Retinoic acid receptor-related orphan receptor alpha and synthetic RORα agonist against invasion and metastasis in tongue squamous cell carcinoma.

Retinoic acid receptor-related orphan receptor alpha (RORα), an essential tumor suppressor in a range of human malignancies, is classified as a member of the orphan nuclear receptor family. The most prevalent form of oral cancer, tongue squamous cell carcinoma (TSCC) is characterized by its severe malignancy and unfavorable prognosis. However, the extent to which its tumorigenesis mechanisms are associated with RORα expression levels is still not fully understood. The objective of this study was to examine the molecular mechanisms by which RORα is involved in TSCC. Through the use of immunohistochemistry (IHC), it was discovered that the expression level of RORα was significantly downregulated in TSCC tissues when compared to adjacent normal tissues in this study. To further investigate the role of RORα in TSCC, we activated the expression of RORα in human TSCC cell line (SCC9 cells) by transfecting RORα cDNA and using the selective RORα agonist SR1078. The results show that RORα can significantly inhibit the invasion, migration, proliferation, and adhesion of TSCC cells and induce cell apoptosis. In addition, xenograft models confirmed the conclusion that stable activation or treatment with SR1078 to increase RORα content significantly inhibited tumor growth and development. Taken together, this study provides solid evidence for the inhibitory role of RORα in the progression of TSCC. In addition, the preliminary application results of SR1078 in TSCC show that SR1078 is expected to be a potential therapeutic medication for TSCC. These findings provide innovative perspectives on the development of potential biomarkers and agents for TSCC therapy. The objective is to introduce novel strategy and alternatives for the prevention and treatment of TSCC.

MRI-derived brain iron, grey matter volume, and risk of dementia and Parkinson's disease: Observational and genetic analysis in the UK Biobank cohort.

BACKGROUND: Iron overload is observed in neurodegenerative diseases, especially Alzheimer's disease (AD) and Parkinson's disease (PD). Homozygotes for the iron-overload (haemochromatosis) causing HFE p.C282Y variant have increased risk of dementia and PD. Whether brain iron deposition is causal or secondary to the neurodegenerative processes in the general population is unclear. METHODS: We analysed 39,533 UK Biobank participants of European genetic ancestry with brain MRI data. We studied brain iron estimated by R2* and quantitative susceptibility mapping (QSM) in 8 subcortical regions: accumbens, amygdala, caudate, hippocampus, pallidum, putamen, substantia nigra, and thalamus. We performed genome-wide associations studies (GWAS) and used Mendelian Randomization (MR) methods to estimate the causal effect of brain iron on grey matter volume, and risk of AD, non-AD and PD. We also used MR to test whether genetic liability to AD or PD causally increased brain iron (R2* and QSM). FINDINGS: In GWAS of R2* and QSM we replicated 83% of previously reported genetic loci and identified 174 further loci across all eight brain regions. Higher genetically predicted brain iron, using both R2* and QSM, was associated with lower grey matter volumes in the caudate, putamen and thalamus (e.g., Beta-putamenQSM: -0.37, p = 2*10-46). Higher genetically predicted thalamus R2* was associated with increased risk of non-AD dementia (OR 1.36(1.16;1.60), p = 2*10-4) but not AD (p > 0.05). In males, genetically predicted putamen R2* increased non-AD dementia risk, but not in females. Higher genetically predicted iron in the caudate, putamen, and substantia nigra was associated with an increased risk of PD (Odds Ratio QSM âˆ¼ substantia-nigra 1.21(1.07;1.37), p = 0.003). Genetic liability to AD or PD was not associated with R2* or QSM in the dementia or PD-associated regions. INTERPRETATION: Our genetic analysis supports a causal effect of higher iron deposition in specific subcortical brain regions for Parkinson's disease, grey matter volume, and non-Alzheimer's dementia.

An antagonist-based two-photon fluorogenic probe for imaging metabotropic glutamate receptor 5 in neuronal cells.

