIRPαD1-FD03 reduced serum lipids, augmented the efferocytosis rate and macrophage M2 polarization, and decreased the reactive oxygen species (ROS) and lipid peroxidation level in atherosclerotic plaques. Collectively, our project suggests an effective approach for AS by simultaneously blocking ANGPTL3 and CD47 to regulate lipid metabolism, macrophage activity and lipid peroxidation.

Simultaneously blocking ANGPTL3 and IL-1ß for the treatment of atherosclerosis through lipid-lowering and anti-inflammation.

OBJECTIVE: Blood lipid levels play a critical role in the progression of atherosclerosis. However, even with adequate lipid reduction, significant residual cardiovascular risk remains. Therefore, it is necessary to seek novel therapeutic strategies for atherosclerosis that can not only lower lipid levels but also inhibit inflammation simultaneously. METHODS: The fusion protein FD03-IL-1Ra was designed by linking the Angiopoietin-like 3 (ANGPTL3) nanobody and human interleukin-1 receptor antagonist (IL-1Ra) sequences to a mutated human immunoglobulin gamma 1 (IgG1) Fc. This construct was transfected into HEK293 cells for expression. The purity and thermal stability of the fusion protein were assessed using SDS-PAGE, SEC-HPLC, and differential scanning calorimetry. Binding affinities of the fusion protein to ANGPTL3 and IL-1 receptor were measured using Biacore T200. The biological activity of the fusion protein was validated through in vitro experiments. The therapeutic efficacy of the fusion protein was evaluated in an ApoE-/- mouse model of atherosclerosis, including serum lipid level determination, histological analysis of aorta and aortic sinus sections, and detection of inflammatory and oxidative stress markers. ImageJ software was utilized for quantitative image analysis. Statistical analysis was performed using one-way ANOVA followed by Bonferroni post hoc test. RESULTS: The FD03-IL-1Ra fusion protein was successfully expressed, with no polymer formation detected, and it demonstrated good thermal and conformational stability. High affinity for both murine and human ANGPTL3 was exhibited by FD03-IL-1Ra, and it was able to antagonize hANGPTL3's inhibition of LPL activity. FD03-IL-1Ra also showed high affinity for both murine and human IL-1R, inhibiting IL-6 expression in A549 cells induced by IL-1ß stimulation, as well as suppressing IL-1ß-induced activity inhibition in A375.S2 cells. Our study revealed that the fusion protein effectively lowered serum lipid levels and alleviated inflammatory responses in mice. Furthermore, the fusion protein enhanced plaque stability by increasing collagen content within atherosclerotic plaques. CONCLUSIONS: These findings highlighted the potential of bifunctional interleukin-1 receptor antagonist and ANGPTL3 antibody fusion proteins for ameliorating the progression of atherosclerosis, presenting a promising novel therapeutic approach targeting both inflammation and lipid levels.

Exploration of rich-club reorganization in facial synkinesis: insights from structural and functional brain network analysis.

Facial palsy therapies based on cortical plasticity are in development, but facial synkinesis progress is limited. Studying neural plasticity characteristics, especially network organization and its constitutive elements (nodes/edges), is the key to overcome the bottleneck. We studied 55 participants (33 facial synkinesis patients, 22 healthy controls) with clinical assessments, functional magnetic resonance imaging (fMRI), and diffusion tensor imaging (DTI). We analyzed rich-club organization and metrics of structural brain networks (rich-club coefficients, strength, degree, density, and efficiency). Functional brain network metrics, including functional connectivity and its coupling with the structural network, were also computed. Patients displayed reduced strength and density of rich-club nodes and edges, as well as decreased global efficiency. All nodes exhibited decreased nodal efficiency in patients. Patients had significantly increased functional connectivity and decreased structural-functional coupling strength in rich-club nodes, rich-club edges, and feeder edges. Our study indicates that facial synkinesis patients have weakened structural connections but enhanced functional transmission from rich-club nodes. The loss of connections and efficiency in structural network may trigger compensatory increases in functional connectivity of rich-club nodes. Two potential biomarkers, rich-club edge density and structural-functional coupling strength, may serve as indicators of disease outcome. These findings provide valuable insights into synkinesis mechanisms and offer potential targets for cortical intervention.

