Subsequent Escape Research Articles

Decoupling the Failure Mechanism of Li‐Rich Layered Oxide Cathode During High‐Temperature Storage in Pouch‐Type Full‐Cell: A Practical Concern on Anionic Redox Reaction

AbstractIn addressing the global climate crisis, the energy storage performance of Li‐ion batteries (LIBs) under extreme conditions, particularly for high‐energy‐density Li‐rich layered oxide (LRLO) cathode, is of the essence. Despite numerous researches into the mechanisms and optimization of LRLO cathodes under ideal moderate environment, there is a dearth of case studies on their practical/harsh working environments (e.g., pouch‐type full‐cell, high‐temperature storage), which is a critical aspect for the safety and commercial application. In this study, using pouch‐type full‐cells as prototype investigation target, the study finds the cell assembled with LRLO cathode present severer voltage decay than typical NCM layered cathode after high‐temperature storage. Further decoupling elucidates the primary failure mechanism is the over‐activation of lattice oxidized oxygen (aggravate by high‐temperature storage) and subsequent escape of oxidized oxygen species (On−), which disrupts transition metal (TM) coordination and exacerbates electrolyte decomposition, leading to severe TM dissolution, interfacial film reconstruction, and harmful shuttle effects. These chain behaviors upon high‐temperature storage significantly influence the stability of both electrodes, causing substantial voltage decay and lithium loss, which accelerates full‐cell failure. Although the anionic redox reaction can bring additional energy, but the escape of metastable On− species would introduce new concerns in practical cell working conditions.

NIR-Actuated Ferroptosis Nanomotor for Enhanced Tumor Penetration and Therapy.

Ferroptosis nano-inducers have drawn considerable attention in the treatment of malignant tumors. However, low intratumoral hydrogen peroxide level and complex biological barriers hinder the ability of nanomedicines to generate sufficient reactive oxygen species (ROS) and achieve tumor penetration. Here a near-infrared (NIR)-driven ROS self-supplying nanomotor is successfully designed for synergistic tumor chemodynamic therapy (CDT) and photothermal therapy (PTT). Janus nanomotor is created by the asymmetrical modification of polydopamine (PDA) with zinc peroxide (ZnO2) and subsequent ferrous ion (Fe2+) chelation via the polyphenol groups from the PDA, here refer as ZnO2@PDA-Fe (Z@P-F). ZnO2 is capable of slowly releasing hydrogen peroxide (H2O2) into an acidic tumor microenvironment (TME) providing sufficient ingredients for the Fenton reaction necessary for ferroptosis. Upon NIR laser irradiation, the loaded Fe2+ is released and a thermal gradient is simultaneously formed owing to the asymmetric PDA coating, thus endowing the nanomotor with self-thermophoresis based enhanced diffusion for subsequent lysosomal escape and tumor penetration. Therefore, the release of ferrous ions (Fe2+), self-supplied H2O2, and self-thermophoresis of nanomotors with NIR actuation further improve the synergistic CDT/PTT efficacy, showing great potential for active tumor therapy.

Modeling Multiple Radius Valley Emergence Mechanisms with Multitransiting Systems

Close-in planets smaller than Neptune form two distinct populations composed of rocky super-Earths and sub-Neptunes that may host primordial H/He envelopes. The origin of the radius valley separating these two planet populations remains an open question and has been posited to emerge either directly from the planet formation process or via subsequent atmospheric escape. Multitransiting systems that span the radius valley are known to be useful diagnostics of XUV-driven mass loss. Here, we extend this framework to test XUV-driven photoevaporation, core-powered mass loss, and an accretion-limited primordial radius valley model. Focusing on multitransiting systems allows us to eliminate unobservable quantities that are shared within individual systems such as stellar XUV luminosity histories and the properties of the protoplanetary disk. We test each proposed radius valley emergence mechanism on all 221 known multitransiting systems and calculate the minimum masses of the systems’ enveloped planets to be consistent with the models. We compare our model predictions to 75 systems with measured masses and find that the majority of systems can be explained by any of the three proposed mechanisms. We also examine model consistency as a function of stellar mass and stellar metallicity but find no significant trends. More multitransiting systems with mass characterizations are required before multitransiting systems can serve as a viable diagnostic of radius valley emergence models. Our software for the model evaluations presented herein is available on GitHub and may be applied to future multitransiting system discoveries.

