Galloyl-boosted gold nanorods: Unleashing personalized cancer immunotherapy potential.

Cancer immunotherapy has emerged as a potent treatment strategy by harnessing the host immune system to target cancer cells. However, challenges including low tumor vaccine immunogenicity and tumor heterogeneity hinder its clinical efficacy. To address these issues, we propose a novel nanoplatform integrating photothermal material gold nanorods (GNRs) with polyphenols for enhanced immunotherapy efficacy via photothermal therapy. Polyphenols, natural compounds with phenolic hydroxyl groups, are known for their ability to bind tightly to various molecules, making them ideal for antigen capture. We synthesized GNRs modified with polyphenols (GNR-PA and GNR-GA) and demonstrated their ability to induce immunogenic cell death upon laser irradiation, releasing tumor-associated antigens (TAAs). The surface polyphenols on GNRs effectively captured released TAAs to shield them from clearance. In vivo studies confirmed increased accumulation of GNR-GA in lymph nodes and enhanced dendritic cell maturation, leading to promoted effector T cell infiltration into tumors. Furthermore, treatment combined with PD-1/PD-L1 pathway blockade demonstrated potent tumor regression and systemic immunotherapy efficacy. Our findings highlight the potential of this photothermal nanoplatform as a promising strategy to overcome the limitations of current cancer immunotherapy approaches and improve therapeutic outcomes.

Macrophage migration inhibitory factor facilitates replication of Senecavirus A by enhancing the glycolysis via hypoxia inducible factor 1 alpha.

Senecavirus A (SVA) induced porcine idiopathic vesicular disease (PIVD) has been spread worldwide due to persistent infection, causing economic losses in swine industry. Host factors play an important role in replication of SVA, while, the interaction of migration inhibitory factor (MIF) and the virus has not been verified. Here, MIF facilitates the replication of SVA by enhancing the glycolysis via hypoxia-inducible factor alpha (HIF-1α) was reported. SVA infection up-regulates the expression of MIF in 3D4/21 cells, and infection experiment of cells with overexpression and interference expression of MIF showed that MIF facilitates the replication of SVA. MIF promoted the glycolysis in SVA infection to facilitate its replication by enhancing the accumulation of lactate and decreasing the production of adenosine triphosphate (ATP) and inhibiting the expression of retinoic acid-inducible gene I (RIG-I), mitochondrial antiviral-signaling protein (MAVS), interferon regulatory factor 3 (IRF3), interferon-beta (IFN-ß), IFN-α, interferon-stimulating gene 15 (ISG15), and ISG56. Meanwhile, specific inhibitor verified MIF facilitates the replication of SVA by enhancing glycolysis. Further results showed MIF induces the increased expression of HIF-1α, which enhances MIF-induced glycolysis. These results provide new data on host factors in replication of SVA, as well as better understanding the role of MIF in virus infection.

Prostate cancer cell-derived exosomes ZNF667-AS1 reduces TGFBR1 mRNA stability to inhibit Treg expansion and DTX resistance by binding to U2AF1.

