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Clinical evidence has demonstrated that combining immune checkpoint blockade (ICB) therapy with chemotherapy significantly improves response rates to ICB therapy and therapeutic efficacy in various tumor types. However, a convenient method for achieving synergistic ICB therapy and chemotherapy with precise co-delivery of both agents is still highly desirable. In this study, a strategy for co-delivering small interfering RNA (siRNA) encapsulated in vesicle-like nanoparticles (VNP siRNA ) and chemotherapeutic drugs is aimed to develop. It is discovered that the hydrophilic chemotherapeutic drug mitoxantrone hydrochloride (MTO·2HCl) can be captured into VNP siRNA . The resulting VNP siRNA Cp MTO can simultaneously block immune checkpoints via RNA silencing and induce chemotherapeutic effects on tumor cells. The mechanism of MTO·2HCl is elucidates, captures, and demonstrates the superior therapeutic effect of VNP siRNA Cp MTO through chemo-immunotherapy. This strategy can also be extended to deliver other hydrochloride anticancer drugs, such as doxorubicin hydrochloride (DOX·HCl), for achieving synergistic combination therapy. This study provides a facile strategy for enhancing combined ICB and chemotherapy via co-delivering siRNA and chemotherapeutic drugs, offering a promising approach to cancer treatment., (© 2024 Wiley‐VCH GmbH.)

The past decades have witnessed great strides in phototherapy as an experimental option or regulation-approved treatment in numerous cancer indications. Of particular interest is nanoscale photosensitizer-based phototherapy, which has been established as a prominent candidate for advanced tumor treatment by virtue of its high efficacy and safety. Despite considerable research progress on materials, methods and devices in nanoscale photosensitizing agent-based phototherapy, their mechanisms of action are not always clear, which impedes their practical application in cancer treatment. Hence, from a new perspective, this review elaborates the working mechanisms, involving impairment and moderation effects, of diverse phototherapies on cells, organelles, organs, and tissues. Furthermore, the most current available phototherapy modalities are categorized as photodynamic, photothermal, photo-immune, photo-gas, and radio therapies in this review. A comprehensive understanding of the inferiority and superiority of various phototherapies will facilitate the advent of a new era of cancer phototherapy. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor with a dismal prognosis. Gemcitabine‐based chemotherapy has emerged as a first‐line treatment for PDAC. However, the development of gemcitabine resistance often results in therapeutic failure. In order to uncover the underlying mechanisms of gemcitabine resistance, gemcitabine‐resistant PDAC cell lines and patient‐derived xenograft (PDX) models are established and subjected to RNA sequencing. It is found that CMTM6 is closely related to gemcitabine resistance in PDAC. Multi‐omics analysis revealed that EP300‐mediated H3K27ac modification is involved in the transcriptional activation of CMTM6, which maintains IGF2BP1 expression by preventing its ubiquitination. The m6A reader IGF2BP1 stabilizes the EP300 and MYC mRNAs by recognizing m6A modifications, forming a positive feedback loop that enhances tumor stemness and ultimately contributes to PDAC resistance. The combined application of the EP300 inhibitor inobrodib and gemcitabine exerts a synergistic effect on PDAC. Overall, these findings reveal that the EP300–CMTM6–IGF2BP1 positive feedback loop facilitates gemcitabine resistance via epigenetic reprogramming and the combined use of inobrodib and gemcitabine represents a promising strategy for overcoming chemoresistance in PDAC, warranting further investigation in clinical trials. [ABSTRACT FROM AUTHOR]

Stereoscopic capacities vary widely across the normal population. It has become increasingly apparent, however, that mechanisms underlying stereoscopic depth perception retain a considerable degree of plasticity through adulthood. Here, we contrast the capacity for neurostimulation in the form of continuous theta-burst stimulation (cTBS) over strategically-chosen sites in the visual cortex to bring about improvements in stereoscopic depth perception. cTBS was delivered to occipital cortex (V1/V2), lateral occipital complex (LOC), along with a control site (Cz). We measured performance on depth and luminance discrimination tasks before and after stimulation. We found a significant improvement in depth (but not luminance) discrimination performance following cTBS over LOC. By contrast, cTBS over occipital cortex and Cz did not affect performance on either task. These findings suggest that ventral (lateral-occipital) cortex is a key node for governing plasticity of stereoscopic vision in visually normal human observers. We speculate that cTBS exerts inhibitory influences that may suppress internal noise within the nervous system, leading to an improved read-out of depth features. [ABSTRACT FROM AUTHOR]

Lung cancer remains the most prevalent malignant tumor worldwide and is the leading cause of cancer‐related mortality. Although immune checkpoint blockade has revolutionized the treatment of advanced lung cancer, many patients still do not respond well, often due to the lack of functional T cell infiltration. Adoptive cell therapy (ACT) using expanded immune cells has emerged as an important therapeutic modality. Tumor‐infiltrating lymphocytes (TIL) therapy is one form of ACT involving the administration of expanded and activated autologous T cells derived from surgically resected cancer tissues and reinfusion into patients and holds great therapeutic potential for lung cancer. In this review, TIL therapy is introduced and its suitability for lung cancer is discussed. Then its historical and clinical developments are summarized, and the methods developed up‐to‐date to identify tumor‐recognizing TILs and optimize TIL composition. Some perspectives toward future TIL therapy for lung cancer are also provided. [ABSTRACT FROM AUTHOR]

