Comparing the prognostic impact of 131I or/and artificial liver support system on liver function failure combined with hyperthyroidism.

OBJECTIVE: Hyperthyroidism, a prevalent endocrine disorder, can lead to complications such as liver failure due to the liver's essential role in thyroid hormone metabolism. The study aimed to elucidate the respective contributions of 131I or/and ALSS in managing hyperthyroidism alongside liver failure. METHODS: A retrospective analysis was carried out on 74 patients diagnosed with severe liver failure in the context of Graves' disease. Patients were categorized into three groups: Group A (n=34) received 131I treatment, group B (n=17) underwent 131I and ALSS treatment, and group C (n=24) received ALSS treatment alone. RESULTS: Throughout the treatment period, the liver function indexes in all groups exhibited a decline trend. The thyroid function of group A and group B treated with 131I was significantly improved compared with that before treatment. There was no significant change in thyroid function in group C. After the correction of hyperthyroidism, significant improvements were observed in the liver function of individuals in group A and B, particularly with more noticeable amelioration compared to group C. After two months of treatment, the efficacy rates for the three groups were 79.41%, 82.35%, and 60.87% respectively. Mortality rates of the three groups were 5.88%,17.65% and 36% (p<0.01). Group B, receiving both 131I and ALSS treatments, exhibited a lower mortality rate than group C. CONCLUSION: In cases of severe liver failure accompanied by hyperthyroidism, prompt administration of 131I is recommended to alleviate the adverse effects of hyperthyroidism on liver function and facilitate a conducive environment for the recovery of liver functionality.

Metal-phenolic network crosslinked nanogel with prolonged biofilm retention for dihydroartemisinin/NIR synergistically enhanced chemodynamic therapy.

Chemodynamic therapy (CDT) is emerging as a promising treatment for biofilm infections. However, its effectiveness is significantly hindered by several factors: the body's stable temperature, a limited supply of Fe2+ ions, and inadequate endogenous levels of H2O2 at the infection sites. Herin, our study introduces MPN-crosslinked hyaluronic acid (HA) nanogels as an effective strategy for treating biofilm-associated infections. The DHA@HA-TA/Fe (DHTF) nanogel is synthesized through the coordination reaction between Fe2+ ions and tannic acid (TA)-modified HA, with dihydroartemisinin (DHA) encapsulated within the structure. DHTF exhibits pH-/hyaluronidase-responsiveness in the biofilm infection microenvironment, enabling sustained release of DHA as a substitute for H2O2 and Fe2+ for CDT. The incorporation of Fe2+/TA-based MPN and DHA within the nanogels enables photothermal/DHA dually-enhanced CDT, facilitating efficient disruption of biofilm matrices and bacterial eradication through boosting reactive oxygen species production. In vivo studies demonstrate that DHTF exhibit prolonged retention within biofilms. This ensures a sustained release of therapeutic agents and continuous anti-biofilm activity. Eventually, both in vitro and in vivo evaluations consistently confirm the significant anti-biofilm capacity of DHTF. Our findings highlight the potential of DHTF as a promising nanomedicine for biofilm-related infections, offering efficient treatment strategies that could improve clinical management of these challenging conditions.

Transferrin receptor-targeted immunostimulant for photodynamic immunotherapy against metastatic tumors through ß-catenin/CREB interruption.

The immunosuppressive phenotype of tumor cells extensively attenuates the immune activation effects of traditional treatments. In this work, a transferrin receptor (TfR) targeted immunostimulant (PTI) is fabricated for photodynamic immunotherapy against metastatic tumors by interrupting ß-catenin signal pathway. To synthesize PTI, the photosensitizer conjugated TfR targeting peptide moiety (Palmitic-K(PpIX)-HAIYPRH) is unitized to encapsulate the transcription interrupter of ICG-001. On the one hand, the recognition of PTI and TfR can promote drug delivery into tumor cells to destruct primary tumors through photodynamic therapy and initiate an immunogenic cell death with the release of tumor-associated antigens. On the other hand, PTI will interrupt the binding between ß-catenin and cAMP response element-binding protein (CREB), regulating the gene transcription to downregulate programmed death ligand 1 (PD-L1) while upregulating C-C motif chemokine ligand 4 (CCL4). Furthermore, the elevated CCL4 can recruit the dendritic cells to present tumor-specific antigens and promote T cells activation and infiltration, and the downregulated PD-L1 can avoid the immune evasion of tumor cells and activate systemic anti-tumor immunity to eradicate lung metastasis. This work may inspire the development of antibody antibody-free strategy to activate systemic immune response in consideration of immunosuppressive conditions.

