Release Of Molecules Research Articles

Fiber from elicited butternut pumpkin (Cucurbita moschata D. cv. Ariel) modulates the human intestinal microbiota dysbiosis

Elicited pumpkin was evaluated as a potential daily consumption product able to modulate the gut microbiota. An in vitro dynamic colonic fermentation performance with microbiota from obese volunteers was used. Prebiotic effects were observed after the pumpkin treatment. Bifidobacterium abundance was maintained during the treatment period whereas Lactobacillus increased in the transversal and descending colon. Conversely, Enterobacteriaceae and Clostridium groups were more stable, although scarce decreasing trends were observed for same species. Increments of Lactobacillus acidophilus and Limosilactobacillus fermentum (old Lactobacillus fermentum) were observed in the whole colonic tract after the treatment period. However, modulatory effects were mainly observed in the transversal and descending colon. Diverse bacteria species were increased, such as Akkermansia muciniphila, Bacteroides dorei, Cloacibacillus porcorum, Clostridium lactatifermentans, Ruminococcus albus, Ruminococcus lactaris, Coprococcus catus, Alistipes shahii or Bacteroides vulgatus. The prebiotic effect of the elicited pumpkin was provided by the fiber of the pumpkin, suggesting a release of pectin molecules in the transversal and distal colonic tract through low cellulosic fiber degradation, explaining the increases in the total propionic and butyric acid in these colonic sections. Also, a possible modulatory role of carotenoids from the sample was suggested since carotenes were found in the descending colon. Hence, the results of this research highlighted pumpkin as a natural product able to modulate the microbiota towards a healthier profile.

Application of alginate saline gel for drug delivery, cancer treatment and wound dressing

Development of new drug delivery system has attracted much attention. Alginate has been widely used in the field of drug delivery due to its biocompatibility, degradability and non-toxicity. Alginate can be gelated and crosslinked through the exchange of sodium ions and polyvalent cations, and the resulting crosslinked hydrogels can be used for controlled release of bioactive molecules. Alginate polysalts also have biological inertness and structural stability, which can make anti-tumor drug efficacy better predictive. Alginate gel-based composite system can improve drug efficacy and reduce adverse reactions, so that it is widely used in the treatment of cancer. Based on the basic properties of alginate and the preparation of cross-linking methods, this research aims to discuss alginate brine gel composite system and its application status in cancer treatment and wound dressing, in order to provide reference for the development and research of alginate composite hydrogel for drug delivery in the future. Of course, alginate also has some disadvantages, such as high hydrophilicity will affect cell adhesion and proliferation, which also limits its use for cell delivery. Therefore, it needs to develop more advantageous alginate composite hydrogels in the application of biomedicine.

The bispecific B7H3xCD3 antibody CC-3 induces T cell immunity against bone and soft tissue sarcomas

Sarcomas are rare and heterogeneous malignancies that are difficult to treat. Approximately 50% of patients diagnosed with sarcoma develop metastatic disease with so far very limited treatment options. The transmembrane protein B7-H3 reportedly is expressed in various malignancies, including different sarcoma subtypes. In several cancer entities B7-H3 expression is associated with poor prognosis. In turn, B7-H3 is considered a promising target for immunotherapeutic approaches. We here report on the preclinical characterization of a B7-H3xCD3 bispecific antibody in an IgG-based format, termed CC-3, for treatment of different sarcoma subtypes. We found B7-H3 to be expressed on all sarcoma cells tested and expression on sarcoma patients correlated with decreased progression-free and overall survival. CC-3 was found to elicit robust T cell responses against multiple sarcoma subtypes, resulting in significant activation, release of cytokines and effector molecules. In addition, CC-3 promoted T cell proliferation and differentiation, resulting in the generation of memory T cell subsets. Finally, CC-3 induced potent target cell lysis in a target cell restricted manner. Based on these results, a clinical trial evaluating CC-3 in soft tissue sarcoma is currently in preparation.

