Evaluation of tear film function by Oculus Keratograph 5M and IDRA ocular surface analyser.

PURPOSE: The aim of this study was to evaluate the function of tear film with Oculus Keratograph 5M (Oculus K5M) and IDRA ocular surface analyser (IDRA), analyse their consistency and explore the potential of IDRA in the diagnosis of dry eye disease (DED). METHODS: This cross-sectional study enrolled 36 participants (DED group, 14 eyes; non-DED group, 22 eyes). The parameters of tear film function, including the first noninvasive breakup time (fNIBUT), average NIBUT (aNIBUT), tear meniscus height (TMH), lipid layer thickness (LLT), lipid layer colour (LLC), lipid layer uniformity (LLU), morphology of meibomian glands (MGs) and MG loss, were obtained with Oculus K5M and IDRA. The consistency of parameter measurements between the two devices was evaluated. RESULTS: All the parameters except LLT, which can be measured only by IDRA, were not significantly different between the two instruments in DED eyes. However, IDRA reported lower values of fNIBUT, aNIBUT and TMH as well as higher MG loss scores in non-DED eyes than Oculus K5M did (p < 0.001, < 0.001, = 0.002, and = 0.002, respectively). Further regression analysis revealed that aNIBUT and LLT measured by IDRA were the optimal parameters for diagnosing DED (OR = 0.567 and 0.845, p = 0.057 and 0.043, respectively), and their combination had the strongest diagnostic potential (AUC = 0.841, sensitivity = 85.7%, and specificity = 77.3%). CONCLUSION: As a user-friendly noninvasive device, the tear film function parameters measured by IDRA were highly consistent with those measured by Oculus K5M in DED patients. The combination of aNIBUT and LLT measured by IDRA had the best diagnostic accuracy for DED.

Elevated ALT/AST ratio as a marker for NAFLD risk and severity: insights from a cross-sectional analysis in the United States.

Background: The prevalence and incidence of Nonalcoholic fatty liver disease (NAFLD) are increasing worldwide, and NAFLD has emerged as a prominent global health concern. The link between serum alanine aminotransferase (ALT) to aspartate aminotransferase (AST) ratio and NAFLD remains unclear. This study investigated the association between the ALT/AST ratio and NAFLD prevalence, including liver steatosis and fibrosis levels in the population. Methods: We conducted a cross-sectional study using data from the National Health and Nutrition Examination Survey (NHANES) 2017-2018, including 4753 participants. Subgroup analyses, stratified by age, gender, and body mass index (BMI), were performed, along with adjusted multivariable logistic regression analyses to evaluate the relationship between ALT/AST levels and the likelihood of NAFLD, liver steatosis, and hepatic fibrosis stage. A generalized additive model examined the non-linear relationship between ALT/AST and the probability of developing NAFLD. Results: Among 4753 participants, 1508 (31.73%) were diagnosed with NAFLD. Significant positive correlations between ALT/AST and NAFLD risk were found across all models. In addition, the subgroup analysis by gender, age, and BMI suggested that ALT/AST showed a positive correlation with NAFLD. The ALT/AST ratio was positively correlated with the degree of liver steatosis and liver fibrosis. The correlation between ALT/AST and the incidence of NAFLD showed a non-linear pattern. In women, the non-linear trend is particularly evident, showing an inverted U-shaped curve with an inflection point of 1.302. A receiver operating characteristic (ROC) analysis showed that the predictive value of ALT/AST for NAFLD was better than that of traditional liver enzyme parameters. Conclusion: A higher ALT/AST ratio was independently associated with a significantly higher risk of NAFLD and liver fibrosis within American cohorts. This link is robust among females, children, and adolescents. ALT/AST ratio can be used as a simple and effective noninvasive biomarker to identify individuals with high risk of NAFLD.

Comprehensive assessment of corneal microstructural changes following V4c implantable collamer lens surgery using in vivo confocal microscopy.