A cross-sectional study of the association between physical activity and depressive symptoms among adolescents in southwest China stratified by parental absence: the mediating role of insomnia and the moderating role of resilience.

OBJECTIVES: This study explored the mechanisms by which physical activity was associated with depressive symptoms in multi-ethnic (Han, Yi and Tibetan) adolescents in southwest China. The mediating role of insomnia in the association of physical activity with depressive symptoms, the moderating role of resilience in this mediation model and the moderating role of parental absence in the moderated mediation model were also examined. DESIGN: A cross-sectional survey. SETTING: In southwest China (Sichuan Province and Tibet Autonomous Region). PARTICIPANTS: 3195 adolescents from a school-based survey conducted between April and October 2020. METHODS: There were 3143 valid samples in this study (47.2% males with mean age=12.88±1.68 years). Structural equation models were developed to estimate the direct and mediating effect, and the moderating effect. Multigroup comparison was performed to examine the differences and similarities of the moderated mediation model across three parental absence subgroups: (1) both parents present, (2) one parent absent and (3) both parents absent. RESULTS: As hypothesised, physical activity was significantly and positively associated with the reduction of depressive symptoms in adolescents. Insomnia partially mediated the effect of physical activity on depressive symptoms. In addition, resilience moderated the direct and indirect effects of physical activity (through insomnia) on depressive symptoms. Finally, the multigroup comparison indicated the moderating effect of parental absence on the moderated mediation model. CONCLUSIONS: Physical activity was associated with alleviating insomnia symptoms among adolescents, thus correlating with the improvement of their depressive symptoms. Resilience was associated with enhancing the beneficial effects of physical activity, further improving depressive symptoms among adolescents, especially those with both absent parents. It is evident that physical activity interventions should be further incorporated into public health programmes to foster the physical and mental health of left-behind adolescents in southwest China.

HOLI-1-to-3: Transient-Enhanced Holistic Image-to-3D Generation.

We introduce HOLI-1-to-3, a novel technique for holistic 3D shape recovery from a single-viewpoint input, by effectively combining line-of-sight (LOS) and non-line-of-sight (NLOS) imaging. We leverage advancements in ultrafast time-of-flight (ToF) sensors and learning-based 3D shape inference techniques, such as diffusion models. HOLI-1-to-3 employs a new neural plenoptic representation, which unifies radiance fields (for LOS RGB images) and transient fields (for NLOS transients). HOLI-1-to-3 is optimized through a two-stage pipeline involving diffusion priors and transients prior. Our technique allows for accurate and continuous reconstruction of both visible and invisible parts of objects from a single view. Comprehensive experiments on both simulated and real-world datasets demonstrate the effectiveness of HOLI-1-to-3 in resolving ambiguities in invisible parts of objects and significantly improving overall generation quality. The datasets used in our experiments will be made available to the research community to facilitate further achievements in holistic 3D shape recovery.

Enhanced Therapeutic Potential of Liposome-Coated Bushen Jianpi Recipe for Hepatocellular Carcinoma.

OBJECTIVE: Hepatocellular carcinoma (HCC) poses a major healthcare burden globally. Traditional Chinese medicine formula Bushen Jianpi (BSJP) recipe shows inhibitory effects on HCC but suffers from low bioavailability. This study aims to develop a BSJP-loaded liposome (BSJP@Lip) for targeted HCC treatment. METHODS: BSJP@Lip was prepared using a microfluidic device. Particle characterization included size, morphology, drug loading, encapsulation efficiency, and release kinetics analysis. In vitro cytotoxicity, cellular uptake, apoptosis, and protein expression were evaluated in hepG2, Smmc-7721, and hepa 1-6 hepatic cancer cell lines treated with BSJP@Lip. RESULTS: BSJP@Lip nanoparticles showed a uniform spherical shape with an average size of 50 nm and zeta potential at around -2.24 mV. They significantly inhibited cell viability and induced apoptosis in a dose-dependent manner compared with traditional decoction formulations. Enhanced cellular uptake of BSJP@Lip increased the expression of proinflammatory factors IL-18 and NLRP3. CONCLUSION: BSJP@Lip nanoparticles were found to be efficiently internalized by hepatic cancer cell lines, resulting in a dose-dependent inhibition of cell viability and induction of apoptosis. This effect was accompanied by the upregulation of IL-18 and NLRP3.