Enhanced muonization by active-sterile neutrino mixing in protoneutron stars

We study νμ−νs and ν¯μ−ν¯s mixing in the protoneutron star (PNS) created in a core-collapse supernova (CCSN). We point out the importance of the feedback on the general composition of the PNS in addition to the obvious feedback on the νμ lepton number. We show that for our adopted mixing parameters δm2∼102 keV2 and sin22θ consistent with the current constraints, sterile neutrino production is dominated by the Mikheyev–Smirnov–Wolfenstein conversion of ν¯μ into ν¯s and that the subsequent escape of ν¯s increases the νμ lepton number, which in turn enhances muonization of the PNS primarily through νμ+n→p+μ−. While these results are qualitatively robust, their quantitative effects on the dynamics and active neutrino emission of core-collapse supernovae should be evaluated by including νμ−νs and ν¯μ−ν¯s mixing in the simulations. Published by the American Physical Society 2024

Kinetic pathway of HIV-1 TAR cotranscriptional folding.

The Trans-Activator Receptor (TAR) RNA, located at the 5'-end untranslated region (5' UTR) of the human immunodeficiency virus type 1 (HIV-1), is pivotal in the virus's life cycle. As the initial functional domain, it folds during the transcription of viral mRNA. Although TAR's role in recruiting the Tat protein for trans-activation is established, the detailed kinetic mechanisms at play during early transcription, especially at points of temporary transcriptional pausing, remain elusive. Moreover, the precise physical processes of transcriptional pause and subsequent escape are not fully elucidated. This study focuses on the folding kinetics of TAR and the biological implications by integrating computer simulations of RNA folding during transcription with nuclear magnetic resonance (NMR) spectroscopy data. The findings reveal insights into the folding mechanism of a non-native intermediate that triggers transcriptional pause, along with different folding pathways leading to transcriptional pause and readthrough. The profiling of the cotranscriptional folding pathway and identification of kinetic structural intermediates reveal a novel mechanism for viral transcriptional regulation, which could pave the way for new antiviral drug designs targeting kinetic cotranscriptional folding pathways in viral RNAs.

Black Carp Mylopharyngodon piceus (Richardson, 1846) Mouth Gape and Size Preference of a Bivalve Prey

Black carp Mylopharyngodon piceus (Richardson, 1846) have been widely used as biological control of snails in aquaculture and were imported to the United States in the 1970s and 1980s for this purpose. Prior research emphasizes the species’ propensity to control gastropods, but since subsequent escape and establishment of black carp in portions of the Mississippi River Basin, concerns now focus on the numerous endangered and endemic bivalve species upon which black carp may predate. Black carp mouth gape may limit predation on larger bivalves, but bite force is also a factor. We used regression of fish length to mouth gape of wild-caught black carp and compared these results to tank forage size preference trials with bivalve prey Corbicula fluminea clams. Wild-caught black carp ranged from 429 to 1580 mm total length, a size range larger than measured in previous studies. Regression of fish length and mouth gape indicated greater variability among sizes, as expected from wild versus cultured populations. Clam consumption was size-dependent. Black carp commonly engulfed but did not consume the largest clams in tank feeding trials. Shell width was a better predictor of successful consumption than length or height. Predation was restricted at sizes less than the mouth gape of test black carp as observed by individuals engulfing but failing to consume prey. This result indicates that either bite force or the pharyngeal apparatus gape (i.e., the distance between the pharyngeal teeth and keratinous pad) limited successful crushing of engulfed shells. Bivalve predation by black carp is limited by both a fish’s ability to engulf prey and the ability to fracture the shell of larger prey items that cannot be broken or swallowed whole. The results of this research may be used to assess potential prey sizes of wild black carp and anticipated effects of predation on bivalve communities.

