Disclosure: K. Taniguchi-Ponciano: None. F. Martinez-Mendoza: None. S. Andonegui-Elguera: None. E. Sosa-Eroza: None. E. Gomez-Apo: None. A. Escobar-España: None. G. Guinto-Nishimura: None. B. Lopez-Felix: None. E. Zepeda-Fernandez: None. E. Estrada-Estrada: None. E. Cantu-Chavez: None. R. Arreola-Rosales: None. D. Marrero-Rodríguez: None. M. Mercado: None.Resistant and sensitive GH pituitary neuroendocrine tumors resolved by spatial transcriptomics Acromegaly results from a growth hormone secreting pituitary neuroendocrine tumor (GH-PitNET) in more than 98% of cases. GH-PitNET are the second most common functioning pituitary adenomas. Acromegaly is a chronic and systemic condition that significantly compromises life expectancy and quality of life as a consequence of its metabolic, cardiovascular, cerebrovascular and respiratory comorbidities. Surgical removal of the adenoma is the treatment of choice, yet over 30% of these patients require adjuvant pharmacological treatment with first generation somatostatin receptor ligands (fgSRL) to achieve disease control. SRL normalize IGF-1 levels in 30-50% of patients; thus, a significant proportion of patients are resistant to this treatment. The molecular mechanisms underlying such resistance to fgSRL are largely unknown. This study aimed to identify molecular markers of aggressiveness and SRL resistance using spatial transcriptomics in patients with GH-PitNET. WE also performed bulk RNAseq on a second group of SRL-resistant and SRL-sensitive GH-PitNET. Ethical approval was obtained from our institutional review board, and patients were recruited with signed informed consent. High intratumoral heterogeneity was observed in patients with SRL-sensitive tumors with 8 and 10 transcriptomic clusters, whereas the SRL-resistant patients had 8 and 9 transcriptomic clusters. Differential gene expression revealed a distinct profile of SRL-sensitive and SRL-resistant patients. The 3 predominantly expressed genes were HLA-A, LMO3 and PCP4L1 in SRL-resistant patients, and CBLN1, NF1 and PRL in SRL-sensitive patients. Enrichment analysis showed that ECM-receptor interaction, MAPK signaling pathway and WNT signaling pathway are altered in SRL-resistant, whereas Sphingolipid signaling pathway, various types of N-glycan biosynthesis and Cell adhesion molecules are altered in SRL-sensitive PitNET. Similar findings were observed in the second group. We then performed a cell cycle analysis, showing that most spots/clusters are in G0/G1 cell cycle phase with very low number of spots in S, G2/M and early G1, this results in disregard of the SA-response status. We previously showed that sphingolipid and MAPK signaling pathways are altered in aggressive and recurrent PitNET and could represent an attractive molecular target.Presentation: Monday, July 14, 2025

Disclosure: A. Hashmi: None. S. Sidhu: None. G. Hutvagner: None.Background: Adrenocortical carcinoma (ACC) is an aggressive malignancy with limited diagnostic and prognostic biomarkers and therapeutic options. Immunoglobulin Superfamily Member 11 (IGSF11), a cell adhesion molecule and known ligand of VISTA (V-domain Ig suppressor of T cell activation), has been associated with tumour progression in various cancers due to its role in inhibiting T-cell activation and promoting immune evasion. Elevated IGSF11 expression is linked to poor prognosis in gliomas, colorectal, and hepatocellular carcinomas. However, its role in ACC remains unexplored, and understanding its function could provide novel insights into ACC pathogenesis and treatment. Methods: Bioinformatic analyses were conducted using GTEx adrenal cortex and The Cancer Genome Atlas (TCGA)-ACC datasets to assess IGSF11 mRNA expression and its correlation with clinical outcomes. Quantitative RT-qPCR and ELISA assays were performed on H295R ACC cell lines transiently transfected with an IGSF11 expression plasmid. Cell proliferation was assessed using live-cell imaging and WST-8 assays. Additionally, IGSF11 protein levels were measured in tissue homogenates from normal adrenal cortex, adrenal adenoma, and ACC samples. Results: IGSF11 mRNA expression was significantly lower in ACC tissues compared to normal adrenal cortex (p < 0.001). Survival analysis demonstrated that reduced IGSF11 expression correlated with poorer patient outcomes, particularly in the aggressive COC3 TCGA-ACC cluster. In H295R cells, IGSF11 overexpression led to a marked increase in mRNA and protein levels (p < 0.0001) and significantly reduced cell proliferation (p < 0.005). ELISA assays confirmed significantly reduced IGSF11 protein levels in ACC tissues compared to benign and normal tissues (p < 0.0001). Comparative prognostic analysis across 32 TCGA cancer types highlighted a unique role for IGSF11 in ACC, with a hazard ratio of 0.22 (p = 0.00034), contrasting with its tumour-promoting role in other cancers. Conclusion: IGSF11 exhibits a tumour-suppressive role in ACC, contrasting its immune-inhibitory, tumour-promoting function in other malignancies. Its downregulation in ACC correlates with poorer survival outcomes, positioning it as a promising diagnostic and prognostic biomarker and potential therapeutic target. Restoring IGSF11 expression may offer new avenues for ACC treatment, emphasizing the need for further investigation into its tissue-specific functions and therapeutic potential.Presentation: Monday, July 14, 2025