BACKGROUND: Implantable Collamer Lense (ICL) presents a viable alternative to conventional refractive surgeries, but their impact on corneal microstructure remains unclear. By employing in vivo confocal microscopy (IVCM), we examined changes in stromal and endothelial cells following the insertion of V4c ICLs, with the goal of enhancing post-surgical care and outcomes. METHODS: In this longitudinal investigation, we conducted detailed preoperative assessments on 103 eyes from 53 participants. Follow-up evaluations were carried out after surgery at set intervals: one day, one week, one month, three months, six months, and twelve months. We used IVCM to analyze changes in stromal and endothelial cells. To assess differences between pre- and post-surgery variables and to investigate correlations with age, axial length (AL), and spherical equivalent refraction (SER), we applied a repeated measures mixed-effects model, with statistical significance set at P < 0.05. RESULTS: No vision-threatening complications were reported post-surgery. Significant reductions in stromal cell density (SCD) were observed postoperatively, with anterior and mid- SCD reaching their lowest values at 3 months and posterior SCD at 1 month, remaining below baseline at 12 months. endothelial cell density (ECD) and percentage of hexagonal cells (PHC) decreased initially, recovering by 12 months. Conversely, endothelial cellular area (ECA) and coefficient of variation of cell size (CoV) increased postoperatively, with the most significant change at 1 week. Endothelial deposits were detected in 49 of 101 eyes on postoperative day 1, half of them were absorbed within 3 months post-surgery. Changes in posterior SCD were negatively related to AL, while AL, SER, lens thickness showed associated with endothelium changes. CONCLUSION: Our findings elucidate the corneal microstructural changes following V4c ICL implantation, particularly the significant early reductions in stromal and endothelial cell densities. We recommend careful management of viscoelastics during surgery to minimize endothelial deposits that may harm the endothelium. Enhanced early postoperative monitoring and these surgical adjustments can lead to improved surgical and post-surgical care, ultimately supporting better patient recovery.

Presence of polycyclic aromatic compounds in river sediment and surrounding soil: Possible impact from shale gas wastewater.

Shale gas has been extensively extracted in the Sichuan Basin in China in recent years. To gain insight into the potential impact of shale gas wastewater (SGW) discharge, sediment in a small river receiving treated SGW, as well as cultivated soil and paddy soil irrigated by the river water were collected. The occurrence and distribution of polycyclic aromatic compounds (PACs), including polycyclic aromatic hydrocarbons (PAHs) and their alkylated/oxygenated derivatives (APAHs/OPAHs), and thiophenes were investigated, the resultant potential ecological risks were assessed subsequently. The total concentration of PACs varied in the range of 1299.9-9286.4, 2069.4-11,512.3, and 475.7-2927.9 ng/g in sediment, cultivated soil and paddy soil, respectively, with thiophenes followed by APAHs being the abundant components in all the studied samples, demonstrating the potential impact of SGW discharge on sediment and surrounding soil environment. Based on the measured concentrations, potential ecological risks posed by PAHs and APAHs were calculated, and moderate to high ecological risks were observed in partial sampling sites, which mainly caused by 3-4 rings PAHs and APAHs.

An immunotherapeutic hydrogel booster inhibits tumor recurrence and promotes wound healing for postoperative management of melanoma.