Qntrolling the LncRNA HULC-Tregs-PD-1 axis inhibits immune escape in the tumor microenvironment

BackgroundImmune escape remains a major challenge in the treatment of malignant tumors. Here, we studied the mechanisms underlying immune escape in the tumor microenvironment and identified a potential therapeutic target. MethodsPathological specimens from patients with liver cancer, soft tissue sarcoma, and liver metastasis of colon cancer were subjected to immunohistochemistry analysis to detect the expression of programmed death-1 (PD-1) in the tumor microenvironment (TME). Additionally, the expression of regulatory T cells (Tregs) and long non-coding RNAs (lncRNAs), such as highly upregulated in liver cancer (HULC) was evaluated by fluorescence in situ hybridization, and the relationship between HULC, Treg cells, and PD-1 was determined. The animals were divided into H22 hepatic carcinoma and S180 sarcoma groups. Each group was divided into Foxp3−/-C57BL/6J and C57BL/6J mice. Thereafter, mice were inoculated with 0.1 ml S180 sarcoma cells or 0.1 ml H22 hepatoma cells, at a concentration of 1 × 107/ml. The number of splenic CD4+CD25+Foxp3+ T cells was detected by flow cytometry, and serum interleukin-10 (IL-10) and transforming growth factor β1 (TGF-β1) levels were detected using a Luminex liquid suspension chip. Expression of PD-1, fork head box P3 (Foxp3), and HULC in the TME, were analyzed and the therapeutic effect of inhibiting the lncRNA HULC-Treg-PD-1 axis in malignant tumors was determined. ResultsHigh expression of lncRNA HULC promotes the proliferation of Treg cells and increases PD-1 expression in the tumor microenvironment. The HULC-Treg-PD-1 axis plays an immunosuppressive role and promotes the proliferation of malignant tumors. Knocking out the Foxp3 gene can affect the HULC-Treg-PD-1 axis and reduce PD-1, IL-10, and TGF-β1 expression to control the growth of malignant tumors. ConclusionThe lncRNA HULC-Treg-PD-1 axis promotes the growth of malignant tumors. This axis could be modulated to reduce PD-1, IL-10, and TGF-β1 expression and the subsequent immune escape. The inhibition of immune escape in the tumor microenvironment can be achieved by controlling the LncRNA HULC-Treg-PD-1 axis.

Characterizing airway obstruction syndrome in preterm neonates: A neonatology service study

IntroductionAirway Blockage Syndrome (ABS) comprises a group of clinically recognizable disorders caused by alveolar rupture and subsequent escape of air into tissues where it should not be present. ObjectiveTo characterize the airway blockage syndrome in preterm newborns admitted in a Neonatology Service during the years 2020 and 2021. Materials and methodsA descriptive study was conducted on newborns with a gestational age of less than 36.6 weeks who were treated for ABS. Data collected were statistically processed, represented in tables, and graphs. Results and discussionThe incidence of airway blockage was found to be low. There was a predominance of births from dystocic cesarean delivery (55.5%), late preterm births (78.8%) with birth weight between 2000 and 2499 g (44.4%). Pneumomediastinum (50%) was the most common form of presentation. Diagnosis occurred within the first 24 h of life (88.9%). The 55,6 % did not receive ventilatory therapy, while in ventilated cases, invasive modality predominated, showing optimal recovery in most preterm newborns. ConclusionsVariables most associated with this syndrome were gestational age, birth weight, the newborn's clinical condition at birth, and the use of ventilatory support.