Saffron improves the efficacy of immunotherapy for colorectal cancer through the IL-17 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Saffron is one of the traditional medicinal herbs, which contains various active ingredients, such as safranal, crocin, saffron acid, etc. It has anti-inflammatory, antioxidant, and anti-cancer properties, and is widely used in clinical practice. The anti-cancer efficacy of saffron has been previously confirmed, but its anti-cancer mechanism in colorectal cancer remains unclear. OBJECTIVE: We investigated the effect of active compounds of saffron on the efficacy of immunotherapy for colorectal cancer. METHODS: TCMSP and liquid chromatography-mass spectrometry analysis (LC-MS), GeneCards, and DisGeNET databases were used to identify the active compounds of saffron, drug targets and the disease targets of colorectal cancer. They were then subjected to Gene Ontology Enrichment (GO) and Signalling Pathway Enrichment (KEGG) analyses. The core targets and corresponding compounds were selected for molecular docking. The effect of active components of saffron on the proliferation of CT26 and HCT116 cells was investigated using the cell counting kit-8 (CCK-8). In vitro experiments were conducted by subcutaneous injection of CT26 cells to establish a colon cancer model. Enzyme-linked immunosorbent assay (ELISA), western blotting (WB), real-time polymerase chain reaction (RT-PCR), immunohistochemistry (IHC), and flow cytometry (FCM) were employed to validate the effects of saffron on colorectal cancer immunotherapy. RESULTS: 1. LC-MS analysis revealed that the main active component of saffron extract was crocin. The active chemicals of saffron intersected with 170 colorectal cancer targets, with 17 predicting targets for saffron treatment. GO and KEGG enrichment analyses revealed that the active components of saffron can prevent colorectal cancer development by enhancing Th17 cell differentiation and the IL-17 signaling pathway. 2. In vitro studies revealed that saffron alcohol extract, crocin, and safranal can suppress the proliferation of CT26 and HCT116 cells. 3. In vivo studies showed that crocin and safranal can increase the body mass and decrease the tumor mass of loaded mice, decrease the serum level of IL-17, and lower the mRNA expression level of IL-17, IL-6, TNF-α, TGF-ß, and PD-L1 and IL-17, PD-L1 protein in tumors. This inhibitory effect was strengthened after combined immunotherapy. In addition, saffron modulated CD4+ and CD8+ T cells and the CD4+/CD8+T ratio in mouse spleens. CONCLUSION: The active components of saffron can reduce the expression of inflammatory factors and ameliorate the immunological microenvironment of tumors via the IL-17 signaling pathway, thereby improving the efficacy of immunotherapy for colorectal cancer. This study provides pharmacological support for the application of saffron in enhancing the efficacy of immunotherapy for colorectal cancer.

Oscillatory potential findings in patients with acute ischaemic central retinal vein occlusion.

AIMS: To explore the sensitive components of full-field electroretinography (ERG) as indicators of retina function at the onset of acute ischaemic central retinal vein occlusion (CRVO). METHODS: 11 patients (11 eyes) with ischaemic CRVO and 32 patients (32 eyes) with non-ischaemic CRVO who presented with first-episode unilateral CRVO within 1 month of symptom onset and with no previous intervention were examined by the International Society for Clinical Electrophysiology of Vision standard ERG. RESULTS: A significant amplitude decline and peak time delay in light-adapted (LA) 3 ERG and LA 30 Hz flicker ERG (p<0.05 for all) was found in the ischaemic CRVO eyes, compared with the non-ischaemic CRVO eyes. The b/a amplitude ratio of dark-adapted (DA) 3 ERG, DA 10 ERG and LA 3 ERG was significantly different between the ischaemic and non-ischaemic groups (p<0.05 for all). Regarding oscillatory potentials (OPs), the amplitudes of OP1, OP2 and OP3 as well as the sum of DA 3 OP1-4 amplitudes (∑OPs) showed significant changes (p<0.01 for all) between two groups. No peak time delay of OPs was found between the ischaemic and non-ischaemic CRVO eyes. CONCLUSION: The amplitude of DA 0.01 ERG, components of LA 3 ERG and LA 30 Hz flicker ERG, and the b/a amplitude ratio could be among the most sensitive indicators in patients with acute ischaemic CRVO. The amplitudes of OP1, OP2, OP3 and ∑OPs in the CRVO eyes were reduced to 40% of the control values, showing that this quantitative method is reliable for detecting ischaemic retinal diseases, even in early stage.

