PPARδ dysregulation of CCL20/CCR6 axis promotes gastric adenocarcinoma carcinogenesis by remodeling gastric tumor microenvironment.

BACKGROUND: Peroxisome proliferator-activated receptor delta (PPARδ) promotes inflammation and carcinogenesis in many organs, but the underlying mechanisms remains elusive. In stomachs, PPARδ significantly increases chemokine Ccl20 expression in gastric epithelial cells while inducing gastric adenocarcinoma (GAC). CCR6 is the sole receptor of CCL20. Here, we examine the role of PPARδ-mediated Ccl20/Ccr6 signaling in GAC carcinogenesis and investigate the underlying mechanisms. METHODS: The effects of PPARδ inhibition by its specific antagonist GSK3787 on GAC were examined in the mice with villin-promoter-driven PPARδ overexpression (PpardTG). RNAscope Duplex Assays were used to measure Ccl20 and Ccr6 levels in stomachs and spleens. Subsets of stomach-infiltrating immune cells were measured via flow cytometry or immunostaining in PpardTG mice fed GSK3787 or control diet. A panel of 13 optimized proinflammatory chemokines in mouse sera were quantified by an enzyme-linked immunosorbent assay. RESULTS: GSK3787 significantly suppressed GAC carcinogenesis in PpardTG mice. PPARδ increased Ccl20 level to chemoattract Ccr6+ immunosuppressive cells, including tumor-associated macrophages, myeloid-derived suppressor cells and T regulatory cells, but decreased CD8+ T cells in gastric tissues. GSK3787 suppressed PPARδ-induced gastric immunosuppression by inhibiting Ccl20/Ccr6 axis. Furthermore, Ccl20 protein levels increased in sera of PpardTG mice starting at the age preceding gastric tumor development and further increased with GAC progression as the mice aged. GSK3787 decreased the PPARδ-upregulated Ccl20 levels in sera of the mice. CONCLUSIONS: PPARδ dysregulation of Ccl20/Ccr6 axis promotes GAC carcinogenesis by remodeling gastric tumor microenvironment. CCL20 might be a potential biomarker for the early detection and progression of GAC.

Comparison of iridolenticular contact area under different light brightness between post primary acute angle closure and cataract eyes.

BACKGROUND: To study the iridolenticular contact area (ILCA) under different light conditions in acute primary angle closure (APAC). METHODS: This cross-sectional, observational study involved 22 unilateral APAC patients and 59 cataract patients (59 eyes). Images of the APAC eyes, fellow eyes and cataract eyes were collected by anterior segment optical coherence tomography (ASOCT) under different light conditions respectively. The ILCA, anterior chamber width (ACW), anterior chamber area (ACA), lens vault (LV), angle opening distance at 750 µm (AOD750), trabecular iris space area at 750 µm (TISA750) and iris area at 750 µm (IA750) were measured using Image J software. RESULTS: The ILCA of cataract eyes were significantly larger than APAC eyes (4.424 ± 1.208 vs 4.049 ± 2.725mm2, P = 0.034) and fellow eyes (4.424 ± 1.208 vs 3.651 ± 1.629 mm2, P = 0.008) under dark condition. Under dark condition, ILCA of APAC eyes was negatively correlated with AOD750 (r = -0.444, P = 0.038), TISA750 (r = -0.498, P = 0.018). The ILCA of cataract eyes under dark condition was significantly greater than under bright condition (4.424 ± 1.208 vs 2.526 ± 0.992 mm2, P < 0.001). CONCLUSIONS: This study showed that ILCA in both APAC eye and fellow eye were smaller than cataract eye. Future study should focus on both the contact area and force at the interface of lens and iris with larger sample size.

Vessel-Targeting Nanoclovers Enable Noninvasive Delivery of Magnetic Hyperthermia-Chemotherapy Combination for Brain Cancer Treatment.

Despite being promising, the clinical application of magnetic hyperthermia for brain cancer treatment is limited by the requirement of highly invasive intracranial injections. To overcome this limitation, here we report the development of gallic acid-coated magnetic nanoclovers (GA-MNCs), which allow not only for noninvasive delivery of magnetic hyperthermia but also for targeted delivery of systemic chemotherapy to brain tumors. GA-MNCs are composed of clover-shaped MNCs in the core, which can induce magnetic heat in high efficiency, and polymerized GA on the shell, which enables tumor vessel-targeting. We demonstrate that intravenous administration of GA-MNCs following alternating magnetic field exposure effectively inhibited brain cancer development and preferentially disrupted tumor vasculature, making it possible to efficiently deliver systemic chemotherapy for further improved efficacy. Due to the noninvasive nature and high efficiency in killing tumor cells and enhancing systemic drug delivery, GA-MNCs have the potential to be translated for improved treatment of brain cancer.