Abstract B038: CD4Th1 cytokine interferon gamma regulates genome profiles and inhibits tumorigenesis of disseminated cancer cells in breast cancer

Abstract Detection and persistence of disseminated cancer cells (DCCs) in the bone marrow (BM) of breast cancer (BC) patients has been identified as a primary source for late recurrence and distant metastasis in multiple organs and the central nervous system. Selective targeting and eradication of DCCs in BM can be of a significant advantage to prevent future recurrence and enhance disease-free survival in BC patients. Unfortunately, no such targeted therapy presently exists. Instead, intense chemotherapy in the adjuvant or neoadjuvant setting are given with the ultimate goal to prevent DCC-driven metastasis in these patients. Clinical studies have confirmed that DCCs have not been effectively eradicated by conventional chemotherapies. DCCs express unique gene signatures that differ from circulating tumor cells (CTC) in BC, but only limited knowledge is available for the genome profiles of DCCs compared to primary and metastatic lesions in BC patients. Here we investigated the detailed gene expression profiles of DCCs compared to primary and metastatic lesions from a murine spontaneous metastasis model and BC patients. Using a two-step immunomagnetic enrichment assay, we were able to successfully isolate highly enriched EpCAM+ DCCs from both the BM aspirates of HER2+ early BC patients and BALB-HER2/neu transgenic (BALB-neuT) spontaneous metastasis mice. RNA sequencing revealed that DCCs from HER2+ BC patients and BALB-neuT mice displayed remarkably similar genomic expression profiles, but both had substantially different profiles when comparing to primary and metastatic lesions. We identified highly enriched signatures in DCCs associated with cancer stemness, epithelial to mesenchymal transition (EMT), cell cycle, cell adhesion, progesterone signaling and cholesterol biosynthesis. Notably, these DCCs showed loss of MHC class I, MHC class II, and CD1d expression leading to a defect in antigen presentation machinery and their subsequent escape from CD4 T, CD8 T, B and NKT-cell mediated clearance. Interestingly, we observed for the first time that anti-tumor CD4Th1 cells, through interferon gamma (IFN-γ) production, upregulated CD1d, MHC class I and II expressions in DCCs leading to high infiltration of CD4Th1, NKT and B cells into the BM to selectively target and eliminate DCC burden. IFN-γ remarkably downregulated stemness, EMT, self-renewing potential and their genome signatures and induced apoptosis and irreversible senescence in DCCs of HER2+ BC patients. Notably, these IFN-γ treated patient DCCs lost their ability to grow into tumors in an immunodeficient NSG mouse model. Collectively, these results provide a detailed genome profile of DCCs from HER2+ BC patients and a novel role for anti-tumor CD4Th1 response in inhibiting DCC-driven tumorigenesis and metastasis. Citation Format: Ganesan Ramamoorthi, Marie Catherine Lee, Krithika Kodumudi, Colin Snyder, Namrata Gautam, Saurabh K. Garg, Shari Pilon-Thomas, Brian Czerniecki. CD4Th1 cytokine interferon gamma regulates genome profiles and inhibits tumorigenesis of disseminated cancer cells in breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B038.

STING-driven activation of T cells: relevance for the adoptive cell therapy of cancer

Adoptive cell therapy (ACT) can successfully treat hema-topoietic cancers but lacks efficacy against solid tumors. This is due to insufficient T cell infiltration, high tumor heterogeneity, frequent antigen loss with subsequent tumor escape, and the immunosup-pressive tumor microenvironment (TME). Alternative methods to boost the anticancer efficacy of adoptively transferred cells are ac-tively pursued. Among adjuvants that are utilized to stimulate anti-cancer immune responses, ligands of the stimulator of interferon genes (STING) pathway have received increasing attention. STING activation can trigger dendritic cell (DC) activation and endogenous immune responses, thereby preventing tumor escape. Activation of the STING pathway in the context of ACT was accordingly associated with improved T cell trafficking and persistence in the TME com-bined with the reduced presence of immunosuppressive cells. Re-cent findings also suggest cell-intrinsic effects of STING ligands on T cells. Activation of the STING signaling pathway was in this regard shown to enhance effector functions of CD4+ and CD8+ T cells, sug-gesting that the STING signaling could be exploited to harness T cell anticancer functions. In this review, we will discuss how the STING signaling can be used to enhance the anticancer efficacy of ACT.

