Amongst various fish species, some have been found to school efficiently, even while blind. Fish have the capacity for sensing beyond specialized sensory systems like lateral lines. This involves proprioceptive perception, where the movement of fins and tails provides environmental information. This paper demonstrates how the motion of a body possessing a passive tail carries information regarding the surrounding fluid flow, a pattern which can be extracted using machine learning techniques. We present experimental data showcasing the angular velocity of a hydrofoil with a passive tail situated within the wake of an upstream oscillating object, thereby demonstrating this principle. Our findings, using convolutional neural networks, suggest that kinematic data from a downstream body equipped with a tail enhances the classification of wakes compared to a body without a tail. click here A body with a tail exhibits this outstanding sensory capability, even when the machine learning algorithm's input is confined to the kinematic data of the central body. Beyond generating extra inputs, passive tails exert an effect on the primary body's response, facilitating hydrodynamic sensing in a useful manner. These observations directly translate to augmenting the perception systems of biomimetic swimming robots.
The propensity for invasive infections in early life predominantly affects a select group of microbes; conversely, pathogens linked to later-life diseases, including Streptococcus pneumoniae, are seldom observed in newborns. To explore age-related vulnerabilities to invasive Spn infection, we contrasted age-specific mouse models. Opsonophagocytosis by neonatal neutrophils, facilitated by CD11b, shows a significant improvement, resulting in enhanced protection against Spn during the early life stages. The augmented function of neonatal neutrophils, a consequence of lower efferocytosis levels, was apparent in the higher population-level expression of CD11b on their surface. This mechanism also led to a rise in CD11bhi aged neutrophils in the peripheral circulation. The dampened efferocytic capacity observed in early life may be explained by a lack of CD169+ macrophages in neonates and a reduced systemic presence of several efferocytic mediators, among which is MerTK. Experimentally impairing efferocytosis later in life caused CD11bhi neutrophils to multiply, thereby improving protection against the pathogen Spn. Our research illuminates the age-related variations in efferocytosis, demonstrating their impact on infection resolution by altering CD11b-mediated opsonophagocytosis and immune responses.
Whilst the combination of chemotherapy and PD-1 blockade (chemo+anti-PD-1) is now the standard first-line treatment for advanced esophageal squamous cell carcinoma (ESCC), there are presently no reliable indicators for this treatment. Employing whole-exome sequencing on tumor specimens from 486 patients in the JUPITER-06 study, we constructed a copy number alteration-corrected tumor mutational burden. This burden offers a more precise measure of immunogenicity, enhancing the prediction of efficacy for chemo+anti-PD-1 therapies. Further analysis reveals additional beneficial immunologic characteristics (e.g., HLA-I/II diversity) and cancer-promoting genetic variations (e.g., PIK3CA and TET2 mutations) as significant factors influencing the efficacy of the chemo-anti-PD-1 approach. An established immuno-oncology classification (EGIC) for esophageal cancer, derived from genomic analysis, now incorporates immunogenic attributes and oncogenic mutations. The combined chemo-anti-PD-1 treatment strategy demonstrates a significant survival benefit in EGIC1 (immunogenic feature-favorable, oncogenic alteration-absent) and EGIC2 (immunogenic feature-favorable or oncogenic alteration-absent) patient subgroups of advanced esophageal squamous cell carcinoma (ESCC), but not in the EGIC3 (immunogenic feature-unfavorable, oncogenic alteration-present) subgroup. Consequently, the EGIC classification may serve as a framework for future personalized treatment approaches and guide mechanistic investigations into chemo-anti-PD-1 therapy.
Although lymphocytes are fundamental to tumor immune surveillance, the spatial layout and physical interactions mediating their anti-cancer effects are insufficiently understood. By combining multiplexed imaging, quantitative spatial analysis, and machine learning, high-resolution maps of lung tumors were constructed from both Kras/Trp53-mutant mouse models and human resection specimens. Lymphocytes, interacting in networks termed lymphonets, were a key element of the immune system's anti-cancer response. Lymphonets, formed from nucleated small T cell clusters, progressively increased in size due to the incorporation of B cells. CXCR3-mediated trafficking influenced lymphonet size and quantity, while T cell antigen expression dictated intratumoral positioning. Immune checkpoint blockade (ICB) therapy responses involved TCF1+ PD-1+ progenitor CD8+ T cells, which preferentially localized within lymphonets. Treatment of mice with ICB or an antigen-targeted vaccine resulted in lymphonets that retained their progenitor cells and developed cytotoxic CD8+ T cell populations, potentially via a progenitor differentiation pathway. These observations regarding lymphonets highlight their role in creating a spatial environment that supports anti-tumor responses by CD8+ T cells.