Dynamic monitoring soft tissue healing via visualized Gd-crosslinked double network MRI microspheres.

By integrating magnetic resonance-visible components with scaffold materials, hydrogel microspheres (HMs) become visible under magnetic resonance imaging(MRI), allowing for non-invasive, continuous, and dynamic monitoring of the distribution, degradation, and relationship of the HMs with local tissues. However, when these visualization components are physically blended into the HMs, it reduces their relaxation rate and specificity under MRI, weakening the efficacy of real-time dynamic monitoring. To achieve MRI-guided in vivo monitoring of HMs with tissue repair functionality, we utilized airflow control and photo-crosslinking methods to prepare alginate-gelatin-based dual-network hydrogel microspheres (G-AlgMA HMs) using gadolinium ions (Gd (III)), a paramagnetic MRI contrast agent, as the crosslinker. When the network of G-AlgMA HMs degrades, the cleavage of covalent bonds causes the release of Gd (III), continuously altering the arrangement and movement characteristics of surrounding water molecules. This change in local transverse and longitudinal relaxation times results in variations in MRI signal values, thus enabling MRI-guided in vivo monitoring of the HMs. Additionally, in vivo data show that the degradation and release of polypeptide (K2 (SL)6 K2 (KK)) from G-AlgMA HMs promote local vascular regeneration and soft tissue repair. Overall, G-AlgMA HMs enable non-invasive, dynamic in vivo monitoring of biomaterial degradation and tissue regeneration through MRI, which is significant for understanding material degradation mechanisms, evaluating biocompatibility, and optimizing material design.

The role of SEMG1 overexpression in OSCC tumorigenesis and its relation with metabolic molecules.

OBJECTIVES: This study aimed to investigate the expression and biological significance of Semenogelin 1 (SEMG1), a member of the cancer-testis antigen family, in oral squamous cell carcinoma (OSCC). Further, we explored its potential association with metabolism-related molecules. METHODS: SEMG1 expression levels in OSCC were determined through immunohistochemistry, flow cytometry, and Western blot analyses. To decipher the biological implications of SEMG1 in OSCC, the CAL27 OSCC cell line was either stably overexpressed with SEMG1 or subjected to SEMG1-shRNA knockdown. The relationship between clinicopathological parameters and SEMG1 expression in OSCC patients was also assessed. RESULTS: SEMG1 was found to be overexpressed in OSCC, though its expression was not influenced by the pathological grade. The fluorescent dihydroethidium assay indicated that SEMG1 augmented reactive oxygen species production. The mitochondrial membrane potential assay suggested a significant upregulation of mitochondrial membrane potential by SEMG1. Cell cycle assessments highlighted that SEMG1 overexpression led to a notable rise in cells entering the S-phase. Additionally, a strong correlation between SEMG1 expression and both ENO1 and PKM2 expression in OSCC was observed. CONCLUSIONS: The findings underscore the elevated expression of SEMG1 in OSCC and its contributory role in the tumorigenesis of OSCC patients.

Effect of Regulation of Chemerin/Chemokine-like Receptor 1/Stimulator of Interferon Genes Pathway on Astrocyte Recruitment to Aß Plaques.

Recruitment and accumulation of reactive astrocytes around senile plaques are common pathological features of Alzheimer's disease (AD), with unclear mechanisms. Chemerin, an adipokine implicated in neuroinflammation, acts through its receptor, chemokine-like receptor 1 (CMKLR1), which also functions as a receptor for amyloid ß (Aß). The impact of the chemerin/CMKLR1 axis on astrocyte migration towards Aß plaques is unknown. Here we investigated the effect of CMKLR1 on astrocyte migration around Aß deposition in APP/PS1 mice with Cmklr1 knockout (APP/PS1-Cmklr1-/-). CMKLR1-expressed astrocytes were upregulated in the cortices and hippocampi of 9-month-old APP/PS1 mice. Chemerin mainly co-localized with neurons, and its expression was reduced in the brains of APP/PS1 mice, compared to WT mice. CMKLR1 deficiency decreased astrocyte colocalization with Aß plaques in APP/PS1-Cmklr1-/- mice, compared to APP/PS1 mice. Activation of the chemerin/CMKLR1 axis promoted the migration of primary cultured astrocytes and U251 cells, and reduced astrocyte clustering induced by Aß42. Mechanistic studies revealed that chemerin/CMKLR1 activation induced STING phosphorylation. Deletion of STING attenuated the promotion of the chemerin/CMKLR1 axis relative to astrocyte migration and abolished the inhibitory effect of chemerin on Aß42-induced astrocyte clustering. These findings suggest the involvement of the chemerin/CMKLR1/STING pathway in the regulation of astrocyte migration and recruitment to Aß plaques/Aß42.