Fabrication of Rhenium Disulfide/Mesoporous Silica Core-Shell Nanoparticles for a pH-Responsive Drug Release and Combined Chemo-Photothermal Therapy.

A stimuli-responsive drug delivery nanocarrier with a core-shell structure combining photothermal therapy and chemotherapy for killing cancer cells was constructed in this study. The multifunctional nanocarrier ReS2@mSiO2-RhB entails an ReS2 hierarchical nanosphere coated with a fluorescent mesoporous silica shell. The three-dimensional hierarchical ReS2 nanostructure is capable of effectively absorbing near-infrared (NIR) light and converting it into heat. These ReS2 nanospheres were generated by a hydrothermal synthesis process leading to the self-assembly of few-layered ReS2 nanosheets. The mesoporous silica shell was further coated on the surface of the ReS2 nanospheres through a surfactant-templating sol-gel approach to provide accessible mesopores for drug uploading. A fluorescent dye (Rhodamine B) was covalently attached to silica precursors and incorporated during synthesis in the mesoporous silica walls toward conferring imaging capability to the nanocarrier. Doxorubicin (DOX), a known cancer drug, was used in a proof-of-concept study to assess the material's ability to function as a drug delivery carrier. While the silica pores are not capped, the drug molecule loading and release take advantage of the pH-governed electrostatic interactions between the drug and silica wall. The ReS2@mSiO2-RhB enabled a drug loading content as high as 19.83 mg/g doxorubicin. The ReS2@mSiO2-RhB-DOX nanocarrier's cumulative drug release rate at pH values that simulate physiological conditions showed significant pH responsiveness, reaching 59.8% at pH 6.8 and 98.5% and pH 5.5. The in vitro testing using HeLa cervical cancer cells proved that ReS2@mSiO2-RhB-DOX has a strong cancer eradication ability upon irradiation with an NIR laser owing to the combined drug delivery and photothermal effect. The results highlight the potential of ReS2@mSiO2-RhB nanoparticles for combined cancer therapy in the future.

The immune response to systemically administered endotoxin in the murine intestinal microcirculation under pentobarbital versus isoflurane anesthesia.

Pentobarbital and isoflurane are commonly used veterinary anesthetics. Due to the dangers of overdose by repeat-bolus regimen of pentobarbital, isoflurane has been recommended. However, literature suggests isoflurane-induced inhibition of cytokine and adhesion molecule release, impacting leukocyte adhesion. This study aims to characterize the impacts of pentobarbital versus isoflurane on leukocyte interactions within the intestinal microcirculation with and without endotoxin challenge. Female BALB/c mice were subjected to pentobarbital or isoflurane (N = 20) and challenged with endotoxin or saline by intraperitoneal injection. The mice were kept under anesthesia for 2 hours. Fluorochromes, rhodamine-6 G and fluorescein isothiocyanate, were injected intravenously. To visualize leukocyte adhesion within the intestinal microcirculation, laparotomy and intravital microscopy was performed. Leukocyte rolling and adhesion was quantified offline in a blinded fashion. Within collecting venules, leukocyte rolling and adhesion showed no significant differences between pentobarbital and isoflurane anesthesia under basal conditions. Endotoxin challenge caused a similar response in both anesthetic groups. Within postcapillary venules, no statistical differences between the two anesthetics were found for adhering leukocytes under basal conditions or following endotoxin challenge either. However, leukocyte rolling after LPS-challenge was significantly decreased in postcapillary venules during isoflurane anesthesia compared to pentobarbital anesthesia. Isoflurane anesthesia showed only minor differences in the immune response to endotoxin within the intestinal microcirculation compared to pentobarbital anesthesia. Due to the superior safety profile of volatile anesthetics, immunological studies may choose isoflurane over pentobarbital as the veterinary anesthetic of choice.