BACKGROUND: Docetaxel (DTX) resistance attenuates anti-tumor effects of DTX on prostate cancer (mCRPC) and drug resistance was related to Treg expansion in tumors. ZNF667-AS1 played a suppressing role in various tumors and tumor-derived exosomes carry lncRNAs to participate in tumor progression. Here, the effects of ZNF667-AS1 on malignant characteristics and DTX resistance in PC and the effect and its underlying molecular mechanism of tumor-derived exosomes carrying ZNF667-AS1 on Treg expansion were investigated. METHODS: The identification of exosomes were determined using TEM, NTA and western blot. The abundance of genes and proteins were evaluated using IHC, RT-qPCR, western blot and FISH. Malignant phenotypes of PC cells were evaluated by means of Edu, scratch test, transwell, CCK-8 and flow cytometry. The percentage of CD4+CD25+Foxp3+ Tregs was detected using flow cytometry. The location of ZNF667-AS1 was detected using nuclear-cytoplasmic fractionation. The co-location of ZNF667-AS1 and U2AF1 protein was detected using IF-FISH assay. The interactions among ZNF667-AS1, TGFBR1 and U2AF1 were verified using RNA pull-down, RIP and dual luciferase activity. RESULTS: ZNF667-AS1 expression in PC samples was lowered, which was negatively relative to poor prognosis and DTX resistance. ZNF667-AS1 overexpression inhibited malignant phenotypes of PC cells, tumor growth and DTX resistance. Besides, DTX resistant cell-derived exosomes expressed lower ZNF667-AS1 expression. Exosomes carrying exogenously high ZNF667-AS1 expression derived PC cells or serum of mice suppressed Treg expansion. On the mechanism, ZNF667-AS1 interacted with U2AF1 to destabilize TGFBR1 mRNA and reduce TGFBR1 expression in CD4+T cells. CONCLUSION: ZNF667-AS1 suppressed cell growth of PC cells, tumor growth of mice and DTX resistance to PC cells and exogenously high ZNF667-AS1 expression in tumor-derived exosomes destabilized TGFBR1 mRNA and reduce TGFBR1 expression through interacting with U2AF1, thus resulting in attenuated Treg expansion, which was related to DTX resistance.

Machine Learning-Based Detection of Bladder Cancer by Urine cfDNA Fragmentation Hotspots that Capture Cancer-Associated Molecular Features.

BACKGROUND: cfDNA fragmentomics-based liquid biopsy is a potential option for noninvasive bladder cancer (BLCA) detection that remains an unmet clinical need. METHODS: We assessed the diagnostic performance of cfDNA hotspot-driven machine-learning models in a cohort of 55 BLCA patients, 51 subjects with benign conditions, and 11 healthy volunteers. We further performed functional bioinformatics analysis for biological understanding and interpretation of the tool's diagnostic capability. RESULTS: Urinary cfDNA hotspots-based machine-learning model enabled effective BLCA detection, achieving high performance (area under curve 0.96) and an 87% sensitivity at 100% specificity. It outperformed models using other cfDNA-derived features. In stage-stratified analysis, the sensitivity at 100% specificity of the urine hotspots-based model was 71% and 92% for early (low-grade Ta and T1) and advanced (high-grade T1 and muscle-invasive) disease, respectively. Biologically, cfDNA hotspots effectively retrieved regulatory elements and were correlated with the cell of origin. Urine cfDNA hotspots specifically captured BLCA-related molecular features, including key functional pathways, chromosome loci associated with BLCA risk as identified in genome-wide association studies, or presenting frequent somatic alterations in BLCA tumors, and the transcription factor regulatory landscape. CONCLUSIONS: Our findings support the applicability of urine cfDNA fragmentation hotspots for noninvasive BLCA diagnosis, as well as for future translational study regarding its molecular pathology and heterogeneity.

Supramolecular nanomedicine in the intelligent cancer therapy: recent advances and future.

In recent years, the incidence of cancer has been increasing year by year, and the burden of the disease and the economic burden caused by it has been worsening. Although chemotherapy, immunotherapy, targeted therapy and other therapeutic means continue to progress, they still inevitably have problems such as high toxicity and side effects, susceptibility to drug resistance, and high price. Photothermal therapy and photodynamic therapy have demonstrated considerable advantages in cancer imaging and treatment due to their minimally invasive and selective nature. However, their development has been constrained by challenges related to drug delivery. In recent times, drug delivery systems constructed based on supramolecular chemistry have been the subject of considerable interest, particularly in view of their compatibility with the high permeability and long retention effect of tumors. Furthermore, the advantage of dissociating the active ingredient under pH, light and other stimuli makes them unique in cancer therapy. This paper reviews the current status of supramolecular nanomedicines in cancer therapy, elucidating the challenges faced and providing a theoretical basis for the efficient and precise treatment of malignant tumors.

UM-Net: Rethinking ICGNet for polyp segmentation with uncertainty modeling.