The expression of metabotropic glutamate receptor 5 (mGluR5) is subject to developmental regulation and undergoes significant changes in neuropsychiatric disorders and diseases. Visualizing mGluR5 by fluorescence imaging is a highly desired innovative technology for biomedical applications. Nevertheless, there are substantial problems with the chemical probes that are presently accessible. In this study, we have successfully developed a two-photon fluorogenic probe, mGlu-5-TP, based on the structure of mGluR5 antagonist 6-methyl-2-(phenylethynyl)pyridine (MPEP). Due to this antagonist-based probe selectively recognizes mGluR5, high expression of mGluR5 on living SH-SY5Y human neuroblastoma cells has been detected during intracellular inflammation triggered by lipopolysaccharides (LPS). Of particular significance, the probe can be employed along with two-photon fluorescence microscopy to enable real-time visualization of the mGluR5 in Aß fiber-treated neuronal cells, thereby establishing a connection to the progression of Alzheimer's disease (AD). These results revealed that the probe can be a valuable imaging tool for studying mGluR5-related diseases in the nervous system.

Multi-omics reveals the molecular mechanism of the combined toxic effects of PFOA and 4-HBP exposure in MCF-7 cells and the key player: mTORC1.

With the discovery of evidence that many endocrine-disrupting chemicals (EDCs) in the environment influence human health, their toxic effects and mechanisms have become a hot topic of research. However, investigations into their endocrine-disrupting toxicity under combined binary exposure, especially the molecular mechanism of combined effects, have rarely been documented. In this study, two typical EDCs, perfluorooctanoic acid (PFOA) and 4-hydroxybenzophenone (4-HBP), were selected to examine their combined effects and molecular mechanism on MCF-7 cell proliferation at environmentally relevant exposure concentrations. We have successfully established a model to evaluate the binary combined toxic effects of endocrine disruptors, presenting combined effects in a simple and direct way. Results indicated that the combined effect changed from additive to synergistic from 1.25 × 10-8 M to 4 × 10-7 M. Metabolomics analyses suggested that exposure to PFOA and 4-HBP caused significant alterations in purine metabolism, arginine, and proline metabolism and had superimposed influences on metabolism. Enhanced combined effects were observed in glycine, serine, and threonine metabolic pathways compared to exposure to PFOS and 4-HBP alone. Additionally, the differentially expressed genes (DEGs) are primarily involved in Biological Processes, especially protein targeting the endoplasmic reticulum, and significantly impact the oxidative phosphorylation and thermogenesis-related KEGG pathway. By integrating metabolome and transcriptome analyses, PFOA and 4-HBP regulate purine metabolism, the TCA cycle, and endoplasmic reticulum protein synthesis in MCF-7 cells via mTORC1, which provides genetic material, protein, and energy for cell proliferation. Furthermore, molecular docking confirmed the ability of PFOA and 4-HBP to stably bind the estrogen receptor, indicating that they have different binding pockets. Collectively, these findings will offer new insights into understanding the mechanisms by which EDCs produce combined toxicity.

Exposure to emissions generated by 3-dimensional printing with polycarbonate: effects on peripheral vascular function, cardiac vascular morphology and expression of markers of oxidative stress in male rat cardiac tissue.

Three-dimensional (3D) printing with polycarbonate (PC) plastic occurs in manufacturing settings, homes, and schools. Emissions generated during printing with PC stock and bisphenol-A (BPA), an endocrine disrupter in PC, may induce adverse health effects. Inhalation of 3D printer emissions, and changes in endocrine function may lead to cardiovascular dysfunction. The goal of this study was to determine whether there were any changes in markers of peripheral or cardiovascular dysfunction in animals exposed to PC-emissions. Male Sprague Dawley rats were exposed to PC-emissions generated by 3D printing for 1, 4, 8, 15 or 30 d. Exposure induced a reduction in the expression of the antioxidant catalase (Cat) and endothelial nitric oxide synthase (eNos). Endothelin and hypoxia-induced factor 1α transcripts increased after 30 d. Alterations in transcription were associated with elevations in immunostaining for estrogen and androgen receptors, nitrotyrosine, and vascular endothelial growth factor in cardiac arteries of PC-emission exposed animals. There was also a reduction eNOS immunostaining in cardiac arteries from rats exposed to PC-emissions. Histological analyses of heart sections revealed that exposure to PC-emissions resulted in vasoconstriction of cardiac arteries and thickening of the vascular smooth muscle wall, suggesting there was a prolonged vasoconstriction. These findings are consistent with studies showing that inhalation 3D-printer emissions affect cardiovascular function. Although BPA levels in animals were relatively low, exposure-induced changes in immunostaining for estrogen and androgen receptors in cardiac arteries suggest that changes in the action of steroid hormones may have contributed to the alterations in morphology and markers of cardiac function.