Nephron loss is a key event during onset and progression of chronic kidney disease, yet the mechanisms dictating tubule repair versus atrophy remain poorly understood. While fibrosis has been proposed to drive progressive organ damage, antifibrotic therapies have failed in clinical trials. Here, we reveal that tubular vascular cell adhesion molecule 1 (VCAM1) expression precedes nephron loss, fibrosis, and long-term kidney dysfunction. Using serial intravital microscopy in transgenic mice, we track tubulointerstitial remodeling between injured and intact tissue over 3 weeks. VCAM1 is rapidly induced in a distinct subset of injured tubules, preceding atrophy with sustained fibroblast recruitment. However, fibroblasts remain confined to injury sites and do not cause secondary damage in uninjured tubules. Last, in human kidney transplant biopsies, tubular VCAM1 expression, but not kidney injury molecule 1, correlates negatively with early and 12-month graft function, underscoring its potential as a biomarker of adverse outcomes. These findings position VCAM1 as an early indicator of tubular fate and nephron loss.

Abstract Background and Aims Systemic lupus erythematosus (SLE) is characterized by a complex and variable disease course, necessitating continuous clinical and laboratory assessments to monitor organ involvement and disease progression. Lupus nephritis (LN), the most common organ-threatening manifestation of SLE, is commonly monitored using kidney biopsies, alongside blood and urine parameters. While kidney biopsy remains the gold standard for diagnosis, it is an invasive procedure and provides only a snapshot in time. Therefore, there is growing interest in non-invasive biomarkers that could improve clinical management of LN, aiding in diagnosis, prognostic assessment, and treatment decisions. By critically assessing the quality of existing studies on potential biomarkers—urinary, serum-based, or others—correlating with histological findings, we here explore the challenges in implementing these biomarkers in clinical practice and identify promising candidates for future validation. Method A systematic literature search on LN biomarkers was conducted, extending a previous review by Palazzo et al. [1]. Studies in English, published between 2012 and 2024, and involving adult patients with biopsy-proven LN were included. The search focused on studies demonstrating significant correlations between biomarkers and histological findings, particularly the National Institutes of Health (NIH) activity index (AI) and chronicity index (CI), the International Society of Nephrology/Renal Pathology Society (ISN/RPS) histological classes, and specific active or chronic lesions. From this search, 96 articles were selected, investigating the potential utility of over 100 biomarkers, which were categorized into groups. The quality of each article was assessed by a multidisciplinary panel of experts utilizing the scoring system by Guyatt et al. [2]. Results The 96 publications were stratified into various biomarker categories: autoantibodies (n = 6), complement factors (n = 4), cytokines, chemokines, growth factors (n = 26), cell adhesion and surface molecules (n = 8), immune cells (n = 8), markers of kidney damage (n ≈ 20), micro-RNA (n ≈ 10), others (n ≈ 30). The biomarkers were tested against various lesions, both individual and combined, as well as measurements such as NIH AI and CI, and ISN/RPS classes. In quality assessment, over 50% of the articles were weak, 17% were very weak (score &amp;lt;5), and only 1 was deemed robust (score &amp;gt;8). Considering the scores of the respective articles, transforming growth factor beta 1 (TGF-β1) emerged as the biomarker deriving from the most robust study, followed by pentraxin 3 (PTX3), CD163, CD11b, hemopexin, and interleukin 16 (IL-16) (Figure 1). Conclusion Our findings highlight the challenges in translating biomarker research into clinical practice for LN. Methodological heterogeneity across studies is a limitation to the interpretation of results. Furthermore, by focusing on selected markers, many studies oversimplify the intricate landscape of histological findings in a kidney biopsy. All clinical trials in LN should store samples for biomarker assessment and validation, prioritizing their ability to accurately reflect specific histological features, evolve with biopsy parameters over time, and demonstrate predictive value for long-term outcomes. Until substantial progress is made in the development of new biomarkers for LN, their clinical applicability will remain limited.