Low tumor immunogenicity, immunosuppressive tumor microenvironment, and bacterial infections have emerged as significant challenges in postsurgical immunotherapy and skin regeneration for preventing melanoma recurrence. Herein, an immunotherapeutic hydrogel booster (GelMA-CJCNPs) was developed to prevent postoperative tumor recurrence and promote wound healing by incorporating ternary carrier-free nanoparticles (CJCNPs) containing chlorine e6 (Ce6), a BRD4 inhibitor (JQ1), and a glutaminase inhibitor (C968) into methacrylic anhydride-modified gelatin (GelMA) dressings. GelMA-CJCNPs reduced glutathione production by inhibiting glutamine metabolism, thereby preventing the destruction of reactive oxygen species generated by photodynamic therapy, which could amplify oxidative stress to induce severe cell death and enhance immunogenic cell death. In addition, GelMA-CJCNPs reduced M2-type tumor-associated macrophage polarization by blocking glutamine metabolism to reverse the immunosuppressive tumor microenvironment, recruiting more tumor-infiltrating T lymphocytes. GelMA-CJCNPs also downregulated IFN-γ-induced expression of programmed cell death ligand 1 to mitigate acquired immune resistance. Benefiting from the amplified systemic antitumor immunity, GelMA-CJCNPs markedly inhibited the growth of both primary and distant tumors. Moreover, GelMA-CJCNPs demonstrated satisfactory photodynamic antibacterial effects against Staphylococcus aureus infections, thereby promoting postsurgical wound healing. Hence, this immunotherapeutic hydrogel booster, as a facile and effective postoperative adjuvant, possesses a promising potential for inhibiting tumor recurrence and accelerating skin regeneration.

Highly Efficient Synergistic Chemotherapy and Magnetic Resonance Imaging for Targeted Ovarian Cancer Therapy Using Hyaluronic Acid-Coated Coordination Polymer Nanoparticles.

The diagnosis and treatment of ovarian cancer (OC) are still a grand challenge, more than 70% of patients are diagnosed at an advanced stage with a dismal prognosis. Magnetic resonance imaging (MRI) has shown superior results to other examinations in preoperative assessment, while cisplatin-based chemotherapy is the first-line treatment for OC. However, few previous studies have brought together the two rapidly expanding fields. Here a technique is presented using cisplatin prodrug (Pt-COOH), Fe3+, and natural polyphenols (Gossypol) to construct the nanoparticles (HA@PFG NPs) that have a stable structure, controllable drug release behavior, and high drug loading capacity. The acidic pH values in tumor sites facilitate the release of Fe3+, Pt-COOH, and Gossypol from HA@PFG NPs. Pt-COOH with GSH consumption and cisplatin-based chemotherapy plus Gossypol with pro-apoptotic effects displays a synergistic effect for killing tumor cells. Furthermore, the release of Fe3+ at the tumor sites promotes ferroptosis and enables MRI imaging of OC. In the patient-derived tumor xenograft (PDX) model, HA@PFG NPs alleviate the tumor activity. RNA sequencing analysis reveals that HA@PFG NPs ameliorate OC symptoms mainly through IL-6 signal pathways. This work combines MRI imaging with cisplatin-based chemotherapy, which holds great promise for OC diagnosis and synergistic therapy.

Characterizing organophosphate esters and chlorinated paraffins in surface soils affected by diverse e-waste disassembling process in South China: Occurrence, distinct emission, and risk assessment.

E-waste recycling activities are a crucial emission source of organic pollutants, posing potential risks to the surrounding environment and human health. To understand the potential impact related to diverse e-waste dismantling activities, we investigated two categories of popular flame retardants (i.e., organophosphate esters (OPEs) and chlorinated paraffins (CPs) and their resultant possible ecological risk in 53 surface soil samples from Qingyuan, a well-known e-waste recycling region in South China. Varied concentrations of ΣOPEs (20.5-8720 ng/g) and ΣCPs (920-16800 ng/g) were observed at diverse dismantling sites, while relatively low levels of ΣOPEs (6.13-1240 ng/g) and ΣCPs (14.8-2870 ng/g) were found in surrounding soils. These results indicated that primitive e-waste dismantling processes were the primary emission source of OPEs and CPs in the studied area, with e-waste dumping and manual dismantling being the most important emission sources for OPEs and CPs. More importantly, CPs could be degraded/transformed into more toxic intermediates via dechlorination and decarbonization during the burning of e-waste. Furthermore, our results indicated the potential ecological risks posed by OPEs and CPs related to e-waste recycling.

[Determination of ten bisphenols and five parabens in urine by solid supported liquid-liquid extraction and liquid chromatography-tandem mass spectrometry].