Comparing the Effect of Mechanical Loading on Deep and Superficial Cartilage Using Quantitative UTE MRI.

BACKGROUND: The biomechanical properties of deep and superficial cartilage may be different, yet in vivo MRI validation is required. PURPOSE: To compare the effect of mechanical loading on deep and superficial cartilage in young healthy adults using ultrashort echo time (UTE)-T2* mapping. STUDY TYPE: Prospective, intervention. SUBJECTS: Thirty-one healthy adults (54.8% females, median age = 23 years). FIELD STRENGTH/SEQUENCE: 3-T, PD-FS, and UTE sequences with four echo times (TEs = 0.1, 0.5, 2.8, and 4.0 msec; 0.6 mm isotropic spatial resolution) of the left knee, acquired before and after loading exercise. ASSESSMENT: Quantitative UTE-T2* maps of the entire knee were generated using UTE images of four TEs. In deep and superficial cartilage of patella, medial and lateral femur, medial and lateral tibia cartilage (PC, MFC, LFC, MTC, and LTC), which were segmented manually, cartilage thickness and T2* values before and after loading were measured, extracted, taken averages of, and compared. Scan-rescan repeatability was evaluated. Body weight and body mass index (BMI) data were collected. Physical activity levels were evaluated using International Physical Activity Questionnaire. STATISTICAL TESTS: Paired sample t-tests, paired Wilcoxon Mann-Whitney tests, Pearson and Spearman correlation analyses, Kruskal-Wallis tests with post-hoc Bonferroni correction. A P-value <0.05 was considered statistically significant. RESULTS: The scan-rescan repeatability was good (RMSA-CV < 10%). After exercise, deep cartilage exhibited no significant differences in cartilage thickness (PPC = 0.576, PMTC = 0.991, PMFC = 0.899, PLTC = 0.861, PLFC = 0.290) and T2* values (PPC = 0.914, PMTC = 0.780, PMFC = 0.754, PLTC = 0.327, PLFC = 0.811), which both significantly decreased in superficial PC, MFC, LFC, and MTC. The T2* values of superficial MTC and deep MFC were moderately correlated with higher body weight (ρ = 0.431) and lower BMI (ρ = -0.499), respectively. DATA CONCLUSION: Deep and superficial cartilage may respond differently to mechanical loading as assessed by UTE-T2*. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 3.

Age-Related Changes in the Spatial Variation of Magnetic Susceptibility of Human Articular Cartilage.