Mechanistic modelling of within-mosquito viral dynamics: Insights into infection and dissemination patterns.

Vector or host competence can be defined as the ability of an individual to become infected and subsequently transmit a pathogen. Assays to measure competence play a key part in the assessment of the factors affecting mosquito-borne virus transmission and of potential pathogen-blocking control tools for these viruses. For mosquitoes, competence for arboviruses can be measured experimentally and results are usually analysed using standard statistical approaches. Here we develop a mechanistic approach to studying within-mosquito virus dynamics that occur during vector competence experiments. We begin by developing a deterministic model of virus replication in the mosquito midgut and subsequent escape and replication in the hemocoel. We then extend this to a stochastic model to capture the between-individual variation observed in vector competence experiments. We show that the dose-response of the probability of mosquito midgut infection and variation in the dissemination rate can be explained by stochastic processes generated from a small founding population of virions, caused by a relatively low rate of virion infection of susceptible cells. We also show that comparing treatments or species in competence experiments by fitting mechanistic models could provide further insight into potential differences. Generally, our work adds to the growing body of literature emphasizing the importance of intrinsic stochasticity in biological systems.

Cytoplasmic SIRT1 promotes paclitaxel resistance in ovarian carcinoma through increased formation and survival of polyploid giant cancer cells.

Therapeutic resistance is a notable cause of death in patients with ovarian carcinoma. Polyploid giant cancer cells (PGCCs), commonly arising in tumor tissues following chemotherapy, have recently been considered to contribute to drug resistance. As a type III deacetylase, Sirtuin1 (SIRT1) plays essential roles in the cell cycle, cellular senescence, and drug resistance. Accumulating evidence has suggested that alteration in its subcellular localization via nucleocytoplasmic shuttling is a critical process influencing the functions of SIRT1. However, the roles of SIRT1 subcellular localization in PGCC formation and subsequent senescence escape remain unclear. In this study, we compared the differences in the polyploid cell population and senescence state of PGCCs following paclitaxel treatment between tumor cells overexpressing wild-type SIRT1 (WT SIRT1) and those expressing nuclear localization sequence (NLS)-mutated SIRT1 (SIRT1NLSmt ). We investigated the involvement of cytoplasmic SIRT1 in biological processes and signaling pathways, including the cell cycle and cellular senescence, in ovarian carcinoma cells' response to paclitaxel treatment. We found that the SIRT1NLSmt tumor cell population contained more polyploid cells and fewer senescent PGCCs than the SIRT1-overexpressing tumor cell population. Comparative proteomic analyses using co-immunoprecipitation (Co-IP) combined with liquid chromatography-mass spectrometry (LC-MS)/MS showed the differences in the differentially expressed proteins related to PGCC formation, cell growth, and death, including CDK1 and CDK2, between SIRT1NLSmt and SIRT1 cells or PGCCs. Our results suggested that ovarian carcinoma cells utilize polyploidy formation as a survival mechanism during exposure to paclitaxel-based treatment via the effect of cytoplasmic SIRT1 on PGCC formation and survival, thereby boosting paclitaxel resistance. © 2023 The Pathological Society of Great Britain and Ireland.

Truth in Fiction is Truth Infection: A Study of Emma Donoghue’s Room

Inspired by the 2008 Austrian case of Fritzl, who locked his daughter in a basement for twenty-four years, raped her repeatedly and fathered her seven children, three of whom he imprisoned with her, Emma Donoghue’s Room (2010) is not a mere retelling of the actual story of kidnap and escape. Donoghue’s fictional universe is comprised of several possible fictional worlds: a metafictional world that implicitly directs the model reader’s attention to the process of fictive composition, a “superfictional” world that takes the shape of moments of enlightenment, a “subfictional” world that houses the author’s beliefs and memories that are not in focal awareness, and a “nonfictional” world that houses the author’s repressed thoughts that are hidden. The present study aims at unraveling these possible fictional worlds in a novel the naïve reader receives as a five-year-old boy’s account of his confinement and subsequent escape to the outside world.