Comparing the monetary value of a quality-adjusted life year from the payment card and the open-ended format.

BACKGROUND: The payment card (PC) format and the open-ended (OE) format are common methods in eliciting willingness-to-pay (WTP) of one additional quality-adjusted life year (QALY). The aim of this research is to compare these two formats in eliciting the monetary value of a QALY. METHODS: A contingent valuation survey was carried out using a pre-designed questionnaire with various hypothetical scenarios. The difference between the PC and the OE formats was evaluated by a two-sample equality test. Furthermore, generalized linear models were carried out to control observed heterogeneity and to test theoretical validity. RESULTS: In total, 461 individuals were involved, among whom 235 (51%) answered the PC question, while 226 (49%) answered the OE question. Excluding zero response, the mean WTP values of these two formats for different scenarios varied dramatically, which was from 13,278 to 280,177 RMB for the PC, 18,119 to 620,913 RMB for the OE. The OE format tended to elicit lower values for less serious condition and higher values for more serious condition. However, equality test of mean and median demonstrated insignificant difference of these two formats for all scenarios. For both OE and PC format, most variables were found to have significant effect on the value of WTP/QALY. Moreover, joint estimation indicated a statistically significant positive effect on the OE results. Further analysis demonstrated that the imbalanced zero response distribution caused the main difference of these two formats. CONCLUSIONS: This research indicated insignificantly different WTP/QALY estimates of the PC format and OE format with the grouped data whereas significantly higher estimates of the OE format from the pooled data. These two formats were found to be valid. More research about the difference and the validity of various WTP eliciting methods would be recommended for a robust estimation of WTP/QALY.

Copresentation of Tumor Antigens and Costimulatory Molecules via Biomimetic Nanoparticles for Effective Cancer Immunotherapy.

Nanoparticle (NP)-based cancer immunotherapy has been extensively explored. However, the efficacy of existing strategies is often limited by the lack of effective tumor-specific antigens or the inability to present costimulatory signal or both. Here, we report a novel approach to overcoming these limitations through surface coating with dendritic-tumor fusion cell membranes, which present whole repertories of tumor-associated antigens in the presence of costimulatory molecules. Because antigen-presenting and costimulatory molecules are displayed on their surface, these NPs can efficiently penetrate immune organs and activate T cells. We show that these NPs can be utilized to prevent tumor development and regress established tumors, including tumors in the brain. We demonstrate that encapsulation of immune adjuvants further improves their efficacy. Due to their significant efficacy, the whole tumor antigen-presenting costimulatory NPs have the potential to be translated into clinical applications for treatment of various cancers.

PPARD and Interferon Gamma Promote Transformation of Gastric Progenitor Cells and Tumorigenesis in Mice.

BACKGROUND & AIMS: The peroxisome proliferator-activated receptor delta (PPARD) regulates cell metabolism, proliferation, and inflammation and has been associated with gastric and other cancers. Villin-positive epithelial cells are a small population of quiescent gastric progenitor cells. We expressed PPARD from a villin promoter to investigate the role of these cells and PPARD in development of gastric cancer. METHODS: We analyzed gastric tissues from mice that express the Ppard (PPARD1 and PPARD2 mice) from a villin promoter, and mice that did not carry this transgene (controls), by histology and immunohistochemistry. We performed cell lineage-tracing experiments and analyzed the microbiomes, chemokine and cytokine production, and immune cells and transcriptomes of stomachs of these mice. We also performed immunohistochemical analysis of PPARD levels in 2 sets of human gastric tissue microarrays. RESULTS: Thirty-eight percent of PPARD mice developed spontaneous, invasive gastric adenocarcinomas, with severe chronic inflammation. Levels of PPARD were increased in human gastric cancer tissues, compared with nontumor tissues, and associated with gastric cancer stage and grade. We found an inverse correlation between level of PPARD in tumor tissue and patient survival time. Gastric microbiomes from PPARD and control mice did not differ significantly. Lineage-tracing experiments identified villin-expressing gastric progenitor cells (VGPCs) as the origin of gastric tumors in PPARD mice. In these mice, PPARD up-regulated CCL20 and CXCL1, which increased infiltration of the gastric mucosa by immune cells. Immune cell production of inflammatory cytokines promoted chronic gastric inflammation and expansion and transformation of VGPCs, leading to tumorigenesis. We identified a positive-feedback loop between PPARD and interferon gamma signaling that sustained gastric inflammation to induce VGPC transformation and gastric carcinogenesis. CONCLUSIONS: We found PPARD overexpression in VPGCs to result in inflammation, dysplasia, and tumor formation. PPARD and VGPCs might be therapeutic targets for stomach cancer.