Cascading Detection of Hydrogen Sulfide and N-Acetyltransferase 2 in Hepatocellular Carcinoma Cells Using a Two-Photon Fluorescent Probe.

Hydrogen sulfide (H2S), a critical gas signaling molecule, and N-acetyltransferase 2 (NAT2), a key enzyme in drug metabolism, are both known active biomarkers for liver function. However, the interactions and effects of H2S and NAT2 in living cells or lesion sites remain unknown due to the lack of imaging tools to achieve simultaneous detection of these two substances, making it challenging to implement real-time imaging and precise tracking. Herein, we report an activity-based two-photon fluorescent probe, TPSP-1, for the cascade detection of H2S and NAT2 in living liver cells. Continuous conversion from TPSP-1 to TPSP-3 was achieved in liver cells and tissues. Significantly, leveraging the outstanding optical properties of this two-photon fluorescent probe, TPSP-1, has been effectively used to identify pathological tissue samples directly from clinical liver cancer patients. This work provides us with this novel sensing and two-photon imaging probe, which can be used as a powerful tool to study the physiological functions of H2S and NAT2 and will help facilitate rapid and accurate diagnosis and therapeutic evaluation of hepatocellular carcinoma.

Activatable Dual-Optical Molecular Probe for Bioimaging Superoxide Anion in Epilepsy.

Superoxide anion (O2•-) plays a pivotal role in the generation of other reactive oxygen species within the body and is closely linked to epilepsy. Despite this connection, achieving precise imaging of O2•- during epilepsy pathology remains a formidable challenge. Herein, we develop an activatable molecular probe, CL-SA, to track the fluctuation of the level of O2•- in epilepsy through simultaneous fluorescence imaging and chemiluminescence sensing. The developed probe CL-SA demonstrated its efficacy in imaging of O2•- in neuronal cells, showcasing its dual optical imaging capability for O2•- in vitro. Furthermore, CL-SA was successfully used to observe aberrantly expressed O2•- in a mouse model of epilepsy. Overall, CL-SA provides us with a valuable tool for chemical and biomedical studies of O2•-, promoting the investigation of O2•- fluctuations in epilepsy, as well as providing a reliable means to explore the diagnosis and therapy of epilepsy.

Multisensory gamma stimulation promotes glymphatic clearance of amyloid.

The glymphatic movement of fluid through the brain removes metabolic waste1-4. Noninvasive 40 Hz stimulation promotes 40 Hz neural activity in multiple brain regions and attenuates pathology in mouse models of Alzheimer's disease5-8. Here we show that multisensory gamma stimulation promotes the influx of cerebrospinal fluid and the efflux of interstitial fluid in the cortex of the 5XFAD mouse model of Alzheimer's disease. Influx of cerebrospinal fluid was associated with increased aquaporin-4 polarization along astrocytic endfeet and dilated meningeal lymphatic vessels. Inhibiting glymphatic clearance abolished the removal of amyloid by multisensory 40 Hz stimulation. Using chemogenetic manipulation and a genetically encoded sensor for neuropeptide signalling, we found that vasoactive intestinal peptide interneurons facilitate glymphatic clearance by regulating arterial pulsatility. Our findings establish novel mechanisms that recruit the glymphatic system to remove brain amyloid.

PEGylated AIEgens for dual sensing of ATP and H2S and cancer cells photodynamic therapy.

Fluorescent sensors have been widely applied for biosensing, but probes for both multiple analytes sensing and photodynamic therapy (PDT) effect are less reported. In this article, we reported three AIE-based probes anchored with different mass-weight polyethylene glycol (PEG) tails, i.e., TPE-PEG160, TPE-PEG350, and TPE-PEG750, for both adenosine-5'-triphosphate (ATP) and hydrogen sulfide (H2S) detection and also cancer cells photodynamic therapy. TPE-PEGns (n = 160, 350 and 750) contain the tetraphenylethylene-based fluorophore core, the pyridinium and amide anion binding sites, the H2S cleavable disulfide bond, and the hydrophilic PEG chain. They exhibit a good amphiphilic property and can self-assemble nona-aggregation with a moderated red emission in an aqueous solution. Importantly, the size of aggregation, photophysical property, sensing ability and photosensitivity of these amphiphilic probes can be controlled by tuning the PEG chain length. Moreover, the selected probe TPE-PEG160 has been successfully used to detect environmental H2S and image ATP levels in living cells, and TPE-PEG750 has been used for photodynamic therapy of tumor cells under light irradiation.