PH-responsive polyzwitterion covered nanocarriers for DNA delivery

The success of gene therapy relies on gene nanocarriers to achieve therapeutic effects in vivo. Surface shielding of poly(ethylene glycol) (PEG), known as PEGylation, onto gene delivery carriers is a predominant strategy for extending blood circulation and improving therapeutic outcomes in vivo. Nevertheless, PEGylation frequently compromises the transfection efficiency by decreasing the interactions with the cellular membrane of the targeted cells, thereby preventing the cellular uptake and the subsequent endosomal escape. Herein, we developed a stepwise pH-responsive polyplex micelle for the plasmid DNA delivery with the surface covered by ethylenediamine-based polycarboxybetaines. This polyplex micelle switched its surface charge from neutral at pH 7.4 to positive at tumorous and endo−/lysosomal pH (i.e., pH 6.5 and 5.5, respectively), thus enhancing the cellular uptake and facilitating the endosomal escape toward efficient gene transfection. Additionally, the polyplex micelle demonstrated prolonged blood circulation as well as enhanced tumor accumulation, leading to highly effective tumor growth suppression by delivering an antiangiogenic gene. These results suggest the usefulness of a pH-responsive charge-switchable shell polymer on the surface of the polyplex micelle for the efficient nucleic acid delivery.

Mutations in the S gene of hepatitis B virus in three generations of patients with chronic hepatitis B.

Failure to neutralize HBsAg and subsequent escape from the host immune system may be caused by HBsAg mutations, particularly in the "a" determinant, which alters the antigenicity of the protein. The purpose of this study was to examine the frequency of S gene mutations in three generations of HBV cases in northeastern Iran. In this study, 90 patients with chronic HBV were assigned to three groups according to the inclusion criteria. The plasma were utilized to extract viral DNA, and the PCR was applied. Direct sequencing and alignment were performed on the S gene, using reference sequence. The results indicated that all HBV genomes were categorized as the genotype D/ayw2. Among 79 point mutations detected, 36.8% were silent, and 56.2% were missense. In the S region, mutations were observed in 88.9% of CHB subjects studied. In the three-generation group, 21.5% of mutations were in the "a" determinant, and 2.6%, 19.5%, and 87.0% of these mutations were observed in antigenic epitopes of CTLs, CD4+, and B cells, respectively. In addition, 56.7% of mutations occurred at Major Hydrophilic Region. S143L and G145R mutations which the most prevalent in the three-generation (36.7%, 20%), and two-generation (42.5%, 20%) groups, related to the failure of HBsAg detection, vaccine, and immunotherapy escape. The findings showed that most of the mutations were concentrated in the B cell epitope. Most CHB cases from the three-generation, especially grandmothers, had HBV S gene mutations and subsequent amino acid mutations, suggesting that these mutations may be critical for pathogenesis and vaccine evasion.

Exploring the Effect of Amphiphile Architecture on Intracellular Protein Delivery Capacity: Dimeric versus Trimeric Amphiphiles.

Carrier-mediated intracellular protein delivery holds tremendous application potential in biology and medicine. The ideal carrier should be well-controlled and cost-effective and able to facilitate robust delivery of diverse types of proteins into the target cells, thus ensuring efficacy in different application scenarios. Here, we describe a modular chemistry approach for generating a small-molecule amphiphile molecular library based on the Ugi four-component reaction under one-pot and mild conditions. Then, two different types of amphiphiles with the dimeric or trimeric architecture were obtained for intracellular protein delivery through in vitro screening test. Depending on the precise adjustment of the hydrophobic tails of amphiphiles, the optimized trimeric amphiphile (TA) exhibited more superior protein loading performance and a higher efficiency of delivering proteins into cells through the endocytosis pathway and subsequent endosomal escape. Furthermore, we demonstrated that the TA could be a universal delivery carrier capable of transporting broad-spectrum proteins, especially for the hard-to-deliver native antibodies, into the cytosol. Overall, we describe a robust amphiphile platform with a well-defined and cost-effective design to improve the cytosolic protein delivery capacity, exhibiting great promise for developing intracellular protein-based therapeutics.