Several cancers have benefited from the clinical efficacy of neoadjuvant immunotherapies (NITs). A deeper understanding of the molecular processes triggered by NIT exposure could lead to the development of improved therapeutic strategies. We demonstrate that fatigued, tumor-infiltrating CD8+ T (Tex) cells exhibit both localized and systemic reactions in response to simultaneous neoadjuvant TGF- and PD-L1 blockade. NIT's influence results in a notable and selective augmentation of circulating Tex cells, concurrently linked to a diminished intratumoral expression of the tissue-retention marker CD103. TGF-'s influence on CD103 expression on CD8+ T cells, as demonstrated by its reversal following TGF- neutralization in vitro, underscores its part in tissue-based T cell retention and the impairment of systemic immunity. Transcriptional alterations indicate a role for T cell receptor signaling and glutamine metabolism in modulating the intensity of the Tex treatment response, either amplified or reduced. Our analysis explores the underlying physiological and metabolic changes in T cell responses to NIT, highlighting the interconnectedness of immunosuppression, tissue retention, and systemic anti-tumor immunity, and thus proposes that strategies targeting T cell tissue retention may yield promising neoadjuvant treatment outcomes.
Key phenotypic changes, brought about by senescence, can modify immune responses. In Cancer Discovery, Nature, and Nature Cancer, four recent studies highlight how senescent cells, stemming from normal aging or chemotherapy treatment, showcase antigen presentation machinery, leading to antigen display and subsequent interaction with T cells and dendritic cells, consequently activating the immune system robustly and facilitating anti-tumor immunity.
A heterogeneous group of tumors, soft tissue sarcomas (STS) are of mesenchymal origin. The p53 gene is often the target of mutations in human samples of STS. This study demonstrated a significant link between the loss of p53 in mesenchymal stem cells (MSCs) and the occurrence of adult undifferentiated soft tissue sarcoma (USTS). Variations in stem cell properties, including differentiation, cell cycle progression, and metabolic function, are observed in MSCs devoid of p53. click here The genetic mutations and transcriptomic alterations displayed by murine p53-deficient USTS are analogous to those seen in human STS. Significantly, RNA sequencing at the single-cell level showed that mesenchymal stem cells exhibit transcriptomic adjustments related to aging, a critical risk factor for specific types of USTS, while p53 signaling is concurrently reduced. Importantly, we found that human STS could be categorized into six transcriptomic clusters, exhibiting differing prognoses, thereby differing significantly from the current histopathological classification. The investigation of MSC-mediated tumorigenesis is advanced by this study, further providing a suitable murine model for sarcoma research.
Primary liver cancers are frequently addressed initially through liver resection, a procedure with the potential for a complete recovery. However, the prospect of post-hepatectomy liver failure (PHLF), a leading cause of mortality in the wake of extensive liver resection, has limited the patient population. Our engineered clinical-grade bioartificial liver (BAL) device utilizes human-induced hepatocytes (hiHeps), manufactured under Good Manufacturing Practices (GMP) standards. In a porcine model of PHLF, there was a noticeable survival benefit observed with the hiHep-BAL treatment. In addition to its supportive action, hiHep-BAL treatment not only restored the remnant liver's ammonia detoxification capacity but also encouraged liver regeneration. A study focused on seven individuals undergoing extended liver resection showed hiHep-BAL treatment to be well-tolerated, positively influencing liver function and promoting regeneration. Success was achieved in the primary outcome measures of safety and feasibility. In light of these positive results from hiHep-BAL's application in PHLF, further testing is required. Successful trials could increase the number of individuals eligible for liver resection.
In the context of tumor immunotherapy, Interleukin-12 (IL-12) has emerged as a particularly strong cytokine, its strength deriving from its capability to stimulate interferon (IFN) production and promote Th1 polarization. The clinical application of IL-12 is constrained by its brief half-life and limited therapeutic window.
The half-life-extended, monovalent IL-12-Fc fusion protein, mDF6006, was generated. Its design ensured the maintenance of the strong potency of native IL-12 and a substantial improvement in its therapeutic window. In vitro and in vivo studies assessed the anti-tumor effect of mDF6006 on murine models. click here To translate our research findings into clinical application, a fully human IL-12-Fc, designated DF6002, was developed and its properties assessed in vitro on human cells and in vivo in cynomolgus monkeys, paving the way for future clinical trials.