Iron and risk of dementia: Mendelian randomisation analysis in UK Biobank.

BACKGROUND: Brain iron deposition is common in dementia, but whether serum iron is a causal risk factor is unknown. We aimed to determine whether genetic predisposition to higher serum iron status biomarkers increased risk of dementia and atrophy of grey matter. METHODS: We analysed UK Biobank participants clustered into European (N=451284), African (N=7477) and South Asian (N=9570) groups by genetic similarity to the 1000 genomes project. Using Mendelian randomisation methods, we estimated the association between genetically predicted serum iron (transferrin saturation [TSAT] and ferritin), grey matter volume and genetic liability to clinically defined dementia (including Alzheimer's disease [AD], non-AD dementia, and vascular dementia) from hospital and primary care records. We also performed time-to-event (competing risks) analysis of the TSAT polygenic score on risk of clinically defined non-AD dementia. RESULTS: In Europeans, higher genetically predicted TSAT increased genetic liability to dementia (Odds Ratio [OR]: 1.15, 95% Confidence Intervals [CI] 1.04 to 1.26, p=0.0051), non-AD dementia (OR: 1.27, 95% CI 1.12 to 1.45, p=0.00018) and vascular dementia (OR: 1.37, 95% CI 1.12 to 1.69, p=0.0023), but not AD (OR: 1.00, 95% CI 0.86 to 1.15, p=0.97). Higher TSAT was also associated with increased risk of non-AD dementia in participants of African, but not South Asian groups. In survival analysis using a TSAT polygenic score, the effect was independent of apolipoprotein-E ε4 genotype (with adjustment subdistribution Hazard Ratio: 1.74, 95% CI 1.33 to 2.28, p=0.00006). Genetically predicted TSAT was associated with lower grey matter volume in caudate, putamen and thalamus, and not in other areas of interest. DISCUSSION: Genetic evidence supports a causal relationship between higher TSAT and risk of clinically defined non-AD and vascular dementia, in European and African groups. This association appears to be independent of apolipoprotein-E ε4.

Abnormal S100A8 expression associates with postoperative recurrence in chronic rhinosinusitis with nasal polyps.

Objective: To investigate the role of S100A8 in chronic rhinosinusitis with nasal polyps (CRSwNP) and assess its value in predicting disease recurrence after surgery. Methods: Thirty healthy controls (HC), 30 patients with chronic rhinosinusitis without nasal polyp (CRSsNP), and 60 patients with CRSwNP were enrolled. Serum S100A8 concentration was measured by ELISA. Immunohistochemistry (IHC), western blotting (WB), and reverse transcription-polymerase chain reaction (RT-PCR)were performed to examine tissue expression levels of S100A8. The potential values of S100A8 in predicting postoperative recurrence of CRSwNP were assessed by the receiver operating characteristic (ROC)curve. Results: Serum S100A8 concentrations in the CRSwNP group were higher than the HC group and the CRSsNP group， especially in the recurrent CRSwNP group (P < 0.05). Serum S100A8 levels were positively correlated with peripheral blood eosinophil numbers (r = 0.263, P = 0.043) and percentages (r = 0.336, P = 0.009), tissue eosinophil percentages (r = 0.273, P = 0.035), VAS score (r = 0.385, P = 0.002) and Lund-Kennedy score (r = 0.283, P = 0.029). IHC, WB, and RT-PCR results showed tissue S100A8 expression was significantly enhanced in the CRSwNP group, especially in the recurrence group (P < 0.05). Binary regression analysis showed that serum S100A8 concentration and tissue eosinophil percentage were correlated with postoperative recurrence of CRSwNP. ROC curve analysis showed that compared with tissue eosinophil percentage, the S100A8 level had a higher value for postoperative recurrence of CRSwNP. Conclusion: Serum and tissue S100A8 levels were elevated in patients with CRSwNP， especially in the recurrent CRSwNP patients, and were correlated with the degree of peripheral blood and tissue eosinophilic inflammation. S100A8 seemed to be a potential objective biomarker to predict the postoperative recurrence of CRSwNP.

