Biodegradable Metal Complex-Gated Organosilica for Dually Enhanced Chemodynamic Therapy through GSH Depletions and NIR Light-Triggered Photothermal Effects.

Hollow silica spheres have been widely studied for drug delivery because of their excellent biosecurity and high porosity. However, difficulties with degradation in the tumor microenvironment (TME) and premature leaking during drug delivery limit their clinical applications. To alleviate these problems, herein, hollow organosilica spheres (HOS) were initially prepared using a "selective etching strategy" and loaded with a photothermal drug: new indocyanine green (IR820). Then, the Cu2+-tannic acid complex (Cu-TA) was deposited on the surface of the HOS, and a new nanoplatform named HOS@IR820@Cu-TA (HICT) was finally obtained. The deposition of Cu-TA can gate the pores of HOS completely to prevent the leakage of IR820 and significantly enhance the loading capacity of HOS. Once in the mildly acidic TME, the HOS and outer Cu-TA decompose quickly in response, resulting in the release of Cu2+ and IR820. The released Cu2+ can react with the endogenous glutathione (GSH) to consume it and produce Cu+, leading to the enhanced production of highly toxic ·OH through a Fenton-like reaction due to the overexpressed H2O2 in the TME. Meanwhile, the ·OH generation was remarkably enhanced by the NIR light-responsive photothermal effect of IR820. These collective properties of HICT enable it to be a smart nanomedicine for dually enhanced chemodynamic therapy through GSH depletions and NIR light-triggered photothermal effects.

A novel mitochondria-related core gene signature to predict the prognosis and evaluate tumour microenvironment in CESC single-cell validation.

Mitochondria and their related genes (MTRGs) are pivotal in the tumour microenvironment (TME) of cervical cancer, influencing prognosis and treatment response. This study developed a prognostic model using MTRGs to predict overall survival (OS) in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), aiming for personalized therapy. Analysing 14 MTRGs like ISCU and NDUFA11 through techniques such as univariate Cox regression, we found that a low mitochondrial (MT) score is associated with better survival, while a high MT score predicts poorer outcomes. The TME score, particularly influenced by CD8 T cells, also correlates with prognosis, with a high score indicating favourable outcomes. The interplay between MT and TME subtypes revealed that the best prognosis is seen in patients with a low MT and high TME score. Our findings highlight the role of MTRGs as potential biomarkers and therapeutic targets in cervical cancer, offering a novel approach to improving patient outcomes through a more nuanced understanding of mitochondrial function and immune interactions within the TME. This model presents a promising avenue for enhancing the precision of prognostic assessments in CESC.

Abnormal phosphorylation / dephosphorylation and Ca2+ dysfunction in heart failure.

Heart failure (HF) can be caused by a variety of causes characterized by abnormal myocardial systole and diastole. Ca2+ current through the L-type calcium channel (LTCC) on the membrane is the initial trigger signal for a cardiac cycle. Declined systole and diastole in HF are associated with dysfunction of myocardial Ca2+ function. This disorder can be correlated with unbalanced levels of phosphorylation / dephosphorylation of LTCC, endoplasmic reticulum (ER), and myofilament. Kinase and phosphatase activity changes along with HF progress, resulting in phased changes in the degree of phosphorylation / dephosphorylation. It is important to realize the phosphorylation / dephosphorylation differences between a normal and a failing heart. This review focuses on phosphorylation / dephosphorylation changes in the progression of HF and summarizes the effects of phosphorylation / dephosphorylation of LTCC, ER function, and myofilament function in normal conditions and HF based on previous experiments and clinical research. Also, we summarize current therapeutic methods based on abnormal phosphorylation / dephosphorylation and clarify potential therapeutic directions.

TRIB3 promotes malignancy of head and neck squamous cell carcinoma via inhibiting ferroptosis.

Tribbles pseudokinase 3 (TRIB3) has been identified recently as a novel oncogene in several cancers. Still, further extensive research is imperative to elucidate its function and the molecular mechanisms underlying its involvement in the progression of head and neck squamous cell carcinoma (HNSCC). In our study, we found that TRIB3 silencing significantly promoted cell death by inducing ferroptosis. The interaction of TRIB3 with Transcription Factor 4 (TCF4) and ß-catenin created a heterotrimeric complex, which directly interacts with the ALOXE3 promoter, detrimentally impacting its activation. The consequential partial neutralization of ferroptosis induced by TRIB3 deficiency is observed through the implementation of ALOXE3 knockdown. Furthermore, the study demonstrated that the molecular inhibitor hesperidin, targeting TRIB3, not only reduced cell malignancy but also induced ferroptosis, thereby suppressing tumor growth. Overall, our findings unequivocally validate the proposition that TRIB3 deficiency precipitates the iron death mechanism, thereby indicating that the strategic targeting of TRIB3 could emerge as an innovative therapeutic strategy for HNSCC.