BACKGROUND: Quantitative susceptibility mapping (QSM) has shown great potential for revealing the layer structure of articular cartilage based on the laminar susceptibility difference at different depths. However, more information is needed on the effects of age on the spatial distribution of magnetic susceptibility in human cartilage. PURPOSE: To assess the ability of QSM to quantify the age-related differences in depth-wise cartilage susceptibility values in healthy populations. STUDY TYPE: Prospective. POPULATION: A total of 94 healthy asymptomatic subjects in three age cohorts: 19-30 (n = 36, 20 males), 31-50 (n = 45, 27 males), and 51-66 years (n = 13, 7 males). FIELD STRENGTH/SEQUENCE: 3D gradient echo sequences at 3.0 T. ASSESSMENT: Four cartilage compartments were analyzed, including the central lateral/medial femur (cLF/cMF) and the lateral/medial tibia (LT/MT). The spatial susceptibility profile and the corresponding 95% confidence interval (CI) of each age cohort were obtained as functions of the normalized distance from the bone-cartilage interface to the cartilage surface (cartilage depth from 0.0 to 1.0). STATISTICAL TESTS: The relationship between age and cartilage thickness of each cartilage subregion was tested by Pearson correlation with P < 0.05 considered significant. Cartilage depths with separations of 95% CIs were considered to have significant susceptibility differences between two age cohorts with a Bonferroni-corrected P < 0.05. RESULTS: The cartilage thickness did not change significantly with age (P value range: 0.06-0.85). Susceptibilities were significantly higher in the 51-66-year-olds compared with the 31-50-year-olds in the deep layer of cMF (cartilage depth: 0.0-0.22) and LT (0.05-0.28). Susceptibilities were significantly higher in the 51-66-year-olds compared with the 19-30-year-olds near the cartilage-bone interface of cMF (0.0-0.34), cLF (0.0-0.28), and LT (0.0-0.58). There were also significantly higher susceptibilities in the 31-50-year-olds compared with the 19-30-year-olds in the deeper regions of cMF (0.26-0.57), cLF (0.0-0.40), and LT (0.07-0.80). DATA CONCLUSION: Age-related susceptibility changes in the deeper regions of knee cartilage were observed using QSM. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

FXR1 impedes the development of osteoarthritis by targeting SND1.

OBJECTIVES: To investigate the role of fragile X mental retardation syndrome-related protein 1 (FXR1), an RNA binding protein, in the development of osteoarthritis (OA), to define its mechanism of action in cartilage, and to determine whether targeting FXR1 can prevent OA in mice. METHODS: Western blot analysis and quantitative polymerase chain reaction were performed using cartilage tissue from control and osteoarthritic mice. FXR1 expression was detected by immunofluorescence staining using cartilage tissue from mice. OA was induced by destabilising the medial meniscus in the mice. Infection of mouse chondrocytes with FXR1 lentivirus, as well as viral injection into the mouse knee joint cavity, resulted in high FXR1 protein expression. Chondrocyte apoptosis was detected by TUNEL assay and cell senescence was detected by SA-ß-gal staining assay. RESULTS: FXR1 expression was significantly reduced in cartilage and soft tissue from mice with OA compared with the controls. FXR1 overexpression reduced staphylococcal nuclease domain protein 1 (SND1) levels. Furthermore, FXR1 is able to inhibit apoptosis and senescence of chondrocytes via SND1 and hinder the development of OA in mice. CONCLUSIONS: FXR1 down-regulates SND1 expression, thereby alleviating osteoarthritic symptoms in mice. In summary, FXR1 may have a therapeutic approach to the treatment of OA.

Joint Design of a Simultaneous Reflection and Transmission RIS in Mode-Switching Mode to Assist NOMA Systems.

Simultaneous transmitting and reflecting reconfigurable intelligent surfaces (STAR-RISs) can reflect signals and transmissive signals simultaneously and can extend the coverage of signals. A conventional RIS mainly focuses on the case where the signal source and the target are on the same side. In this paper, a STAR-RIS-assisted non-orthogonal multiple access (NOMA) downlink communication system is considered to maximize the achievable rate for users by jointly optimizing the power-allocation coefficients, active beamforming, and STAR-RIS beamforming under the mode-switching (MS) protocol. The critical information of the channel is first extracted using the Uniform Manifold Approximation and Projection (UMAP) method. Based on the key extracted channel features, STAR-RIS elements and users are clustered individually using the fuzzy C-mean clustering (FCM) method. The alternating optimization method decomposes the original optimization problem into three sub-optimization problems. Finally, the sub-problems are converted to unconstrained optimization methods using penalty functions for the solution. Simulation results show that when the number of elements of RIS is 60, the achievable rate of the STAR-RIS-NOMA system is about 18% higher than that of the RIS-NOMA system.

Visible Light Generation of a Microsecond Long-Lived Potent Reducing Agent.