Autocatalytic Delivery of Brain Tumor-targeting, Size-shrinkable Nanoparticles for Treatment of Breast Cancer Brain Metastases.

Breast cancer brain metastases (BCBMs) represent a major cause of morbidity and mortality among patients with breast cancer. Chemotherapy, which is widely used to treat tumors outside of the brain, is often ineffective on BCBMs due to its inability to efficiently cross the blood-brain barrier (BBB). Although the BBB is partially disrupted in tumor lesions, it remains intact enough to prevent most therapeutics from entering the brain. Here, we report a nanotechnology approach that can overcome the BBB through synthesis of lexiscan-loaded, AMD3100-conjugated, shrinkable NPs, or LANPs. LANPs respond to neutrophil elastase-enriched tumor microenvironment by shrinking in size and disrupt the BBB in tumors through lexiscan-mediated modulation. LANPs recognize tumor cells through the interaction between AMD3100 and CXCR4, which are expressed in metastatic tumor cells. We demonstrate that the integration of tumor responsiveness, tumor targeting, and BBB penetration enables LANPs to penetrate metastatic lesions in the brain with high efficiency, and, when doxorubicin was encapsulated, LANPs effectively inhibited tumor growth and prolonged the survival of tumor-bearing mice. Due to their high efficiency in penetrating the BBB for BCBMs treatment, LANPs have the potential to be translated into clinical applications for improved treatment of patients with BCBMs.

Oxygenated lipid signaling in tumor-associated macrophages-focus on colon cancer.

Polyunsaturated fatty acids (PUFAs) are enzymatically converted to a variety of bioactive products through insertion of molecular oxygen. PUFA-derived mediators can have either inflammatory or anti-inflammatory/pro-resolving properties, depending upon their specific structures. The relative harm or benefit of these mediators can also be tissue and context dependent. These mediators play important roles in maintaining homeostasis and their dysregulation is involved in pathogenesis of cancers, especially those associated with chronic inflammation. There is a well-established link between colorectal cancer (CRC) and chronic inflammation. The colon harbors a large population of immune cells, which must be tightly regulated in order to maintain the balance between pathogenic and commensal microbes in the gut. Macrophages are key to the process of distinguishing between potentially harmful antigens/microbes and benign or beneficial signals. Macrophages are often associated with tumors (tumor-associated macrophages (TAMs), including CRC. There is some debate as to the prognostic significance of these TAMs in CRC, with some work suggesting a beneficial impact. The purpose of this review is to give an overview of what is currently known regarding PUFA-derived mediator signaling in tumor-associated macrophages in CRC.

Targeted Drug Delivery to Stroke via Chemotactic Recruitment of Nanoparticles Coated with Membrane of Engineered Neural Stem Cells.

Cell membrane coating has recently emerged as a promising biomimetic approach to engineering nanoparticles (NPs) for targeted drug delivery. However, simple cell membrane coating may not meet the need for efficient drug delivery to the brain. Here, a novel molecular engineering strategy to modify the surface of NPs with a cell membrane coating for enhanced brain penetration is reported. By using poly(lactic-co-glycolic) acid NPs as a model, it is shown that delivery of NPs to the ischemic brain is enhanced through surface coating with the membrane of neural stem cells (NSCs), and the delivery efficiency can be further increased using membrane isolated from NSCs engineered for overexpression of CXCR4. It is found that this enhancement is mediated by the chemotactic interaction of CXCR4 with SDF-1, which is enriched in the ischemic microenvironment. It is demonstrated that the resulting CXCR4-overexpressing membrane-coated NPs, termed CMNPs, significantly augment the efficacy of glyburide, an anti-edema agent, for stroke treatment. The study suggests a new approach to improving drug delivery to the ischemic brain and establishes a novel formulation of glyburide that can be potentially translated into clinical applications to improve management of human patients with stroke.