Tumor volume instead of recurrent T category predicts clinical outcome of patients with locally recurrent nasopharyngeal carcinoma salvaged by carbon ion radiation therapy.

BACKGROUND: Although carbon ion radiation therapy (CIRT) substantially improves the overall survival (OS) of patients with LR-NPC, approximately 40% of the patients may develop local recurrence. The purpose of study is to assess the value of tumor volume (TV) as a predictive tool to guide individualized CIRT. METHODS: Consecutive patients with LR-NPC treated using CIRT at Shanghai Proton and Heavy Ion Center between April 2015 and May 2019 were included. TV before CIRT was delineated and calculated. The generalized additive Cox model was used to examine the relationship between TV and OS and local progression-free survival (LPFS). A cutoff value of tumor volume was identified to best discriminate patients with different 2-year OS rates, using receiver operating characteristic (ROC) analysis. RESULTS: A total of 157 patients were enrolled. The median tumor volume was 22.49 (2.52-90.13) ml. In the univariable analyses, tumor volume was significantly associated with OS (p < 0.001) and LPFS (p = 0.01). The relationships with OS (p = 0.009) and LPFS (p = 0.020) remained significant in multivariable analyses. Using ROC analysis, a TV of 26.69 ml was identified to predict the 2-year OS rate. To facilitate potential clinical use, 25 ml was designated as the final cutoff value. The 2-year OS and LPFS rates were 88.6 % vs 62.3 %, and 54.7 % vs 35.5 %, for patients with a TV ≤ 25 ml and > 25 ml, respectively. CONCLUSION: Tumor volume could predict the OS and LPFS of patients. We propose that tumor volume should be considered in the risk stratification and CIRT-based treatment for patients with LR-NPC.

A protocol for a randomized trial evaluating the role of carbon-ion radiation therapy plus camrelizumab for patients with locoregionally recurrent nasopharyngeal carcinoma.

PURPOSE: Management of locoregionally recurrent nasopharyngeal carcinoma (LR NPC) is difficult. Although carbon-ion radiation therapy (CIRT) could substantially improve the overall survival (OS) of those patients, around 40% of the patients may still develop local failure. Further improvement of the disease control is necessary. Immunotherapy, such as immune checkpoint inhibitors (ICIs) becomes a promising antitumor treatment. The role of ICIs was proved in head and neck cancers including recurrent/metastatic NPC. Preclinical studies indicated potential synergistic effects between radiation therapy and ICIs. Therefore, we conduct a randomized phase 2 trial to evaluate the efficacy and safety of camrelizumab, an anti-PD-1 monoclonal antibody, along with CIRT in patients with LR NPC. METHODS: Patients will be randomly assigned at 1:1 to receive either standard CIRT with 63 Gy (relatively biological effectiveness, [RBE]) in 21 fractions, or standard CIRT plus concurrent camrelizumab. Camrelizumab will be administered intravenously with a dose of 200 mg, every 2 week, for a maximum of 1 year. We estimate addition of camrelizumab will improve the 2-year progression-free survival (PFS) from 45% to 60%. A total of 146 patients (with a 5% lost to follow-up rate) is required to yield a type I error of 0.2, and a power of 0.8. RESULTS AND CONCLUSION: The results of the trial may shed insights on the combined therapy with ICIs and CIRT.

Responsiveness of three measurements in cone-beam computed tomography transverse analyses during both tooth-supported and mini-screw-assisted rapid maxillary expansion.