Abstract Background and Aims Urine biomarkers for tubular kidney damage have been studied comprehensively and qualified for non-clinical safety assessments. Their use in cohort-level applications during Phase 1 trials with healthy volunteers is well-established, particularly when nephrotoxicity is a concern. Yet, there is a paucity of data on biomarkers for drug-induced glomerular damage, especially for identifying subclinical injury occuring before changes in GFR and/or albuminuria. The Translational Safety Biomarker Pipeline (TransBioLine) project is exploring a range of urinary protein biomarkers to detect drug-induced glomerular damage. Its goal is to address this gap by evaluating candidate glomerular injury biomarkers in at-risk patients. The project focuses on how a panel of biomarkers for both glomerular and tubular damage can provide insights into the mechanisms of drug-induced kidney injury. Here, we present findings from the learning phase studies, which were used to select protein biomarkers to be included in confirmatory phase studies aimed at supporting biomarker qualification. Method We present the results for glomerular protein biomarkers—nephrin (NPHS1), podocin (NPHS2), and podocalyxin (PODXL)—alongside tubular injury biomarkers KIM 1 and NGAL, as well as two vascular component markers, vascular cell adhesion molecule 1 (VCAM1) and matrix metalloproteinase 3 (MMP3). Using IA-LC-MS/MS assays, we quantified these urinary glomerular, tubular, and vascular protein biomarkers in urine samples from patients with confirmed glomerular injury (n = 48) and healthy volunteers (n = 50) as part of an ongoing biomarker qualification initiative. Results Geometric mean ratios (GMRs) calculated for each biomarker in diseased versus healthy cohorts were 3.83 for NGAL (2.17–6.76, P &amp;lt; 0.0001)), 1.43 for PODXL (1.08–1.89, P = 0.0128), 2.9 for MMP3 (1.93–4.38, P &amp;lt; 0.0001), and 6.04 for VCAM1 (4.16–8.78, P &amp;lt; 0.0001), while NPHS1 and NPHS2 showed no significance (p-values = 0.2034 and 0.7515, respectively). In cases with glomerular damage where eGFR was preserved (≥60 ml/min, n = 24), NPHS1, NPHS2, and PODXL displayed GMRs of 1.41, 1.74, and 2.16, respectively, compared to normal healthy volunteers. With respect to overall biomarker performance, VCAM1 and PODXL demonstrated the best discrimination between disease cases and controls with areas under the curve of 0.92 and 0.83, respectively. Conclusion Our findings highlight the potential of biomarkers like PODXL, VCAM1, and MMP3 for detecting glomerular damage in clinical urine samples. NPHS1, NPHS2, and PODXL may offer predictive value, particularly in cases with normal eGFR. To better understand the dynamics of these candidate biomarkers, longitudinal sample analysis is crucial, especially in the context of drug- or disease-related kidney damage. This will help clarify how these biomarkers compare to traditional metrics like eGFR and albuminuria and support their integration as valuable tools in drug development.