Chimeric peptide-engineered immunostimulant for endoplasmic reticulum targeted photodynamic immunotherapy against metastatic tumor.

The combination of therapy-induced immunogenic cell death (ICD) and immune checkpoint blockade can provide a mutually reinforced strategy to reverse the poor immunogenicity and immune escape behavior of tumors. In this work, a chimeric peptide-engineered immunostimulant (ER-PPB) is fabricated for endoplasmic reticulum (ER)-targeted photodynamic immunotherapy against metastatic tumors. Among which, the amphiphilic chimeric peptide (ER-PP) is composed of ER-targeting peptide FFKDEL, hydrophilic PEG8 linker and photosensitizer protoporphyrin IX (PpIX), which could be assembled with a PD-1/PD-L1 blocker (BMS-1) to prepare ER-PPB. After passively targeting at tumor tissues, ER-PPB will selectively accumulate in the ER. Next, the localized PDT of ER-PPB will produce a lot of ROS to destroy the primary tumor cells, while increasing the ER stress to initiate a robust ICD cascade. Moreover, the concomitant delivery of BMS-1 can impede the immune escape of tumor cells through PD-1/PD-L1 blockade, thus synergistically activating the immune system to combat metastatic tumors. In vitro and in vivo results demonstrate the robust immune activation and metastatic tumor inhibition characteristics of ER-PPB, which may offer a promising strategy for spatiotemporally controlled metastatic tumor therapy.

Iron Chelator Deferiprone Restores Iron Homeostasis and Inhibits Retinal Neovascularization in Experimental Neovascular Age-Related Macular Degeneration.

Purpose: Retinal neovascularization is a significant feature of advanced age-related macular degeneration (AMD) and a major cause of blindness in patients with AMD. However, the underlying mechanism of this pathological neovascularization remains unknown. Iron metabolism has been implicated in various biological processes. This study was conducted to investigate the effects of iron metabolism on retinal neovascularization in neovascular AMD (nAMD). Methods: C57BL/6J and very low-density lipoprotein receptor (VLDLR) knockout (Vldlr-/-) mice, a murine model of nAMD, were used in this study. Bulk-RNA sequencing was used to identify differentially expressed genes. Western blot analysis was performed to test the expression of proteins. Iron chelator deferiprone (DFP) was administrated to the mice by oral gavage. Fundus fluorescein angiography was used to evaluate retinal vascular leakage. Immunofluorescence staining was used to detect macrophages and iron-related proteins. Results: RNA sequencing (RNA-seq) results showed altered transferrin expression in the retina and RPE of Vldlr-/- mice. Disrupted iron homeostasis was observed in the retina and RPE of Vldlr-/- mice. DFP mitigated iron overload and significantly reduced retinal neovascularization and vascular leakage. In addition, DFP suppressed the inflammation in Vldlr-/- retinas. The reduced signals of macrophages were observed at sites of neovascularization in the retina and RPE of Vldlr-/- mice after DFP treatment. Further, the IL-6/JAK2/STAT3 signaling pathway was activated in the retina and RPE of Vldlr-/- mice and reversed by DFP treatment. Conclusions: Disrupted iron metabolism may contribute to retinal neovascularization in nAMD. Restoring iron homeostasis by DFP could be a potential therapeutic approach for nAMD.

Preoperative bedside test indicators as predictors of difficult video laryngoscopy in obese patients: a prospective observational study.