OBJECTIVE: To evaluate the responsiveness of three cone-beam computed tomography (CBCT) transverse analyses (University of the Pennsylvania [UPenn] analysis, Boston University analysis and Yonsei University [YU] analysis). MATERIALS AND METHODS: A consecutive cohort sample of patients was retrospectively reviewed for eligibility. CBCT records before treatment (T0) and immediately after maxillary expansion (T1) of 71 patients receiving tooth-supported rapid maxillary expansion (RME) and 57 patients receiving mini-screw-assisted RME (MARME) were finally analyzed. Responsiveness was assessed by comparing changes of measures (T1-T0) to mid-palatal suture opening distance (MSOD) at T1. Correlational responsiveness was assessed by Pearson correlation coefficient (r). Absolute agreement responsiveness was assessed by Bland-Altman analysis. A specialized intraclass correlation coefficient (ICC) was selected to assess responsiveness combining correlation and absolute agreement. RESULTS: Changes of all three measures were moderately to strongly correlated to MSOD (r > 0.5). The highest correlation coefficient (0.79) was found between the YU analysis and MSOD. When exploring absolute agreement responsiveness, the smallest deviation (0.14 mm) was observed in the UPenn analysis. For ICC, the highest ICC value (0.63) was observed when the YU analysis was used. In addition, all three measurements were more responsive to MSOD in the MARME group than to those in RME group. CONCLUSIONS: All three transverse measurements responded well to true changes of maxillary transverse deficiency during both tooth-supported and mini-screw-assisted RME. Deviations of responsive properties of these measurements from true skeletal changes were below a clinically meaningful level (1 mm).

Particle beam radiotherapy in the treatment of WHO grade 2 and 3 meningiomas: an early experience from Shanghai Proton and Heavy Ion Center.

PURPOSE: To investigate the efficacy and safety of particle beam radiotherapy (PBRT) in the management of patients with WHO grade 2 and 3 meningiomas. METHODS: Thirty-six consecutive and non-selected patients with WHO grade 2 (n = 28) and grade 3 (n = 8) meningiomas were treated at the Shanghai Proton and Heavy Ion Center, from May 2015 to March 2022. The median age of the cohort at PBRT was 48 years. There were 25 and 11 patients treated with PBRT in the setting of newly diagnosed diseases and progressive/recurrent diseases, respectively. PBRT was utilized as re-irradiation in 5 patients. Proton radiotherapy (PRT) and carbon-ion radiotherapy (CIRT), with a median dose of 60 Gy-Equivalent (GyE), were provided to 30 and 6 patients, respectively. RESULTS: With a median follow-up of 23.3 months, the local control rates were 92.0%, 82.0%, and 82.0% at 1, 2, and 3 years for the entire cohort, respectively. Patients with WHO grade 2 meningiomas (100%, 94.1%, 94,1% at 1,2,3 years) had a much better local control than those with WHO grade 3 meningiomas (50%, 25%, 25% at 1,2,3 years; P < 0.001). Three patients, all with WHO grade 3 meningiomas, had deceased at the time of this analysis. Multivariate analyses revealed that WHO grade (grade 2 vs. 3) (p = 0.016) was a significant prognosticator for local control. No severe toxicities (G3 or above) were observed. CONCLUSIONS: Treatment-induced efficacy and toxicities to PBRT in WHO grade 2 and 3 meningiomas were both highly acceptable. Longer follow-up is needed to evaluate the long-term outcome in terms of disease control, survival, as well as potential late effects.

Prevalence of Foodborne Trematodes in Small Indigenous Fish Species in Local Markets of Phnom Penh, Cambodia.

Background: This study aimed to determine the prevalence and mean infection intensity of zoonotic foodborne trematodes (FBT) in small indigenous species (SIS) fish hosts. Materials and Methods: A total of 8630 specimens of unknown origin were collected from the markets in Phnom Penh City. Fish were identified, weighed, and separated into 20 g subsamples for each fish species, and were examined using the artificial digestion method. A total of 10 species of FBT were detected in 11 species of fish out of the 23 species of fish in the total sample. Results: All infected FBT species were intestinal flukes. No liver flukes were found. The overall prevalence of FBT infection was 29.3% ± 5.3%, and the mean intensity was 0.85 ± 1.89 metacercariae (Mc)/g. The highest FBT prevalence was observed for Isthmiophora hortensis (10.7%) and Centrocestus formosanus (7.9%). Other species identified were Diplostomum spp., Echinochasmus japonicus, Echinostoma revolutum, Echinostoma sudanense, Haplorchis taichui, Haplorchis pumilio Heterophyes spp., and Procerovum varium. The highest mean intensity was found for Diplostomum spp. (1.75 ± 3.03 Mc/g). Trichopsis vittata was one of the main species constituting the SIS in urban markets (31.72%) and showed the highest prevalence of FBT (75.0%). In addition, T. vittata had the highest diversity of intestinal flukes compared with other fish species. Amblypharyngodon chulabhornae showed the highest mean intensity. but low diversity (only two species) and low prevalence. Conclusions: T. vittata could be considered a potential indicator for targeted monitoring of FBT intestinal flukes, but A. chulabhornae could also be considered for quantitative studies considering its high mean intensity.