Redox-mediated ion separation and exchange by tailored design of immobilized metallopolymers

Mining and harvesting of valuable components from water or organic phases are urgent challenges. Metallopolymers can show excellent control of the binding and release of target molecules or ions without additional external chemical inputs. Here, we report the covalent functionalization of porous polystyrene microparticles with poly(hydroxyethyl methacrylate) (PHEMA) and poly(ferrocenylmethyl methacrylate) (PFMMA) copolymers and block copolymers via surface-initiated living anionic polymerization to tailor the functionality and polarity of the surface. The metallopolymer-decorated particles were characterized by infrared spectroscopy, scanning electron microscopy, and energy-dispersive X-ray spectroscopy, and the redox-responsiveness was analyzed in different media using cyclic voltammetry. The variation in polarity enabled the investigation of the influence of polarity on the electrochemical performance. The metallopolymer particles were used as efficient ion-adsorbers and ion-exchange materials in both static and flow measurements, and the resulting findings were compared to homopolymer functionalized particles. The adsorption of fluoride, nitrate, and sulfate and their adsorption selectivity were investigated. The capacity of sulfate was increased for hydrophilic particles and remained more constant over time. The results demonstrate the importance of the controlled design of surfaces for tailoring the selectivity of ion-adsorption materials. The insights on the structure-property relation of the metallopolymer design and immobilization pave the way for new adsorption technologies and future design of electrochemically switchable surfaces.

Porous PbBr2 Films Modulation by Indium Tribromide Additive for the Fabrication of SnO2-based CsPbBr3 Perovskite Solar Cells

The achievement of complete conversion of PbBr2 films presents a significant challenge in the development of CsPbBr3 films with consistent growth, comprehensive coverage, and controllable components. To address this challenge, introducing a porous structure in the planar PbBr2 film is advantageous for facilitating the immersion of CsBr precursor, thereby reducing impurity phase formation and mitigating strain caused by the film volume expansion. In order to accomplish this, indium tribromide (InBr3) was employed as an additive and the InBr3(DMF)3 adduct was utilized to expedite the release of organic molecules in PbBr2(DMF), resulting in the transformation of planar PbBr2 film into porous structures. The growth orientation of PbBr2 crystals was altered by this transformation, effectively suppressing the generation of metallic Pb impurities in the film. Additionally, it not only optimizes the morphology of CsPbBr3 film but also reduces impurity phase. As a result, the InBr3:CsPbBr3 perovskite solar cell achieved an efficiency of 7.28%. The majority of In3+ ions were concentrated near the buried interface between SnO2 and InBr3:CsPbBr3, leading to significant improvements in both non-radiative recombination defect states within the perovskite film and electron injection and collection capabilities within the device.

Copper Sulfide-based Hollow Nanoarchitectonics for Augmented Photothermal, Chemodynamic, and Chemotherapeutic Modalities

Cancer has become one of the dreadful ailments, accounting for millions of mortalities every year. Despite the advancements, it remains one of the appalling diseases, with numerous casualties due to delayed prognosis and poor survival rate. To this end, combinatorial strategies have garnered enormous interest in improved performance. This study aims to investigate the fabrication of transition metal-based hollow nanoarchitectures for synergistic augmented photothermal (PTT), chemodynamic (CDT), and chemotherapeutic (CT) modalities. Initially, copper sulfide nanoparticles with hollow cavities (hCuS) are synthesized using the facile sacrificial templating-based approach and subsequently loaded with the CT agent (Doxorubicin, DOX), referred to shortly as hCuS-DOX. These hCuS-DOX nanoarchitectures are systematically characterized using various techniques to successfully explore the physicochemical properties. The DOX molecules are encapsulated in hCuS containers through the electrostatic interactions due to their contrary charges and coordination interactions between copper in CuS and nitrogen in DOX molecules. These innovative nanoarchitectures showed pH-responsive release of DOX molecules from the hollow cavities, specifically in the tumor, which could be through the protonation of DOX and progressive degradation of hCuS. In addition, these architectures exhibited substantial PTT properties, on the one hand, by raising the temperature to over 60 °C. On the other hand, the released DOX molecules supported the CDT effect by generating enormous levels of deadly free radical species intracellularly, significantly reducing the viability of 4T1 cells. Finally, the apoptosis assay based on calcein AM/propidium iodide staining using various combinations validated the synergistic therapeutic modalities. In summary, these nanoarchitectures potentiated the synergistic therapeutic efficacy against breast carcinoma towards their ability in pharmaceutics.