Background/Objectives: DAPK-1 plays a crucial role among molecules that may be affected by DNA hypermethylation. The aim of this study is to investigate the DNA methylation of DAPK-1 gene in oral potentially malignant disorders (OPMDs) and oral squamous cell carcinoma (OSCC) compared to normal oral epithelium and to evaluate the possible role of methylated DAPK-1 as an indicator of the early onset of malignant transformation of oral potentially malignant disorders. Methods: The paraffin embedded tissue samples were retrieved from the archives of the Department of Oral Medicine/Pathology, School of Dentistry, Aristotle University of Thessaloniki, Greece and St Lukas Hospital of Thessaloniki, Greece during the period of 2014–2019. The tissue samples included 83 OPMDs samples, 39 OSCC samples and 12 samples of normal oral epithelium. The PCR process followed, targeting four different DAPK-1 gene primers. Results: Regarding OSCC, it was found that all 39 OSCCs samples were methylated in DAPK-1 promoter region, whereas only 2 out of 12 normal tissues samples showed DAPK-1 promoter hypermethylation (p < 0.001 Fisher's exact test). A total of 17 out of 83 OPMDs were DAPK-1 methylated (five erosive oral lichen planus samples, three non-dysplastic oral leukoplakias, eight mildly dysplastic oral leukoplakias and one sample belonging to the group of moderately and severely dysplastic oral leukoplakia). Conclusions: Since epigenetic changes occur early in carcinogenesis and are potentially reversible, they could be used as disease biomarkers for diagnosis, prognosis and prediction, as well as therapeutic targets. DAPK-1 methylation is mostly present in the early stages of dysplasia as well as in all cases of oral cancer. [ABSTRACT FROM AUTHOR]

The poor prognosis of triple‐negative breast cancer (TNBC) results from its high metastasis, whereas inflammation accompanied by excessive reactive oxygen species (ROS) is prone to aggravate tumor metastasis. Although photothermal therapy (PTT) has extremely high therapeutic efficiency, the crafty tumor cells allow an increase in the expression of heat shock proteins (HSPs) to limit its effect, and PTT‐induced inflammation is also thought to be a potential trigger for tumor metastasis. Herein, myricetin, iron ions, and polyvinylpyrrolidone were utilized to develop nanomedicines by self‐assembly strategy for the treatment of metastatic TNBC. The nanomedicines with marvelous water solubility and dispersion can inhibit glucose transporter 1 and interfere with mitochondrial function to block the energy supply of tumor cells, achieving starvation therapy on TNBC cells. Nanomedicines with excellent photothermal conversion properties allow down‐regulating the expression of HSPs to enhance the effect of PTT. Interestingly, the broad spectrum of ROS scavenging ability of nanomedicines successfully attenuates PTT‐induced inflammation as well as influences hypoxia‐inducible factors‐1α/3‐phosphoinositide‐dependent protein kinase 1 related pathway through glycometabolism inhibition to reduce tumor cell metastasis. Moreover, the nanomedicines have negligible side effects and good clinical application prospects, which provides a valuable paradigm for the treatment of metastatic TNBC through glycometabolism interference, anti‐inflammation, starvation, and photothermal synergistic therapy. [ABSTRACT FROM AUTHOR]

Major Depressive Disorder (MDD) is a complex, heterogeneous condition affecting millions worldwide. Computational neuropsychiatry offers potential breakthroughs through the mechanistic modeling of this disorder. Using the Kolmogorov theory (KT) of consciousness, we developed a foundational model where algorithmic agents interact with the world to maximize an Objective Function evaluating affective valence. Depression, defined in this context by a state of persistently low valence, may arise from various factors—including inaccurate world models (cognitive biases), a dysfunctional Objective Function (anhedonia, anxiety), deficient planning (executive deficits), or unfavorable environments. Integrating algorithmic, dynamical systems, and neurobiological concepts, we map the agent model to brain circuits and functional networks, framing potential etiological routes and linking with depression biotypes. Finally, we explore how brain stimulation, psychotherapy, and plasticity-enhancing compounds such as psychedelics can synergistically repair neural circuits and optimize therapies using personalized computational models. [ABSTRACT FROM AUTHOR]

The stability of nanoparticle (NP) production by atmospheric-pressure spark ablation was studied and found to depend on the composition of the electrodes and the carrier gas (here N2 or Ar). For materials that do not react with N2, such as Pd and Ni, NP production was rather stable regardless of the carrier gas employed. In contrast, for materials that can easily produce nitride species (e.g., Al and Mg), both the concentration and size of the resulting NPs exhibited noticeable fluctuations, when ablating them in N2, which are more pronounced when the electrical energy input to the system is low. The variation in concentration and particle size is attributed to the formation of a metal-nitride region on the face of the electrodes where the sparks hit, as a result of its reaction with the carrier gas, altering the electrical and thermal conductivity, and consequently the ablatability of the electrode at that region. This explanation was corroborated by offline analysis of the face surface of the electrodes, showing two chemically distinct regions: one with high content of N and one without. In addition, the concentration of the Al and Mg NPs produced in N2 decreased gradually over time until it reached a plateau after several hours. When using Ar, the fluctuation and decreasing trend in NP production, and consequently the formation of nitride compounds on the face surface of the electrodes, were negligible, providing an effective solution for stable ablation of materials that can easily react with N2. [ABSTRACT FROM AUTHOR]

The process of drug discovery and pre‐clinical testing is currently inefficient, expensive, and time‐consuming. Most importantly, the success rate is unsatisfactory, as only a small percentage of tested drugs are made available to oncological patients. This is largely due to the lack of reliable models that accurately predict drug efficacy and safety. Even animal models often fail to replicate human‐specific pathologies and human body's complexity. These factors, along with ethical concerns regarding animal use, urge the development of suitable human‐relevant, translational in vitro models. [ABSTRACT FROM AUTHOR]

Sub-10 nm metal-based nanoparticles have garnered immense interest due to their unique properties and versatile applications. In this study, we created sub-10 nm Ag-based particles with a spark discharge generator and explored the parameters impacting their size distribution and charging properties, including carrier gas flow rates, spark discharge voltage, electrode gap distances, and capacitance. Our findings illuminate that there is a comparable influence of different factors on both self-charged and neutral particles. Among the different factors, carrier gas flow rates emerging as a paramount determinant in particle size. While increasing spark discharge voltage and capacitance within the spark circuit increases particle concentrations, the associated changes in particle size prove to be less straightforward. Significant differences between the concentration of positive and negative self-charged particles manifest when the carrier gas flow rate surpasses 5.0 L min−1, with positive particles ranging from 0.8 to 1.2 nm and negative particles spanning 0.8 to 3.0 nm. Self-charged particles close to 1 nm tend to exhibit positive charges, whereas those larger than 2 nm tend to acquire negative charges, which suggests the growth of negative particles is faster than positive ones in the spark chamber. Nevertheless, these disparities between bipolar particles diminish with the increase of residence time, leading to the observation of similar particle size distributions. Positive particles consistently bear a single charge, while some negative particles exceeding 3 nm exhibit multiple charges, primarily under carrier gas flow rates exceeding 7.5 L min−1. This study provides insights into the control of properties of nano-sized metal particles, which are crucial for their practical utilization. Copyright © 2024 American Association for Aerosol Research [ABSTRACT FROM AUTHOR]