MicroRNA-199b-5p attenuates TGF-ß1-induced epithelial-mesenchymal transition in hepatocellular carcinoma.

BACKGROUND: Accumulating evidence indicates that N-cadherin is a cell adhesion molecule that has critical roles in tumour progression. However, the role of N-cadherin in hepatocellular carcinoma (HCC) remains controversial. METHODS: This study aims to investigate the expression status of N-cadherin and its molecular mechanisms in HCC. RESULTS: The expression of N-cadherin was markedly overexpressed in HCC tissues and cell lines. We identified that miR-199b-5p binds to the 3'-UTR of N-cadherin mRNA, thus decreasing N-cadherin expression in HCC cells. We also found the downregulation of miR-199b-5p in HCC specimens, which was inversely correlated with N-cadherin upregulation, predicted poor clinical outcomes in HCC patients. Next, we determined that miR-199b-5p overexpression promoted cell aggregation, suppressed cell migration and invasion in HCC cells, and inhibited xenografts tumour metastasis in nude mice. Moreover, we demonstrated that miR-199b-5p attenuated TGF-ß1 induced epithelial-mesenchymal transition (EMT) -associated traits, while its effects could be partially reversed by N-cadherin restoration. Finally, we examined that N-cadherin downregulation or miR-199b-5p overexpression suppressed TGF-ß1-induced Akt phosphorylation, and inhibition of PI3K/Akt pathway blocked TGF-ß1-induced N-cadherin overexpression in HCC cells. CONCLUSIONS: Our data demonstrate that N-Cadherin was markedly overexpressed and miR-199b-5p was significantly downregulated in HCC. MiR-199b-5p exerts inhibitory effects on EMT, and directly targets N-cadherin in HCC, supporting the potential utility of miR-199b-5p as a promising strategy to treat HCC. Also, a positive regulatory loop exists between N-cadherin and Akt signalling represents a novel mechanism of TGF-ß1-mediated EMT in HCC cells.

Targeted Delivery of CRISPR/Cas9-Mediated Cancer Gene Therapy via Liposome-Templated Hydrogel Nanoparticles.

Due to its simplicity, versatility, and high efficiency, the clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 technology has emerged as one of the most promising approaches for treatment of a variety of genetic diseases, including human cancers. However, further translation of CRISPR/Cas9 for cancer gene therapy requires development of safe approaches for efficient, highly specific delivery of both Cas9 and single guide RNA to tumors. Here, novel core-shell nanostructure, liposome-templated hydrogel nanoparticles (LHNPs) that are optimized for efficient codelivery of Cas9 protein and nucleic acids is reported. It is demonstrated that, when coupled with the minicircle DNA technology, LHNPs deliver CRISPR/Cas9 with efficiency greater than commercial agent Lipofectamine 2000 in cell culture and can be engineered for targeted inhibition of genes in tumors, including tumors the brain. When CRISPR/Cas9 targeting a model therapeutic gene, polo-like kinase 1 (PLK1), is delivered, LHNPs effectively inhibit tumor growth and improve tumor-bearing mouse survival. The results suggest LHNPs as versatile CRISPR/Cas9-delivery tool that can be adapted for experimentally studying the biology of cancer as well as for clinically translating cancer gene therapy.

Renal Clearable Peptide Functionalized NaGdF4 Nanodots for High-Efficiency Tracking Orthotopic Colorectal Tumor in Mouse.

The effective delivery of bioimaging probes to a selected cancerous tissue has extensive significance for biological studies and clinical investigations. Herein, the peptide functionalized NaGdF4 nanodots (termed as, pPeptide-NaGdF4 nanodots) have been prepared for highly efficient magnetic resonance imaging (MRI) of tumor by formation of Gd-phosphonate coordinate bonds among hydrophobic NaGdF4 nanodots (4.2 nm in diameter) with mixed phosphorylated peptide ligands including a tumor targeting phosphopeptide and a cell penetrating phosphopeptide. The tumor targeting pPeptide-NaGdF4 nanodots have paramagnetic property with ultrasmall hydrodynamic diameter (HD, c.a., 7.3 nm) which greatly improves their MRI contrast ability of tumor and facilitates renal clearance. In detail, the capability of the pPeptide-NaGdF4 nanodots as high efficient contrast agent for in vivo MRI is evaluated successfully through tracking small drug induced orthotopic colorectal tumor (c.a., 195 mm3 in volume) in mouse.