Human milk oligosaccharides in milk of mothers with term and preterm delivery at different lactation stage.

Human milk oligosaccharides (HMOs) are structurally diverse unconjugated glycans, and play crucial roles in protecting infants from infections. Preterm birth is one of the leading causes of neonatal mortality, and preterm infants are particularly vulnerable and are in need of improved outcomes from breast-feeding due to the presence of bioactive HMOs. However, studies on specific difference in HMOs as a function of gestation time have been very limited. We established an approach to extract and analyze HMOs based on 96-well plate extraction and mass spectrometry, and determined maternal phenotypes through distinctive fragments in product-ion spectra. We enrolled 85 women delivering at different gestation times (25-41 weeks), and observed different HMOs correlating with gestation time based on 233 samples from the 85 donors. With the increase of postpartum age, we observed a regular changing trajectory of HMOs in composition and relative abundance, and found significant differences in HMOs secreted at different postpartum times. Preterm delivery induced more variations between participants with different phenotypes compared with term delivery, and more HMOs varied with postpartum age in the population of secretors. The sialylation level in mature milk decreased for women delivering preterm while such decrease was not observed for women delivering on term.

Carbon ion radiotherapy combined with immunotherapy: synergistic anti-tumor efficacy and preliminary investigation of ferroptosis.

Carbon ion radiotherapy (CIRT) may yield satisfactory clinical outcomes for patients who are resistant to radiotherapy. However, the therapeutic impact of carbon ions is still limited in certain recurring or refractory tumors. Therefore, we aimed to evaluate the synergistic anti-tumor effects of immune checkpoint inhibitors (ICIs) in combination with CIRT. We then explored the involvement of ferroptosis in a preliminary investigation. A tumor-bearing mouse model was established, and mice were inoculated subcutaneously with B16-OVA cells into the flanks of both hind legs. Mice were assigned to four groups to receive CIRT, ICIs, or combined treatment. Thereafter, we conducted transcriptome sequencing (RNA-seq), bioinformatics analysis, and various immune-related experiments on the available tumor tissues to investigate differences in the synergistic anticancer effects and potential mechanisms across the groups. The combination therapies significantly improved the survival of mice and inhibited tumor growth, both at local and distant sites. Based on bioinformatics and RNA-seq data, immune-related pathways and genes, immune cell infiltration, and the production of cytokines and chemokines were the most enhanced in the combined treatment group compared to other groups. Finally, we identified a potential role for ferroptosis in the development of local anti-tumor synergy during CIRT combination treatment. In conclusion, this study showed that CIRT and ICIs can enhance the anti-tumor immune effects. We also proposed that ferroptosis may induce anti-tumor effects in CIRT combination therapy, offering a unique perspective on its ability to enhance immunotherapy responses.

Growth and anemia among children with tuberculosis infection at different sites in Southwest China.

Objectives: To explore the effects of tuberculosis (TB) infection at different sites on anthropometric indicators, malnutrition and anemia incidence in children in Southwest China. Methods: From January 2012 to December 2021, a total of 368 children aged 1 month to 16 years were enrolled. According to the sites of TB infection, they were divided into three groups: tuberculous meningitis (T group), tuberculous meningitis complicated withpulmonary tuberculosis (TP group), and tuberculous meningitis complicated with pulmonary tuberculosis and abdominal tuberculosis (TPA group). Data on weight, height, nutritional risk, blood biochemical indicators and basic descriptions were collected within 48 h after admission. Results: The body mass index-for-age z score (BAZ), height-for-age z score (HAZ), and concentrations of hemoglobin (Hb) and albumin (ALB) decreased in the following order: T group, TP group, and TPA group. The prevalence of malnutrition was the highest in the TPA group (69.5%, 82/118) and 10-to 16-year-old group (72.4%, 63/87). Children aged 0.5-2 years exhibited the highest anemia prevalence of 70.6% (48/68) among the four age groups.The TPA group had the highest incidence of anemia (70.5%, 67/95) compared to T group and TP group.Compared with the treatment group, the abandonment group had a lower BAZ, HAZ and levels of HB and ALB, a higher rate of severe malnutrition, and higher nutritional risk scores. Children who had a low BAZ [odds ratio (OR) = 1.98], nutritional risk (OR = 0.56) and anemia (OR = 1.02) were less likely to obtain treatment with their guardians' support. Conclusions: Children with tuberculous meningitis were at risk for growth disorders and anemia, especially when complicated with pulmonary tuberculosis and abdominal tuberculosis. The prevalence of anemia and malnutrition was the highest among patients aged 1 month to 2 years and 10-16 years, respectively. Nutritional status was one of the causes of abandoning treatment.