Lithium-sulfur (Li-S) batteries has been regarded as one of the most promising next-generation energy storage systems due to their high theoretical energy density. However, the practical application of Li-S batteries is still hindered by the unstable cathode-electrolyte interphase and the early passivation of charge product (Li 2 S), leading to poor cycling stability and low S utilization. Herein, we propose an electrolyte engineering strategy using highly solvating hexamethylphosphoramide (HMPA) as a co-solvent to elucidate the dissociation-precipitation chemistry of lithium polysulfides (LiPSs). The multimode optical spectroscopies confirm that this electrolyte engineering is able to effectively regulate the solvation of LiPSs to initiate a radical-assisted conversion pathway and control three-dimensional (3D) Li 2 S electrodeposition to boost sulfur utilization. More importantly, the dynamic evolution of cathode-electrolyte interphase, featuring with S-/P-containing species, is also assessed by both distribution of relaxation times technology and X-ray photoelectron spectroscopy, which can suppress the passivation of Li 2 S to enhance conversion reversibility. As a proof-of-concept, a Li-S cell with high S loading mass of 7.75 mg cm -2 demonstrates an extremely high area capacity of 7.86 mAh cm -2 at a current density of 1.30 mA cm -2 , representing a significant advancement in promoting the development of practical high-energy-density Li-S batteries., (© 2025 Wiley-VCH GmbH.)

The evolution of antitumor drug development has transitioned from single-agent chemotherapy to targeted therapy, immunotherapy, and more recently, multispecific drugs. These innovative drugs target multiple cellular or molecular pathways simultaneously, offering a more comprehensive anticancer approach and addressing some of the limitations inherent in traditional monotherapies. However, preclinical assessment of multispecific drugs remains challenging, as conventional tumor models often lack the necessary complexity to accurately reflect the interactions between various cell types and targets. Patient-derived immunocompetent tumor organoids (PDITOs), which incorporate both tumor cells and immune cells, present a promising platform for the evaluation of these drugs. Beyond their use in drug evaluation, PDITOs can also be utilized in personalized drug screening and predicting patient-specific treatment outcomes, thus advancing both multispecific drug development and precision medicine. This perspective discusses the current landscape of multispecific drug development and the methodologies for constructing PDITOs. It also addresses the associated challenges and introduces the concept of employing these organoids to optimize the evaluation and rational design of multispecific drug therapies., (© 2025 Wiley-VCH GmbH.)

Cancer immunotherapy, which aims to eliminate cancer immunosuppression and reactivate anticancer immunity, holds great promise in oncology treatments. However, it is challenging to accurately study the efficacy of immunotherapy based on human-derived cells through animal experiments due to xenogeneic immune rejection. Herein, a personalized and precise strategy to evaluate the effectiveness of immunotherapy using the blood samples of cancer patients is presented. Through the utilization of multiple cancer-targeting delivery system decorated with the epidermal growth factor receptor (EGFR)-specific aptamer CL4 and the AXL-specific aptamer GL21.T to achieve superior efficiency in delivering the genome editing plasmid for MUC1 knockout, effective modulation on the behavior of circulating malignant cells (CMCs) is realized. After genome editing, both mucin 1 (MUC1) and programmed death-ligand 1 (PD-L1) are significantly downregulated in CMCs. The elimination of immunosuppression results in markedly enhanced secretion of pro-inflammatory anticancer cytokines encompassing interleukins 2, 12, and 15 and interferon-γ by immune cells. The study not only provides a strategy to overcome immunosuppression but also yields critical insights for personalized immunotherapy approaches., (© 2024 Wiley‐VCH GmbH.)

Tumor‐initiating cells (TICs) resilience and an immunosuppressive microenvironment are aggressive oncogenic phenotypes that contribute to unsatisfactory long‐term outcomes in lung adenocarcinoma (LUAD) patients. The molecular mechanisms mediating the interaction between TICs and immune tolerance have not been elucidated. The role of Galectin‐9 in oncogenesis and immunosuppressive microenvironment is still unknown. This study explored the potential role of galectin‐9 in TIC regulation and immune modulation in LUAD. The results show that galectin‐9 supports TIC properties in LUAD. Co‐culture of patient‐derived organoids and matched peripheral blood mononuclear cells showed that tumor‐secreted galectin‐9 suppressed T cell cytotoxicity and induced regulatory T cells (Tregs). Clinically, galectin‐9 is upregulated in human LUAD. High expression of galectin‐9 predicted poor recurrence‐free survival and correlated with high levels of Treg infiltration. LGALS9, the gene encoding galectin‐9, is found to be transcriptionally regulated by the nuclear factor of activated T cells 2 (NFATc2), a previously reported TIC regulator, via in silico prediction and luciferase reporter assays. Overall, the results suggest that the NFATc2/galectin‐9 axis plays a dual role in TIC regulation and immune suppression. [ABSTRACT FROM AUTHOR]