MIF Inhibition Attenuates Intervertebral Disc Degeneration by Reducing Nucleus Pulposus Cell Apoptosis and Inflammation

Nucleus pulposus cells (NPCs) apoptosis and inflammation are the extremely critical factors of intervertebral disc degeneration (IVDD). Nevertheless, the underlying procedure remains mysterious. Macrophage migration inhibitory factor (MIF) is a cytokine that promotes inflammation and has been demonstrated to have a significant impact on apoptosis and inflammation. For this research, we employed a model of NPCs degeneration stimulated by lipopolysaccharides (LPS) and a rat acupuncture IVDD model to examine the role of MIF in vitro and in vivo, respectively. Initially, we verified that there was a significant rise of MIF expression in the NP tissues of individuals with IVDD, as well as in rat models of IVDD. Furthermore, this augmented expression of MIF was similarly evident in degenerated NPCs. Afterward, it was discovered that ISO-1, a MIF inhibitor, effectively decreased the quantity of cells undergoing apoptosis and inhibited the release of inflammatory molecules (TNF-α, IL-1β, IL-6). Furthermore, it has been shown that the PI3K/Akt pathway plays a vital part in the regulation of NPCs degeneration by MIF. Ultimately, we showcased that the IVDD process was impacted by the MIF inhibitor in the rat model. In summary, our experimental results substantiate the significant involvement of MIF in the degeneration of NPCs, and inhibiting MIF activity can effectively mitigate IVDD.

High-Intensity Focused Ultrasound-Induced Disulfide Mechanophore Activation in Polymeric Nanostructures for Molecule Release

High-Intensity Focused Ultrasound-Induced Disulfide Mechanophore Activation in Polymeric Nanostructures for Molecule Release

Molecular Mechanisms and Cytopathology of Phytophthora: Strategies, Interactions and Future Perspectives

Phytophthora is an aggressive plant pathogen, pose substantial threats to global agriculture, leading to extensive crop losses. Controlling Phytophthora diseases remains challenging, with limited effective methods available. Host resistance emerges as a promising strategy, but its sustainability hinges on a profound comprehension of the intricate molecular dynamics governing Phytophthora-plant interactions. These interactions unveil a hemi-biotrophic lifestyle of Phytophthora, transitioning from biotrophic to necrotrophic phases during infection. The infection process involves a series of orchestrated events, including chemotactic attraction, penetration, and sporulation on the host surface. Molecular cytology elucidates a sophisticated interplay between Phytophthora and plant defense mechanisms. Phytophthora elicits defense responses in host plants through the release of elicitor molecules, triggering PAMP Triggered Immunity (PTI) responses such as antimicrobial compound production and cell wall fortification. Detection and recognition of Phytophthora effectors instigate a second layer of defense in resistant plants, leading to Effector Triggered Immunity (ETI) and hypersensitive response. In response, virulent strains evolve altered effectors to evade detection and suppress host defenses, underscoring the ongoing molecular coevolution between Phytophthora and plants. The pathogenic success of Phytophthora species is attributed to their diverse and rapidly evolving effector gene complements, targeting various host proteins and cellular processes. Future strategies for combating Phytophthora diseases include genome editing using CRISPR/Cas-9 technology to enhance plant immunity and the identification of non-race-specific resistance sources for broad-spectrum protection. In essence, a comprehensive understanding of Phytophthora-plant interactions at the molecular level is imperative for devising effective strategies to mitigate their impact on global agriculture.