Phenethyl isothiocyanate inhibits metastasis potential of non-small cell lung cancer cells through FTO mediated TLE1 m6A modification.

N6-methyladenosine (m6A) modification is a prevalent RNA epigenetic modification, which plays a crucial role in tumor progression including metastasis. Isothiocyanates (ITCs) are natural compounds and inhibit the tumorigenesis of various cancers. Our previous studies show that ITCs inhibit the proliferation and metastasis of non-small cell lung cancer (NSCLC) cells, and have synergistic effects with chemotherapy drugs. In this study, we investigated the molecular mechanisms underlying the inhibitory effects of ITCs on cancer cell metastasis. We showed that phenethyl isothiocyanate (PEITC) dose-dependently inhibited the cell viability of both NSCLC cell lines H1299 and H226 with IC50 values of 17.6 and 15.2 µM, respectively. Furthermore, PEITC dose-dependently inhibited the invasion and migration of H1299 and H226 cells. We demonstrated that PEITC treatment dose-dependently increased m6A methylation levels and inhibited the expression of the m6A demethylase fat mass and obesity-associated protein (FTO) in H1299 and H226 cells. Knockdown of FTO significantly increased m6A methylation in H1299 and H226 cells, impaired their abilities of invasion and migration in vitro, and enhanced the inhibition of PEITC on tumor growth in vivo. Overexpression of FTO promoted the migration of NSCLC cells, and also mitigated the inhibitory effect of PEITC on migration of NSCLC cells. Furthermore, we found that FTO regulated the mRNA m6A modification of a transcriptional co-repressor Transducin-Like Enhancer of split-1 (TLE1) and further affected its stability and expression. TCGA database analysis revealed TLE1 was upregulated in NSCLC tissues compared to normal tissues, which might be correlated with the metastasis status. Moreover, we showed that PEITC suppressed the migration of NSCLC cells by inhibiting TLE1 expression and downstream Akt/NF-κB pathway. This study reveals a novel mechanism underlying ITC's inhibitory effect on metastasis of lung cancer cells, and provided valuable information for developing new therapeutics for lung cancer by targeting m6A methylation.

Novel 1,8-Naphthalimide Derivatives As Antitumor Agents and Potent Demethylase Inhibitors.

Functional 1,8-naphthalimide derivatives are rapidly developing in the field of anticancer research. Herein, we designed and synthesized a series of naphthalimide derivatives with different substituents. Interestingly, 1,8-naphthalimide derivatives 1 and 7 inhibited a human demethylase FTO (the fat mass and obesity-associated protein). Computer simulation studies further indicated that 1 and 7 entered the FTO's structural domain II binding pocket through hydrophobic and hydrogen bonding interactions. Anticancer mechanism studies showed that 1 and 7 induced DNA damage and autophagic cell death in A549 cells. The high antiproliferative activity of 1 and 7 was further confirmed by 3D multicellular A549 tumor spheroid assays. This study focuses on the cytotoxicity and mode of action of naphthalimide derivatives, which not only have potential anticancer activity but also are potent demethylase inhibitors.

3D Wood Microfilter for Fast and Efficient Removal of Heavy Metal Ions from Water.

Adsorption is an effective method for the treatment of heavy metal ions in water; however, the existing adsorbents are complicated to prepare, and costly and difficult to recover. In this work, a 3D wood microfilter was prepared by modifying wood for the removal of heavy metal contaminants from water. First, a green deep eutectic solvent was used to remove lignin from beech wood. Then citric acid and l-cysteine were sequentially used to graft carboxyl and sulfhydryl groups (-SHs) on the surface of cellulose. Finally, a three-dimensional wood microfilter with an abundant porous structure and adsorption sites was formed. The adsorption kinetics and adsorption isotherms of heavy metal ions on the 3D wood microfilter were systematically investigated using Cu2+ and Cd2+ as model species. The results showed that the 3D wood microfilter had a fast adsorption rate and high saturation capacity for both Cu2+ and Cd2+. Based on the advantages of easy processing and multilayer assembly and stacking, a three-layer wood microfilter was designed to achieve high flux rate (1.53 × 103 L m-2 h-1) and high efficiency (>98%) for the removal of heavy metal ions in water. The enhancement mechanism of the adsorption process of Cu2+ and Cd2+ by the 3D wood microfilter was investigated using SEM and EDS, FTIR, and XPS characterization. The simple synthesis method and high adsorption efficiency of this wood microfilter provide a new strategy for the preparation of cheap, efficient, and recyclable adsorbents for heavy metal ions in water.