Cancer drug testing in animals is an extremely poor predictor of the drug's safety and efficacy observed in humans. Hence there is a pressing need for functional testing platforms that better predict traditional and immunotherapy responses in human, live tumor tissue or tissue constructs, and at the same time are compatible with the use of mouse tumor tissue to facilitate building more accurate disease models. Since many cancer drug actions rely on mechanisms that depend on the tumor microenvironment (TME), such platforms should also retain as much of the native TME as possible. Additionally, platforms based on miniaturization technologies are desirable to reduce animal use and sensitivity to human tissue scarcity. Present high-throughput testing platforms that have some of these features, e.g. based on patient-derived tumor organoids, require a growth step that alters the TME. On the other hand, microdissected tumors (μDTs) or "spheroids" that retain an intact TME have shown promising responses to immunomodulators acting on native immune cells. However, difficult tissue handling after microdissection has reduced the throughput of drug testing on μDTs, thereby constraining the inherent advantages of producing numerous TME-preserving units of tissue for drug testing. Here we demonstrate a microfluidic 96-well platform designed for drug treatment of hundreds of similarly-sized, cuboidal μDTs ("cuboids") produced from a single tumor sample. The platform organizes a monodisperse array of four cuboids per well in 384 hydrodynamic traps. The microfluidic device, entirely fabricated in thermoplastics, features 96 microvalves that fluidically isolate each well after the cuboid loading step for straightforward multi-drug testing. Since our platform makes the most of scarce tumor tissue, it can potentially be applied to human biopsies that preserve the human TME while minimizing animal testing. [ABSTRACT FROM AUTHOR]

The ability to respond to emotional events in a context-sensitive and goal-oriented manner is essential for adaptive functioning. In models of behavioral and emotion regulation, the lateral prefrontal cortex (LPFC) is postulated to maintain goal-relevant representations that promote cognitive control, an idea rarely tested with causal inference. Here, we altered mid-LPFC function in healthy individuals using a putatively inhibitory brain stimulation protocol (continuous theta burst; cTBS), followed by fMRI scanning. Participants performed the Affective Go/No-Go task, which requires goal-oriented action during affective processing. We targeted mid-LPFC (vs. a Control site) based on the individualized location of action-goal representations observed during the task. cTBS to mid-LPFC reduced action-goal representations in mid-LPFC and impaired goal-oriented action, particularly during processing of negative emotional cues. During negative-cue processing, cTBS to mid-LPFC reduced functional coupling between mid-LPFC and nodes of the default mode network, including frontopolar cortex-a region thought to modulate LPFC control signals according to internal states. Collectively, these results indicate that mid-LPFC goal-relevant representations play a causal role in governing context-sensitive cognitive control during emotional processing. [ABSTRACT FROM AUTHOR]

Waning antibody responses after COVID-19 vaccination combined with the emergence of the SARS-CoV-2 Omicron lineage led to reduced vaccine effectiveness. As a countermeasure, bivalent mRNA-based booster vaccines encoding the ancestral spike protein in combination with that of Omicron BA.1 or BA.5 were introduced. Since then, different BA.2-descendent lineages have become dominant, such as XBB.1.5, JN.1, or EG.5.1. Here, we report post-hoc analyses of data from the SWITCH-ON study, assessing how different COVID-19 priming regimens affect the immunogenicity of bivalent booster vaccinations and breakthrough infections (NCT05471440). BA.1 and BA.5 bivalent vaccines boosted neutralizing antibodies and T-cells up to 3 months after boost; however, cross-neutralization of XBB.1.5 was poor. Interestingly, different combinations of prime-boost regimens induced divergent responses: participants primed with Ad26.COV2.S developed lower binding antibody levels after bivalent boost while neutralization and T-cell responses were similar to mRNA-based primed participants. In contrast, the breadth of neutralization was higher in mRNA-primed and bivalent BA.5 boosted participants. Combined, our data further support the current use of monovalent vaccines based on circulating strains when vaccinating risk groups, as recently recommended by the WHO. We emphasize the importance of the continuous assessment of immune responses targeting circulating variants to guide future COVID-19 vaccination policies. Waning immunity and the emergence of the SARS-CoV-2 Omicron lineage led to reduced vaccine effectiveness and required vaccine updates. Here, the authors assess how different priming regimens affect the immunogenicity of BA.1 and BA.5 bivalent boosters. [ABSTRACT FROM AUTHOR]

Eurasian rivers provide a quarter of total fresh water to the Arctic, maintaining a persistent fresh layer that covers the surface Arctic Ocean. This freshwater export controls Arctic Ocean stratification, circulation, and basin-wide sea ice concentration. The Lena River supplies the largest volume of runoff and plays a key role in this system, as runoff outflows into the Laptev Sea as a particularly shallow plume. Previous in situ and modelling studies suggest that local wind forcing is a driver of variability in Laptev sea surface salinity (SSS) but there is no consensus on the roles of Lena River discharge and sea ice cover in contributing to this variability or on the dominant driver of variability. Until recently, satellite SSS retrievals were insufficiently accurate for use in the Arctic. However, retreating sea ice cover and continuous progress in satellite product development have significantly improved SSS retrievals, giving satellite SSS data true potential in the Arctic. In this region, satellite-based SSS is found to agree well with in situ data (r>0.8) and provides notable improvements compared to the reanalysis product used in this study (r>0.7) in capturing patterns and variability observed in in situ data. This study demonstrates a novel method of identifying the dominant drivers of interannual variability in Laptev Sea dynamics within reanalysis products and testing if these relationships appear to hold in satellite-based SSS, sea surface temperature (SST) data, and in situ observations. The satellite SSS data firmly establish what is suggested by reanalysis products and what has previously been subject to debate due to the limited years and locations analysed with in situ data; the zonal wind is the dominant driver of offshore or onshore Lena River plume transport. The eastward wind confines the plume to the southern Laptev Sea and drives alongshore transport into the East Siberian Sea, and westward wind drives offshore plume transport into the northern Laptev Sea. This finding is affirmed by the strong agreement in SSS pattern under eastward and westward wind regimes in all reanalyses and satellite products used in this study, as well as with in situ data. The pattern of SST also varies with the zonal wind component and drives spatial variability in sea ice concentration. [ABSTRACT FROM AUTHOR]