Clinical features and prognosis of patients with metastatic ocular and orbital melanoma: A bi-institutional study.

PURPOSE: Metastatic ocular and orbital melanomas are extremely rare. The clinical characteristics and standard treatments for these patients are not fully established. MATERIALS AND METHODS: We retrospectively analyzed patients with metastatic ocular and orbital melanoma from Fudan University Shanghai Cancer Center and Eye & ENT Hospital of Fudan University between January 2012 and May 2022. RESULTS: Overall, 51 patients with metastatic ocular and orbital melanoma were included. The most common primary sites were uvea (73%), followed by conjunctiva (22%), lacrimal sac (4%), and orbit (2%). Patients with uveal melanoma (UM) had a significantly younger age (48 vs. 68 years, p < 0.001), higher incidence of liver metastases (89% vs. 9%, p<0.001), a lower incidence of lymph nodes metastases (16% vs. 46%, p = 0.043) and a lower incidence of BRAF mutation (0% vs. 55%, p<0.001) compared with patients with conjunctival melanoma (CM). The overall response rate of the first-line treatment was 18%. Three of the four patients with BRAF-mutated CM responded to dabrafenib and trametinib treatment. The median progression-free survival (PFS) and overall survival (OS) of first-line treatment were 5.1 and 11.9 months, respectively. Among patients with liver metastases, liver-directed treatment was correlated with better patient PFS (p < 0.001) and OS (p < 0.001) after adjusting for number of metastatic sites and primary sites. CONCLUSION: CM and UM have different characteristics. Patient with CM had a high incidence of BRAF mutation, and the treatment of BRAF and MEK inhibitors conferred clinical benefit. Liver directed therapies had a potential benefit in disease control in patients with liver metastases.

Copper-Bacteriochlorin Nanosheet as a Specific Pyroptosis Inducer for Robust Tumor Immunotherapy.

Pyroptosis is increasingly considered a new weathervane in cancer immune therapy. However, triggering specific pyroptotic tumor cell death while preserving normal cells still remains a major challenge. Herein, a brand-new pyroptosis inducer, copper-bacteriochlorin nanosheet (Cu-TBB), is designed. The synthesized Cu-TBB can be activated to an "on" state in the tumor microenvironment with glutathione (GSH) overexpression, leading to the release of Cu+ and TBB, respectively. Intriguingly, the released Cu+ can drive cascade reactions to produce O2 -• and highly toxic ·OH in cells. Additionally, the released TBB can also generate O2 -• and 1 O2 upon 750 nm laser irradiation. Encouragingly, both Cu+ -driven cascade reactions and photodynamic therapy pathways result in potent pyroptosis along with dendritic cell maturation and T cell priming, thus simultaneously eliminating the primary tumors and inhibiting the distant tumor growth and metastases. Conclusively, the well-designed Cu-TBB nanosheet is shown to trigger specific pyroptosis in vitro and in vivo, leading to enhanced tumor immunogenicity and antitumor efficacy while minimizing systemic side effects.

Fluorination of naphthalimide-cyanostilbene derivatives to achieve dual-state emission luminogens with strong fluorescence in highly polar environments for bioimaging.