Purpose: The aim of this study was to identify factors associated with difficult video laryngoscopy in obese patients. Methods: A total of 579 obese patients undergoing elective laparoscopic weight loss surgery were intubated with a single-lumen endotracheal tube using a video laryngoscopy under general anesthesia, and the patients were divided into two groups based on the Cormack-Lehane classification (difficult video laryngoscopy defined as ≥ 3): the easy video laryngoscopy group and the difficult video laryngoscopy group. Record the general condition of the patient, bedside testing indicators related to the airway, Cormack-Lehane classification during intubation, and intubation failure rate. Results: The findings of this study show that the incidence of difficult video laryngoscopy in obese patients is 4.8%. Multivariate logistic regression analysis indicated that body mass index was significantly associated with difficult video laryngoscopy (OR = 1.082, 95% CI [1.033-1.132], P < 0.001). Conclusion: For Chinese obese patients without known difficult airways, the incidence of difficult video laryngoscopy is 4.8%. Body mass index is associated factors for the occurrence of difficult video laryngoscopy, with an increased risk observed as body mass index rise.

Alarming and calming: Dual functions of S100A9 on Mycoplasma gallisepticun infection in avian cells.

Mycoplasma gallisepticum (MG) is the primary causative agent of chronic respiratory disease (CRD) in chickens, characterized by respiratory inflammation. S100A9 plays a pivotal role in modulating the inflammatory response to microbial pathogens. Our prior investigation revealed a significant upregulation of S100A9 in the lungs of chickens following MG infection. This study delves into the immunomodulatory effects of S100A9 during MG infection, demonstrating a notable increase in S100A9 levels in the lungs, immune organs, alveolar epithelial type II cells (AECII), and macrophage HD11 cells of MG-infected chicks and embryos. In MG-infected AECII cells, S100A9 overexpression significantly enhanced MG proliferation and adhesion, suppressed AVBD1, NFκB, pro-inflammatory factors (IL1ß and TNFα), and chemokines, reduced apoptosis, and promoted cell proliferation, thereby facilitating MG infection. Conversely, inhibiting S100A9 produced opposing effects. In MG-infected HD11 cells, S100A9 impeded MG proliferation and adhesion, increased AVBD1, NFκB, pro-inflammatory factors, and chemokines, and induced cell apoptosis while inhibiting proliferation. Additional results demonstrated that S100A9 facilitates MG infection by modulating the TLR7/NFκB/JAK/STAT pathway in AECII/HD11 cells. In summary, S100A9 exhibits a dual role in activating/inhibiting the natural immune response through TLR7/NFκB/JAK/STAT pathway regulation. This dual role promotes MG infection in AECII cells while enabling MG to evade immune surveillance by HD11 cells, ultimately enhancing the overall infection process. These findings advance our understanding of host-pathogen interactions during MG infection and underscore S100A9's potential as a therapeutic target for CRD in chickens.

Unpaired fundus image enhancement based on constrained generative adversarial networks.

Fundus photography (FP) is a crucial technique for diagnosing the progression of ocular and systemic diseases in clinical studies, with wide applications in early clinical screening and diagnosis. However, due to the nonuniform illumination and imbalanced intensity caused by various reasons, the quality of fundus images is often severely weakened, brings challenges for automated screening, analysis, and diagnosis of diseases. To resolve this problem, we developed strongly constrained generative adversarial networks (SCGAN). The results demonstrate that the quality of various datasets were more significantly enhanced based on SCGAN, simultaneously more effectively retaining tissue and vascular information under various experimental conditions. Furthermore, the clinical effectiveness and robustness of this model were validated by showing its improved ability in vascular segmentation as well as disease diagnosis. Our study provides a new comprehensive approach for FP and also possesses the potential capacity to advance artificial intelligence-assisted ophthalmic examination.

Study on the therapeutic effect of sintilimab combined with modified DCF regimen on advanced gastric cancer and its impact on Th1/Th2 immune balance.