Linking of Chemical Reactions and Silica Nanoparticle Contact Using Synthetic Helical Molecules

Comprehensive SummaryBiological cells exhibit diverse phenomena induced through linking of chemical reactions of molecules and solid surface contact. It is then a significant topic in the field of chemistry to study phenomena induced through this linking using synthetic systems, which can promote our understanding of biological phenomena and can be applied to the development of novel functions. Silica nanoparticles (SNPs), which are synthetic inorganic materials, are attractive for such purposes, because of their following characteristics: they can adsorb large amounts of molecules on their surfaces, they can aggregate through contact between SNPs as well as contact between molecules and SNPs, and the molecules can be easily removed from solutions by precipitation. The contact of SNP surfaces with molecules then affects chemical reactions of molecules and also behaviors of SNPs. This article describes systems derived from synthetic helical molecules and SNPs, which exhibit notable phenomena including selective adsorption and molecular recognition, equilibrium shift, step kinetics with induction period, precipitation with flow and sweeping, and disaggregation and desorption by sonication, in which the high affinity of helical molecules with SNP surfaces plays important roles. Mechanistic models that explain the phenomena are provided. Possible applications are also discussed, including the separation of molecules, capture of intermediates, the storage and release of molecules, equilibrium shift, clocking, and the translation of mechanical stimulations into chemical reactions. Key Scientists

The Ability of Clinically Relevant Chemotherapeutics to Induce Immunogenic Cell Death in Squamous Cell Carcinoma.

Immunogenic cell death (ICD) is a crucial mechanism for triggering the adaptive immune response in cancer patients. Damage-associated molecular patterns (DAMPs) are critical factors in the detection of ICD. Chemotherapeutic drugs can cause ICD and the release of DAMPs. The aim of this study was to assess the potential for paclitaxel and platinum-based chemotherapy regimens to induce ICD in squamous cell carcinoma (SCC) cell lines. In addition, we examined the immunostimulatory effects of clinically relevant chemotherapeutic regimens utilized in the treatment of SCC. We screened for differentially expressed ICD markers in the supernatants of three SCC cell lines following treatment with various chemotherapeutic agents. The ICD markers included Adenosine Triphosphate (ATP), Calreticulin (CRT), Annexin A1 (ANXA 1), High Mobility Group Protein B1 (HMGB1), and Heat Shock Protein 70 (HSP70). A vaccination assay was also employed in C57BL/6J mice to validate our in vitro findings. Lastly, the levels of CRT and HMGB1 were evaluated in Serum samples from SCC patients. Addition of the chemotherapy drugs cisplatin (DDP), carboplatin (CBP), nedaplatin (NDP), oxaliplatin (OXA) and docetaxel (DOC) increased the release of ICD markers in two of the SCC cell lines. Furthermore, mice that received vaccinations with cervical cancer cells treated with DDP, CBP, NDP, OXA, or DOC remained tumor-free. Although CBP induced the release of ICD-associated molecules in vitro, it did not prevent tumor growth at the vaccination site in 40% of mice. In addition, both in vitro and in vivo results showed that paclitaxel (TAX) and LBP did not induce ICD in SCC cells. The present findings suggest that chemotherapeutic agents can induce an adjuvant effect leading to the extracellular release of DAMPs. Of the agents tested here, DDP, CBP, NDP, OXA and DOC had the ability to act as inducers of ICD.