Evoking Ferroptosis by Synergistic Enhancement of a Cyclopentadienyl Iridium-Betulin Immune Agonist.

Ferroptosis is a form of programmed cell death driven by iron-dependent lipid peroxidation (LPO) with the potential for antitumor immunity activation. In this study, a nonferrous cyclopentadienyl metal-based ferroptosis inducer [Ir(Cp*)(Bet)Cl]Cl (Ir-Bet) was developed by a metal-ligand synergistic enhancement (MLSE) strategy involving the reaction of [Ir(Cp*)Cl]2 Cl2 with the natural product Betulin. The fusion of Betulin with iridium cyclopentadienyl (Ir-Cp*) species as Ir-Bet not only tremendously enhanced the antiproliferative activity toward cancer cells, but also activated ferritinophagy for iron homeostasis regulation by PI3K/Akt/mTOR cascade inhibition with a lower dosage of Betulin, and then evoked an immune response by nuclear factor kappa-B (NF-κB) activation of Ir-Cp* species. Further immunogenic cell death (ICD) occurred by remarkable ferroptosis through glutathione (GSH) depletion, glutathione peroxidase 4 (GPX4) deactivation and ferritinophagy. An in vivo vaccination experiment demonstrated desirable antitumor and immunogenic effects of Ir-Bet by increasing the ratio of cytotoxic T cells (CTLs)/regulatory T cells (Tregs).

Genome-wide comprehensive characterization and transcriptomic analysis of AP2/ERF gene family revealed its role in seed oil and ALA formation in perilla (Perilla frutescens).

Perilla (Perilla frutescens) is a potential specific oilseed crop with an extremely high α-linolenic acid (ALA) content in its seeds. AP2/ERF transcription factors (TFs) play important roles in multiple biological processes. However, limited information is known about the regulatory mechanism of the AP2/ERF family in perilla's oil accumulation. In this research, we identified 212 AP2/ERF family members in the genome of perilla, and their domain characteristics, collinearity, and sub-genome differentiation were comprehensively analyzed. Transcriptome sequencing revealed that genes encoding key enzymes involved in oil biosynthesis (e.g., ACCs, KASII, GPAT, PDAT and LPAAT) were up-regulated in the high-oil variety. Moreover, the endoplasmic reticulum-localized FAD2 and FAD3 were significantly up-regulated in the high-ALA variety. To investigate the roles of AP2/ERFs in lipid biosynthesis, we conducted a correlation analysis between non-redundant AP2/ERFs and key lipid metabolism genes using WGCNA. A significant correlation was found between 36 AP2/ERFs and 90 lipid metabolism genes. Among them, 12 AP2/ERFs were identified as hub genes and showed significant correlation with lipid synthase genes (e.g., FADs, GPAT and ACSL) and key regulatory TFs (e.g., LEC2, IAA, MYB, UPL3). Furthermore, gene expression analysis identified three AP2/ERFs (WRI, ABI4, and RAVI) potentially playing an important role in the regulation of oil accumulation in perilla. Our study suggests that PfAP2/ERFs are important regulatory TFs in the lipid biosynthesis pathway, providing a foundation for the molecular understanding of oil accumulation in perilla and other oilseed crops.

Efficacy and Safety of Anti-HER2 Targeted Therapy for Metastatic HR-Positive and HER2-Positive Breast Cancer: A Bayesian Network Meta-Analysis.