Automatic segmentation of polyps from colonoscopy images plays a critical role in the early diagnosis and treatment of colorectal cancer. Nevertheless, some bottlenecks still exist. In our previous work, we mainly focused on polyps with intra-class inconsistency and low contrast, using ICGNet to solve them. Due to the different equipment, specific locations and properties of polyps, the color distribution of the collected images is inconsistent. ICGNet was designed primarily with reverse-contour guide information and local-global context information, ignoring this inconsistent color distribution, which leads to overfitting problems and makes it difficult to focus only on beneficial image content. In addition, a trustworthy segmentation model should not only produce high-precision results but also provide a measure of uncertainty to accompany its predictions so that physicians can make informed decisions. However, ICGNet only gives the segmentation result and lacks the uncertainty measure. To cope with these novel bottlenecks, we further extend the original ICGNet to a comprehensive and effective network (UM-Net) with two main contributions that have been proved by experiments to have substantial practical value. Firstly, we employ a color transfer operation to weaken the relationship between color and polyps, making the model more concerned with the shape of the polyps. Secondly, we provide the uncertainty to represent the reliability of the segmentation results and use variance to rectify uncertainty. Our improved method is evaluated on five polyp datasets, which shows competitive results compared to other advanced methods in both learning ability and generalization capability. The source code is available at https://github.com/dxqllp/UM-Net.

Spontaneous recanalization in acute large core ischemic stroke due to large vessel occlusion: a post-hoc analysis of the ANGEL-ASPECT trial.

BACKGROUND: Previous studies have indicated that a subset of patients with acute ischemic stroke (AIS) due to large vessel occlusion (LVO) experience spontaneous recanalization (SR), but the prognosis and factors associated with SR in these individuals are not well characterized. METHODS: We conducted a post hoc secondary analysis of the Study of Endovascular Therapy in Acute Anterior Circulation Large Vessel Occlusive Patients with a Large Infarct Core (ANGEL-ASPECT) trial. SR in the medical management group was defined as a modified arterial occlusive lesion (AOL) grade of 2 or 3 on computed tomography angiography (CTA) or magnetic resonance angiography (MRA) at 36 hours (±12 hours). RESULTS: SR was detected in 67 out of 184 patients (36.4%) in the medical management (MM) group. The median age of patients was 67 years (interquartile range (IQR) 58-72), and 48 (71.6%) were male. The adjusted odds ratio (aOR) for 90-day modified Rankin Scale (mRS) score shift toward better outcomes of the MM with SR group vs the MM without SR group was 1.83, with marginally significant difference (95% confidence interval (CI) 0.992 to 3.36; P=0.053). No significant difference was found between the MM with SR group and EVT recanalization group (aOR 1.45; 95% CI 0.86 to 2.43; P=0.16) with similar findings in the inverse probability treatment weighting analysis (OR 0.85; 95% CI 0.49 to 1.48; P=0.57). Multivariable regression analysis showed that hypertension, atherothrombotic stroke and higher clot burden score were factors associated with SR. CONCLUSIONS: SR in medically managed patients with acute large ischemic stroke caused by LVO was associated with good functional outcome. An improved understanding of SR patients may be helpful to develop therapeutic strategy in patients with large infarct due to LVO in anterior circulation. TRIAL REGISTRATION NUMBER: NCT04551664.

Charge-Reversal Nano-Drug Delivery Systems in the Tumor Microenvironment: Mechanisms, Challenges, and Therapeutic Applications.

The charge-reversal nano-drug delivery system (CRNDDS) is a promising system for delivering chemotherapy drugs and has gained widespread application in cancer treatment. In this review, we summarize the recent advancements in CRNDDSs in terms of cancer treatment. We also delve into the charge-reversal mechanism of the CRNDDSs, focusing on the acid-responsive, redox-responsive, and enzyme-responsive mechanisms. This study elucidates how these systems undergo charge transitions in response to specific microenvironmental stimuli commonly found in tumor tissues. Furthermore, this review explores the pivotal role of CRNDDSs in tumor diagnosis and treatment, and their potential limitations. By leveraging the unique physiological characteristics of tumors, such as the acidic pH, specific redox potential, and specific enzyme activity, these systems demonstrate enhanced accumulation and penetration at tumor sites, resulting in improved therapeutic efficacy and diagnostic accuracy. The implications of this review highlight the potential of charge-reversal drug delivery systems as a novel and targeted strategy for cancer therapy and diagnosis.