Prediabetes increases oxidative stress and the risk of type 2 diabetes and related cardiovascular diseases. Previous trials have shown antioxidant-rich strawberries improve this risk, but effects on antioxidant markers are inconclusive. This 28-week randomized controlled crossover trial evaluated the effects of freeze-dried strawberries (FDS) on fasting glucose, serum antioxidant status, and vascular inflammation in adults with prediabetes not on glucose-lowering medications. Participants were assigned to FDS (32 g/day ~ 2.5 servings of whole strawberries) or control (usual diet, no strawberries) for 12 weeks each, separated by a 4-week washout (n = 25/treatment period). Biomarkers were measured at baseline, 12, 16 (baseline 2), and 28 weeks. A mixed-model analysis of variance detected differences between groups, adjusting for covariates. Compared to control, FDS significantly improved serum superoxide dismutase (0.08 ± 0.04 U/mL), glutathione [(GSH): 1.8 ± 0.96 µmol/L], antioxidant capacity [(AC): 5.9 ± 3.2 µmol/L], β-carotene (113.9 ± 15.8 nmol/L), fasting glucose (97 ± 12 mg/dL), intercellular adhesion molecule [(ICAM): 56.0 ± 21.8 ng/mL], and vascular cell adhesion molecule [(VCAM): 440 ± 163 ng/mL] (all p < 0.05). ICAM was inversely correlated with GSH (r = −0.21), AC (r = −0.15), and β-carotene (r = −0.13) (all p < 0.05). VCAM was inversely correlated with AC (r = −0.12) (p < 0.05). Catalase, glutathione reductase, glutathione peroxidase, α-carotene, P-selectin, and E-selectin were unaffected. Our findings support strawberry intake as a dietary intervention for improving blood glucose control and antioxidant status in adults with prediabetes.

Glioblastoma multiform (GBM) is a brain cancer that has limited treatment options and a high fatality rate, due in part to limited access of chemotherapeutics to the tumor resulting from the restrictive nature of the blood-brain barrier (BBB). The present study characterized the proteome of endothelial cells forming the BBB in a mouse model of GBM, as a way to identify putative transporters that could be exploited to enhance drug delivery in GBM. Female 6-8 week old C57BL/6 mice were intracranially injected with glioma 261 (GL261) cells or underwent a sham injection. After 28-29 days, brain endothelial cells (CD31+/CD45-) from GL261 (GBM-EC) and sham-injected (control-EC) mice were isolated using magnetic-activated cell sorting, and the proteome of cells was compared by untargeted liquid chromatography dual mass spectrometry. GBM-EC had significantly lower abundance of tight junction proteins (e.g., tight junction protein 1, 0.4-fold) and drug-metabolizing enzymes (e.g., glutathione-S-transferase A4, 0.4-fold) compared to control-EC, alongside an up- and down-regulation of drug transporters (e.g., long-chain fatty acid transport protein 4, 5-fold; adenosine triphosphate binding cassette transporter subfamily B member 1A, 0.3-fold). A large, 7-fold up-regulation of the endothelial cell surface receptor melanoma cell adhesion molecule (MCAM) and scavenger receptor class B member 1 (SCARB1) were identified in GBM-EC compared to control-EC. Immunohistochemistry confirmed cerebral endothelial localization of MCAM and SCARB1 in GBM, in addition to nonvascular patterning within the GBM, suggesting these receptors may be targets that could be exploited for drug delivery. The present study identified changes to BBB markers of paracellular permeability, as well as active and receptor-mediated transcellular transport that could present novel avenues to consider to enhance the permeability and GBM access of current and future therapeutics.