THE BENEFICIAL EFFECTS OF PROPOLIS ON OSTEOBLAST DIFFERENTIATION: A LITERATURE REVIEW

Introduction: Optimal bone regeneration is contingent upon the activities of osteoblasts, which are modulated by signalling molecules. Propolis, an abundantly beneficial natural substance, has the potential to induce the release of signalling molecules. Review: Four essential elements required for tissue regeneration via tissue engineering: scaffolds, signalling molecules, stem cells, and vascularization. Subsequently, osteoblast differentiation and activity are enhanced by signalling molecules induced by propolis. Propolis contains active ingredients that influence every stage of osteoblast differentiation. Propolis-induced increases in the release of signalling molecules (BMP, FGF, TGF) and the transcription factor RUNX2 stimulate the expression of diverse osteoblastogenic markers at each stage of differentiation: type I alpha 1 collagen during proliferation, alkaline phosphatase during maturation, and osteocalcin during mineralization. Conclusion: Propolis has the capacity to promote bone regeneration through its involvement in all phases of osteoblast differentiation (inducing the release of signalling molecules, increasing the transcription factor, and increasing the expression of osteoblastogenic markers). Additional research is required to determine how propolis influences the equilibrium between osteoblast and osteoclast activities in order to maintain optimal bone homeostasis and remodelling. The prolonged duration of bone regeneration necessitates the use of a carrier for propolis to remain on bone defects for an extended period of time.

Graph neural networks-based prediction of drug gene association of P2X receptors in periodontal pain

The P2X7 receptor, a member of the P2X receptor family, plays a crucial role in various physiological processes, particularly pain perception. Its expression across immune, neuronal, and glial cells facilitates the release of pro-inflammatory molecules, thereby influencing pain development and maintenance, as evidenced by its association with pulpitis in rats. Notably, P2X receptors such as P2X3 and P2X7 are pivotal in dental pain pathways, making them promising targets for novel analgesic interventions. Leveraging graph neural networks (GNNs) presents an innovative approach to model graph data, aiding in the identification of drug targets and prediction of their efficacy, complementing advancements in genomics and proteomics for therapeutic development. In this study, 921 drug-gene interactions involving P2X receptors were accessed through https://www.probes-drugs.org/. These interactions underwent meticulous annotation, preprocessing, and subsequent utilization to train and assess GNNs. Furthermore, leveraging Cytoscape, the CytoHubba plugin, and other bioinformatics tools, gene expression networks were constructed to pinpoint hub genes within these interactions. Through analysis, SLC6A3, SLC6A2, FGF1, GRK2, and PLA2G2A were identified as central hub genes within the context of P2X receptor-mediated drug-gene interactions. Despite achieving a 65 percent accuracy rate, the GNN model demonstrated suboptimal predictive power for gene-drug interactions associated with oral pain. Hence, further refinements and enhancements are imperative to unlock its full potential in elucidating and targeting pathways underlying oral pain mechanisms.

Force-controlled release of small molecules with a rotaxane actuator

Force-controlled release of small molecules offers great promise for the delivery of drugs and the release of healing or reporting agents in a medical or materials context1–3. In polymer mechanochemistry, polymers are used as actuators to stretch mechanosensitive molecules (mechanophores)4. This technique has enabled the release of molecular cargo by rearrangement, as a direct5,6 or indirect7–10 consequence of bond scission in a mechanophore, or by dissociation of cage11, supramolecular12 or metal complexes13,14, and even by ‘flex activation’15,16. However, the systems described so far are limited in the diversity and/or quantity of the molecules released per stretching event1,2. This is due to the difficulty in iteratively activating scissile mechanophores, as the actuating polymers will dissociate after the first activation. Physical encapsulation strategies can be used to deliver a larger cargo load, but these are often subject to non-specific (that is, non-mechanical) release3. Here we show that a rotaxane (an interlocked molecule in which a macrocycle is trapped on a stoppered axle) acts as an efficient actuator to trigger the release of cargo molecules appended to its axle. The release of up to five cargo molecules per rotaxane actuator was demonstrated in solution, by ultrasonication, and in bulk, by compression, achieving a release efficiency of up to 71% and 30%, respectively, which places this rotaxane device among the most efficient release systems achieved so far1. We also demonstrate the release of three representative functional molecules (a drug, a fluorescent tag and an organocatalyst), and we anticipate that a large variety of cargo molecules could be released with this device. This rotaxane actuator provides a versatile platform for various force-controlled release applications.