Despite the development of HER2-targeted drugs, achieving favorable outcomes for patients with HR+/HER2+MBC remains challenging. This study utilized Bayesian Network Meta-analysis to compare the efficacy and safety of anti-HER2 combination regimens. The primary analysis focused on progression-free survival (PFS), while secondary analyses included objective response rate, overall survival (OS) and the incidence rate of grade 3/4 adverse events (AEs). A comprehensive search across seven databases identified 25 randomized controlled trials for inclusion in this meta-analysis. For patients eligible for endocrinotherapy, our findings revealed that dual-target combined endocrine therapy, such as Her2-mAb+Her2-mAb+Endo (HR = 0.38; 95%CrI: 0.16-0.88) and Her2-mAb+Her2-tki+Endo (HR = 0.45; 95%CrI: 0.23-0.89), significantly improved PFS compared to endocrine therapy alone. According to the surface under the cumulative ranking curves (SUCRAs), Her2-mAb+Her2-mAb+Endo and Her2-mAb+Her2-tki+Endo ranked highest in terms of PFS and OS, respectively. For patients unsuitable for endocrine therapy, anti-HER2 dual-target combined chemotherapy, such as Her2-mAb+Her2-mAb+Chem (HR = 0.76; 95%CrI: 0.6-0.96) and Her2-mAb+Her2-tki+Chem (HR = 0.48; 95%CrI: 0.29-0.81), demonstrated significant improvements in PFS compared to Her2-mAb+Chem. The results were the same when compared with Her2-tki+Chem. According to the SUCRAs, Her2-mAb+Her2-tki+Chem and Her2-mAb+Her2-mAb+Chem ranked highest for PFS and OS, respectively. Subgroup analyses consistently supported these overall findings, indicating that dual-target therapy was the optimal approach irrespective of treatment line.

Carbon-Encapsulated Magnetite Nanodoughnut as a NIR-II Responsive Nanozyme for Synergistic Chemodynamic-Photothermal Therapy.

Magnetite-based nanozymes have attracted great interest for catalytic cancer therapy enabled by catalyzing hydrogen peroxide (H2 O2 ) to produce highly toxic hydroxyl radicals (•OH) to kill tumor cells. However, their therapeutic efficacies remain low due to insufficient •OH. Here, a light-responsive carbon-encapsulated magnetite nanodoughnuts (CEMNDs) with dual-catalytic activities for photothermal-enhanced chemodynamic therapy (CDT) is reported. The CEMNDs can accumulate in tumor and get into tumor cells and effectively act as peroxidase to convert H2 O2 to •OH that causes tumor cell death. The CEMNDs also possess intrinsic glutathione oxidase-like activity that which catalyzes the oxidation of reduced glutathione and produce lipid peroxidase for enhanced catalytic therapy. Furthermore, the CEMNDs can absorb 1064 nm light to elevate local temperature and increase release of Fe ions for photothermal therapy and enhanced CDT respectively. The in vivo experiments in an aggressive and drug-resistant metastatic mouse model of triple negative breast cancer model demonstrate excellent synergistic anti-tumor function and no measurable systemic toxicity of CEMNDs.

MicroRNA-Based Discovery of Biomarkers, Therapeutic Targets, and Repositioning Drugs for Breast Cancer.

Breast cancer treatment can be improved with biomarkers for early detection and individualized therapy. A set of 86 microRNAs (miRNAs) were identified to separate breast cancer tumors from normal breast tissues (n = 52) with an overall accuracy of 90.4%. Six miRNAs had concordant expression in both tumors and breast cancer patient blood samples compared with the normal control samples. Twelve miRNAs showed concordant expression in tumors vs. normal breast tissues and patient survival (n = 1093), with seven as potential tumor suppressors and five as potential oncomiRs. From experimentally validated target genes of these 86 miRNAs, pan-sensitive and pan-resistant genes with concordant mRNA and protein expression associated with in-vitro drug response to 19 NCCN-recommended breast cancer drugs were selected. Combined with in-vitro proliferation assays using CRISPR-Cas9/RNAi and patient survival analysis, MEK inhibitors PD19830 and BRD-K12244279, pilocarpine, and tremorine were discovered as potential new drug options for treating breast cancer. Multi-omics biomarkers of response to the discovered drugs were identified using human breast cancer cell lines. This study presented an artificial intelligence pipeline of miRNA-based discovery of biomarkers, therapeutic targets, and repositioning drugs that can be applied to many cancer types.