Uterine sarcomas with KAT6B/A::KANSL1 fusion represent a new entity characterized by bland morphology, commonly with hybrid features of low-grade endometrial stromal sarcoma (LG-ESS) and tumors with smooth muscle differentiation. In our study, we performed a detailed morphological, immunohistochemical, and molecular analysis of 9 cases of these tumors. Six of those had been originally diagnosed as LG-ESS, one as leiomyoma, one as leiomyosarcoma, and the remaining case as sarcoma with the KAT6B/A::KANSL1 fusion. Seven cases showed overlapping features between endometrial stromal and smooth muscle tumors, one case resembled cellular leiomyoma, and one case resembled high-grade endometrial stromal sarcoma. Immunohistochemically, the tumors showed a common expression of smooth muscle markers and endometrial stromal markers. Molecular findings showed the KAT6B/A::KANSL1 fusion in all cases (by NGS and FISH). In addition, mutations affecting genes such as TP53, PDGFRB, NF1, RB1, PTEN, ATM, RB1, FANCD2, and TSC1 were present in all 5 cases with aggressive behavior. One patient with no evidence of disease showed no additional mutations, while another harbored a mutation of a single gene (ERCC3). Of the 8 patients with available follow-up, two died of disease, 3 are currently alive with disease, and 3 have no evidence of disease. The correct recognition of tumors with the KAT6B/A::KANSL1 fusion is essential because despite the bland morphological features of most cases, these tumors have a propensity for aggressive behavior.

• MeSH
• Adult MeSH
• Sarcoma, Endometrial Stromal genetics   pathology   MeSH
• Oncogene Proteins, Fusion genetics   MeSH
• Histone Acetyltransferases genetics   MeSH
• Immunohistochemistry MeSH
• Middle Aged MeSH
• Humans MeSH
• Mutation MeSH
• Biomarkers, Tumor * genetics   analysis   MeSH
• Uterine Neoplasms * pathology   genetics   MeSH
• Sarcoma genetics   pathology   MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Cell cycle progression and leukemia development are tightly regulated processes in which even a small imbalance in the expression of cell cycle regulatory molecules and microRNAs (miRNAs) can lead to an increased risk of cancer/leukemia development. Here, we focus on the study of a ubiquitous, multifunctional, and oncogenic miRNA-hsa-miR-155-5p (miR-155, MIR155HG), which is overexpressed in malignancies including chronic lymphocytic leukemia (CLL). Nonetheless, the precise mechanism of how miR-155 regulates the cell cycle in leukemic cells remains the subject of extensive research. METHODS: We edited the CLL cell line MEC-1 by CRISPR/Cas9 to introduce a short deletion within the MIR155HG gene. To describe changes at the transcriptome and miRNome level in miR-155-deficient cells, we performed mRNA-seq/miRNA-seq and validated changes by qRT-PCR. Flow cytometry was used to measure cell cycle kinetics. A WST-1 assay, hemocytometer, and Annexin V/PI staining assessed cell viability and proliferation. RESULTS: The limited but phenotypically robust miR-155 modification impaired cell proliferation, cell cycle, and cell ploidy. This was accompanied by overexpression of the negative cell cycle regulator p21/CDKN1A and Cyclin D1 (CCND1). We confirmed the overexpression of canonical miR-155 targets such as PU.1, FOS, SHIP-1, TP53INP1 and revealed new potential targets (FCRL5, ISG15, and MX1). CONCLUSIONS: We demonstrate that miR-155 deficiency impairs cell proliferation, cell cycle, transcriptome, and miRNome via deregulation of the MIR155HG/TP53INP1/CDKN1A/CCND1 axis. Our CLL model is valuable for further studies to manipulate miRNA levels to revert highly aggressive leukemic cells to nearly benign or non-leukemic types.