Bisphenols (BPs) and parabens (PBs) are of great concern for environmental pollution and human health because of their endocrine-disrupting effects and potential health hazards. Urinary biomonitoring of BPs and PBs can provide basic data for human internal exposure evaluation, which is a prerequisite for accurately assessing their health risks. In this study, we developed a new pretreatment procedure based on solid supported liquid-liquid extraction (SLE) for the simultaneous separation of ten BPs and five PBs in human urine, followed by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) analysis. In the instrumental analysis, the HPLC conditions and MS/MS parameters were comprehensively optimized. Accurate qualitative and quantitative determination of ten BPs and five PBs was achieved by introducing a ternary gradient elution system of water, methanol, and acetonitrile for LC separation. During sample pretreatment, the extraction solvent and elution volume were optimized. Specifically, urine samples were held at room temperature and centrifuged at 3000 r/min for 10 min. The supernatant (2 mL) was then transferred to a glass tube, and the pH was adjusted to 5.0 using HCl (0.5 mL; 0.1 mol/L) and NaAc-HAc buffer (1.5 mL). Thereafter, ß-glucuronidase-arylsulfatase (20 µL) and surrogate standard solutions (10 ng;13C12-BPS,13C12-BPAF,13C6-MeP, and 13C6-BuP) were added, and the mixture was incubated in a shaker bath in the dark at 37 ℃ for 16 h. After incubation, the hydrolyzed sample (4 mL) was loaded onto an SLE cartridge and equilibrated for a minimum of 5 min to ensure the solution was completely absorbed by the packing material. Subsequently, the target chemicals were eluted with a mixed ethyl acetate/n-hexane solution (3∶7, v/v; 15 mL). Separation of the targets was performed on a ZORBAX SB-C18 reversed-phase column (250 mm×4.6 mm, 5 µm) using an acetonitrile-methanol-water system as the mobile phase. The method was verified by spiking mixed urine samples at three levels (1, 5, and 50 µg/L), with the recoveries ranging from 84.3% to 119.8%. Except for bisphenols (BPS), whose matrix effect was calculated as -21.8%, the matrix effects of other analytes were lower than 20%, indicating low matrix interference. The linear ranges of the analytes varied from 0.1-500 µg/L to 1-500 µg/L, with correlation coefficients higher than 0.995. The method limits of quantification for target chemicals ranged from 0.03 to 0.30 µg/L, and the relative standard deviations of intra- and inter-day experiments were 1.4%-8.4% and 5.7%-14.6%, respectively, suggesting high stability and reproducibility. The method was successfully applied to the determination of ten BPs and five PBs in 10 urine samples from a general population. The concentrations of target chemicals in the human urine samples varied. Methylparaben (MeP), ethylparaben (EtP), propylparaben (PrP), and bisphenol A (BPA) were detected in all samples, with median mass concentrations of 1.10, 0.60, 0.21, and 0.55 µg/L, respectively. The detection rates of the other chemicals were less than 50%, which may be related to the production and use of specific chemicals, their bioavailability, and biological metabolism in humans.

Enhanced human activities since 20th century in pearl river delta, southern China: Evidence from high-resolution sedimentary records of polycyclic aromatic hydrocarbons and synthetic musks.

To understand the environmental impact of anthropogenic activities, the high-resolution temporal and compositional variations of polycyclic aromatic hydrocarbons (PAHs), oxygenated PAHs, and synthetic musks, related to human activities were investigated in a sediment core taken from the Pearl River Estuary, southern China. The temporal trend of the target compounds was evidence of the considerable impact of anthropogenic activities in the Pearl River Delta. Two significant increases of the target compounds levels in the sediment core were aligned with two nodes of key periods of economic development in China, namely, the foundation of People's Republic of China (1950s) and China's accession to the World Trade Organization (2000s). Subsequently, the significant decline of the target compounds in sediments from the 2010s indicated the successful regulation of pollutant discharges and pollution control measures. The increase in the contribution of higher molecular weight PAHs suggested a potential transition from agricultural activities to industrial activities.