Discovery of an unconventional lamprey lymphocyte lineage highlights divergent features in vertebrate adaptive immune system evolution.

Lymphocyte receptors independently evolved in both jawed and jawless vertebrates with similar adaptive immune responses. However, the diversity of functional subtypes and molecular architecture in jawless vertebrate lymphocytes, comparable to jawed species, is not well defined. Here, we profile the gills, intestines, and blood of the lamprey, Lampetra morii, with single-cell RNA sequencing, using a full-length transcriptome as a reference. Our findings reveal higher tissue-specific heterogeneity among T-like cells in contrast to B-like cells. Notably, we identify a unique T-like cell subtype expressing a homolog of the nonlymphoid hematopoietic growth factor receptor, MPL-like (MPL-L). These MPL-L+ T-like cells exhibit features distinct from T cells of jawed vertebrates, particularly in their elevated expression of hematopoietic genes. We further discovered that MPL-L+ VLRA+ T-like cells are widely present in the typhlosole, gill, liver, kidney, and skin of lamprey and they proliferate in response to both a T cell mitogen and recombinant human thrombopoietin. These findings provide new insights into the adaptive immune response in jawless vertebrates, shedding new light on the evolution of adaptive immunity.

Tropomodulin1 exacerbates inflammatory response in macrophages by negatively regulating LPS-induced TLR4 endocytosis.

The excessive inflammation caused by the prolonged activation of Toll-like receptor 4 (TLR4) and its downstream signaling pathways leads to sepsis. CD14-mediated endocytosis of TLR4 is the key step to control the amount of TLR4 on cell membrane and the activity of downstream pathways. The actin cytoskeleton is necessary for receptor-mediated endocytosis, but its role in TLR4 endocytosis remains elusive. Here we show that Tropomodulin 1 (Tmod1), an actin capping protein, inhibited lipopolysaccharide (LPS)-induced TLR4 endocytosis and intracellular trafficking in macrophages. Thus it resulted in increased surface TLR4 and the upregulation of myeloid differentiation factor 88 (MyD88)-dependent pathway and the downregulation of TIR domain-containing adaptor-inducing interferon-ß (TRIF)-dependent pathway, leading to the enhanced secretion of inflammatory cytokines, such as TNF-α and IL-6, and the reduced secretion of cytokines, such as IFN-ß. Macrophages deficient with Tmod1 relieved the inflammatory response in LPS-induced acute lung injury mouse model. Mechanistically, Tmod1 negatively regulated LPS-induced TLR4 endocytosis and inflammatory response through modulating the activity of CD14/Syk/PLCγ2/IP3/Ca2+ signaling pathway, the reorganization of actin cytoskeleton, and the membrane tension. Therefore, Tmod1 is a key regulator of inflammatory response and immune functions in macrophages and may be a potential target for the treatment of excessive inflammation and sepsis.

Enhancement of Synergistic Photocatalytic Performance by Anchoring Cadmium Sulfide on Nanosphere Structured Coordination Polymers.

Precisely tuning how and where a reaction occurs in a one-step selective system is important but challenging owing to the similar electronic environments in multiple active sites. In this work, highly selective and effective reaction sites were obtained by generating copper coordination polymers (Cu-CP) of a range of sizes and morphologies, from bulk solid crystals (1) to uniform nanosphere structures (1a), by controlling the amount of surfactant hexadecyl trimethylammonium bromide (CTAB). The results indicated that the morphology and size of the uniform nanosphere structures were affected by the proportion of CTAB; uniform distribution of nanosphere structures was achieved with a premade building carrier when the content of CTAB was 0.005 mmol, generating a well-established platform. Photocatalytic cadmium sulfide (CdS) was then immobilized on the surface of the premade platform unit 1a through an in situ process to generate CdS@1a composites with well-dispersed catalytic CdS active sites. Furthermore, the well-defined CdS@1a composite platform was utilized as photocatalysts to explore the selective one-step depolymerization reaction under blue-light irradiation. Notably, the CdS0.149@1a composite, which featured a unique structure with evenly dispersed, closely spaced catalytic sites, exhibiting remarkable photoelectrochemical behaviors for selective one-step depolymerization of lignin model substances to aromatic monomer phenol and acetophenone framework products. This work demonstrates the use of an inherently morphological process to construct outstanding photocatalysts that could enable a wide range of photocatalytic reactions.