Photoexcitation of molecular radicals can produce strong reducing agents; however, the limited lifetimes of the doublet excited states preclude many applications. Herein, we propose and demonstrate a general strategy to translate a highly energetic electron from a doublet excited state to a ZrO2 insulator, thereby increasing the lifetime by about 6 orders of magnitude while maintaining a reducing potential less than -2.4 V vs SCE. Specifically, red light excitation of a salicylic acid modified perylene diimide radical anion PDI•- anchored to a ZrO2 insulator yields a ZrO2(e-)|PDI charge separated state with an ∼10 µs lifetime in 23% yield. The ZrO2(e-)s were shown to drive CO2 → CO reduction with a Re catalyst present in micromolar concentrations. More broadly, this strategy provides new opportunities to reduce important reagents and catalysts at low concentrations through diffusional electron transfer.

The involvement of extracellular ATP in regulating the stunted growth of Arabidopsis plants by repeated wounding.

BACKGROUND: Extracellular ATP (exATP) has been shown to act as a signal molecule for regulating growth, development, and responses of plants to the external environment. RESULTS: In this study, we investigated the possible involvement of exATP in regulating the stunted growth caused by repeated wounding. The present work showed that the repeated wounding caused the decreases in leaf area, fresh weight, dry weight, and root length of Arabidopsis seedlings, while the exATP level was enhanced by the repeated wounding. Repeated application of exogenous ATP had similar effects on the plant growth, as the repeated wounding. Through the comparison of p2k1-3 mutant (in which T-DNA disrupted the gene coding P2K1, as exATP receptor) and wide type (WT) plants, it was found that the mutation in P2K1 decreased the sensitivity of plant growth to the repeated wounding and exogenous ATP application. Further works showed that the ibuprofen (IBU, an inhibitor of jasmonate biosynthesis) partially rescued the wound-induced growth degradation. In comparison, the P2K1 mutation partly rescued the wound-induced growth degradation, whereas this mutation failed to do so in the wounded seedlings treated with IBU, indicating that the role of exATP in regulating the growth degradation by repeated wounding could be linked to the JA signaling pathway. CONCLUSIONS: In conclusion, these results indicate that exATP could be a regulator for the stunted growth of plants by repeated wounding.

Extracellular ATP is involved in regulating Arabidopsis seed germination.

MAIN CONCLUSION: Extracellular ATP level induced a transient increase during germination of Arabidopsis seeds, and extracellular ATP could negatively regulate the seed germination by its receptor, DORN1. Extracellular ATP (exATP) acts as a signal molecule for regulating growth, development, and responses of plants to external environments. In this study, we investigated the possible involvement of exATP in regulating the seed germination of Arabidopsis thaliana. Treatments of Arabidopsis seeds with exogenous ATP delayed seed germination, suggesting that exATP could be a repressor for seed germination. During the germination of Arabidopsis seeds, the exATP level of the seeds presented a transient increase. When exogenous application of the glucose-hexokinase system effectively decreased the exATP level of the Arabidopsis seeds during germination, the percentage of germination was significantly enhanced, while the products of ATP hydrolysis had no effects on the germination. Further studies showed that the seeds of dorn 1-3 mutant plants (mutation in exATP receptor) showed a higher germination percentage, compared to the seeds of wide type (WT) plants. In addition, the dorn 1-3 mutant seeds were less sensitive to the delay-effect of exogenous ATP on seed germination than the WT seeds. The dorn 1-3 mutant seeds presented a higher GA (gibberellin) content, lower ABA (abscisic acid) content, and lower ratio of ABA/GA contents before the imbibition, compared to the WT seeds. The regulation of seed germination by exATP was dependent on the external temperature. These data suggest that exATP is involved in regulating Arabidopsis seed germination.

Recent advances in porous nanomaterials-based drug delivery systems for cancer immunotherapy.

Cancer immunotherapy is a novel therapeutic regimen because of the specificity and durability of immune modulations to treat cancers. Current cancer immunotherapy is limited by some barriers such as poor response rate, low tumor specificity and systemic toxicities. Porous nanomaterials (PNMs) possess high loading capacity and tunable porosity, receiving intense attention in cancer immunotherapy. Recently, novel PNMs based drug delivery systems have been employed in antitumor immunotherapy to enhance tissue or organ targeting and reduce immune-related adverse events. Herein, we summarize the recent progress of PNMs including inorganic, organic, and organic-inorganic hybrid ones for cancer immunotherapy. The design of PNMs and their performance in cancer immunotherapy are discussed in detail, with a focus on how those designs can address the challenges in current conventional immunotherapy. Lastly, we present future directions of PNMs for cancer immunotherapy including the challenges and research gaps, providing new insights about the design of PNMs for efficient cancer immunotherapy with better performance as powerful weapons against tumors. Finally, we discussed the relevant challenges that urgently need to be addressed in clinical practice, coupled with corresponding solutions to these problems.