Synthesis and Crystal Structure of a 4,4'-bipyridine Linked Dinuclear Copper(II) Complex Derived from 2-{[2-(2-hydroxyethylamino)ethylimino]methyl}-6-methylphenol.

A novel 4,4'-bipyridine linked dinuclear copper(II) complex, [Cu2L2(bipy)](NO3)2·bipy (L = 2-[2-(2-hydroxyethylamino) ethylimino]methyl-6-methylphenol; bipy = 4,4'-bipyridine), was prepared and characterized by elemental analyses, IR spectroscopy, and single-crystal X-ray diffraction. The Cu···Cu distance is 11.129(2) Å. The CuII atom is coordinated by one phenolate O, one imine N, and one amine N atoms of a Schiff base ligand, and one N atom of the bridging 4,4'-bipyridine ligand, forming a square planar geometry. In the crystal structure of the complex, the dinuclear copper complex cations are linked by 4,4'-bipyridine molecules through intermolecular O-H···N hydrogen bonds, to form 1D chains running in the [2 0 -1] direction.

Employing Tryptone as a General Phase Transfer Agent to Produce Renal Clearable Nanodots for Bioimaging.

Hydrophobic ultrasmall nanoparticles synthesized in nonpolar solvents exhibit great potential in biomedical applications. However, a major challenge when applying these nanomaterials in biomedical research is the lack of a versatile strategy to render them water dispersible while preserving the hydrodynamic diameter (HD) to be less than 8 nm for efficient renal clearance. To address this problem, tryptone is employed as the novel ligand to fabricate a simple, versatile, and inexpensive strategy for transferring hydrophobic NaGdF(4) nanodots (3 nm in diameter) from organic phase into aqueous phase without any complicated organic synthesis. The paramagnetic properties of NaGdF(4) nanodots are well retained after the phase transfer process. In particular, the tryptone-NaGdF(4) nanodots have ultrasmall HD (ca., 7.5 nm), which greatly improves their tumor accumulation and facilitates renal clearance within 24 h postinjection. The as-prepared tryptone-NaGdF(4) nanodots can also be further functionalized with other molecules for extensively biomedical and bioanalytical applications. Furthermore, the proposed strategy can easily be extended to transfer other types of inorganic nanoparticles from hydrophobic to hydrophilic for facilitating biomedical applications.

Lectin-conjugated Fe2O3@Au core@Shell nanoparticles as dual mode contrast agents for in vivo detection of tumor.

Here, we report the covalent conjugation of lectin on Fe2O3@Au core@shell nanoparticle (lectin-Fe2O3@Au NP) for T2-weighted magnetic resonance (MR) and X-ray computed tomography (CT) dual-modality imaging. The lectin-Fe2O3@Au NPs are prepared by coupling lectins to the Fe2O3@Au NP surfaces through bifunctional PEG NHS ester disulfide (NHS-PEG-S-S-PEG-NHS) linkers. After the nonspecific adsorption sites on the nanoparticle surface are blocked by thiolated PEG (PEG-SH), the lectin-Fe2O3@Au NPs exhibit excellent stability in biological medium and inappreciable cytotoxicity. A series of in vitro and in vivo experiments were then carried out for evaluating the capabilities of three selected lectin (ConA, RCA and WGA)-Fe2O3@Au NPs. The results revealed that the lectin-Fe2O3@Au NPs had a capacity not only for dual mode MR and CT imaging in vitro but also for MR and CT imaging of colorectal cancer in vivo. The experimental results also suggest that lectin could be used as tumor targeting ligand for synthesizing nanoparticle-based contrast agents.

Nitrogen and energy utilization and methane emissions of sheep grazing on annual pasture vs. native pasture.