Transcriptional Regulation of De Novo Lipogenesis by SIX1 in Liver Cancer Cells.

De novo lipogenesis (DNL), a hallmark of cancer, facilitates tumor growth and metastasis. Therapeutic drugs targeting DNL are being developed. However, how DNL is directly regulated in cancer remains largely unknown. Here, transcription factor sine oculis homeobox 1 (SIX1) is shown to directly increase the expression of DNL-related genes, including ATP citrate lyase (ACLY), fatty acid synthase (FASN), and stearoyl-CoA desaturase 1 (SCD1), via histone acetyltransferases amplified in breast cancer 1 (AIB1) and lysine acetyltransferase 7 （HBO1/KAT7）, thus promoting lipogenesis. SIX1 expression is regulated by insulin/lncRNA DGUOK-AS1/microRNA-145-5p axis, which also modulates DNL-related gene expression as well as DNL. The DGUOK-AS1/microRNA-145-5p/SIX1 axis regulates liver cancer cell proliferation, invasion, and metastasis in vitro and in vivo. In patients with liver cancer, SIX1 expression is positively correlated with DGUOK-AS1 and SCD1 expression and is negatively correlated with microRNA-145-5p expression. DGUOK-AS1 is a good predictor of prognosis. Thus, the DGUOK-AS1/microRNA-145-5p/SIX1 axis strongly links DNL to tumor growth and metastasis and may become an avenue for liver cancer therapeutic intervention.

Radix Rehmanniae Praeparata extracts ameliorate hepatic ischemia-reperfusion injury by restoring lipid metabolism in hepatocytes.

ETHNOPHARMACOLOGICAL RELEVANCE: Hepatic ischemia/reperfusion injury (HIRI) is a common occurrence during or after liver surgery, representing a major cause for postoperative complications or increased morbidity and mortality in liver diseases. Rehmanniae Radix Praeparata (RRP) is a traditional Chinese medicine frequently used and has garnered extensive attention for its therapeutic potential treating cardiovascular and hepatic ailments. Recent studies have indicated the possibility of RRP in regulating lipid accumulation and apoptosis in hepatocytes. AIM OF THE STUDY: This study aimed to investigate the specific mechanisms by which RRP may impede the progression of HIRI through the regulation of lipid metabolism. MATERIALS AND METHODS: High-performance liquid chromatography (HPLC) was used to identify the major components of RRP water extract. C57BL/6J mice were orally given RRP at doses of 2.5 g/kg, 5 g/kg, and 10 g/kg for a duration of 7 days before undergoing HIRI surgery. Furthermore, we established a lipid-loaded in vitro model by exposing hepatocytes to oleic acid and palmitic acid (OAPA). The anti-HIRI effect of RRP was determined through transcriptomics and various molecular biology experiments. RESULTS: After identifying active ingredients in RRP, we observed that RRP exerted lipid-lowering and hepatoprotective effects on HIRI mice and OAPA-treated hepatocytes. RRP activated AMP-activated protein kinase (AMPK) and inhibited mammalian target of rapamycin (mTOR), which further on the one hand, inhibited the cleavage and activation of sterol regulatory element binding protein 2 (SREBP2) by limiting the movement of SREBPs cleavage-activating protein (SCAP)-SREBP2 complex with the help of endoplasmic reticulum lipid raft-associated protein 1 (ERLIN1) and insulin-induced gene 1 (INSIG1), and on the other hand, promoted liver X receptor α (LXRα) nuclear transportation and subsequent cholesterol efflux. Meanwhile, the anti-lipotoxic effect of RRP can be partly reversed by an LXRα inhibitor but largely blocked by the application of compound C, an AMPK inhibitor. CONCLUSION: Our study elucidated that RRP served as a potential AMPK activator to alleviate HIRI by blocking SREBP2 activation and cholesterol synthesis, while also activating LXRα to facilitate cholesterol efflux. These findings shed new light on the potential therapeutic use of RRP for improving HIRI.