The clinical impact of tumor-specific neoantigens as both immunotherapeutic targets and biomarkers has been impeded by the lack of efficient methods for their identification and validation from routine samples. We have developed a platform that combines bioinformatic analysis of tumor exomes and transcriptional data with functional testing of autologous peripheral blood mononuclear cells (PBMCs) to simultaneously identify and validate neoantigens recognized by naturally primed CD4+ and CD8+ T cell responses across a range of tumor types and mutational burdens. The method features a human leukocyte antigen (HLA)–agnostic bioinformatic algorithm that prioritizes mutations recognized by patient PBMCs at a greater than 40% positive predictive value followed by a short-term in vitro functional assay, which allows interrogation of 50 to 75 expressed mutations from a single 50-ml blood sample. Neoantigens validated by this method include both driver and passenger mutations, and this method identified neoantigens that would not have been otherwise detected using an in silico prediction approach. These findings reveal an efficient approach to systematically validate clinically actionable neoantigens and the T cell receptors that recognize them and demonstrate that patients across a variety of human cancers have a diverse repertoire of neoantigen-specific T cells. Editor's summary: Tumors, especially those with a high mutational burden, express neoantigens that may be recognized by an individual's T cells. However, identifying and validating these neoantigens can be a tedious and sometimes unsuccessful effort. To address this, Miller et al. developed a platform that combines whole-exome sequencing and transcriptional analysis of tumors with ex vivo stimulation of peripheral blood cells to more efficiently identify neoantigens that have elicited T cell responses in patients. The approach, termed "identify-prioritize-validate" (IPV), was able to identify clinically meaningful neoantigens in patients with different types of cancer, including those with a lower mutational burden, and with different human leukocyte antigen (HLA) types. Thus, the IPV approach demonstrates an advance in identifying neoantigens that may be useful both as a biomarker and as a therapeutic target. —Courtney Malo [ABSTRACT FROM AUTHOR]

The study investigated the correlation between the intensity of the Aha! experience and participants’ subjective difficulty ratings of problems before and after finding their solutions. We assumed that the Aha! experience arises from a shift in processing fluency triggered by changing from an initially incoherent problem representation to a coherent one, which ultimately leads to the retrieval of a solution with unexpected ease and speed. First, we hypothesized that higher Aha! experience ratings would indicate more sudden solutions, manifesting in a reduced correlation between the initial difficulty ratings and solution times. Second, we hypothesized that higher Aha! experience ratings would correspond to a greater shift in the subjective difficulty ratings between the initial and retrospective assessments. To test our hypotheses, we developed a novel set of rebus puzzles. A total of 160 participants solved rebuses and provided initial (within 5  s of problem presentation) and retrospective difficulty ratings (following the generation or presentation of a correct solution). They also rated their Aha! experience (after solution generation or presentation), confidence in solutions, and the likability of each rebus. Our findings revealed that the initial ratings of the problem’s subjective difficulty were positively correlated with the solution time and that this correlation decreased in the case of a stronger Aha! experience. Aha! experience ratings were positively correlated with the differences between initial and retrospective difficulty ratings, confidence, solution accuracy, and rebus likability. We interpreted our results to be in line with the processing fluency and metacognitive prediction error accounts. [ABSTRACT FROM AUTHOR]

Ocean alkalinity enhancement (OAE) is considered one of the most promising approaches to actively remove carbon dioxide (CO 2) from the atmosphere by accelerating the natural process of rock weathering. This approach involves introducing alkaline substances sourced from natural mineral deposits, such as olivine, basalt, and carbonates or obtained from industrial waste products such as steel slag, into seawater and dispersing them over coastal areas. Some of these natural and industrial substances contain trace metals, which would be released into the oceans along with the alkalinity enhancement. The trace metals could serve as micronutrients for marine organisms at low concentrations but could potentially become toxic at high concentrations, adversely affecting marine biota. To comprehensively assess the feasibility of OAE, it is crucial to understand how the phytoplankton, which forms the base of marine food webs, responds to ocean alkalinization and associated trace metal perturbations. As one of the most abundant metals in OAE source materials, understanding the impacts of nickel (Ni) on the phytoplankton is critical for OAE assessment. In this study, we investigated the influence of nickel (Ni) on three representative phytoplankton species over a gradient of nine Ni concentrations (from 0 to 100 µ mol L -1 with 12 µ mol L -1 synthetic organic ligand). The impacts of elevated Ni varied among the tested phytoplankton species. The coccolithophore Emiliania huxleyi and the dinoflagellate Amphidinium carterae exhibited a growth rate inhibition of about 30 % and 20 %, respectively, at the highest Ni concentrations. The half maximal inhibitory concentration (IC50, at which the growth rate is inhibited by 50 %) of both species exceeded the tested range of Ni. This suggests that both species were only mildly affected by the elevated Ni concentrations. In contrast, the diatom Thalassiosira weissflogii displayed a considerably higher sensitivity to Ni, with a 60 % growth rate inhibition at the highest Ni concentration and an IC50 value of 63.9 µ mol L -1. In conclusion, the variability in phytoplankton sensitivity to Ni exposure suggests that for OAE applications with Ni-rich materials caution is required and critical toxic thresholds for Ni must be avoided. [ABSTRACT FROM AUTHOR]

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This paper studies the epistemic failures to reach understanding in relation to scientific explanations. We make a distinction between genuine understanding and its negative phenomena—lack of understanding and misunderstanding. We define explanatory understanding as inclusive as possible, as the epistemic success that depends on abilities, skills, and correct explanations. This success, we add, is often supplemented by specific positive phenomenology which plays a part in forming epistemic inclinations—tendencies to receive an insight from familiar types of explanations. We define lack of understanding as the epistemic failure that results from a lack of an explanation or from an incorrect one. This can occur due to insufficient abilities and skills, or to fallacious explanatory information. Finally, we characterize misunderstanding by cases where one’s epistemic inclinations do not align with an otherwise correct explanation. We suggest that it leads to potential debates about the explanatory power of different explanatory strategies. We further illustrate this idea with a short meta-philosophical study on the current debates about distinctively mathematical explanations. [ABSTRACT FROM AUTHOR]

