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Background Crosstalk between pericytes and endothelial cells is critical for ocular neovascularization. Endothelial cells secrete platelet-derived growth factor (PDGF)-BB and recruit PDGF receptor β (PDGFRβ)–overexpressing pericytes, which in turn cover and stabilize neovessels, independent of vascular endothelial growth factor (VEGF). Therapeutic agents inhibiting PDGF-BB/PDGFRβ signaling were tested in clinical trials but failed to provide additional benefits over anti-VEGF agents. We tested whether an antibody-drug conjugate (ADC) – an engineered monoclonal antibody linked to a cytotoxic agent - could selectively ablate pericytes and suppress retinal and choroidal neovascularization. Methods Immunoblotting, flow cytometry, cell viability test, and confocal microscopy were conducted to assess the internalization and cytotoxic effect of ADC targeting mPDGFRβ in an in vitro setting. Immunofluorescence staining of whole-mount retinas and retinal pigment epithelium-choroid-scleral complexes, electroretinography, and OptoMotry test were used to evaluate the effect and safety of ADC targeting mPDGFRβ in the mouse models of pathologic ocular neovascularization. Results ADC targeting mPDGFRβ is effectively internalized into mouse brain vascular pericytes and showed significant cytotoxicity compared with the control ADC. We also show that specific ablation of PDGFRβ-overexpressing pericytes using an ADC potently inhibits pathologic ocular neovascularization in mouse models of oxygen-induced retinopathy and laser-induced choroidal neovascularization, while not provoking generalized retinal toxicity. Conclusion Our results suggest that removing PDGFRβ-expressing pericytes by an ADC targeting PDGFRβ could be a potential therapeutic strategy for pathologic ocular neovascularization. Plain language summary Many diseases of the eye, such as age-related macular degeneration, involve abnormal blood vessel formation in the eye. One way to treat these diseases is to block the formation of blood vessels, for example by targeting cells called pericytes that surround small blood vessels. Here, we test a pericyte-targeting antibody-drug conjugate – in which a protein that can target a specific molecule on the cell surface is chemically linked to a drug that kills cells – for its ability to block blood vessel formation. We demonstrate that this approach is safe and effective in two mouse models. Our findings suggest that this might be a potentially useful strategy to treat these diseases in patients, for example when existing therapies no longer work. Lee et al. use an antibody-drug conjugate to treat pathologic ocular neovascularization in mouse models. The antibody-drug conjugate targets PDGFRβ-expressing pericytes, with similar therapeutic effects to an anti-VEGF agent and with limited unwanted toxicity.

Background The polymeric immunoglobulin receptor (pIgR) is a transmembrane transporter of polymeric IgA through the intestinal epithelium. Its overexpression has been reported in several cancers, but its role as a diagnostic and prognostic biomarker of oncogenesis is currently unclear. Method A literature search was conducted to summarize the functions of pIgR, its expression levels, and its clinical implications. Results pIgR expression has previously been investigated by proteomic analysis, RNA sequencing, and tissue microarray at the level of both RNA and protein in various cancers including pancreatic, esophageal, gastric, lung, and liver. However, studies have reported inconsistent results on how pIgR levels affect clinical outcomes such as survival rate and chemotherapy resistance. Possible explanations include pIgR mRNA levels being minimally correlated with the rate of downstream pIgR protein synthesis, and the diversity of antibodies used in immunohistochemistry studies further magnifying this ambiguity. In ovarian cancer cells, the transcytosis of IgA accompanied a series of transcriptional changes in intracellular inflammatory pathways that inhibit the progression of cancer, including the upregulation of IFN-gamma and downregulation of tumor-promoting ephrins. These findings suggest that both the levels of pIgR and secreted IgA from tumor-infiltrating B cells affect clinical outcomes. Conclusion Overall, no direct correlation was observed between the levels of pIgR inside tumor tissue and the clinical features in cancer patients. Measuring pIgR protein levels with a more specific and possibly chemically defined antibody, along with tumoral IgA, is a potential solution to better understand the pathways and consequences of pIgR overexpression in cancer cells.

