Tusamitamab ravtansine demonstrated antitumor activity in the Phase 1/1b study of advanced non-squamous non-small cell lung cancer with high (HE, ≥2+ intensity in ≥50 % of tumor cells) or moderate (ME, ≥2+ intensity in ≥1 % to <50 % of tumor cells) carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) expression. Tumor CEACAM5 expression, biomarker associations and whether biomarkers predict objective response rate (ORR) were explored. We assessed CEACAM5, circulating CEACAM5 (cCEACAM5) and CEA (cCEA). Enrollment was according to immunohistochemistry (IHC) CEACAM5 membrane expression: HE (n=64) and ME (n=28). Patients received tusamitamab ravtansine 100 mg/m2 intravenously every 2 weeks. cCEA and cCEACAM5 were strongly associated (Spearman ρ, 0.99), with moderate associations between IHC CEACAM5 and cCEA or cCEACAM5 (Spearman ρ, 0.43 and 0.38). In patients with baseline cCEA data, 40.3 % (25/62) of HE and 25 % (7/28) of ME had cCEA ≥100 µg/L (median: 71.6 µg/L [1-8809] versus 12.4 µg/L [0.5-684]). Among response-evaluable patients in HE, ORR for high cCEA (≥100 µg/L) was 41.7 % (10/24) versus 8.1 % (3/37) for low cCEA, and in ME, ORR was 0/7 versus 10 % (2/20). Elevated CEACAM5 mRNA was observed in HE versus ME (P = 0.0027). EGFR and KRAS alterations were present in 44.8 % and 65.5 % of HE and in 21.4 % and 78.6 % of ME patients, respectively. In CEACAM5 HE, the ORR was greater with high versus low cCEA. Associations were observed between cCEA and cCEACAM5; IHC CEACAM5, cCEA, and cCEACAM5; IHC CEACAM5 and CEACAM5 mRNA, but not between IHC CEACAM5 and oncogenic drivers. NCT02187848.

Microplastic exposure induces structural hyperplasia in the gill tissue of grass carp (Ctenopharyngodon idellus) through immunosuppression, metabolic disruption, and structural damage.

For neurons to establish the correct connections in animal nervous systems, interactions between cell adhesion molecules (CAMs), expressed presynaptically and postsynaptically, are thought to guide neurons to their targets. Here, we assess the role that affinity between two cognate CAMs-DIP-α and Dpr10-plays in establishing the leg neuromuscular system in Drosophila If affinity decreases or, surprisingly, increases past certain thresholds, motor neuron (MN) terminal branches fail to be maintained. Live imaging during development shows that when affinities are aberrant, MN filopodia are unable to productively engage their muscle targets. Thus, CAM affinities are tuned to achieve proper neuronal morphology.

Multi-omics analysis reveals dynamic proteomic remodeling and metabonomic dysregulation underlying cytokine release syndrome in CAR-T-treated B-ALL.

Gicerin is a member of the immunoglobulin superfamily, which functions as a cell adhesion molecule that is expressed in developing and regenerating tissues, as well as in various types of tumors. In malignant neoplasms, gicerin has been implicated in promoting cellular invasion and metastasis. The present study aimed to investigate whether or not anti‑gicerin antibodies could inhibit the progression of the human gastric cancer cell line NUGC‑4 in a murine model. First, immunofluorescence staining was employed to confirm gicerin expression in the NUGC‑4 cells. The cells were subsequently pretreated with either anti‑gicerin antibodies or pre‑immune IgG and transplanted subcutaneously into nude mice, where the extent of tumor growth and local invasion were both assessed. In a separate hematogenous metastasis model, mice received a tail‑vein injection of NUGC‑4 cells pretreated in an identical manner and pulmonary metastases were evaluated. Anti‑gicerin antibody pretreatment led to a significant suppression of subcutaneous tumor formation, histological invasiveness and lung nodule formation compared with the controls. Taken together, these findings suggested that the antibody‑mediated inhibition of gicerin reduced both local tumor progression and hematogenous spread in gastric cancer, highlighting gicerin as a promising therapeutic target that potentially may be effective when used in combination with conventional chemotherapy.