Photothermal therapy (PTT) ablates tumors by thermal effects of photothermal agents (PTAs), and attracts wide attention due to the non‐invasive characteristic. The ideal PTAs are expected to have high photothermal conversion effect under NIR irradiation, as well as targeting abilities and good biocompatibility satisfying the need of application in vivo. Nanoparticles (NPs) are commonly used as anti‐tumor materials, and plenty of researches on therapeutical NPs for PTT treatment have been developed. Among various building blocks for photothermal NPs, polymer materials for biomedical applications have great advantages due to their negligible toxicity, flexibility for functional modification, and ability to integrate multiple therapeutic strategies. This review focuses on the polymer materials utilized in photothermal NP designing, including their application as excellent carriers and powerful PTAs with great PTT effects. Furthermore, the synergy therapy based on polymeric nanoplatform for enhancing PTT therapeutic efficiency will be introduced. [ABSTRACT FROM AUTHOR]

Ice calved from the Antarctic and Greenland Ice Sheets or tidewater glaciers ultimately melts in the ocean contributing to sea-level rise. Icebergs have also been described as biological hotspots due to their potential roles as platforms for marine mammals and birds, and as micronutrient fertilizing agents. Icebergs may be especially important in the Southern Ocean where availability of the micronutrients iron and manganese extensively limits marine primary production. Whilst icebergs have long been described as a source of iron to the ocean, their nutrient signature is poorly constrained and it is unclear if there are regional differences. Here we show that 589 ice fragments collected from floating ice in contrasting regions spanning the Antarctic Peninsula, Greenland, and smaller tidewater systems in Svalbard, Patagonia and Iceland have similar characteristic (micro)nutrient signatures with limited or no significant differences between regions. Icebergs are a minor or negligible source of macronutrients to the ocean with low concentrations of NOx (NO3 + NO2, median 0.51μM), PO4 (median 0.04 μM), and dissolved Si (dSi, median 0.02 μM). In contrast, icebergs deliver elevated concentrations of dissolved Fe (dFe; mean 82 nM, median 12 nM) and Mn (dMn; mean 26 nM, median 2.6 nM). A tight correlation between total dissolvable Fe and Mn (R² = 0.95) and a Mn:Fe ratio of 0.024 suggested a lithogenic origin for the majority of sediment present in ice. Total dissolvable Fe and Mn retained a strong relationship with sediment load (both R² = 0.43, p<0.001), whereas weaker relationships were observed for dFe, dMn and dSi. Sediment load for Antarctic ice (median 9 mg L-1, n=144) was low compared to prior reported values for the Arctic. A particularly curious incidental finding was that melting samples of ice were observed to rapidly lose their sediment load, even when sediment layers were embedded within the ice and stored in the dark. Our results demonstrated that the nutrient signature of icebergs is consistent with an atmospheric source of NOx and PO4. Conversely, high Fe and Mn, and modest dSi concentrations, are associated with englacial sediment, which experiences limited biogeochemical processing prior to release into the ocean. [ABSTRACT FROM AUTHOR]

Tumor tissue engineering holds great promise for replicating the physiological and behavioral characteristics of tumors in vitro. Advances in this field have led to new opportunities for studying the tumor microenvironment and exploring potential anti‐cancer therapeutics. However, the main obstacle to the widespread adoption of tumor models is the poor understanding and insufficient reconstruction of tumor heterogeneity. In this review, the current progress of engineering heterogeneous tumor models is discussed. First, the major components of tumor heterogeneity are summarized, which encompasses various signaling pathways, cell proliferations, and spatial configurations. Then, contemporary approaches are elucidated in tumor engineering that are guided by fundamental principles of tumor biology, and the potential of a bottom‐up approach in tumor engineering is highlighted. Additionally, the characterization approaches and biomedical applications of tumor models are discussed, emphasizing the significant role of engineered tumor models in scientific research and clinical trials. Lastly, the challenges of heterogeneous tumor models in promoting oncology research and tumor therapy are described and key directions for future research are provided. [ABSTRACT FROM AUTHOR]

Cancer immunotherapy using anti‐programmed death‐ligand 1 (PD‐L1) antibodies has been used in various clinical applications and achieved certain results. However, such limitations as autoimmunity, tumor hyperprogression, and overall low patient response rate impede its further clinical application. Mounting evidence has revealed that PD‐L1 is not only present in tumor cell membrane but also in cytoplasm, exosome, or even nucleus. Among these, the dynamic and spatial heterogeneous expression of PD‐L1 in tumors is mainly responsible for the unsatisfactory efficacy of PD‐L1 antibodies. Hence, numerous studies focus on inhibiting or degrading PD‐L1 to improve immune response, while a comprehensive understanding of the molecular mechanisms underlying spatial heterogeneity of PD‐L1 can fundamentally transform the current status of PD‐L1 antibodies in clinical development. Herein, the concept of spatial heterogeneous expression of PD‐L1 is creatively introduced, encompassing the structure and biological functions of various kinds of PD‐L1 (including mPD‐L1, cPD‐L1, nPD‐L1, and exoPD‐L1). Then an in‐depth analysis of the regulatory mechanisms and potential therapeutic targets of PD‐L1 is provided, seeking to offer a solid basis for future investigation. Moreover, the current status of agents is summarized, especially small molecular modulators development directed at these new targets, offering a novel perspective on potential PD‐L1 therapeutics strategies. [ABSTRACT FROM AUTHOR]

Problem‐solving often requires creativity and is critical in everyday life. However, the neurocognitive mechanisms underlying creative problem‐solving remain poorly understood. Two mechanisms have been highlighted: the formation of new connections among problem elements and insight solving, characterized by sudden realization of a solution. In this study, we investigated EEG activity during a modified version of the remote associates test, a classical insight problem task that requires finding a word connecting three unrelated words. This allowed us to explore the brain correlates associated with the semantic remoteness of connections (by varying the remoteness of the solution word across trials) and with insight solving (identified as a Eurêka moment reported by the participants). Semantic remoteness was associated with power increase in the alpha band (8–12 Hz) in a left parieto‐temporal cluster, the beta band (13–30 Hz) in a right fronto‐temporal cluster in the early phase of the task, and the theta band (3–7 Hz) in a bilateral frontal cluster just prior to participants' responses. Insight solving was associated with power increase preceding participants' responses in the alpha and gamma (31–60 Hz) bands in a left temporal cluster and the theta band in a frontal cluster. Source reconstructions revealed the brain regions associated with these clusters. Overall, our findings shed new light on some of the mechanisms involved in creative problem‐solving. [ABSTRACT FROM AUTHOR]