Simple pot modification improves catch efficiency and species composition in a tropical estuary mud crab (Scylla serrata) fishery

Pots are widely used fishing gear type for targeting different crustacean and fish species. Pot entrance size and design are among the most important technical parameters that influence the catch efficiency of certain species. An optimal pot entrance design should allow an efficient entry for the target species while preventing subsequent escape. The tropical estuary pot fishery targeting mud crab (Scylla serrata) in Vembanad Lake, India, employs rectangular pots with rectangular-shaped entrances. Low catch rates for target species and high bycatch rates are observed in this fishery. This study was carried out to investigate if a simple pot modification by extending the entrance of the traditional pots, can improve the catch efficiency of mud crab. Further, we estimated and compared the catch composition in this small-scale fishery using the traditional and modified entrance pots. The results showed that the catch efficiency for all sizes of mud crab is on average more than six times higher with the modified entrance pots compared to the traditional pots (622% (CI: 344–1867%)). However, significant quantities of juvenile crabs are caught in modified pots. Further, the bycatch ratio was significantly reduced for modified compared to the standard entrance pots in this fishery. These results show that such pot modifications have potential to significantly improve the catches in mud crab pot fisheries without increase in capture of bycatch species. However, additional mechanisms for excluding undersized crabs from pot catches should be investigated.

From Tethyan subduction to Arabia-Eurasia continental collision: Multiple geo-thermochronological signals from granitoids in NW Iran

NW Iran, situated between the Arabian and Eurasian plates, carries a record of both Paleo-Tethyan and Neo-Tethyan tectonic evolution. During the Wilson Cycle of Tethys Ocean opening and closing, several episodes of magmatism from Late Paleozoic to latest Cenozoic generated a massive volume of intrusive rocks. These intrusives, which record cooling histories from high-temperatures to final exhumation, are ideal for multiple geo-thermochronological studies. Our new zircon and apatite U-Pb results suggest three regional magmatic events in the Late Carboniferous, mid-Cretaceous and middle Eocene, which could be related to Paleo-Tethys subduction, Neo-Tethys subduction and Neo-Tethyan ridge subduction, respectively. New apatite fission track and (U-Th)/He data reveal post-magmatic cooling and differential exhumation related to subduction and collision. By integrating published regional thermochronological data from northeastern part of the Middle East, a broader tectono-thermal framework is outlined as follows: 1) Cretaceous cooling signals are most pronounced in the Alborz and Caucasus, and reflect back-arc extension during Neo-Tethyan subduction; 2) diachronous Neo-Tethyan evolution led to the Paleocene assemblage of Anatolia in the west, and subduction associated with a late Paleocene-Eocene magmatic flare-up in Iran. Subsequent westward escape of Anatolia and extensive surface uplift were driven by propagation of Arabia-Eurasia collision in the Miocene; 3) Continuous northward indentation of Arabia into Eurasia triggered late Miocene-Pliocene fast exhumation of the Zagros, Alborz and the Caucasus.

Abstract CT100: A new therapeutic cancer vaccine inducing multifunctional immunity, artificial adjuvant vector cells