ABSTRACTGenetic variants in the X‐chromosomal gene coding for the calcium−/calmodulin‐dependent serine protein kinase (CASK) are associated with a neurodevelopmental disorder. CASK is a member of the membrane‐associated guanylate kinase (MAGUK) family of proteins. It acts as a scaffold at presynaptic sites, as a regulator of the transport of glutamate receptors, and as a transcriptional regulator. The PDZ domain of CASK has been reported to bind to presynaptic cell adhesion molecules such as Neurexin1‐3, CNTNAP2, SynCAM and SALM1. Structural analyses of related MAGUKs indicate that the canonical SH3 and GK domains combine with the PDZ domain to form the so‐called PSG supramodule. Conserved aromatic residues (Y723 and W914) flanking the GK domain contribute to the formation of a dimeric structure of two PSG modules, which is required for high‐affinity binding to the type 2 PDZ ligand motif of, for example, Neurexin. Here we identify previously uncharacterized patient variants in the SH3 domain of CASK (I672V; P673L), which alter the intermolecular binding pocket for Y723. Both variants interfere with the binding of Neurexin‐1β, in a manner similar to the previously reported Y723C variant. Intriguingly, binding to the type 1 PDZ ligand of the cell adhesion molecule SALM1 is not altered. Using a set of highly selective patient variants, we show that the binding of SALM1 to CASK is actually not mediated by the CASK PDZ domain or the PSG supramodule, but depends on other type 1 PDZ domain‐containing proteins such as SAP97 and Veli, which associate with CASK through its L27 domains. Our data underline the relevance of an intact PSG tandem of CASK for human health.

The role of Myocyte Enhancer Factor 2 C (MEF2C) in lung adenocarcinoma (LUAD) is unclear. To address this gap in knowledge, we employed bioinformatics analysis and experimental validation in this study. This study investigated MEF2C expression across a spectrum of cancers, with a specific focus on lung adenocarcinoma (LUAD), utilizing Cancer Genome Atlas (TCGA) data to assess its potential as a diagnostic marker. The study also investigated correlations between MEF2C expression and clinical traits and prognostic indicators of LUAD. Additionally, this study also delved into the regulatory mechanisms of MEF2C, examining its connections to immune system interactions, immune checkpoint genes, tumor mutational burden (TMB), and the sensitivity of LUAD to various drugs. Through single-cell sequencing of LUAD cells and genetic variation of MEF2C in LUAD, we explored the expression of MEF2C in cell lines and verified it by quantitative real-time PCR (qRT-PCR). MEF2C exhibited aberrant expression in both pan-cancer and LUAD. In individuals with LUAD, diminished levels of MEF2C expression were notably linked to the effectiveness of primary therapy outcome (p = 0.025), gender (p < 0.001), and the subdivision of anatomic neoplasms 2 (p = 0.011). A decline in MEF2C levels was also found to be significantly related to reduced overall survival (OS) in LUAD patients (p = 0.026). The presence of MEF2C was recognized as a standalone factor predictive of prognosis in LUAD (p = 0.029). MEF2C was found to be involved in multiple biological pathways, such as those involving cell adhesion molecules. Additionally, its expression was correlated with the extent of immune cell presence, the activity of immune checkpoint genes, and TMB in LUAD. Notably, an inverse relationship was observed between MEF2C expression and the sensitivity to several agents, including Topotecan, Irinotecan, Panobinostat, Nilotinib, and Tp38-279, within the context of LUAD. Furthermore, MEF2C was found to be significantly negatively regulated in LUAD cell lines. The results imply that MEF2C could be a valuable indicator for predicting outcomes and a possible target for immunotherapy for LUAD patients.

Long COVID is associated with female sex; Anti-NCAM1 autoantibodies are absent in patients with long COVID.

Boosted breast cancer treatment with cell membrane-coated PLGA nanocarriers: Investigating the interactions with various cell types.

Targeting Epac1 to protect the blood brain barrier from inflammation-induced dysfunction: Evidence from an in vitro model.

In-situ cell extraction by open microfluidics combined with mass spectrometry for EpCAM analysis via DNA-mediated rolling circle amplification.