Spinal Cord Astroblastoma With EWSR1-BEND2 Fusion in Female Patients : A Report of Four Cases From China and a Comprehensive Literature Review.

Astroblastoma is an extremely rare central nervous system tumor characterized by astroblastic pseudorosettes and vascular hyalinization. Despite these histologic hallmarks, its morphology can vary, occasionally resembling other central nervous system tumors such as ependymoma. A novel tumor entity, astroblastoma, meningioma 1 ( MN1 )-altered, has been identified, featuring MN1 gene rearrangements typically involving BEN-domain containing 2 ( BEND2 ) as a fusion partner. Most astroblastomas arise in the cerebral hemisphere. Here, we report 4 cases of spinal cord astroblastoma in female patients, all showing Ewing sarcoma RNA-binding protein 1 fusion with BEND2 , rather than MN1 . These tumors displayed growth patterns akin to traditional intracranial astroblastomas, with three cases demonstrating high-grade histology, including elevated mitotic activity and necrosis. Interestingly, some cases exhibited positive staining for pan-cytokeratin and hormone receptors. DNA methylation profiling clustered three of the four cases with the reference "AB_EWSR," whereas one case exhibited an independent methylation signature near the reference methylation group "AB_EWSR" and "pleomorphic xanthoastrocytoma." Together with the existing literature, we summarized a total of eleven cases, which predominantly affected children and young adults with female predilection. Eight of 10 patients experienced recurrence, underscoring the aggressive nature of this disease. We suggest recognizing a new molecular subgroup of spinal astroblastoma and recommend testing newly diagnosed infratentorial astroblastomas for Ewing sarcoma RNA-binding protein 1-BEND2 fusion.

Intestinal epithelial damage-derived mtDNA activates STING-IL12 axis in dendritic cells to promote colitis.

Rationale: The treatment of ulcerative colitis (UC) presents an ongoing clinical challenge. Emerging research has implicated that the cGAS-STING pathway promotes the progression of UC, but conflicting results have hindered the development of STING as a therapeutic target. In the current study, we aim to comprehensively elucidate the origins, downstream signaling and pathogenic roles of myeloid STING in colitis and colitis-associated carcinoma (CAC). Methods: Tmem173 fl/fl Lyz2-Cre ert2 mice were constructed for inducible myeloid-specific deletion of STING. RNA-sequencing, flow cytometry, and multiplex immunohistochemistry were employed to investigate immune responses in DSS-induced colitis or AOM/DSS-induced carcinogenesis. Colonic organoids, primary bone marrow derived macrophages and dendritic cells, and splenic T cells were used for in vitro studies. Results: We observed that myeloid STING knockout in adult mice inhibited macrophage maturation, reduced DC cell activation, and suppressed pro-inflammatory Th1 and Th17 cells, thereby protecting against both acute and chronic colitis and CAC. However, myeloid STING deletion in neonatal or tumor-present mice exhibited impaired immune tolerance and anti-tumor immunity. Furthermore, we found that TFAM-associated mtDNA released from damaged colonic organoids, rather than bacterial products, activates STING in dendritic cells in an extracellular vesicle-independent yet endocytosis-dependent manner. Both IRF3 and NF-κB are required for STING-mediated expression of IL-12 family cytokines, promoting Th1 and Th17 differentiation and contributing to excessive inflammation in colitis. Conclusions: Detection of the TFAM-mtDNA complex from damaged intestinal epithelium by myeloid STING exacerbates colitis through IL-12 cytokines, providing new evidence to support the development of STING as a therapeutic target for UC and CAC.

Synergistic antitumor activity of baicalein combined with almonertinib in almonertinib-resistant non-small cell lung cancer cells through the reactive oxygen species-mediated PI3K/Akt pathway.