Blood Adhesion Molecules as Biomarkers in Children with Chronic Urticaria.

The prevailing etiological model of both acute and chronic urticaria implicates specific allergen exposure that triggers the local release of vasoactive factors and inflammatory adhesion molecules, including vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), endothelial leukocyte adhesion molecule 1 (ELAM-1), P-selectin and E-selectin in the superficial dermis. This study focused on the possible role of VCAM-1 and ICAM-1 as biomarkers in children with acute and chronic urticaria. This study involved 184 children, 40 with acute urticaria, 71 with chronic urticaria, and 73 matched comparison subjects. The serum levels of ICAM-1 and VCAM-1 were determined in venous blood in all the participants on enrollment. Antihistamine treatment was administered to all the patients. In the children with chronic urticaria, the Urticaria Activity Score Questionnaire (UAS7) was completed daily by the parents. In 16 of the patients with acute urticaria and 43 with chronic urticaria, the serum levels of ICAM-1 and VCAM-1 were determined at follow-up after 6-8 weeks of treatment. The mean serum levels of both VCAM-1 and ICAM-1 were higher in both groups of children with urticaria than in the comparison subjects at the start of the study. In the chronic urticaria group, the levels decreased significantly (p = 0.03 and p = 0.01, respectively) following treatment. Similarly, the acute urticaria group exhibited significant reduction in the mean levels of VCAM and ICAM (p < 0.001). In both groups, the mean level of ICAM after treatment was comparable with that of the comparison group. VCAM-1 and ICAM-1 are suggested as promising biomarkers for monitoring both acute and chronic urticaria in children. Future research should explore their utility in larger cohorts and investigate their role in personalized treatment strategies.

Abstract CT078: Phase 1 study of SGN-EGFRd2 in solid tumors (SGNEGFRd2-001)

Abstract Background: Epidermal growth factor receptor (EGFR) is a cell surface receptor expressed in a variety of solid tumors. Gamma delta (γδ)-T cells represent a conserved T cell subset that can induce cell death in a wide range of malignancies. The presence of γ9δ2-T cells in solid tumors strongly correlates with better patient survival (Gentles 2015; Tosolini 2017). In addition to direct, potent killing by release of cytotoxic molecules, activated γ9δ2-T cells process and present antigen and contribute to a cascade response resulting in downstream activation of innate and adaptive immune cells to mediate further tumor cell killing (Brandes 2005; Devilder 2006; Vantourout 2013). Novel approaches that improve targeting and activation of γ9δ2-T cells may lead to the development of effective and safe cancer treatments. SGN-EGFRd2 is an investigational, bispecific humanized heavy chain-only antibody (HcAb). Advantages of HcAbs include their small size, high solubility, high stability, and excellent tissue penetration in vivo (Bannas 2017). SGN-EGFRd2 simultaneously binds EGFR and the γ9δ2-T cell receptor, resulting in the conditional activation of γ9δ2-T cells. Importantly, full activation of γ9δ2-T cells requires a secondary phosphoantigen stress signal present only in malignant and certain infected cells (Deseke 2020; Herrmann 2020; Rigau 2020; Vantourout 2013), but not normal healthy cells, conferring preferential tumor-directed cytotoxicity. The proposed cytotoxic mechanism of action is independent of KRAS and BRAF mutations (King 2023) known to confer resistance to approved anti-EGFR therapies in colorectal cancer (CRC). This first-in-human study is evaluating the safety, tolerability, and antitumor activity of SGN-EGFRd2 in patients with advanced solid tumors. Methods: SGNEGFRd2-001 (NCT05983133) is an open-label, multicenter, phase 1, dose escalation and expansion study evaluating SGN-EGFRd2 monotherapy in patients with relapsed/refractory (R/R) CRC, head and neck squamous cell cancer, non-small cell lung cancer, and pancreatic ductal adenocarcinoma in 3 parts: dose escalation (Part A; n ~ 75), dose optimization (Part B; optional; up to n = 40), and dose expansion (Part C; up to n = 160). Patients must have R/R disease, or be intolerant to standard of care therapies, with no appropriate standard therapy available. Patients must have measurable disease per RECIST v1.1, an ECOG performance status of 0 or 1, and adequate organ function. Patients are eligible regardless of tumor EGFR expression or EGFR/KRAS/BRAF mutation status. Patients will receive SGN-EGFRd2 as an intravenous infusion. Primary study objectives are safety and tolerability, maximum tolerated dose, and recommended dose and schedule. Secondary objectives include pharmacokinetics, immunogenicity, and antitumor activity. Tumor samples will be analyzed for exploratory biomarkers. Accrual is ongoing in the US. Additional sites in Europe and Canada are planned. Citation Format: Hirva Mamdani, Joel Randolph Hecht, Rachel E. Sanborn, Maria Corinna Palanca-Wessels, Mingjin Yan, Martin Gutierrez, David L. Bajor. Phase 1 study of SGN-EGFRd2 in solid tumors (SGNEGFRd2-001) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT078.