Organic luminogens (OLs) that emit strong fluorescence in both solution and the aggregated state, referred to as dual-state emission luminogens (DSEgens), are highly desirable because of their capability to achieve multiple functions within onefold materials. The fluorescence of OLs, including DSEgens, with intramolecular charge transfer characteristics, often decreases in solution as the solvent polarity increases, namely the positive solvatokinetic effect, resulting in inferior environmental stability. In this work, fluorination to naphthalimide (NI)-cyanostilbene (CS) derivatives was adopted to construct novel DSEgens (NICSF-X, X = B, P, M, and T, respectively). Steady-state and transient spectroscopies were utilized to study their photophysical properties, evidencing their DSE properties with fluorescence quantum yields (φ) ∼0.2-0.4 in solution and ∼0.5-0.9 as solids. In particular, strong fluorescence emission in highly polar solvents i.e., φ up to ∼0.4-0.5 in ethanol, was sustained for NICSF-Xs, possibly assisted by hydrogen bonding (H-bonding) formation. Theoretical calculations and single-crystal structure analysis rationalized the intense photoluminescence (PL) emission of NICSF-Xs in the solid state. In addition, NICSF-Xs showed two-photon absorption (2PA) behaviors in dual states and were successfully applied for HepG2 cell imaging with one-photon and 2PA excitation, with lipid droplet targeting. Our study suggests that functionalization of molecules by fluorination to introduce H-bonding is a promising strategy to enhance the environmental stability of fluorescence in solution and realize strong PL emission in highly polar solvents, which could be favorable for bioimaging.

Lysosome-targeted silicon quantum dots theranostics for simultaneous fluorescent imaging and photodynamic therapy.

As an emerging treatment method, photodynamic therapy (PDT) has attracted considerable interest due to the characteristics of non-invasiveness, repeatable treatment, high spatiotemporal resolution and few side effects. However, the life span (<40 ns) and diffusion distance (<20 nm) of reactive oxygen species such as singlet oxygen (1O2) in tumor cells are extremely short, which has seriously limited therapeutic efficacy of PDT. The enrichment site of photosensitizers in cancer cells is usually the first site of PDT action, which will not only affect the biological signaling pathway of cancer cell death, but also is closely related to the final therapeutic effect. Therefore, the design and preparation of photosensitizers targeting specific subcellular organelles can directly break the biological function of the organelle and trigger the corresponding cell death signaling pathway, which can significantly improve the efficacy of PDT. Herein, a lysosome-targeted silicon quantum dots (L-Si QDs) was first made by diethylene glycol-mediated synthetic route as a multicolor fluorescent imaging reagents and a new photosensitizer. The as-prepared L-Si QDs exhibit bright fluorescence with excellent pH stability and time stability, excitation-dependent emission, and good biocompatibility. Furthermore, the results of cell experiments showed that L-Si QDs was accumulated in lysosomes after being taken up by cancer cells, and can efficiently produce1O2upon 635 nm laser irradiation, which can damage lysosomes, up-regulate cleavage caspase-3, increase Bax release, down-regulate Bcl-2 and induce cell apoptosis finally. This study significantly broadens the biomedical applications of silicon quantum dots and provides excellent nanomaterials candidates for tumor phototherapy.

Protection of taraxasterol against acetaminophen-induced liver injury elucidated through network pharmacology and in vitro and in vivo experiments.

BACKGROUND: Drug-induced liver injury (DILI) is primarily caused by drugs or their metabolites. Acetaminophen (APAP) is an over-the-counter antipyretic analgesic that exhibits high hepatotoxicity when used for long-term or in overdoses. Taraxasterol is a five-ring triterpenoid compound extracted from traditional Chinese medicinal herb Taraxacum officinale. Our previous studies have demonstrated that taraxasterol exerts protective effects on alcoholic and immune liver injuries. However, the effect of taraxasterol on DILI remains unclear. HYPOTHESIS/PURPOSE: This study aimed to elucidate the effects and mechanisms of action of taraxasterol on APAP-induced liver injury using network pharmacology and in vitro and in vivo experiments. METHODS: Online databases of drug and disease targets were used to screen the targets of taraxasterol and DILI, and a protein-protein interaction network (PPI) was constructed. Core target genes were identified using the tool of Analyze of Cytoscape, gene ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) enrichment analyses were performed. Oxidation, inflammation and apoptosis were evaluated to determine the effect of taraxasterol on APAP-stimulated liver damage in AML12 cells and mice. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting were used to explore the potential mechanisms of taraxasterol against DILI. RESULTS: Twenty-four intersection targets for taraxasterol and DILI were identified. Among them, 9 core targets were identified. GO and KEGG analysis showed that core targets are closely related to oxidative stress, apoptosis, and inflammatory response. The in vitro findings showed that taraxasterol alleviated mitochondrial damage in AML12 cells treated with APAP. The in vivo results revealed that taraxasterol alleviated pathological changes in the livers of mice treated with APAP and inhibited the activity of serum transaminases. Taraxasterol increased the activity of antioxidants, inhibited the production of peroxides, and reduced inflammatory response and apoptosis in vitro and in vivo. Taraxasterol promoted Nrf2 and HO-1 expression, suppressed JNK phosphorylation, and decreased the Bax/Bcl-2 ratio and caspase-3 expression in AML12 cells and mice. CONCLUSION: By integrating network pharmacology with in vitro and in vivo experiments, this study indicated that taraxasterol inhibits APAP-stimulated oxidative stress, inflammatory response and apoptosis in AML12 cells and mice by regulating the Nrf2/HO-1 pathway, JNK phosphorylation, and apoptosis-related protein expression. This study provides a new evidence for the use of taraxasterol as a hepatoprotective drug.