Metagenomic analyses of aerobic bacterial enrichment cultures that degraded Tris(2-chloroethyl) phosphate (TCEP) and its transformation products.

Tris(2-chloroethyl) phosphate (TCEP) is of growing public concern worldwide because of its ubiquitous contamination, toxicity, and persistence. In this study, we investigated bacterial communities in aerobic enrichment cultures with TCEP and its two major transformation products bis(2-chloroethyl) phosphate (BCEP) and 2-chloroethanol (2-CE) as the sole carbon source. Burkholderiales and Rhizobiales were likely two main bacterial guilds involved in the hydrolysis of TCEP, while Rhizobiales and Sphingomonadales may play an important role in the hydrolysis of BCEP, given the increase of Rhizobiales and Sphingomonadales-related phosphoesterase genes when the carbon source was switched from TCEP to BCEP. All Burkholderiales, Rhizobiales, Sphingomonadales were probably efficient in 2-CE metabolism, because their dehydrogenase genes and dehalogenase genes increased after 2-CE enrichment. The different substrate preference of different bacterial guilds highlighted the importance to understand the diversity and collaboration among functional bacteria. Meanwhile, two TCEP-degrading strains affiliated with Xanthobacter and Ancylobacter were isolated. Xanthobacter sp. strain T2-1 was able to degrade both TCEP and BCEP following the pseudo-first-order kinetics with reaction rates of 1.66 h-1 for TCEP and 1.02 h-1 for BCEP, respectively. Ancylobacter sp. strain T3-4 could degrade TCEP following the pseudo-first-order kinetics with a reaction rate of 2.54 h-1, but is unable to degrade BCEP. Additionally, strains that were phylogenetically closely related were found to have different degradation capabilities toward TCEP and/or BCEP, indicating the importance to investigate functional genes such as phosphoesterase genes.

Tumor microenvironment activation amplify oxidative stress promoting tumor energy remodeling for mild photothermal therapy and cuproptosis.

Tumor metabolic reprogramming requires high levels of adenosine triphosphate (ATP) to maintain treatment resistance, which poses major challenges to chemotherapy and photothermal therapy. Especially, high levels of ATP promote copper ion efflux for limiting the curative effect of cuproptosis. Here, an H2S-responsive mesoporous Cu2Cl(OH)3-loading chemotherapeutic cisplatin (CDDP) was synthesized, and the final nanoparticle, CDDP@Cu2Cl(OH)3-CDs (CDCuCDs), was encapsulated by electrostatic action with carbon dots (CDs). CDCuCDs reacted with overproduction H2S in colon tumor to produce photothermic copper sulfide for photothermal therapy. CDDP was released by lysis to achieve chemotherapeutic effects. Importantly, CDDP elevated H2O2 levels in cells through a cascade reaction and continuously transforms H2O2 into highly cytotoxic •OH through chemodynamic therapy between H2O2 and Cu+, which enables nanoparticles to generate •OH and improve the chemotherapeutic efficacy. Highly toxic •OH disrupts mitochondrial homeostasis, prohibiting it from performing normal energy-supplying functions. Down-regulated ATP inhibits heat shock protein expression, which promotes the therapeutic effect of mild photothermal therapy and reduces the efflux of intracellular copper ions, thus improving the therapeutic effect of cuproptosis. Our research provides a potential therapeutic strategy using overproduction H2S responses in tumors, allowing tumor microenvironment-activated •OH nanogenerators to promote tumor energy remodeling for cancer treatment.

Posterior corneal stability after small incision lenticule extraction with different optical zones.