Immunoglobulin superfamily member 9b (IgSF9b) is a cell adhesion protein that has been linked to the etiology of several neuropsychiatric disorders, most notably schizophrenia and major depression. Based on previous studies in cultures, IgSF9b was proposed to specifically regulate the structure and function of inhibitory synapses in the brain through an indirect interaction with the synaptic adhesion protein Neuroligin-2 (Nlgn2). However, very little is known about the protein expression pattern of IgSF9b in the intact brain, and the synaptic localization of IgSF9b in different brain regions has never been investigated. To address this question, we conducted an immunohistochemical characterization of IgSF9b expression across the mouse brain and investigated its colocalization with gephyrin, Nlgn2 and VIAAT as markers of GABAergic inhibitory synapses, as well as with PSD-95 and VGLUT1 as markers of glutamatergic excitatory synapses. Unexpectedly, we observed that in the brain regions assessed, only a small fraction of IgSF9b puncta colocalized with inhibitory marker puncta, with a similarly small fraction colocalizing with excitatory synapses. The majority of IgSF9b puncta were not associated with any of the investigated synaptic markers, indicating that IgSF9b may have additional functions beyond those at GABAergic and glutamatergic synapses. Moreover, deletion of IgSF9b resulted in alterations in inhibitory synapse markers in the stratum lacunosum moleculare of hippocampal area CA1 as well as in the lateral and medial habenula, which play key roles in the regulation of cognitive and affective behaviors, respectively. Together, our findings provide an important context for the assessment of the role of IgSF9b in neuropsychiatric disorders. KEY MESSAGES: IgSF9b is expressed in psychiatrically relevant brain regions in the mouse brain. Loss of IgSF9b leads to a small but significant reduction in inhibitory synapses. Only a subset of inhibitory synapses in the regions assessed contain IgSF9b. IgSF9b is additionally present at a subset of excitatory synapses in these regions. Only 20% of IgSF9b is localized to synapses, while the majority is non-synaptic.

The proper development of excitatory/inhibitory (E/I) balance is critical for brain function, as any imbalance has been associated with myriad neuropsychiatric disorders. How this balance evolves during synaptic development remains unclear. To address this question, we examine how manipulations of signal-regulatory protein α (SIRPα), a cell adhesion molecule that organizes excitatory synaptogenesis in the hippocampus, affect inhibitory synaptogenesis to maintain E/I balance, using mice of either sex. SIRPα primarily localizes to excitatory synapses. Overexpression or inactivation of SIRPα in a single neuron in hippocampal cultures affects excitatory, but not inhibitory, synapses formed onto the SIRPα-manipulated neuron, indicating that SIRPα is an excitatory, but not inhibitory, synapse organizer. Despite this, bath application of SIRPα's ectodomain increases inhibitory synapses in culture, and global inactivation of SIRPα during critical periods functionally decreases both excitatory and inhibitory synapses in the hippocampus. By using various conditional knock-out mice, we found that SIRPα from pyramidal neurons, but not from interneurons, astrocytes, or microglia, is necessary for proper inhibitory synapse development. Interestingly, inactivation of SIRPα from most pyramidal neurons is necessary to impact inhibitory synaptic development, suggesting that inhibitory synaptogenesis in the hippocampus is driven by the strength of excitation in the pyramidal-neuron network, and not by a change in excitatory input to a single cell. Consistently, the effect of SIRPα's ectodomain on inhibitory, but not excitatory, synaptogenesis is blocked by global neural activity inhibition. We propose that the development of inhibitory synapses in the hippocampus is regulated by network-level excitatory activity to evolve E/I balance.

Dynamic regulation of cell-cell adhesion is fundamental to numerous biological processes and is the key to engineering multicellular structures. Optogenetic tools offer precise spatiotemporal control over cell-cell adhesions, but current methods often require the genetic modification of each participating cell type. To address this limitation, we engineered a single-component synthetic cell adhesion molecule based on the blue-light-responsive, plasma membrane-binding protein BcLOV4. We tagged BcLOV4 with a transmembrane domain to display it on the outer plasma membrane (BcLOV4-PM). Under blue light but not in the dark, BcLOV4-PM cells formed both homotypic adhesions with other BcLOV4-PM cells and heterotypic adhesions with a range of unmodified wild-type cells. While these adhesions were not reversed in the dark, they could be efficiently disrupted by increasing the temperature to 37 °C, leveraging BcLOV4's thermosensitivity. Using BcLOV4-PM-based adhesions, we demonstrated light-controlled compaction of spheroids in both monocultures and cocultures with wild-type cells. Altogether, BcLOV4-PM enables promiscuous, modular, light-dependent control of cell-cell adhesions without requiring genetic modification of all cell types involved, offering promising applications in tissue engineering and the study of multicellular process.

