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VEXAS syndrome, a monogenic X-linked disorder resulting from mutations in the UBA1 gene, has emerged as a key model for unraveling the links between systemic inflammatory or autoimmune diseases (SIAD) and myelodysplastic syndromes (MD). This syndrome is characterized by the presence of vacuoles, X-linked inheritance, autoinflammation, and somatic mutation patterns, highlighting a unique intersection between genetic and immunological dysregulation. Apart from VEXAS, 10% to 30% of individuals diagnosed with MDS exhibit SIAD phenotypes, a significant increase compared to the 5% incidence in the general population. In this comprehensive review, we aim to elucidate the molecular mechanisms driving the pro-inflammatory environment in MDS, focusing on the contribution of VEXAS syndrome to this complex interplay. We examine how UBA1 mutations disrupt cellular homeostasis, triggering inflammatory pathways. Furthermore, we explore the broader implications of these findings for the pathogenesis of MDS, proposing that the inflammatory dysregulation of VEXAS may shed light on mechanisms of disease progression and identify potential therapeutic targets in MDS. Through an integrated analysis of genetic, immunological, and clinical data, this review seeks to deepen our understanding of the complex relationship between systemic inflammation and hematological malignancies, paving the way for new diagnostic and therapeutic strategies.

Gastrointestinal diseases are becoming a growing public health problem. One of them is inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn's disease (CD). The incidence of IBD is increasing in developing countries and declining in developed countries, affecting people of all ages. Researchers have been exploring new treatment options including insulin signaling pathways in the inflammation of the gastrointestinal tract. It seems that a better understanding of the mechanism of IGF-1, GLP-1 and TL1A on the gut microbiota and inflammation may provide new advances in future therapeutic strategies for patients with IBD, but also other intestinal diseases. This review aims to synthesize insights into the effects of GLP, IGF and anti-TL1A on inflammation and the gut microbiota, which may enable their future use in therapy for people with intestinal diseases.

Early life stress (ELS) increases predisposition to major depressive disorder (MDD), with neuroinflammation playing a crucial role. This study investigated the long-term effects of the fatty acid amide hydrolase (FAAH) inhibitor URB597 on ELS-induced depressive-like behavior and messenger RNA (mRNA) of pro-inflammatory cytokines in the medial prefrontal cortex (mPFC) and CA1 regions. We also assessed whether these gene expression alterations were present at the onset of URB597 treatment during late adolescence. ELS induced a depressive-like phenotype in adult male and female rats, which was reversed by URB597. In the mPFC, ELS downregulated nuclear factor kappa B1 (nfκb1) in both sexes, while URB597 normalized this expression exclusively in males. In females, ELS downregulated interleukin (il) 6 and tumor necrosis factor alpha (tnfα) but upregulated il1β and corticotropin-releasing factor (crf); URB597 normalized il6, il1β, and crf. In the CA1, ELS downregulated il1β and tnfα in males and upregulated il1β expression in females, which was reversed by URB597. Some of these effects began in late adolescence, including mPFC-nfκb1 expression in both sexes, mPFC-il6 and mPFC-il1β in females, CA1-il1β and CA1-tnfα in males, and CA1-il1β in females. These findings highlight URB597 as a therapeutic approach for reversing ELS-induced depressive-like behavior by associating with changes in the gene expression of neuroinflammatory cytokines, with notable sex differences.