BACKGROUND: To assess the changes in the posterior corneal surface following small incision lenticule extraction (SMILE) with different optical zones. METHODS: In this retrospective study, 106 eyes of 106 patients who underwent SMILE were recruited 3 years after the procedure. Eyes were divided into two groups according to the size of the surgical optical zone: group A (52 eyes, ≤6.2 mm) and group B (54 eyes, ≥6.5 mm). Posterior central elevation (PCE) and 12 other points at 45°, 135°, 225° and 315° with distances of 1 mm, 2 mm and 3 mm from the centre were recorded from Pentacam. RESULTS: No iatrogenic keratectasia was identified, and eyes in the two groups showed comparable visual results. The overall trend in posterior corneal elevation changes was consistent for both groups. PCE decreased significantly from 1.33 ± 2.32 to 0.75 ± 2.41 in group A (P = 0.024) and from 0.87 ± 2.61 to 0.06 ± 2.74 in group B (P = 0.003). All points in the central 2 mm region in both groups were reduced postoperatively. In the 4 mm and 6 mm corneal annulus, almost all points at 225°and 315° showed backward displacement, with the most prominent change occurring at 315° in the 6 mm annulus (P < 0.001), indicating no forward protrusion in the inferior area. CONCLUSIONS: No forward protrusion in the posterior corneal surface was observed 3 years after SMILE with different optical zones. Comprehensive preoperative measurements are essential for ensuring corneal stability and avoiding iatrogenic keratectasia.

Carrier-Free Photodynamic Bioregulators Inhibiting Lactic Acid Efflux Combined with Immune Checkpoint Blockade for Triple-Negative Breast Cancer Immunotherapy.

Abnormal tumor metabolism creates a complex tumor immune microenvironment that plays a dominant role in the metastasis of triple-negative breast cancer (TNBC). TNBC is insensitive to immune checkpoint blockade (ICB) therapy because of insufficient cytotoxic T lymphocyte (CTL) infiltration and a hyper-lactic acid-suppressive immune microenvironment caused by abnormal glycolysis. Herein, we propose an amplified strategy based on lactic acid regulation to reprogram the immunosuppressive tumor microenvironment (ITM) and combine it with ICB therapy to achieve enhanced antitumor immunotherapy effects. Specifically, we constructed CASN, a carrier-free photodynamic bioregulator, through the self-assembly of the photosensitizer Chlorin e6 and monocarboxylate transporter 1 (MCT1) inhibitor AZD3965. CASN exhibited a uniform structure, good stability, and drug accumulation at the tumor site. CASN-mediated photodynamic therapy following laser irradiation inhibited primary tumor growth and induced immunogenic cell death. Furthermore, CASN reduced lactic acid-mediated regulatory T cell generation and M2 tumor-associated macrophage polarization by blocking MCT1-mediated lactic acid efflux to attenuate immune suppression, inducing the recruitment and activation of CTLs. Ultimately, CASN-mediated immunopotentiation combined with ICB therapy considerably strengthened tumor immunotherapy and effectively inhibited tumor growth and metastasis of TNBC. This synergistic amplification strategy overcomes the limitations of an acidic ITM and presents a potential clinical treatment option for metastatic tumors.

Synthesis and Preclinical Evaluation of Novel 68Ga-DOTA-RBB as Potential PET Radiotracer for Imaging CDK4/6 in Tumors.

Many malignant tumors, including breast cancer, exhibit amplification and overexpression of cyclin-dependent kinase 4 and 6 (CDK4/6). Ribociclib, approved and used in clinical treatment, acts as a highly selective CDK4/6 inhibitor for ER+/HER2- breast cancer. By modifying ribociclib with the chelator DOTA, we designed and synthesized a novel CDK4/6-positive PET imaging agent, which was radiolabeled by 68Ga for radioactive tagging. The radiotracer demonstrates high radiochemical purity, excellent stability in vitro and in vivo, and favorable pharmacokinetic characteristics. Cell uptake experiments using MCF-7 cells indicate that an excess of ribociclib (RBB) can inhibit cellular uptake of 68Ga-DOTA-RBB. Imaging and biodistribution experiments in MCF-7 tumor-bearing nude mice show significant radioactive accumulation in the tumor. However, preadministration of excess ribociclib results in a substantial reduction in radioactive accumulation within the tumor. On the basis of our explorations, 68Ga-DOTA-RBB, as a targeted imaging agent for CDK4/6-positive tumors, holds significant potential application values.