BackgroundNRXN1 deletion (NRXN1 del) is a rare copy number variant associated with several neurodevelopmental, neuropsychiatric, and cognitive outcomes. The NRXN1 gene encodes for a pre-synaptic cell adhesion molecule that is important for synapse formation, regulation and neurotransmission. We used a gene-first approach to investigate neurocognitive and brain phenotypes in NRXN1 del carriers.MethodsForty-two participants (21 NRXN1 del carriers and 21 neurotypical age and sex-matched comparisons) completed IQ assessments, and a neurocognitive battery, including, executive function, attention, and social cognition tasks. Magnetic resonance imaging (MRI) data, including T1-weighted anatomical scans, resting state functional MRI and diffusion tensor imaging, were acquired in 36 participants (17 NRXN1 del carriers and 19 comparisons).ResultsNRXN1 del carriers had lower mean IQ and poorer spatial working memory performance compared to comparisons (p ≤ 0.05). Neuroimaging results revealed group differences in visual and ventral attention resting state networks (p < 0.05). Network-based statistical analysis showed a significant effect of group status for 28/115 connections, with poorer segregation between visual and default networks in NRXN1 del carriers relative to comparisons. No differences in brain structural volume or cortical thickness, or diffusion measures of white matter structural architecture were observed between groups.ConclusionsThis exploratory study provides evidence for neurocognitive impacts and brain functional differences related to underlying synaptic mechanisms. Brain functional differences in NRXN1 del carriers may support altered excitation/inhibition dynamics within the brain. Gene-first approaches may establish brain-based translational markers to identify neurobiologically informed subgroups within neurodevelopmental and neuropsychiatric conditions, and ultimately transdiagnostic therapeutic strategies.Supplementary InformationThe online version contains supplementary material available at 10.1186/s11689-025-09625-5.

The role of VCAM1 in post-stroke cognitive impairment: Molecular mechanisms and therapeutic potential.

Crosstalk via ICAM-1 enhances supportive phenotype of stellate cells and drives hepatocyte proliferation in iPSC-derived hepatic organoids.

Lymph node (LN) excision is critical in oncologic surgery to provide important therapeutic and diagnostic information. LN evaluation helps in staging cancers, predicting prognosis and improving survival. The ultimate wish of a surgical oncologist would be to localize and dissect all pathologically positive LNs while avoiding the morbidity of removing true negative LNs. The goal of our study was to identify a reliable marker for intraoperative molecular imaging of LNs with cancer cells from non-small cell lung cancer versus a LN without. We identified Epithelial Cell Adhesion Molecule (EpCAM), a membrane protein normally expressed in epithelial tissues including lung. We performed immunofluorescence staining on human specimens with a conjugated anti-EpCAM monoclonal antibody. Fluorescence was significantly higher in LNs with metastases as shown in 48 positive LNs from patients with resected primary lung cancer. There was high fluorescence in both hilar and mediastinal LNs, and in all primary tumor histologies. EpCAM may be useful for the surgical oncologist for intraoperative molecular imaging of positive LNs from lung cancer.

Mesenchymal stromal cells (MSCs) are considered a promising cell-based therapy for inflammatory bowel disease (IBD), due to their potent immunomodulatory properties and robust regenerative potential. However, their therapeutic efficacy against IBD is hindered by poor homing capacity and excessive leukocyte infiltration at inflamed colonic sites. In this study, MSCs with a Y-shaped bispecific antibody (YMV) assembled via DNA nanotechnology, which integrates anti-vascular cell adhesion molecule-1 (anti-VCAM-1) and anti-mucosal addressing cell adhesion molecules-1 (anti-MAdCAM-1) antibodies are engineered, to enhance targeted delivery and inhibit leukocyte recruitment. YMV-modified MSCs show an approximately threefold enhancement in adhesion efficiency compared with native MSCs. Notably, they effectively compete for MAdCAM-1 binding sites and significantly suppress leukocyte adhesion. In a mouse model of IBD, YMV-MSCs demonstrate enhanced homing to the colon, promote mucosal repair, reduce leukocyte infiltration, and attenuate local inflammation. This DNA-mediated bispecific antibody modification strategy improves MSCs targeting and exerts anti-inflammatory effects by blocking leukocyte recruitment, offering a promising platform for MSC-based therapy.