Cell adhesion molecules and junctions

Vascular cell adhesion molecule 1 (VCAM-1), a known downstream target of the Forkhead box O (FoxO) family of transcription factors, has well-established roles in development, cell-cell interactions, and cell survival. However, the specific role and mechanisms whereby VCAM-1 governs cardiomyocyte homeostasis in ischemic heart disease are incompletely understood. Here, we report that ischemia/reperfusion (I/R)-induced myocardial damage resulted in marked attenuation of FoxO1 and Vcam1 mRNA levels in wild-type (WT) mice, suggesting a protective role of the FoxO1/VCAM-1 axis in I/R injury. Indeed, compared with WT littermates, cardiomyocyte-specific loss of Vcam1 significantly exacerbated I/R-induced myocardial damage, apoptotic cardiomyocyte death, contractile dysfunction, and maladaptive cardiac remodeling. We go on to show that after exposure to ischemia, Vcam1-deficient cardiomyocytes (both in vivo and in vitro) manifested marked attenuation of essential pro-survival cues. These include a decrease in the cardiomyocyte-leukocyte interaction-mediated induction of Ezrin and its downstream Akt and ERK1/2 phosphorylation, as well as decreased expression of tumor necrosis factor α (TNFα) and manganese superoxide dismutase 2 (Sod2) genes. Collectively, our findings uncover a VCAM-1/Ezrin axis as an essential and previously unrecognized protective mediator of cardiomyocyte homeostasis in ischemic myocardium.

Liver involvement of lymphomas is not rare in clinical patients. Metabolic dysfunction-associated steatohepatitis (MASH, formerly known as nonalcoholic steatohepatitis) is well accepted as a potential precursor for liver cancer, but it is unknown whether MASH could promote extranodal infiltration of lymphoma. In this study, the subpopulation of tumor-initiating cells and Wnt signaling pathway activation were studied in T-lymphoblastic lymphoma cells. Tumor growth, Wnt/β-catenin signaling, and fenofibrate therapy were investigated in an MASH-lymphoma mouse model. We found that up-regulated Wnt/β-catenin and epithelial cell adhesion molecule signaling contributed to aggressive growth of T-lymphoblastic lymphoma in vitro and in vivo. Lack of fibroblast growth factor 21 (FGF21) worsened lipid metabolic disorder in the hepatic microenvironment which further promoted lymphoma growth in the MASH liver. Fenofibrate therapy upregulated the peroxisome proliferator-activated receptor alpha (PPAR-α)-FGF21 axis, thereby alleviated not only MASH but also liver infiltration of T-lymphoblastic lymphoma. In addition, down-regulated FGF21 but up-regulated Wnt signaling was found in T-cell lymphoma patient samples. In conclusion, aberrant lipid metabolism contributed to the aggressive growth of T-lymphoblastic lymphoma cells in MASH liver. Wnt/β-catenin signaling could be a potential lymphomagenetic mechanism for extranodal infiltration of T-lymphoblastic lymphoma. Fenofibrate has the potential to be an effective therapeutic strategy against liver infiltration of T-lymphoblastic lymphoma in MASH liver.

Extracellular vesicles (EVs) are considered to be a promising tool in disease diagnosis. However, the clinical translation of EV-based liquid biopsy faces significant challenges due to the lack of inexpensive, rapid, and high-throughput methods of EV analysis. Bead-based platforms, combined with conventional flow cytometry, allow for the simultaneous capture and immunolabeling of EVs. In this study, we present a new approach based on the label-free isolation of EVs by tannic acid-coated superparamagnetic beads (TASPMB) combined with immunofluorescence detection of EV membrane proteins using flow cytometry. First, we tested the molecular profiling capabilities of the approach using EVs derived from human breast and colorectal cancer cell lines and from plasma of colorectal cancer patients to recognize the tetraspanin protein CD63 and the epithelial cell adhesion molecule (EpCAM). Subsequently, the developed approach was validated to identify proteins on EVs enriched with TASPMB from the conditioned media of SKBR3 and HT29 cell cultures without preliminary purification by a size-exclusion chromatography (SEC) column. The developed approach demonstrates a high capacity for isolating EVs and subsequently profiling of their membrane proteins, with a total assay time of approximately 2 h. The approach presented here can be a promising tool for rapid detection of EV membrane proteins using conventional instruments, such as flow cytometry.

The adrenocorticotropic hormone (ACTH) is a key regulator of adrenal cortex function, promoting glucocorticoid synthesis and modulating cell proliferation. However, the role of extracellular steroid availability in shaping ACTH responses is still not fully defined. In this study, the functional and transcriptomic effects of ACTH were investigated in primary rat adrenocortical cells cultured under standard conditions and under simulating serum starvation (charcoal-stripped serum). The cells were treated with ACTH (10 nM), and proliferation was monitored using xCELLigence RTCA, while corticosterone secretion was assessed via ELISA. The RNA extracted from these samples was then utilised for the purpose of microarray-based gene expression profiling. The present study revealed that charcoal-stripped serum markedly improved ACTH-induced corticosterone output, suggesting that the absence of endogenous steroids sensitises cells to ACTH stimulation possibly by removing negative feedback constraints. This enhanced steroidogenic response was accompanied by a significant suppression of proliferation, confirming that the stimulation of specialised functions (such as steroid secretion) reduces proliferative capacity of adrenocortical cells. Transcriptomic data revealed that the steroids stimulating effect on corticosterone output was mainly mediated via steroid biosynthetic and lipid metabolic processes while inhibitory effect on proliferation rate was mediated mainly by cell adhesion molecules. These results suggest that, in primary culture of rat adrenocortical cells, the stimulatory effect of ACTH on their specialised function (corticosteroid secretion) simultaneously reduces their basal function, which is their proliferation process. Changes in this type are also observed in cells cultured in steroid-depleted conditions.