How does a train of TMS pulses modify neural activity in humans? Despite adoption of repetitive TMS (rTMS) for the treatment of neuropsychiatric disorders, we still do not understand how rTMS changes the human brain. This limited understanding stems in part from a lack of methods for noninvasively measuring the neural effects of a single TMS train—a fundamental building block of treatment—as well as the cumulative effects of consecutive TMS trains. Gaining this understanding would provide foundational knowledge to guide the next generation of treatments. Here, to overcome this limitation, we developed methods to noninvasively measure causal and acute changes in cortical excitability and evaluated this neural response to single and sequential TMS trains. In 16 healthy adults, standard 10 Hz trains were applied to the dorsolateral prefrontal cortex in a randomized, sham-controlled, event-related design and changes were assessed based on the TMS-evoked potential (TEP), a measure of cortical excitability. We hypothesized that single TMS trains would induce changes in the local TEP amplitude and that those changes would accumulate across sequential trains, but primary analyses did not indicate evidence in support of either of these hypotheses. Exploratory analyses demonstrated non-local neural changes in sensor and source space and local neural changes in phase and source space. Together these results suggest that single and sequential TMS trains may not be sufficient to modulate local cortical excitability indexed by typical TEP amplitude metrics but may cause neural changes that can be detected outside the stimulation area or using phase or source space metrics. This work should be contextualized as methods development for the monitoring of transient noninvasive neural changes during rTMS and contributes to a growing understanding of the neural effects of rTMS. [ABSTRACT FROM AUTHOR]

Immune cells can protect against tumor progression by killing cancer cells, while aberrant expression of the immune checkpoint protein PD‐L1 (programmed death ligand 1) in cancer cells facilitates tumor immune escape and inhibits anti‐tumor immunotherapy. As a serine/threonine kinase, CK2 (casein kinase 2) regulates tumor progression by multiple pathways, while it is still unclear the effect of CK2 on tumor immune escape. Here it is found that ING4 induced PD‐L1 autophagic degradation and inhibites non‐small cell lung cancer (NSCLC) immune escape by increasing T cell activity. However, clinical analysis suggests that high expression of CK2 correlates with low ING4 protein level in NSCLC. Further analysis shows that CK2 induce ING4‐S150 phosphorylation leading to ING4 ubiquitination and degradation by JFK ubiquitin ligase. In contrast, CK2 gene knockout increases ING4 protein stability and T cell activity, subsequently, inhibites NSCLC immune escape. Furthermore, the combined CK2 inhibitor with PD‐1 antibody effectively enhances antitumor immunotherapy. These findings provide a novel strategy for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

The Gestalt psychologists' theory of insight problem-solving was based on a direct parallelism between perceptual experience and higher-order forms of cognition (e.g., problem-solving). Similarly, albeit not exclusively, to the sudden recognition of bistable figures, these psychologists contended that problem-solving involves a restructuring of one's initial representation of the problem's elements, leading to a sudden leap of understanding phenomenologically indexed by the "Aha!" feeling. Over the last century, different scholars have discussed the validity of the Gestalt psychologists' perspective, foremost using the behavioral measures available at the time. However, in the last two decades, scientists have gained a deeper understanding of insight problem-solving due to the advancements in cognitive neuroscience. This review aims to provide a retrospective reading of Gestalt theory based on the knowledge accrued by adopting novel paradigms of research and investigating their neurophysiological correlates. Among several key points that the Gestalt psychologists underscored, we focus specifically on the role of the visual system in marking a discrete switch of knowledge into awareness, as well as the perceptual experience and holistic standpoints. While the main goal of this paper is to read the previous theory in light of new evidence, we also hope to initiate an academic discussion and encourage further research about the points we raise. [ABSTRACT FROM AUTHOR]

Patients affected by resectable locally advanced gastric cancer (GC) should receive perioperative chemotherapy as a standard of care. However, an additional benefit of adjuvant chemoradiation (CRT) has been negated by modern trials in the era of extended surgical dissection, and CRT is currently only considered on an individual basis in case of suboptimal resection. However, the dismal prognosis of GC and the modest treatment completion rates of perioperative chemotherapy have pushed to reconsider CRT, particularly as a preoperative treatment, in light of modern treatment techniques, advances in the understanding of the immune landscape and development of targeted agents. The aim of this review is to critically assess the historical role of CRT, the limitations of current evidence and to debate its potential role in an integrated neoadjuvant strategy for patients with resectable GC., Competing Interests: Declarations Conflict of interest Lorenzo Livi is an Editor in this Journal. The authors have no other competing interests to disclose. Ethics approval Institutional Review Board approval was not required because no patient data were used for this study. Consent to participate and informed consent Written informed consent was not required for this study because no patient data were used for this study., (© 2024. Italian Society of Medical Radiology.)

Saccadic eye movements, a critical aspect of real-world visual behavior, are preceded by an initial accumulation of visual information followed by the selection of a single location to move one's eyes. However, it is currently unclear how each of these stages uniquely affects saccadic timing. In this study, participants searched for a contour integration target while EEG was used to measure posterior cortical activity between search display onset and first saccade initiation. The goal was to determine whether saccade timing could be attributed to differences in early ERP amplitudes, with the P1 reflecting the magnitude of early perceptual information accumulation and the N1 reflecting the strength of selection leading to the saccadic decision. EOG was used to measure saccade timing, and trials were divided into fast, middle, and slow bins. The N1 response was smallest in the slow saccade tertile, relative to both the fast and middle tertiles, suggesting weak selection. In contrast, the P1 response was largest for this same slow saccadic tertile relative to the middle saccadic tertile, suggesting vigorous information accumulation. Therefore, delays in saccadic behavior may occur when the visual system is overwhelmed with visual input, thus increasing the time to reach a saccadic decision. These findings reconcile models of eye movement behavior which often prioritize either the impact of information accrual or selection, rather than regarding both as an integrated whole., (© 2024 Society for Psychophysiological Research.)