The active form of vitamin D, 1,25-dihydroxyvitamin D (1,25D), binds to the vitamin D receptor (VDR) with high affinity. The VDR then heterodimerizes with the retinoid X receptor (RXR) and associates with vitamin D response elements (VDREs) to regulate the transcription of target genes. Bexarotene (Bex) is an RXR ligand (rexinoid) developed to treat cutaneous T-cell lymphoma and is a putative therapeutic for other diseases. We postulate that VDR ligands (1,25D) and RXR ligands (Bex/analogs) can "synergize" to "super-activate" the VDR-RXR heterodimer. This "cross-talk" could allow disorders treated with high-dose Bex therapy (leading to significant adverse side effects) to instead be treated using both low-dose Bex and vitamin D. Thus, we designed experiments to examine the effect of both VDR and RXR ligands, alone and in combination, to activate VDR-RXR-mediated transcription. The goal was to determine if selected RXR-specific ligands can synergize with vitamin D to amplify RXR-VDR activity. The results demonstrate a synergistic effect with both Bex and 1,25D which could be further modulated by (1) the protein levels (or polymorphic version) of VDR present in the cell, (2) the concentration of the ligands, (3) the cellular "background" (e.g., brain cells versus kidney cells), (4) the nature of the VDRE platform, or (5) the type of rexinoid (Bex analogs). Our findings suggest that diseases that respond to treatment with either vitamin D, or with rexinoids, may be amenable to enhanced therapeutic potential by employing multi-ligand dosing via combinatorial therapy.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with a high tendency for developing a recurrent disease. Circulating micro-RNAs (cmiRNAs) obtained through liquid biopsy are potential prognostic biomarkers for the assessment of TNBC recurrence risk. In this study, we sequenced cmiRNAs from the serum samples of 14 recurrent and 19 non-recurrent TNBC cases and compared expression profiles in relation to recurrence status, survival data and miRNA expression in matched tumor samples. Differential expression analysis between recurrent and non-recurrent cases identified ten differentially expressed (DE) cmiRNAs, of which cmiRNAs miR-21-5p (p = 0.030, HR = 1.87, 95% CI 1.06-3.30), miR-16-5p (p = 0.032, HR = 0.53, 95% CI 0.30-0.95), and miR-26b-5p (p = 0.023, HR = 0.52, 95% CI 0.29-0.91) were associated with recurrence-free survival in multivariable survival analysis. Expression profiles of matched tumor and serum samples were shown to correlate with each other. DE cmiRNAs were associated with common cancer-related signaling pathways and improved the overall predictive performance of the logistic regression model assessing the recurrence risk. Our results indicate that recurrent and non-recurrent TNBC differ in their cmiRNA expression profiles, and that three specific cmiRNAs can be used to assess the risk of recurrence in TNBC.

The rate of spontaneous action potentials (APs) generated by sinoatrial node cells (SANC) is regulated by local Ca²⁺ release (LCR) from the sarcoplasmic reticulum via Ca²⁺ release channels (ryanodine receptors, RyRs). LCR events propagate and self-organize within the network of RyR clusters (Ca release units, CRUs) via Ca-induced-Ca-release (CICR) that depends on CRU sizes and locations: While larger CRUs generate stronger release signals, the network's topology governs signal diffusion and propagation. This study used super-resolution structured illumination microscopy to image the 3D network of CRUs in rabbit SANC. The peripheral CRUs formed a spatial mesh, reflecting the cell surface geometry. Two distinct subpopulations of CRUs were identified within each cell, with size distributions conforming to a two-component Gamma mixture model. Furthermore, neighboring CRUs exhibited repulsive behavior. Functional properties of the CRU network were further examined in a novel numerical SANC model developed using our experimental data. Model simulations revealed that heterogeneities in both CRU sizes and locations facilitate CICR and increase the AP firing rate in a cooperative manner. However, these heterogeneities reduce the effect of β-adrenergic stimulation in terms of its relative change in AP firing rate. The presence of heterogeneities in both sizes and locations allows SANC to reach higher absolute AP firing rates during β-adrenergic stimulation. Thus, the CICR facilitation by heterogeneities in CRU sizes and locations regulates and optimizes cardiac pacemaker cell operation under various physiological conditions. Dysfunction of this optimization could be a key factor in heart rate reserve decline in aging and disease.

CAR T cell therapy has been an effective treatment option for hematological malignancies. However, the therapeutic potential of CAR T cells can be reduced by several constraints, partly due to immunogenicity and toxicities. The lack of established workflows enabling thorough evaluation of new candidates, limits comprehensive CAR assessment. To improve the selection of lead CAR candidates, we established a stringent, multistep workflow based on specificity assessments, employing multiple assays and technologies. Moreover, we characterized a human FOLR1-directed CAR binding domain. Selection of binding domains was based on extensive specificity assessment by flow cytometry and imaging, to determine on-/off-target and off-tumor reactivity. CAR T cell functionality and specificity were assessed by high-throughput screening and advanced in vitro assays. Our validation strategy highlights that assays comprehensively characterizing CAR functionality and binding specificity complement each other. Thereby, critical specificity considerations can be addressed early in the development process to overcome current limitations for future CAR T cell therapies.