Introduction: Almonertinib is an important third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) exhibiting high selectivity to EGFR-sensitizing and T790M-resistant mutations. Almonertinib resistance is a major obstacle in clinical use. Baicalein possesses antitumor properties, but its mechanism of antitumor action against almonertinib-resistant non-small cell lung cancer (NSCLC) remains unelucidated. Methods: CCK-8 assay was used to examine the survival rate of H1975/AR and HCC827/AR cells following treatment for 24 h with different concentrations of baicalein, almonertinib or their combination. The changes in colony formation ability, apoptosis, and intracellular reactive oxygen species (ROS) levels of the treated cells were analyzed using colony formation assay and flow cytometry. Western blotting was performed to detect the changes in protein expressions in the cells. The effects of pre-treatment with NAC on proliferation, apoptosis, and PI3K/Akt signaling pathway were observed in baicalein- and/or almonertinib-treated cells. A nude mouse model bearing subcutaneous HCC827/AR cell xenograft were treated with baicalein (20 mg/kg) or almonertinib (15 mg/kg), and the tumor volume and body mass changes was measured. Results: Both baicalein and almonertinib represses the viability of HCC827/AR and H1975/AR cells in a concentration-dependent manner. Compared with baicalein or almonertinib alone, the combined application of the two drugs dramatically attenuates cell proliferation; triggers apoptosis; causes cleavage of Caspase-3, PARP, and Caspase-9; downregulates the protein expressions of p-PI3K and p-Akt; and significantly inhibits tumor growth in nude mice. Furthermore, baicalein combined with almonertinib results in massive accumulation of reactive oxygen species (ROS) and preincubation with N-acetyl-L-cysteine (ROS remover) prevents proliferation as well as inhibits apoptosis induction, with partial recovery of the decline of p-PI3K and p-Akt. Discussion: The combination of baicalein and almonertinib can improve the antitumor activity in almonertinib-resistant NSCLC through the ROS-mediated PI3K/Akt pathway.

Evidence modeling for reliability learning and interpretable decision-making under multi-modality medical image segmentation.

Reliability learning and interpretable decision-making are crucial for multi-modality medical image segmentation. Although many works have attempted multi-modality medical image segmentation, they rarely explore how much reliability is provided by each modality for segmentation. Moreover, the existing approach of decision-making such as the softmax function lacks the interpretability for multi-modality fusion. In this study, we proposed a novel approach named contextual discounted evidential network (CDE-Net) for reliability learning and interpretable decision-making under multi-modality medical image segmentation. Specifically, the CDE-Net first models the semantic evidence by uncertainty measurement using the proposed evidential decision-making module. Then, it leverages the contextual discounted fusion layer to learn the reliability provided by each modality. Finally, a multi-level loss function is deployed for the optimization of evidence modeling and reliability learning. Moreover, this study elaborates on the framework interpretability by discussing the consistency between pixel attribution maps and the learned reliability coefficients. Extensive experiments are conducted on both multi-modality brain and liver datasets. The CDE-Net gains high performance with an average Dice score of 0.914 for brain tumor segmentation and 0.913 for liver tumor segmentation, which proves CDE-Net has great potential to facilitate the interpretation of artificial intelligence-based multi-modality medical image fusion.

Optic nerve decompression through pterional and supraorbital approaches in the treatment of severe traumatic optic neuropathy.

To investigate the effectiveness of optic nerve decompression (OND) in the treatment of severe traumatic optic neuropathy (TON) through pterional and supraorbital approaches, and to identify the prognostic factor for postoperative visual acuity (VA) following OND. Patients with severe TON treated with OND through either pterional or supraorbital approach in our institute from September 2019 to June 2022 were retrospectively reviewed in this study. Demographic information, trauma factors, the interval between trauma and complete blindness, the interval between trauma and surgery, and the associated craniofacial traumas were recorded. Hospitalization days and the postoperative VA of patients in two groups were compared. There were 54 severe TON patients with NLP included in this study; 21 patients underwent OND through the pterional approach, and the other 33 underwent the supraorbital approach. Respectively, in groups of pterional and supraorbital approaches, the average hospitalization days were 9.8 ± 3.2 and 10.7 ± 2.9 days (p = 0.58), the mean durations of follow-up were 18.9 ± 4.3 and 20.8 ± 3.7 months (p = 0.09), and the average circumference of OND were 53.14 ± 15.89 ◦ (range 220 ◦ -278◦) and 181.70 ± 6.56◦ (range 173 ◦ -193◦) (p<0.001). The overall improvement rates of pterional and supraorbital approaches are 57.1% and 45.5% (p = 0.40), respectively. Optic canal fracture (OCF) was revealed to be significantly associated with postoperative VA in the supraorbital approach (Binary: p = 0.014, CI: 1.573-57.087; Ordinal: p = 0.003, CI: 1.517-5.503), but not in the pterional approach. In the group of supraorbital approach, patients with OFC had a higher rate of a better outcome (78.6%) than those without (21.4%). Patients with severe traumatic TON may benefit from OND through either the pterional or supraorbital approach. OCF is a potential prognostic factor for postoperative VA following OND through the supraorbital approach.