Abstract Background: Cancer immunotherapy is an effective way of battling cancer, and is based on artificial stimulation of the immune system to attack cancer cells. Although several strategies show successful results, it remains to prevent the subsequent cancer escape from the immune surveillance. The further success depends on a variety of functional effector cell types involved and their sustenance following activation. For this purpose, simultaneous induction of innate and adaptive immunity should be one of ideal strategies. We focus on DCs, which play a pivotal role in determining the quality and magnitude of innate and adaptive immunity. To effectively utilize the DC in situ, we have developed a system using allogeneic cells as artificial adjuvant vector cells (aAVCs), comprised of a CD1d-NKT ligand complex on the cell surface and containing tumor antigen inside of the cells. This approach induces adjuvant effects by combining NKT cell activation with delivery of tumor antigen to DCs in vivo. In addition to linking innate and adaptive immunity, aAVC therapy can lead to efficient trafficking of specific anti-tumor CD8+ T cells to the tumor site and also the formation of long-term memory T cells. This novel design of aAVC therapy is a platform and allows for a replacement of any cancer antigens as the therapeutic package. After completion of the regulatory science consultation for discussing the pharmaceutical quality and the design of a clinical study with PMDA in Japan, we developed the WT1-expressing aAVC (aAVC-WT1) for the clinical application. Methods: This first-in-human, open label, single-center trial involves a bifurcated 3+3 design with aAVC-WT1 dose escalations (1 × 106, 1 × 107, and 1 × 108 per body). The three patients in each cohort had not received any chemotherapy during more than 2 weeks before the therapy and had received aAVC-WT1 intravenously twice in a 4-week interval. Nine of the ten enrolled patients with relapsed and refractory AML underwent complete analysis per-protocol set and were evaluated in our phase I dose-escalation trial of aAVC-WT1. Results: No dose-limiting toxicities were observed, whereas activation of NKT and/or NK cells was observed in all patients. Five patients experienced objective leukemic regression, which correlated with WT1-specific T-cell responses. Paired single-cell RNA and TCR sequencing demonstrated effector CD8+ T cell clones in the bone marrow. Some bone marrow CD8+ T cells underwent transition from pre-existing precursor exhausted T cells to functional T cells or emerged as newly activated T cells, some of which were maintained long-term. These demonstrate the feasibility and safety of aAVC-WT1 therapy and the capacity of this platform to activate both innate and adaptive immunity in humans. Conclusion: aAVC-WT1 therapy showed an acceptable safety profile at doses tested and encouraging signs of clinical response. These data support further development of aAVC-WT1 for patients with AML. Clinical trial registry number: UMIN 000028083. Citation Format: Shin-ichiro Fujii, Toyotaka Kawamata, Kanako Shimizu, Jun Nakabayashi, Satoru Yamasaki, Tomonori Iyoda, Jun Jun Shinga, Michihiro Hidaka, Masanori Nojima, Fumitaka Nagamura, Arinobu Tojo. A new therapeutic cancer vaccine inducing multifunctional immunity, artificial adjuvant vector cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT100.

Neutrophil-Membrane-Coated Biomineralized Metal-Organic Framework Nanoparticles for Atherosclerosis Treatment by Targeting Gene Silencing.

Antisense oligonucleotides (ASOs) are promising tools for gene silencing and have been exploited as therapeutics for human disease. However, delivery of therapeutic ASOs to diseased tissues or cells and subsequent escape from the endosomes and release of ASO in the cytosol remain a challenge. Here, we reported a neutrophil-membrane-coated zeolitic imidazolate framework-8 (ZIF-8) nanodelivery platform (AM@ZIF@NM) for the targeted transportation of ASOs against microRNA-155 (anti-miRNA-155) to the endothelial cells in atherosclerotic lesions. Neutrophil membrane could improve plaque endothelial cells targeting through the interaction between neutrophil membrane protein CD18 and endothelial cell membrane protein intercellular adhesion molecule-1 (ICAM-1). The ZIF-8 "core" provided high loading capacity and efficient endolysosomal escaping ability. Delivery of anti-miR-155 effectively downregulated miR-155 expression and also saved the expression of its target gene BCL6. Moreover, RELA expression and the expression of its downstream target genes CCL2 and ICAM-1 were correspondingly reduced. Consequently, this anti-miR-155 nanotherapy can inhibit the inflammation of atherosclerotic lesions and alleviate atherosclerosis. Our study shows that the designed biomimetic nanodelivery system has great application prospects in the treatment of other chronic diseases.