Deconvoluting the Effect of Cell-Penetrating Peptides for Enhanced and Controlled Insertion of Large-Scale DNA Nanopores.

DNA nanopores have emerged as powerful tools for molecular sensing, but the efficient insertion of large DNA nanopores into lipid membranes remains challenging. In this study, we investigate the potential of cell-penetrating peptides (CPPs), specifically SynB1 and GALA, to enhance the insertion efficiency of large DNA nanopores. We constructed SynB1- or GALA-functionalized DNA nanopores with an 11 nm inner diameter and visualized and quantified their membrane insertion using a TIRF microscopy-based single-liposome assay. The results demonstrated that incorporating an increasing number of SynB1 or GALA peptides into the DNA nanopore significantly enhanced the membrane perforation. Kinetic analysis revealed that the DNA nanopore scaffold played a role in prearranging the CPPs, which facilitated membrane interaction and pore formation. Notably, the use of pH-responsive GALA peptides allowed highly efficient and pH-controlled insertion of large DNA pores. Furthermore, single-channel recording elucidated that the insertion process of single GALA-modified nanopores into planar lipid bilayers was dynamic, likely forming transient large toroidal pores. Overall, our study highlights the potential of CPPs as insertion enhancers for DNA nanopores, which opens avenues for improved molecule sensing and the controlled release of cargo molecules.

Tobacco smoke condensate-induced senescence in endothelial cells was ameliorated by colchicine treatment via suppression of NF-κB and MAPKs P38 and ERK pathways activation

Smoking is the major cause of cardiovascular diseases and cancer. It induces oxidative stress, leading to DNA damage and cellular senescence. Senescent cells increase the expression and release of pro-inflammatory molecules and matrix metalloproteinase, which are known to play a vital role in the initiation and progression of cardiovascular diseases and metastasis in cancer. The current study investigated the smoking induced cellular senescence and employed colchicine that blocked senescence in endothelial cells exposed to tobacco smoke condensate. Colchicine prevented oxidative stress and DNA damage in tobacco smoke-condensate-treated endothelial cells. Colchicin reduced β-gal activity, improved Lamin B1, and attenuated cell growth arrest markers P21 and P53. Colchicine also ameliorated the expression of SASP factors and inhibited the activation of NF-kB and MAPKs P38 and ERK. In summary, colchicine inhibited tobacco smoke condensate-induced senescence in endothelial cells by blocking the activation of NF-kB and MAPKs P38 and ERK.Graphical