Metabolomics combined with network pharmacology reveals the potential development value of Campanumoea javanica Bl. and its metabolite differences with Codonopsis Radix.

Campanumoea javanica Bl. (CJ) traditionally used in Southwestern China, is now widely consumed as a health food across the nation. Due to its similar efficacy to Codonopsis Radix (CR) and their shared botanical family, CJ is often used as a substitute for CR. According to the Chinese Pharmacopoeia, Codonopsis pilosula var. modesta (Nannf.) L.T. Shen (CPM), Codonopsis pilosula (Franch.) Nannf. (CP), and Codonopsis tangshen Oliv. (CT) are the primary sources of CR. However, details on the differences in composition, effectiveness, and compositional between CJ and CR are still limited. Besides, there is little evidence to support the application of CJ as a drug. In this study, we employed widely targeted metabolomics, network pharmacology analysis, and molecular docking to explore the disparities in metabolite profiles between CJ and CR and to predict the pharmacological mechanisms of the dominant differential metabolites of CJ and their potential medicinal applications. The widely targeted metabolomics results indicated that 1,076, 1,102, 1,102, and 1,093 compounds, most phenolic acids, lipids, amino acids, and flavonoids, were characterized in CJ, CPM, CP, and CT, respectively. There were an average of 1061 shared compounds in CJ and CRs, with 95.07% similarity in metabolic profiles. Most of the metabolites in CJ were previously unreported. Twelve of the seventeen dominant metabolites found in CJ were directly associated with treating cancer and lactation, similar to the traditional medicinal efficacy. The molecular docking results showed that the dominant metabolites of CJ had good docking activity with the core targets PIK3R1, PIK3CA, ESR1, HSP90AA1, EGFR, and AKT1. This study provides a scientific basis for understanding the similarities and differences between CJ and CR at the metabolome level, offering a theoretical foundation for developing innovative medications from CJ. Additionally, it significantly enhances the metabolite databases for both CJ and CR.

SiO 2 Induces Iron Overload and Ferroptosis in Cardiomyocytes in a Silicosis Mouse Model.

Objective: The aim of this study was to explore the role and mechanism of ferroptosis in SiO 2-induced cardiac injury using a mouse model. Methods: Male C57BL/6 mice were intratracheally instilled with SiO 2 to create a silicosis model. Ferrostatin-1 (Fer-1) and deferoxamine (DFO) were used to suppress ferroptosis. Serum biomarkers, oxidative stress markers, histopathology, iron content, and the expression of ferroptosis-related proteins were assessed. Results: SiO 2 altered serum cardiac injury biomarkers, oxidative stress, iron accumulation, and ferroptosis markers in myocardial tissue. Fer-1 and DFO reduced lipid peroxidation and iron overload, and alleviated SiO 2-induced mitochondrial damage and myocardial injury. SiO 2 inhibited Nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream antioxidant genes, while Fer-1 more potently reactivated Nrf2 compared to DFO. Conclusion: Iron overload-induced ferroptosis contributes to SiO 2-induced cardiac injury. Targeting ferroptosis by reducing iron accumulation or inhibiting lipid peroxidation protects against SiO 2 cardiotoxicity, potentially via modulation of the Nrf2 pathway.