The cluster of differentiation 44 (CD44) is a member of the hyaluronic acid (HA) receptor family of cell adhesion molecules. Besides HA, this transmembrane protein also serves as a receptor for other components of the extracellular matrix (ECM), including fibronectin, collagen, and osteopontin (OPN). The CD44-HA axis is involved in a wide range of physiological and cancer-related processes, particularly in cell adhesion and migration, lymphocyte activation, as well as tumour progression and metastasis. The possibility of modulating the CD44-HA interaction with a pharmacological inhibitor has therefore been recognized as an emerging anti-cancer strategy. With its expression in a wide variety, CD44 has also become the most common surface biomarker of cancer stem cells. Due to the rapid progress of research on this crucial receptor, some published and deposited variants were often poorly described or lacked accession numbers in the available protein databases, which created confusion and hindered relevant research. In this work, we attempted to examine the protein sequences of the known CD44 variants and match them between the two UniProt and the National Centre for Biotechnology Information (NCBI) Protein databases. The deposited sequences were aligned to the CD44 canonical sequence and grouped based on the observed differences. Analysis of CD44–ligand experimental structures available in the Protein Data Bank (PDB) was also performed to identify the most promising small-molecule inhibitors of the CD44-HA interaction.

Resistance to 5-fluorouracil (5-FU) remains an obstacle to effective colorectal cancer (CRC) treatment. Genetic alterations play significant roles in the development of drug-induced chemoresistance, leading to tumor recurrence and increased aggressiveness. This study sought to characterize the transcriptomic profiles of 5-FU-resistant CRC cells. HCT116 colon cancer cells were progressively exposed to increasing concentrations of 5-FU to induce resistance. Chemoresistance and aggressiveness were investigated using MTT, clonogenic, and scratch assays. Transcriptomic alterations were analyzed with next-generation sequencing (NGS). Our results revealed that 5-FU-resistant cells exhibited cross-resistance and enhanced invasive potential compared to parental HCT116 cells (HCT116-PT cells), characteristics that were associated with upregulation of matrix metalloproteinases (MMP-2 and MMP-9). Notably, we also observed significant overexpression of T cell immunoreceptor with Ig and ITIM domains (TIGIT) and cell adhesion-related genes, including neurexophilin and PC-esterase domain family member 1 (NXPE1) and neural cell adhesion molecule 1 (NCAM1). Non-coding RNAs such as microRNA-6789 (miR-6789), miR-5006, and miR-7107 were also upregulated. Pathway analysis suggested that enhanced cell survival, invasion, and apoptosis resistance in 5-FU-resistant cells may be due to the activation of several genes in the PI3K-AKT signaling pathway. In conclusion, our findings describe the transcriptomic features of chemoresistant CRC cells that are associated with aggressive tumor behavior. These insights may support the development of targeted therapies to overcome 5-FU resistance in CRC.

Background: Ameloblastoma is a benign tumor that can cause deformity and functional disorders in the craniomaxillofacial region. The invasion process of ameloblastoma requires degradation of the extracellular matrix (ECM) and basement membrane to support tumor cell proliferation. SDC-1 (CD-138) functions as a heparan sulfate proteoglycan that regulates cellular adhesion and extracellular matrix attachment, while E-Cadherin (E-Cad) serves as a calcium-dependent transmembrane glycoprotein critical for epithelial morphogenesis and homotypic cellular adhesion. Aim: The present study was designed to evaluate differences in SDC-1 and E-Cad expression patterns according to ameloblastoma histopathological classification. Materials and Methods: This research is an analytical observational study with a cross-sectional approach. The research sample used 24 post-operative paraffin blocks from ameloblastoma patients from the period 2015–2023 who were histopathologically diagnosed. SDC-1 and E-Cad expression was analyzed using immunohistochemical methods. Statistical analysis used the Tukey HSD test. This research has received ethical approval from the local ethics committee. Results: The lowest expression of SDC-1 and E-Cad was found in the follicular type, while the mixed type (follicular-plexiform) showed the highest expression values. The Tukey HSD test showed significant differences in SDC-1 expression between the mixed type and the plexiform type (p=0.040) and follicular type (p=0.032). E-Cad expression also showed significant differences between the follicular type and mixed type (p=0.032). Conclusion: There are significant differences in SDC-1 and E-Cad expression between follicular type and mixed type ameloblastoma, while no significant differences were found between follicular type and plexiform type. These results indicate that histopathological variation is related to cell adhesion molecule expression in ameloblastoma.