The aim of this study was to observe the therapeutic effect of sintilimab combined with a modified docetaxel + cisplatin + fluorouracil (DCF) regimen on advanced gastric cancer and its effect on Th1/Th2 immune balance. Ninety-eight cases of advanced gastric cancer patients who visited our hospital from April 2020 to May 2022 were selected and divided into 48 cases each in the conventional group and the research group by random number table method; the DCF regimen was adopted in the conventional group, and sintilimab combined with modified DCF regimen was adopted in the research group, and the therapeutic effects of the patients in the two groups and the changes of Th1/Th2 immune indexes were compared. CEA, CA199, CA242, CD168 AQ3, and IL-4 in the study group were lower than those in the conventional group at the end of three cycles of treatment, and the difference was statistically significant ( P  < 0.001). The levels of IFN-γ and IL-4 in the study group at the end of three cycles of treatment were higher than those in the conventional group ( P  < 0.001). The incidence of adverse reactions during treatment in the study group was lower than that in the conventional group ( P  < 0.001), and the grading of adverse reactions in the study group was milder than that in the conventional group. Sintilimab combined with a modified DCF regimen in the treatment of advanced gastric cancer not only improves the therapeutic effect but also positively affects the Th1/Th2 immune balance, which provides better immune regulation for patients with advanced gastric cancer.

Left Ventricular Papillary Muscle: Anatomy, Pathophysiology, and Multimodal Evaluation.

As an integral part of the mitral valve apparatus, the left ventricle papillary muscle (PM) controls mitral valve closure during systole and participates in the ejection process during left ventricular systole. Mitral regurgitation (MR) is the most immediate and predominant result when the PM is structurally or functionally abnormal. However, dysfunction of the PM is easily underestimated or overlooked in clinical interventions for MR-related diseases. Therefore, adequate recognition of PM dysfunction and PM-derived MR is critical. In this review, we systematically describe the normal anatomical variations in the PM and the pathophysiology of PM dysfunction-related diseases and summarize the commonly used parameters and the advantages and disadvantages of various noninvasive imaging modalities for the structural and functional assessment of the PM.

Adsorption Behavior of Co2+, Ni2+, Sr2+, Cs+, and I- by Corrosion Products α-FeOOH from Typical Metal Tanks.

Throughout the nuclear power production process, the disposal of radioactive waste has consistently raised concerns about environmental safety. When the metal tanks used for waste disposal are corroded, radionuclides seep into the groundwater environment and eventually into the biosphere, causing significant damage to the environment. Hence, investigating the adsorption behavior of radionuclides on the corrosion products of metal tanks used for waste disposal is an essential component of safety and evaluation protocols at disposal sites. In order to understand the adsorption behavior of important radionuclides 60Co, 59Ni, 90Sr, 135Cs and 129I on α-FeOOH, the influences of different pH values, contact time, temperature and ion concentration on the adsorption rate were studied. The adsorption mechanism was also discussed. It was revealed that the adsorption of key nuclides onto α-FeOOH is significantly influenced by both pH and temperature. This change in surface charge corresponds to alterations in the morphology of nuclide ions within the system, subsequently impacting the adsorption efficiency. Sodium ions (Na+) and chlorate ions (ClO3-) compete for coordination with nuclide ions, thereby exerting an additional influence on the adsorption process. The XPS analysis results demonstrate the formation of an internal coordination bond (Ni-O bond) between Ni2+ and iron oxide, which is adsorbed onto α-FeOOH.

Sensitize Tumor Immunotherapy: Immunogenic Cell Death Inducing Nanosystems.

Low immunogenicity of tumors poses a challenge in the development of effective tumor immunotherapy. However, emerging evidence suggests that certain therapeutic approaches, such as chemotherapy, radiotherapy, and phototherapy, can induce varying degrees of immunogenic cell death (ICD). This ICD phenomenon leads to the release of tumor antigens and the maturation of dendritic cells (DCs), thereby enhancing tumor immunogenicity and promoting immune responses. However, the use of a single conventional ICD inducer often fails to achieve in situ tumor ablation and establish long-term anti-tumor immune responses. Furthermore, the induction of ICD induction varies among different approaches, and the distribution of the therapeutic agent within the body influences the level of ICD and the occurrence of toxic side effects. To address these challenges and further boost tumor immunity, researchers have explored nanosystems as inducers of ICD in combination with tumor immunotherapy. This review examines the mechanisms of ICD and different induction methods, with a specific focus on the relationship between ICD and tumor immunity. The aim is to explore the research advancements utilizing various nanomaterials to enhance the body's anti-tumor effects by inducing ICD. This paper aims to contribute to the development and clinical application of nanomaterial-based ICD inducers in the field of cancer immunotherapy by providing important theoretical guidance and practical references.