c-Met is a promising target in cancer therapy for its intrinsic oncogenic properties. However, there are currently no c-Met-specific inhibitors available in the clinic. Antibodies blocking the interaction with its only known ligand, hepatocyte growth factor, and/or inducing receptor internalization have been clinically tested. To explore other therapeutic antibody mechanisms like Fc-mediated effector function, bispecific T cell engagement, and chimeric antigen T cell receptors, a diverse panel of antibodies is essential. We prepared a chicken immune scFv library, performed four rounds of bio-panning, obtained 641 clones using a high-throughput clonal retrieval system (TrueRepertoireTM, TR), and found 149 antigen-reactive scFv clones. We also prepared phagemid DNA before the start of bio-panning (round 0) and, after each round of bio-panning (round 1–4), performed next-generation sequencing of these five sets of phagemid DNA, and identified 860,207 HCDR3 clonotypes and 443,292 LCDR3 clonotypes along with their clonal abundance data. We then established a TR data set consisting of antigen reactivity for scFv clones found in TR analysis and the clonal abundance of their HCDR3 and LCDR3 clonotypes in five sets of phagemid DNA. Using the TR data set, a random forest machine learning algorithm was trained to predict the binding properties of in silico HCDR3 and LCDR3 clonotypes. Subsequently, we synthesized 40 HCDR3 and 40 LCDR3 clonotypes predicted to be antigen reactive (AR) and constructed a phage-displayed scFv library called the AR library. In parallel, we also prepared an antigen non-reactive (NR) library using 10 HCDR3 and 10 LCDR3 clonotypes predicted to be NR. After a single round of bio-panning, we screened 96 randomly-selected phage clones from the AR library and found out 14 AR scFv clones consisting of 5 HCDR3 and 11 LCDR3 AR clonotypes. We also screened 96 randomly-selected phage clones from the NR library, but did not identify any AR clones. In summary, machine learning algorithms can provide a method for identifying AR antibodies, which allows for the characterization of diverse antibody libraries inaccessible by traditional methods.

During cancer immunoediting, cancer cells deregulate cell death executioner mechanisms to escape immunotherapy-induced antitumor immunity. Ferroptosis, a type of regulated necrosis triggered by lipid peroxidation, plays a pivotal role in the anti-tumor activity of T cell-based immunotherapies; however, mechanisms for the modulation of ferroptosis in immune-refractory tumor cells are unclear. In this study, using preclinical models of immune refractory tumors obtained following the course of immunoediting by PD-1 blockade and adoptive T cell therapy (ACT), we find that T cell-based immunotherapy drives the development of ferroptosis resistance of tumor cells. In this process, E2F1 is upregulated by immunotherapy and it in turn binds to the promoter of the HMGCR gene to upregulate HMGCR, thereby contributing to the resistance to ferroptosis. Notably, HMGCR inhibition renders immune-refractory tumor cells susceptible to ACT and PD-1 blockade. Thus, our results reveal a mechanism by which cancer cells modulate ferroptosis to acquire resistance to immunotherapy and implicate the E2F1-HMGCR axis as a central molecular target for controlling ferroptosis resistance of immune-refractory cancer. HMGCR is upregulated by E2F1, driving ferroptosis resistance by reducing oxidative damage triggered by T cell-based therapy. Notably, targeting HMGCR restores ferroptosis sensitivity in immune-refractory tumors, enhancing response to PD-1 blockade as well as adoptive T cell transfer therapy.

Crosstalk between pericytes and endothelial cells is critical for ocular neovascularization. Endothelial cells secrete platelet-derived growth factor (PDGF)-BB and recruit PDGF receptor β (PDGFRβ)-overexpressing pericytes, which in turn cover and stabilize neovessels, independent of vascular endothelial growth factor (VEGF). Therapeutic agents inhibiting PDGF-BB/PDGFRβ signaling were tested in clinical trials but failed to provide additional benefits over anti-VEGF agents. We tested whether an antibody-drug conjugate (ADC) - an engineered monoclonal antibody linked to a cytotoxic agent - could selectively ablate pericytes and suppress retinal and choroidal neovascularization. Immunoblotting, flow cytometry, cell viability test, and confocal microscopy were conducted to assess the internalization and cytotoxic effect of ADC targeting mPDGFRβ in an in vitro setting. Immunofluorescence staining of whole-mount retinas and retinal pigment epithelium-choroid-scleral complexes, electroretinography, and OptoMotry test were used to evaluate the effect and safety of ADC targeting mPDGFRβ in the mouse models of pathologic ocular neovascularization. ADC targeting mPDGFRβ is effectively internalized into mouse brain vascular pericytes and showed significant cytotoxicity compared with the control ADC. We also show that specific ablation of PDGFRβ-overexpressing pericytes using an ADC potently inhibits pathologic ocular neovascularization in mouse models of oxygen-induced retinopathy and laser-induced choroidal neovascularization, while not provoking generalized retinal toxicity. Our results suggest that removing PDGFRβ-expressing pericytes by an ADC targeting PDGFRβ could be a potential therapeutic strategy for pathologic ocular neovascularization.