Immunoregulatory Engineering of Semiconducting Charge-Reversal Nanoantioxidant for Ameliorating Cancer Radioimmunotheranostics.

Radiotherapy (RT) is a crucial clinical modality for cancer. However, nonselectivity, toxicity to normal tissues, and radio-resistance severely limit RT applications. This study develops a versatile X-ray theranostic nano-antioxidant (XTN) to prevent normal tissues from oxidative damage and induce systematic and robust anticancer immunity. XTN owns NIR-II photoacoustic (PA) imaging properties for precise discrimination of the tumor margin through, thereby improving the accuracy of RT. Additionally, XTN is a nano-antioxidant to enhance the cell viability of normal cells after irradiation. Most importantly, XTN scavenges reactive oxygen species (ROS) in the TME to preserve the stimulatory activity of released high mobility group protein B1 to dendritic cells (DCs) and recover T cells' immune function. Meanwhile, XTN achieves charge-reversal specifically releasing an immunomodulator (demethylcantharidin, DMC) in the acidic TME. Moreover, the specifically released DMC inhibits protein phosphatase-2A activity and reduces regulatory T cell (Treg) differentiation. In the bilateral 4T1 tumor model, XTN-mediated radioimmunotherapy remarkably boosts a systemic antitumor immune response and induces durable immunological memory against tumor growth.

Mitochondria-targeted polyprodrug nanoparticles induce mitochondrial stress for immunogenic chemo-photodynamic therapy of ovarian cancer.

Hypoimmunogenicity and the immunosuppressive microenvironment of ovarian cancer severely restrict the capability of immune-mediated tumor killing. Immunogenic cell death (ICD) introduces a theoretical principle for antitumor immunity by increasing antigen exposure and presentation. Despite recent research progress, the currently available ICD inducers are still very limited, and many of them can hardly induce sufficient ICD based on traditional endoplasmic reticulum (ER) stress. Accumulating evidence indicates that inducing mitochondrial stress usually shows a higher efficiency in evoking large-scale ICD than that via ER stress. Inspired by this, herein, a mitochondria-targeted polyprodrug nanoparticle (named Mito-CMPN) serves as a much superior ICD inducer, effectively inducing chemo-photodynamic therapy-caused mitochondrial stress in tumor cells. The rationally designed stimuli-responsive polyprodrugs, which can self-assemble into nanoparticles, were functionalized with rhodamine B for mitochondrial targeting, cisplatin and mitoxantrone (MTO) for synergistic chemo-immunotherapy, and MTO also serves as a photosensitizer for photodynamic immunotherapy. The effectiveness and robustness of Mito-CMPNs in reversing the immunosuppressive microenvironment is verified in both an ovarian cancer subcutaneous model and a high-grade serous ovarian cancer model. Our results support that the induction of abundant ICD by focused mitochondrial stress is a highly effective strategy to improve the therapeutic efficacy of immunosuppressive ovarian cancer.

Manganese-induced Photothermal-Ferroptosis for Synergistic Tumor Therapy.

Ferroptosis-related tumor therapy based on nanomedicines has recently gained significant attention. However, the therapeutic performance is still hindered by the tumor's physical barriers such as the fibrotic tumor matrix and elevated interstitial fluid pressure, as well as chemical barriers like glutathione (GSH) overabundance. These physicochemical barriers impede the bioavailability of nanomedicines and compromise the therapeutic efficacy of lipid reactive oxygen species (ROS). Thus, this study pioneers a manganese-mediated overcoming of physicochemical barriers in the tumor microenvironment using organosilica-based nanomedicine (MMONs), which bolsters the synergy of photothermal-ferroptosis treatment. The MMONs display commendable proficiency in overcoming tumor physical barriers, due to their MnO2-mediated shape-morphing and softness-transformation ability, which facilitates augmented cellular internalization, enhanced tumor accumulation, and superior drug penetration. Also, the MMONs possess excellent capability in chemical barrier overcoming, including MnO2-mediated dual GSH clearance and enhanced ROS generation, which facilitates ferroptosis and heat shock protein inhibition. Notably, the resulting integration of physical and chemical barrier overcoming leads to amplified photothermal-ferroptosis synergistic tumor therapy both in vitro and in vivo. Accordingly, the comparative proteomic analysis has identified promoted ferroptosis with a transient inhibitory response observed in the mitochondria. This research aims to improve treatment strategies to better fight the complex defenses of tumors.