Self-Assembled PD-L1 Downregulator to Boost Photodynamic Activated Tumor Immunotherapy Through CDK5 Inhibition.

The immunosuppressive characteristics and acquired immune resistance can restrain the therapy-initiated anti-tumor immunity. In this work, an antibody free programmed death receptor ligand 1 (PD-L1) downregulator (designated as CeSe) is fabricated to boost photodynamic activated immunotherapy through cyclin-dependent kinase 5 (CDK5) inhibition. Among which, FDA approved photosensitizer of chlorin e6 (Ce6) and preclinical available CDK5 inhibitor of seliciclib (Se) are utilized to prepare the nanomedicine of CeSe through self-assembly technique without drug excipient. Nanoscale CeSe exhibits an increased stability and drug delivery efficiency, contributing to intracellular production of reactive oxygen species (ROS) for robust photodynamic therapy (PDT). The PDT of CeSe can not only suppress the primary tumor growth, but also induce the immunogenic cell death (ICD) to release tumor associated antigens. More importantly, the CDK5 inhibition by CeSe can downregulate PD-L1 to re-activate the systemic anti-tumor immunity by decreasing the tumor immune escape and therapy-induced acquired immune resistance. This work provides an antibody free strategy to activate systemic immune response for metastatic tumor treatment, which may accelerate the development of translational nanomedicine with sophisticated mechanism.

Chlorin e6 and BLZ945 Based Self-Assembly for Photodynamic Immunotherapy Through Immunogenic Tumor Induction and Tumor-Associated Macrophage Depletion.

Immunotherapeutic effect is restricted by the nonimmunogenic tumor phenotype and immunosuppression behaviors of tumor-associated macrophages (TAMs). In this work, a drug self-assembly (designated as CeBLZ) is fabricated based on chlorin e6 (Ce6) and BLZ945 to activate photodynamic immunotherapy through tumor immunogenic induction and tumor-associated macrophage depletion. It is found that Ce6 tends to assemble with BLZ945 without any drug excipients, which can enhance the cellular uptake, tumor penetration, and blood circulation behaviors. The robust photodynamic therapy effect of CeBLZ efficiently suppresses the primary tumor growth and also triggers immunogenic cell death to reverse the nonimmunogenic tumor phenotype. Moreover, CeBLZ can deplete TAMs in tumor tissues to reverse the immunosuppression microenvironment, activating abscopal effect for distant tumor inhibition. In vitro and in vivo results confirm the superior antitumor effect of CeBLZ with negligible side effect, which might promote the development of sophisticated drug combinations for systematic tumor management.

Overexpression of TRIM44 mediates the NF-κB pathway to promote the progression of ovarian cancer.

BACKGROUND: Ovarian cancer (OC) is the second most commonly seen cancer in the US, and patients with OC are commonly diagnosed in the advanced stage. Research into the molecular mechanisms and potential therapeutic targets of OC is becoming increasingly urgent. In our study, we worked to discover the role of TRIM44 in OC development. OBJECTIVE: This study explored whether the overexpression of TRIM44 mediates the NF-kB pathway to promote the progression of OC. METHODS: A TRIM44 overexpression model was constructed in SKOV3 cells, and the proliferation ability of the cells was detected using the CCK-8 assay. The migration healing ability of cells was detected using cell scratch assay. Cell migration and invasion were detected using Transwell nesting. TUNEL was applied to detect apoptosis, and ELISA and western blot were used to detect the expression of NF-κB signaling pathway proteins. The pathological changes of the tumor tissues were observed using HE staining in a mouse ovarian cancer xenograft model. Immunofluorescence double staining, RT-PCR, and western blot were used to determine the expression of relevant factors in tumour tissues. RESULTS: TRIM44 overexpression promoted the proliferation, migration, and invasion of SKOV3 cells in vitro and inhibited apoptosis while enhancing the growth of tumours in vivo. TRIM44 regulated the NF-κB signaling pathway. CONCLUSIONS: TRIM44 overexpression can regulate the NF-κB signaling pathway to promote the progression of OC, and TRIM44 may be a potential therapeutic target for OC.