A novel nanobody-heavy chain antibody against Angiopoietin-like protein 3 reduces plasma lipids and relieves nonalcoholic fatty liver disease.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a metabolic disease mainly on account of hypercholesterolemia and may progress to cirrhosis and hepatocellular carcinoma. The discovery of effective therapy for NAFLD is an essential unmet need. Angiopoietin-like protein 3 (ANGPTL3), a critical lipid metabolism regulator, resulted in increased blood lipids and was elevated in NAFLD. Here, we developed a nanobody-heavy chain antibody (VHH-Fc) to inhibit ANGPTL3 for NAFLD treatment. RESULTS: In this study, we retrieved an anti-ANGPTL3 VHH and Fc fusion protein, C44-Fc, which exhibited high affinities to ANGPTL3 proteins and rescued ANGPLT3-mediated inhibition of lipoprotein lipase (LPL) activity. The C44-Fc bound a distinctive epitope within ANGPTL3 when compared with the approved evinacumab, and showed higher expression yield. Meanwhile, C44-Fc had significant reduction of the triglyceride (~ 44.2%), total cholesterol (~ 36.6%) and LDL-cholesterol (~ 54.4%) in hypercholesterolemic mice and ameliorated hepatic lipid accumulation and liver injury in NAFLD mice model. CONCLUSIONS: We discovered a VHH-Fc fusion protein with high affinity to ANGPTL3, strong stability and also alleviated the progression of NAFLD, which might offer a promising therapy for NAFLD.

ENO1 Binds to ApoC3 and Impairs the Proliferation of T Cells via IL-8/STAT3 Pathway in OSCC.

Lymph node metastasis is associated with poor prognosis of oral squamous cell carcinoma (OSCC), and few studies have explored the relevance of postoperative lymphatic drainage (PLD) in metastatic OSCC. Alpha-enolase (ENO1) is a metabolic enzyme, which is related to lymphatic metastasis of OSCC. However, the role of ENO1 in PLD in metastatic OSCC has not been elucidated. Herein, we collected lymphatic drainage after lymphadenectomy between metastatic and non-metastatic lymph nodes in OSCC patients to investigate the relationship between ENO1 expression and metastasis, and to identify the proteins which interacted with ENO1 in PLD of patients with metastatic OSCC by MS/GST pulldown assay. Results revealed that the metabolic protein apolipoprotein C-III (ApoC3) was a novel partner of ENO1. The ENO1 bound to ApoC3 in OSCC cells and elicited the production of interleukin (IL)-8, as demonstrated through a cytokine antibody assay. We also studied the function of IL-8 on Jurkat T cells co-cultured with OSCC cells in vitro. Western blot analysis was applied to quantitate STAT3 (signal transducer and activator of transcription 3) and p-STAT3 levels. Mechanistically, OSCC cells activated the STAT3 signaling pathway on Jurkat T cells through IL-8 secretion, promoted apoptosis, and inhibited the proliferation of Jurkat T cells. Collectively, these findings illuminate the molecular mechanisms underlying the function of ENO1 in metastasis OSCC and provide new strategies for targeting ENO1 for OSCC treatment.

PKD1 alleviates oxidative stress-inhibited osteogenesis of rat bone marrow-derived mesenchymal stem cells through TAZ activation.