The purpose of this study was to evaluate the differences in annual pasture and native pasture on dry matter (DM) intake, nutrient digestibility, nitrogen (N) and energy utilization, and methane (CH4) emission of grazing sheep, and to provide the basis for rational livestock grazing in salinized regions. The study used 10 male Hu sheep ♀ × thin-tailed Han sheep ♂ rams (20 ±â€…5 kg) aged 5 mo. Sheep grazing was conducted in annual pasture and native pasture using a 2 × 2 Latin square design. After a 15-d adaptation period for grazing, the digestion and metabolism experiment of sheep were conducted, while CH4 emissions were measured using sulfur hexafluoride tracer gas. DM intake did not differ between annual pasture and native pasture (P = 0.386). Meanwhile, the digestibility of DM (P < 0.001), neutral detergent fiber (P < 0.001), acid detergent fiber (P < 0.01), crude protein (P < 0.001), and ether extract (P < 0.001) of sheep grazing on native pasture was significantly higher than that of annual pasture. Sheep grazing on native pasture had increased N intake (P < 0.001) and N retained (P < 0.001) compared with those grazing on annual pasture. Digestion energy (P < 0.05) and metabolic energy (P < 0.01) of sheep grazing on annual pasture were significantly improved compared with those on native pasture, while fecal energy (P < 0.001), urine energy (P < 0.001) and CH4 energy (CH4-E) output (P < 0.001) and CH4 emission (P < 0.001) of sheep grazing on annual pasture were significantly decreased. The CH4-E/gross energy (GE) values of sheep grazing on annual pasture and native pasture were 0.09 and 0.10, respectively. In conclusion, grazing sheep have higher N utilization on native pasture, whereas grazing sheep have higher energy utilization and low CH4 emissions in annual pasture. In conclusion, annual pasture has a lower CH4-E/GE compared to native pasture, which helps in reducing environmental pollution.

The reduction of methane (CH4) emissions and nitrogen (N) excretion from livestock production systems can help mitigate environmental impact and improve feeding efficiency. The energy requirements of livestock are crucial for enhancing their performance and minimizing environmental impact. It is imperative to accurately ascertain the N and energy efficiency, and CH4 emissions associated with sheep grazing across diverse grassland ecosystems to optimize forage resource utilization without compromising livestock production performance, thereby facilitating sustainable grassland management and grazing practices. Sheep grazing on native pasture had higher nutrient digestibility and N utilization, while sheep grazing on annual pasture showed higher energy utilization and less CH4 emissions. CH4-energy/gross energy for grazing sheep on annual pasture and native pasture was 0.09 and 0.10, respectively. This study assessed the differences in N and energy utilization and CH4 emissions, among sheep grazing on different grasses, providing data support for the development of more rational livestock grazing methods.

Protocol for deep mining the correlation between acute pancreatitis and ferroptosis using the MIMIC-III database and STATA software.

The limitations associated with distinguishing serum Fe2+ and Fe3+ hinder the widespread application of ferroptosis, beyond laboratory settings. Here, we present a protocol for deep mining the correlation between acute pancreatitis and ferroptosis using the MIMIC-III database and STATA software. We describe steps for using Cox regression, decision curve analysis (DCA), and receiver operating characteristic (ROC) approaches to establish the relationship between them and determine the relevant factors. This protocol has potential application in establishing novel research models that integrate both fundamental and clinical methodologies. For complete details on the use and execution of this protocol, please refer to Yueling Deng et al.1.

Tumor Microenvironment Remodeling-Mediated Sequential Drug Delivery Potentiates Treatment Efficacy.

Toll-like receptor 7/8 agonists, such as imidazoquinolines (IMDQs), are promising for the de novo priming of antitumor immunity. However, their systemic administration is severely limited due to the off-target toxicity. Here, this work describes a sequential drug delivery strategy. The formulation is composed of two sequential modules: a tumor microenvironment remodeling nanocarrier (poly(l-glutamic acid)-graft-methoxy poly(ethylene glycol)/combretastatin A4, termed CA4-NPs) and an immunotherapy nanocarrier (apcitide peptide-decorated poly(l-glutamic acid)-graft-IMDQ-N3 conjugate, termed apcitide-PLG-IMDQ-N3). CA4-NPs, as a vascular disrupting agent, are utilized to remodel the tumor microenvironment for enhancing tumor coagulation and hypoxia. Subsequently, the apcitide-PLG-IMDQ-N3 could identify and target tumor coagulation through the binding of surface apcitide peptide to the GPIIb-IIIa on activated platelets. Afterward, IMDQ is activated selectively through the conversion of "-N3" to "-NH2" in the presence of hypoxia. The biodistribution results confirm their high tumor uptake of activated IMDQ (22.66%ID/g). By augmenting the priming and immunologic memory of tumor-specific CD8+ T cells, 4T1 and CT26 tumors with a size of ≈500 mm3 are eradicated without recurrence in mouse models.