Preliminary clinical outcomes of head and neck squamous cell carcinoma treated with particle beam radiation therapy.

PURPOSE: Further improvement in clinical outcomes is needed for patients with head and neck squamous cell carcinoma (HNSCC), as there is typically a poor prognosis at diagnosis. This study aimed to report the preliminary therapeutic outcomes and side effects in patients with HNSCC receiving particle beam radiotherapy (PBRT), owing to the physical and biological advantages of this approach. METHODS: We retrospectively analyzed 68 patients with newly diagnosed HNSCC who received PBRT at the Shanghai Proton and Heavy Ion Center (SPHIC) between August 2015 and December 2020. The Kaplan-Meier approach was used to determine overall survival (OS), disease-specific survival (DSS), progression-free survival (PFS), local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), and distant metastasis-free survival (DMFS). Common Terminology Criteria for Adverse Events (CTCAE) 4.03 was also used to grade acute and late toxicities. RESULTS: With a median follow-up time of 24.5 months (range, 3-65), the 3-year OS, DSS, PFS, LRFS, RRFS, and DMFS rates for the entire cohort were 79.0%, 84.7%, 67.9%, 83.5%, 83.3%, and 96.1%, respectively. Univariate and multivariate analyses showed that N category was a significant predictor of OS, PFS, and RRFS. In terms of acute toxicities, two patients demonstrated severe mucositis or dysphagia, and two patients also displayed a late toxicity of significant mucosal necrosis. CONCLUSION: These findings suggest that PBRT can provide patients with HNSCC with a promising therapeutic benefit and manageable toxicity. Prospective evaluation of clinical outcomes with PBRT for HNSCC is warranted, with an emphasis on clinical effectiveness as well as adverse effects and patient quality of life.

In vitro evaluation of photon and carbon ion radiotherapy in combination with cisplatin in head and neck squamous cell carcinoma cell lines.

Background: Heavy ion radiotherapy, such as carbon ion radiotherapy (CIRT), has multiple advantages over conventional photon therapy. Cisplatin, as a classic anti-tumor drugs, has been tested and discovered as a photon radiosensitizer in several cell lines, including head and neck squamous cell carcinoma (HNSCC). Hence, the aim of our study is to evaluate whether cisplatin can sensitize CIRT towards HNSCC cell lines in vitro. Methods: Human nasopharyngeal carcinoma cell line CNE-2, human tongue squamous carcinoma cell line TCA 8113 and human hypopharynx squamous carcinoma cell line FADU were all irradiated with photon beam of 2, 4, 6, 8 Gy (physical dose) and carbon ion beam of 1, 2, 3, 4 Gy (physical dose) and treated with cisplatin. Cell survival was assessed by clonogenic survival assay. Results: CIRT showed significantly stronger cytotoxic effect than standard photon radiotherapy. The relative biological effectiveness (RBE) of carbon ion beam at 10% survival ( R B E 10 ) was calculated 3.07 for CNE-2, 2.33 for TCA 8113 and 2.36 for FADU. Chemoradiotherapy (both photon radiotherapy and CIRT) was more effective than radiotherapy alone. In vitro sensitizer enhancement ratios (SERs) of cisplatin in CNE-2, TCA 8113 and FA DU cell lines after photon irradiation were 1.33, 1.14 and 1.21, while after carbon ion irradiation were 1.02, 1.00 and 0.96, showed that cisplatin sensitized photon irradiation but showed no sensitization effect in carbon ion irradiation in all tested cell lines. Conclusions: In conclusion, high linear energy transfer (LET) CIRT was more effective than photon irradiation to prevent the proliferation of HNSCC cell lines. Additional treatment with cisplatin could sensitize photon irradiation but showed no effect on carbon ion irradiation.