Oxidative stress is known to inhibit osteogenesis and PKD1 is implicated in bone remodeling and skeletogenesis. In the present study, we explored the role of PKD1 in osteogenesis under oxidative stress. H2 O2 was used to induce oxidative stress in rat bone marrow (BM)-mesenchymal stem cells (MSCs) during osteoblast differentiation. Alkaline phosphatase (ALP) activity, calcium deposits, and the RUNX2 marker were assayed to determine osteogenic differentiation. The correlation of PKD1, Sirt1, c-MYC, and TAZ was further confirmed by chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assay. We found that H2 O2 induced the downregulation of PKD1 expression and the upregulation of c-MYC, and Sirt1 was accompanied by decreasing cell viability in BM-MSCs. During osteogenic differentiation, the expression of PKD1 was upregulated significantly whereas Sirt1 tended to be upregulated mildly under normal conditions. Both PKD1 and Sirt1 were upregulated upon oxidative stress. The positive correlation of PKD1 expression with osteogenic differentiation under normal conditions might be hindered by oxidative stress and PKD1 could interact with TAZ under oxidative stress to regulate osteogenic differentiation. Our results suggest that PKD1 may alleviate oxidative stress-inhibited osteogenesis of rat BM-MSCs through TAZ activation.

Gelatinase-sensitive nanoparticles loaded with photosensitizer and STAT3 inhibitor for cancer photothermal therapy and immunotherapy.

Matrix metalloproteinase (MMP) 2 and 9 are the family members of proteases normally up-regulated in tumor to enhance the invasion and metastatic of tumor cells, and are associated with poor outcome of head and neck squamous cell carcinomas (HNSCCs). In the present work, MMPs-degradable gelatin nanoparticles (GNPs) are simultaneously loaded with photosensitizer indocyanine green (ICG) along with signal transducer activator of transcription 3 (STAT3) inhibitor NSC74859 (NSC, N) for efficient photothermal therapy (PTT) and immunotherapy of HNSCCs. In the tumor tissue, Gel-N-ICG nanoparticle was degraded and encapsulated ICG and NSC were effectively released. Under near-infrared (NIR) irradiation, the released ICG nanoparticles enabled effective photothermal destruction of tumors, and the STAT3 inhibitor NSC elicited potent antitumor immunity for enhanced cancer therapy. Based on two HNSCC mouse models, we demonstrated that Gel-N-ICG significantly delayed tumor growth without any appreciable body weight loss. Taken together, the strategy reported here may contribute that the stimuli-responsive proteases triggered nanoplatform could reduce tumor size more effectively in complex tumor microenvironment (TME) through combination of PTT and immunotherapy.

Automatic opportunistic osteoporosis screening using low-dose chest computed tomography scans obtained for lung cancer screening.

OBJECTIVE: Osteoporosis is a prevalent and treatable condition, but it remains underdiagnosed. In this study, a deep learning-based system was developed to automatically measure bone mineral density (BMD) for opportunistic osteoporosis screening using low-dose chest computed tomography (LDCT) scans obtained for lung cancer screening. METHODS: First, a deep learning model was trained and tested with 200 annotated LDCT scans to segment and label all vertebral bodies (VBs). Then, the mean CT numbers of the trabecular area of target VBs were obtained based on the segmentation mask through geometric operations. Finally, a linear function was built to map the trabecular CT numbers of target VBs to their BMDs collected from approved software used for osteoporosis diagnosis. The diagnostic performance of the developed system was evaluated using an independent dataset of 374 LDCT scans with standard BMDs and osteoporosis diagnosis. RESULTS: Our deep learning model achieved a mean Dice coefficient of 86.6% for VB segmentation and 97.5% accuracy for VB labeling. Line regression and Bland-Altman analyses showed good agreement between the predicted BMD and the ground truth, with correlation coefficients of 0.964-0.968 and mean errors of 2.2-4.0 mg/cm3. The area under the curve (AUC) was 0.927 for detecting osteoporosis and 0.942 for distinguishing low BMD. CONCLUSION: The proposed deep learning-based system demonstrated the potential to automatically perform opportunistic osteoporosis screening using LDCT scans obtained for lung cancer screening. KEY POINTS: • Osteoporosis is a prevalent but underdiagnosed condition that can increase the risk of fracture. • A deep learning-based system was developed to fully automate bone mineral density measurement in low-dose chest computed tomography scans. • The developed system achieved high accuracy for automatic opportunistic osteoporosis screening using low-dose chest computed tomography scans obtained for lung cancer screening.