Colorectal ALOX15 as a host factor determinant of EPA and DHA effects on colorectal carcinogenesis.

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), omega-3 polyunsaturated fatty acids (ω-3 PUFAs) derived from fish oil, are widely used as dietary supplements and FDA-approved treatments for hypertriglyceridemia. However, studies investigating the effects of EPA and DHA on colorectal carcinogenesis (CRC) have yielded conflicting results. The factors that determine these discrepant results remain unknown. Resolvins, oxidative metabolites of EPA and DHA, inhibit key pro-tumorigenic cytokine and chemokine signaling of colorectal cancer (e.g., IL-6, IL-1ß, and CCL2). 15-lipoxygenase-1 (ALOX15), a critical enzyme for resolvin generation is commonly lost during human CRC. Whether ALOX15 expression, as a host factor, modulates the effects of EPA and DHA on CRC remains unknown. Therefore, we evaluated the effects of ALOX15 transgenic expression in colonic epithelial cells on resolvin generation by EPA and DHA and CRC in mouse models representative of human CRC. Our results revealed that 1) EPA and DHA effects on CRC were diverse, ranging from suppressive to promotive, and these effects were occasionally altered by the formulations of EPA and DHA (free fatty acid, ethyl ester, triglyceride); 2) EPA and DHA uniformly suppressed CRC in the presence of intestinal ALOX15 transgenic expression, which induced the production of resolvins, decreased colonic CCL3-5 and CXCL-5 expression and tumor associated macrophages while increasing CD8 T cell abundance in tumor microenvironment; and 3) RvD5, the predominant resolvin produced by ALOX15, inhibited macrophage generation of pro-tumorigenic cytokines. These findings demonstrate the significance of intestinal ALOX15 expression as a host factor in determining the effects of EPA and DHA on CRC. Significance: Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are widely used as dietary supplements and FDA-approved treatments for hypertriglyceridemia. Studies of EPA and DHA effects on colorectal carcinogenesis (CRC) have revealed inconsistencies; factors determining the direction of their impact on CRC have remained unidentified. Our data show that EPA and DHA effects on CRC were divergent and occasionally influenced by their formulations. More importantly, intestinal 15-lipoxgenase-1 (ALOX15) expression modulated EPA and DHA effects on CRC, leading to their consistent suppression of CRC. ALOX15 promoted EPA and DHA oxidative metabolism to generate resolvins, which inhibited key pro-tumorigenic inflammatory cytokines and chemokines, including IL-6. IL-1ß, and CCL2. ALOX15 is therefore an important host factor in determining EPA and DHA effects on CRC.

Neutrophil Targeting Platform Reduces Neutrophil Extracellular Traps for Improved Traumatic Brain Injury and Stroke Theranostics.

Traumatic brain injuries (TBI) and stroke are major causes of morbidity and mortality in both developing and developed countries. The complex and heterogeneous pathophysiology of TBI and cerebral ischemia-reperfusion injury (CIRI), in addition to the blood-brain barrier (BBB) resistance, is a major barrier to the advancement of diagnostics and therapeutics. Clinical data showed that the severity of TBI and stroke is positively correlated with the number of neutrophils in peripheral blood and brain injury sites. Furthermore, neutrophil extracellular traps (NETs) released by neutrophils correlate with worse TBI and stroke outcomes by impairing revascularization and vascular remodeling. Therefore, targeting neutrophils to deliver NETs inhibitors to brain injury sites and reduce the formation of NETs can be an optimal strategy for TBI and stroke therapy. Herein, the study designs and synthesizes a reactive oxygen species (ROS)-responsive neutrophil-targeting delivery system loaded with peptidyl arginine deiminase 4 (PAD4) inhibitor, GSK484, to prevent the formation of NETs in brain injury sites, which significantly inhibited neuroinflammation and improved neurological deficits, and improved the survival rate of TBI and CIRI. This strategy may provide a groundwork for the development of targeted theranostics of TBI and stroke.