Recently, the conversion of livestock manure to solid fuel via torrefaction has brought more attention to moving forward to a carbon neutral society. A proper design of livestock manure to solid fuel is key for sustainable waste management. In this study, cow manure, as a representative of livestock manure, was examined for solid fuel production, focusing on enhancing the heating value. The torrefaction process was adopted as a main solid fuel generation process and compared to simple drying. The heating value of the torrefied cow manure was increased as the torrefaction temperature increased from 200 °C to 300 °C. The heating value was nearly saturated at around 30 min when the torrefaction temperature was increased from 20 min to 40 min. The heating value was further increased when the cow manure was mixed with sawdust or rice straw. The sawdust, which originally possessed a higher heating value, showed its potential as a candidate for additives to the torrefaction of cow manure. Compared to simple drying, torrefaction showed a higher heating value and energy density, successfully converting to stable carbon material.

Background/Objectives: Lactobacillus delbrueckii subsp. lactis CKDB001 (LL) has demonstrated anti-inflammatory, antioxidant, and lipid-regulatory effects in vitro and in vivo, including attenuation of hepatic steatosis and modulation of lipid metabolism. Given the known interactions between host metabolism and gut microbiota, these findings suggest a potential role for LL in modulating microbial composition under conditions of diet-induced obesity. This study aimed to investigate the microbiome-related effects of LL using an established murine model. To evaluate the effect of LL supplementation on gut microbial composition and predict microbial metabolic functions in mice with high-fat diet-induced obesity. Methods: Male C57BL/6J mice were fed a high-fat diet and administered LL orally for 12 weeks. Fecal samples were collected and analyzed using 16S rRNA gene sequencing. Microbial taxonomic profiles were assessed using linear discriminant analysis effect size, and functional predictions were performed using PICRUSt2. Results: LL supplementation significantly altered the gut microbiota by increasing the relative abundance of Lactobacillus and other commensal taxa while reducing the prevalence of pro-inflammatory genera such as Alistipes and Bilophila. Functional prediction analysis revealed a downregulation of lipopolysaccharide and ADP-L-glycero-β-D-manno-heptose biosynthesis pathways. Microbial functions associated with carbohydrate metabolism and short-chain fatty acid production were enriched in the LL-treated group. Conclusions: LL modulated gut microbial composition and suppressed pro-inflammatory microbial pathways while enhancing beneficial metabolic functions in high-fat diet-fed mice. These findings support the potential of LL as a safe and effective microbiota-targeted probiotic for managing obesity-related metabolic disorders.

Rice paddies are a major source of methane emissions. To meet the food demand of the growing population and to cope with global warming, reducing greenhouse gases and enhancing yields are critical. Here we demonstrate that a loss-of-function rice allele, gs3, mitigates methane emissions from methanogens by allocating more photosynthates to the grain and less to the root and increases yield by enlarging grain size and weight.Rice paddies are a source of the potent greenhouse gas methane. The authors demonstrate that a rice variety containing naturally lost function in the gene GS3 has reduced allocation of photosynthates to roots, which results in a reduction of methane emissions during growth.

The biophysical properties of therapeutic antibodies influence their manufacturability, efficacy, and safety. To develop an anti-cancer antibody, we previously generated a human monoclonal antibody (Ab417) that specifically binds to L1 cell adhesion molecule with a high affinity, and we validated its anti-tumor activity and mechanism of action in human cholangiocarcinoma xenograft models. In the present study, we aimed to improve the biophysical properties of Ab417. We designed 20 variants of Ab417 with reduced aggregation propensity, less potential post-translational modification (PTM) motifs, and the lowest predicted immunogenicity using computational methods. Next, we constructed these variants to analyze their expression levels and antigen-binding activities. One variant (Ab612)—which contains six substitutions for reduced surface hydrophobicity, removal of PTM, and change to the germline residue—exhibited an increased expression level and antigen-binding activity compared to Ab417. In further studies, compared to Ab417, Ab612 showed improved biophysical properties, including reduced aggregation propensity, increased stability, higher purification yield, lower pI, higher affinity, and greater in vivo anti-tumor efficacy. Additionally, we generated a highly productive and stable research cell bank (RCB) and scaled up the production process to 50 L, yielding 6.6 g/L of Ab612. The RCB will be used for preclinical development of Ab612.

RuO2 has been used for various applications because of its good catalytic properties. To further improve its electrocatalytic properties, we used a nanocasting technique. By using this technique, we obtained structure-controlled (SC) RuO2 with a high surface area and an ordered porous structure, which created enhanced electrocatalytic properties over commercial RuO2 nanoparticles for both oxygen and chlorine evolution reactions.