Cell adhesion molecules (CAMs) have emerged as pivotal regulators of tumor biology, influencing invasion, metastasis, and the tumor microenvironment (TME) through their roles in cell-cell and cell-matrix interactions. Despite their critical roles, the prognostic value and clinical potential of CAMs in lower-grade gliomas (LGGs) remain underexplored. In this study, we utilized machine learning algorithms and multi-omics data from the Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) to systematically evaluate CAM-associated features in LGGs. A novel CAM-related prognostic signature (CAMSig) was developed, incorporating 13 key genes, including CD58, ITGB1, and VCAM1. The CAMSig score effectively stratified patients into distinct risk groups with varying survival outcomes, showed improved prognostic accuracy compared to some traditional biomarkers such as IDH mutation and 1p/19q co-deletion in prognostic accuracy. Patients in the high-risk CAMSig group exhibited significant activation of tumor progression pathways, such as epithelial-mesenchymal transition (EMT) and PI3K-AKT signaling, along with substantial remodeling of the TME. These patients showed increased infiltration of immunosuppressive cells, including regulatory T cells (Tregs) and macrophages, as well as upregulation of immune checkpoint molecules such as PD-L1 and PD-L2, suggestive of an immunosuppressive microenvironment. Importantly, the CAMSig score also revealed differential therapeutic sensitivities. Patients with high CAMSig scores demonstrated reduced responsiveness to immune checkpoint blockade (ICB) therapy but increased sensitivity to chemotherapeutic agents, such as temozolomide. This study highlights the multifaceted role of CAMs in LGG and their potential impact across cancers, establishing the CAMSig score as a robust tool for prognostic assessment and personalized therapy guidance. By integrating insights into tumor progression, immune modulation, and therapeutic response, this research offers novel strategies for advancing the clinical management of LGG.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12672-025-03247-y.

Vascular inflammation is involved in the pathophysiology of post-stroke cognitive impairment. We aimed to assess whether blood-based biomarkers of inflammation and endothelial dysfunction, such as interleukin 6 (IL-6), vascular cell adhesion molecule (VCAM-1), and tumor necrosis factor-alpha (TNF-α), are associated with cognitive function over time in a prospective cohort of first-ever ischemic stroke patients. Data were obtained from the Prospective Cohort with Incident Stroke Berlin (NCT01363856). Cognitive function was assessed with the Telephone Interview for Cognitive Status-modified (TICS-m) at 1 to 3 years of follow-up. Associations of baseline levels of IL-6, VCAM-1, and TNF-α with cognitive function over time were estimated using a linear mixed model adjusted for demographics, education, vascular risk factors, stroke severity, ischemic stroke subtype, and severity of white matter hyperintensity. We included 570 patients with mild-to-moderate ischemic stroke and baseline data on biomarker levels. The mean age was 67 (± 12 SD), 38.6% were female, and the median National Institutes of Health Stroke Scale (NIHSS) was 2 (IQR 1-4). Frequency of cognitive impairment defined as TICS-m score ≤ 31 was 21.9% at year one, 15.4% at year two, and 11.6% at year three. Higher log-transformed levels of IL-6 and VCAM-1 were associated with lower TICS-m scores over time in the adjusted linear mixed model including white matter hyperintensity burden (IL-6: β = -2.0, 95% CI -3.3 to -0.7, p = 0.003; VCAM-1: β = -4.1, 95% CI -7.3 to -1.0, p = 0.01). In patients with mild-to-moderate first-ever ischemic stroke, higher baseline levels of IL-6 and VCAM-1 were associated with lower Telephone Interview for Cognitive Status-modified during 3 years of follow-up.ClinicalTrials.gov Identifier: NCT01363856.