Cancer immunotherapy is used to treat tumors by modulating the immune system. Although the anticancer efficacy of cancer immunotherapy has been evaluated prior to clinical trials, conventional in vivo animal and endpoint models inadequately replicate the intricate process of tumor elimination and reflect human-specific immune systems. Therefore, more sophisticated models that mimic the complex tumor-immune microenvironment must be employed to assess the effectiveness of immunotherapy. Additionally, using real-time imaging technology, a step-by-step evaluation can be applied, allowing for a more precise assessment of treatment efficacy. Here, an overview of the various imaging-based evaluation platforms recently developed for cancer immunotherapeutic applications is presented. Specifically, a fundamental technique is discussed for stably observing immune cell-based tumor cell killing using direct imaging, a microwell that reproduces a confined space for spatial observation, a droplet assay that facilitates cell-cell interactions, and a 3D microphysiological system that reconstructs the vascular environment. Furthermore, it is suggested that future evaluation platforms pursue more human-like immune systems., (© 2024 The Author(s). Advanced Healthcare Materials published by Wiley‐VCH GmbH.)

Purpose: Increased expression of leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2) is associated with immune evasion in breast cancer (BC). The aim of this study to elucidate the role of LILRB2 in BC progression., Methods: LILRB2 expression in tumor tissues was detected by immunohistochemical staining. Human leukocyte antigen A (HLA-A) expression in BC cells was detected by Western blotting, and HLA-A ubiquitination was detected by immunoprecipitation and histidine pulldown assay. An in-situ tumor model was established in nude BALB/c mice to verify the role of LILRB2 in immune escape. Finally, the functions and potential mechanisms of LILRB2 in BC progression were explored using in silico data., Results: LILRB2 was upregulated in BC tissues and cells, and correlated positively with poor prognosis. LILRB2 promoted BC progression by downregulating HLA-A expression. Mechanistically, LILRB2 facilitates the ubiquitination and subsequent degradation of HLA-A by promoting the interaction between the ubiquitin ligase membrane-associated ring finger protein 9 (MARCH9) and HLA-A. In syngeneic graft mouse models, LILRB2-expressing BC cells evaded CD8 + T cells and inhibited the secretion of cytokines by the cytotoxic CD8 + T cells., Conclusion: LILRB2 downregulates HLA-A to promote immune evasion in BC cells and is a promising new target for BC treatment., (© 2024. Springer Nature Switzerland AG.)

Though platinum (Pt)-based complexes have been recently exploited as immunogenic cell death (ICD) inducers for activating immunotherapy, the effective activation of sufficient immune responses with minimal side effects in deep-seated tumors remains a formidable challenge. Herein, we propose the first example of a near-infrared (NIR) light-activated and lysosomal targeted Pt(II) metallacycle (1) as a supramolecular ICD inducer. 1 synergistically potentiates immunomodulatory response in deep-seated tumors via multiple-regulated approaches, involving NIR light excitation, boosted reactive oxygen species (ROS) generation, good selectivity between normal and tumor cells, and enhanced tumor penetration/retention capabilities. Specifically, 1 has excellent depth-activated ROS production (~7 mm), accompanied by strong anti-diffusion and anti-ROS quenching ability. In vitro experiments demonstrate that 1 exhibits significant cellular uptake and ROS generation in tumor cells as well as respective multicellular tumor spheroids. Based on these advantages, 1 induces a more efficient ICD in an ultralow dose (i.e., 5 μM) compared with the clinical ICD inducer-oxaliplatin (300 μM). In vivo, vaccination experiments further demonstrate that 1 serves as a potent ICD inducer through eliciting CD8 + /CD4 + T cell response and Foxp3 + T cell depletion with negligible adverse effects. This study pioneers a promising avenue for safe and effective metal-based ICD agents in immunotherapy., (© 2024 Wiley-VCH GmbH.)

Metastatic triple‐negative breast cancer (TNBC) has a poor prognosis and high mortality with no effective treatment options, and immunotherapy is highly anticipated as a potential treatment but is limited by the lack of tumor‐infiltrating T lymphocytes in TNBC. Herein, red blood cell (RBC) membrane‐camouflaged polyphosphoester (PPE) nanoparticles (RBC@PPEMTO/PFA) are prepared as the nanocarriers of mitoxantrone (MTO) and perfluoroalkane (PFA) for synergized immunotherapy. The encapsulated MTO can generate heat and reactive oxygen species (ROS) to achieve photothermal and photodynamic therapy; moreover, ROS further triggers the self‐accelerating release of MTO from the ROS‐sensitive PPE core to enable chemotherapy. The RBC@PPEMTO/PFA‐mediated sequential photothermal/photodynamic/chemotherapy efficiently promotes the infiltration of CD8+ T cells into TNBC tumor tissue and synergizes the therapeutic activity of an immune checkpoint blockade antibody for metastatic TNBC treatment in distant and lung metastasis models. This biomimetic nanomedicine of MTO provides a convenient and available strategy to sensitize TNBC to immune checkpoint blockade antibody. [ABSTRACT FROM AUTHOR]

Radiotherapy is one of the main treatments for cervical cancer. Early cervical cancer is usually considered postoperative radiotherapy alone. Radiotherapy combined with cisplatin is the standard treatment for locally advanced cervical cancer (LACC), but sometimes the disease will relapse within a short time after the end of treatment. Tumor recurrence is usually related to the inherent radiation resistance of the tumor, mainly involving cell proliferation, apoptosis, DNA repair, tumor microenvironment, tumor metabolism, and stem cells. In the past few decades, the mechanism of radiotherapy resistance of cervical cancer has been extensively studied, but due to its complex process, the specific mechanism of radiotherapy resistance of cervical cancer is still not fully understood. In this review, we discuss the current status of radiotherapy resistance in cervical cancer and the possible mechanisms of radiotherapy resistance, and provide favorable therapeutic targets for improving radiotherapy sensitivity. In conclusion, this article describes the importance of understanding the pathway and target of radioresistance for cervical cancer to promote the development of effective radiotherapy sensitizers. [ABSTRACT FROM AUTHOR]