Dnah5 is associated with primary ciliary dyskinesia in humans. Dnah5-knockout (Dnah5-/- mice develop acute hydrocephalus shortly after birth owing to impaired ciliary motility and cerebrospinal fluid (CSF) stagnation. In contrast to chronic adult-onset hydrocephalus observed in other models, this rapid ventricular enlargement indicates additional factors beyond CSF stagnation. Herein, we investigated the contributors to rapid ventricular enlargement in congenital hydrocephalus. Dnah5-/- mice were generated using CRISPR/Cas9. The expression of dynein, N-cadherin, and nestin in the cerebral cortex was assessed using microarrays and immunostaining. Real-time PCR and Western blotting were performed for gene and protein quantification, respectively. All Dnah5-/- mice developed hydrocephalus, confirmed by electron microscopy, indicating the absence of axonemal outer dynein arms. Ventricular enlargement occurred rapidly, with a 25% reduction in the number of mature neurons in the motor cortex. Dync1h1 expression was decreased, while cytoplasmic dynein levels were 56.3% lower. Levels of nestin and N-cadherin in the lateral ventricular walls decreased by 31.7% and 33.3%, respectively. Reduced cytoplasmic dynein disrupts neurogenesis and axonal growth and reduces neuron cortical density. Hydrocephalus in Dnah5-/- mice may result from cortical maldevelopment due to cytoplasmic dynein deficiency, further exacerbating ventricular enlargement due to CSF stagnation caused by impaired motile ciliary function.

Background: Previous works have shown that the expression of Class-II-Transactivator (CIITA) in tumor cells reduces the growth of glioblastoma (GB) in animal models, but immune effects cannot solely explain this. Here, we searched for immune-independent effects of CIITA on the proliferation of GB.

Methods: Murine GL261 and human U87, GM2 and GM3 malignant glioma cells were transfected with CIITA. NSG (immunodeficient) and nude (athymic) mice were injected in the striatum with GL261-wildtype (-WT) and -CIITA, and tumor growth was assessed by immunohistology and luminescence reporter genes. Clonogenic, sphere-formation, and 3D Matrigel-based in vitro growth assays were performed to compare the growth of WT versus CIITA-expressing murine and human cells. Bulk RNA sequencing and RT² qRT-PCR profiler arrays were performed on these four cell lines to assess RNA expression changes following CIITA transfection. Western blot analysis on several proliferation-associated proteins was performed.

Results: The intracerebral growth of murine GL261-CIITA cells was drastically reduced both in immunodeficient and athymic mice. Tumor growth was reduced in vitro in three of the four cell types. RNA sequencing and RT² profiler array experiments revealed a modulation of gene expression in the PI3-Akt, MAPK- and cell-cycle regulation pathways following CIITA overexpression. Western blot analysis showed an upregulation of p27 in the growth-inhibited cells following this treatment. PDGFR-beta was downregulated in all cells. We did not find consistent regulation of other proteins involved in GB proliferation.

Conclusions: Proliferation is drastically reduced by CIITA in GB, both in vivo and in vitro, notably in association with p27-mediated inhibition of cell-cycle pathways.

The aim of this in vitro study was to evaluate the effect of xanthohumol and thymol on the impact of Candida albicans on the structure, size and cell viability of subgingival biofilms formed on dental implant surfaces. The structure and microbial biomass of biofilms developed after 72 h, treated and untreated with both extracts, were compared by scanning electron microscopy (SEM) and confocal laser microscopy (CLSM). Quantitative polymerase chain reaction (qPCR) was used to quantify the number of viable and total microorganisms of each of the biofilm-forming strains in each condition. A general linear model was used to compare and validate the CLSM and qPCR results. The presence of xanthohumol and thymol during biofilm development inhibited the filamentous growth of C. albicans. The biofilm incubated with xanthohumol had significantly lower bacterial biomass and cell viability than the biofilm not exposed to the extract (p < 0.05). In contrast, these global parameters showed no differences when the biofilm was incubated with thymol. In the presence of xanthohumol, there was a decrease in counts and cell viability of Fusobacterium nucleatum, Porphyromonas gingivalis, and Aggregatibacter actinomycetemcomitans. Thymol treatment reduced the viability of F. nucleatum and P. gingivalis. The presence of these vegetable extracts during the development of a dynamic in vitro multispecies biofilm model inhibited the filamentous growth of C. albicans, partially reversing the effect that the fungus exerted on the structure, size and vitality of periodontopathogenic bacteria.