Electrically activated polymetallic nanocrystals for long-term tumor suppression via oxygen-independent ROS generation and electro-immunotherapy.

The low oxidation level and immunosuppressive microenvironment within hypoxic tumor tissue are critical factors contributing to the inefficacy of various anti-tumor strategies. Herein, we have designed a novel intravenous injection nanoplatform to conduct electro-immunotherapy, based on phospholipid-modified PtPd nanocrystals loaded with the immunoregulator IPI549 (LP@Pt-Pd@IPI549 nanoparticles, LPPI). LPPI responds to reactive oxygen species (ROS), triggering a cascade of therapeutic effects that overcome hypoxia-related resistance and effectively eradicate hypoxic tumors. Firstly, under electric field exposure, LPPI relied on water rather than oxygen to generate abundant ROS under hypoxic conditions for tumor electrodynamic therapy (EDT). Moreover, the generated ROS further induced the disintegration of the outer phospholipid membrane of LPPI, leading to the release of the immunoregulator and inhibition of myeloid-derived suppressor cells (MDSCs), triggering cascade immune responses. Additionally, the immunomodulatory effects of IPI549, in synergy with the immunogenic cell death (ICD) induced by EDT, reversed the immunosuppressive microenvironment contributing to tumor resistance. In summary, EDT transiently killed tumor cells while simultaneously generating antigen release, instigating an adaptive immune response for electro-immunotherapy, resulting in a potent and long-lasting tumor inhibition effect.

PROTAC: Novel degradable approach for different targets to treat breast cancer.

The revolutionary Proteolysis Targeting Chimera (PROTACs) have the exciting potential to reshape the pharmaceutical industry landscape by leveraging the ubiquitin-proteasome system for targeted protein degradation. Breast cancer, the most prevalent cancer in women, could be treated using PROTAC therapy. Although substantial work has been conducted, there is not yet a comprehensive overview or progress update on PROTAC therapy for breast cancer. Hence, in this article, we've compiled recent research progress focusing on different breast cancer target proteins, such as estrogen receptor (ER), BET, CDK, HER2, PARP, EZH2, etc. This resource aims to serve as a guide for future PROTAC-based breast cancer treatment design.

Deep Learning Bridged Bioactivity, Structure, and GC-HRMS-Readable Evidence to Decipher Nontarget Toxicants in Sediments.

Identifying causative toxicants in mixtures is critical, but this task is challenging when mixtures contain multiple chemical classes. Effect-based methods are used to complement chemical analyses to identify toxicants, yet conventional bioassays typically rely on an apical and/or single endpoint, providing limited diagnostic potential to guide chemical prioritization. We proposed an event-driven taxonomy framework for mixture risk assessment that relied on high-throughput screening bioassays and toxicant identification integrated by deep learning. In this work, the framework was evaluated using chemical mixtures in sediments eliciting aryl-hydrocarbon receptor activation and oxidative stress response. Mixture prediction using target analysis explained <10% of observed sediment bioactivity. To identify additional contaminants, two deep learning models were developed to predict fingerprints of a pool of bioactive substances (event driver fingerprint, EDFP) and convert these candidates to MS-readable information (event driver ion, EDION) for nontarget analysis. Two libraries with 121 and 118 fingerprints were established, and 247 bioactive compounds were identified at confidence level 2 or 3 in sediment extract using GC-qToF-MS. Among them, 12 toxicants were analytically confirmed using reference standards. Collectively, we present a "bioactivity-signature-toxicant" strategy to deconvolute mixtures and to connect patchy data sets and guide nontarget analysis for diverse chemicals that elicit the same bioactivity.