The ability to noninvasively map vascular inflammation with high spatial and molecular resolution remains a major challenge in biomedical imaging. The integration of both positron emission tomography (PET) and magnetic resonance imaging (MRI) through a dual-modality imaging probe represents a highly attractive approach. Here, we introduce a 18F-labeled hydrophilic sulfotetrazine engineered for rapid and robust bioorthogonal inverse electron demand Diels-Alder (IEDDA) conjugation to BCN (bicyclo[6.1.0]nonyne)-functionalized microsized particles of iron oxides (MPIOs) targeting vascular cell adhesion molecules-1 (VCAM-1) known as key markers of endothelial inflammation. The clickable 18F-reagent exhibits exceptional aqueous solubility and stability, fast second-order kinetics (k2 = 827 M-1·s-1) in the reaction with BCN, and compatibility with automated radiosynthesis platforms. We exploited this tool to generate dual-modality PET/MR 18F-MPIOs@αVCAM-1 by conjugation with MPIOs coated with anti-VCAM-1 antibodies incorporating BCN. Dynamic immuno-PET/MR imaging in a murine model of LPS-induced sepsis revealed strong and specific tracer accumulation in lungs and kidneys in accordance with VCAM-1 overexpression, while high-resolution T2*-MRI confirmed cortical kidney retention with high precision. Thus, the 18F-sulfotetrazine offers a powerful and modular strategy for late-stage functionalization of nanocarriers and sets the stage for the next generation of multimodal probes tailored for real-time tracking of inflammatory pathologies.

Phenotypical screening assays involving adherent cellculture areessential for research in cell biology and toxicology as well as drugdiscovery. Such assays often involve hundreds of culture chambersand monitor cell responses for hours. Microfluidic arrays have beenwidely used for cell assays; however, creating dense arrays of adherentcells is challenging because adherent cells may migrate over time.To confine cells, existing techniques rely on actuators such as valvesor surface micropatterning; yet, both present important drawbacks.The actuator-based systems often require complex fabrication and equipmentfor operation. Noncontact surface patterning techniques for closedmicrofluidic channels typically require expensive reagents (e.g.,photosensitive ones) and precise alignment, whereas contact techniquesto pattern open surfaces make sealing the device after patterningdifficult and are susceptible to contamination. Here, we present aninexpensive, selective surface-coating method for micropatterningproteins to confine adherent cells in closed microfluidic devices.Using capillary valves, pressure-driven flow, and sequential reagentdelivery, we can spatially and temporally expose the channels to celladhesion molecules and blocking agents separately. We show a largewindow of operating pressures, up to 4 psi, ensuring robust selectivepatterning. In the patterned devices, we also demonstrate successfulcell culture for over 20 h, with cells remaining spatially confined.This technique offers a cost-effective and scalable solution for creatingmicroarrays of adherent cells without complex equipment or expensivereagents. Its simplicity and ability to pattern in closed microchannelsmay also benefit applications beyond cell-based assays such as biomoleculedetection and other surface-based processes.

Oral squamous cell carcinoma (OSCC) is a common malignancy with a poor prognosis, highlighting the need for reliable molecular biomarkers. CD44s, a cell adhesion molecule, has been implicated in tumor progression, but its prognostic role in OSCC is unclear. This retrospective study evaluated CD44s expression in 50 OSCC cases using immunohistochemistry and an immunoreactive scoring system. High CD44s expression significantly correlated with advanced stage, lymph node metastasis and poor histological grade. CD44s overexpression may serve as a prognostic biomarker to identify high-risk OSCC patients requiring aggressive therapy.

Lithium restores inhibitory function and neuronal excitability through GSK-3β inhibition in a bipolar disorder-associated Ank3 variant mouse model.