• MeSH
• Leukemia, Lymphocytic, Chronic, B-Cell * genetics   pathology   MeSH
• Cyclin D1 genetics   metabolism   MeSH
• Cyclin-Dependent Kinase Inhibitor p21 * genetics   metabolism   MeSH
• Cell Cycle Checkpoints * genetics   MeSH
• Humans MeSH
• MicroRNAs * genetics   metabolism   MeSH
• Cell Line, Tumor MeSH
• Cell Proliferation genetics   MeSH
• Heat-Shock Proteins MeSH
• Gene Expression Regulation, Leukemic MeSH
• Carrier Proteins genetics   metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

Around 180 genes have been associated with congenital anomalies of the kidney and urinary tract (CAKUT) in mice, and represent promising novel candidate genes for human CAKUT. In whole-exome sequencing data of two siblings with genetically unresolved multicystic dysplastic kidneys (MCDK), prioritizing variants in murine CAKUT-associated genes yielded a rare variant in the teashirt zinc finger homeobox 3 (TSHZ3) gene. Therefore, the role of TSHZ3 in human CAKUT was assessed. Twelve CAKUT patients from 9/301 (3%) families carried five different rare heterozygous TSHZ3 missense variants predicted to be deleterious. CAKUT patients with versus without TSHZ3 variants were more likely to present with hydronephrosis, hydroureter, ureteropelvic junction obstruction, MCDK, and with genital anomalies, developmental delay, overlapping with the previously described phenotypes in Tshz3-mutant mice and patients with heterozygous 19q12-q13.11 deletions encompassing the TSHZ3 locus. Comparable with Tshz3-mutant mice, the smooth muscle layer was disorganized in the renal pelvis and thinner in the proximal ureter of the nephrectomy specimen of a TSHZ3 variant carrier compared to controls. TSHZ3 was expressed in the human fetal kidney, and strongly at embryonic day 11.5-14.5 in mesenchymal compartments of the murine ureter, kidney, and bladder. TSHZ3 variants in a 5' region were more frequent in CAKUT patients than in gnomAD samples (p < 0.001). Mutant TSHZ3 harboring N-terminal variants showed significantly altered SOX9 and/or myocardin binding, possibly adversely affecting smooth muscle differentiation. Our results provide evidence that heterozygous TSHZ3 variants are associated with human CAKUT, particularly MCDK, hydronephrosis, and hydroureter, and, inconsistently, with specific extrarenal features, including genital anomalies.

• MeSH
• Child MeSH
• Heterozygote * MeSH
• Homeodomain Proteins genetics   MeSH
• Infant MeSH
• Kidney abnormalities   metabolism   MeSH
• Humans MeSH
• Mutation, Missense MeSH
• Urinary Tract abnormalities   metabolism   MeSH
• Multicystic Dysplastic Kidney genetics   MeSH
• Mice MeSH
• Child, Preschool MeSH
• Transcription Factors genetics   MeSH
• Urogenital Abnormalities genetics   pathology   MeSH
• Vesico-Ureteral Reflux MeSH
• Animals MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Male MeSH
• Mice MeSH
• Child, Preschool MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Despite secondary prevention with aspirin, patients with stable cardiovascular disease (CVD) remain at elevated long-term risk of major adverse cardiovascular events. The Cardiovascular Outcomes in People Using Anticoagulant Strategies (COMPASS) double-blind, randomized clinical trial demonstrated that aspirin plus low-dose rivaroxaban (COMPASS regime) significantly decreased the incidence of major adverse cardiovascular events by 24% compared with aspirin alone. However, the mechanisms underlying these potential synergistic/nonantithrombotic effects remain elusive. Extracellular vesicles (EVs) are crucial messengers regulating a myriad of biological/pathological processes and are highly implicated in CVD. OBJECTIVES: We hypothesized that circulating EV profiles reflect the cardioprotective properties of the COMPASS regime. METHODS: A cohort of stable CVD patients (N = 40) who participated in the COMPASS trial and were previously randomized to receive aspirin were prospectively recruited and assigned a revised regimen of open-label aspirin plus rivaroxaban. Blood samples were obtained at baseline (aspirin only) and 6-month follow-up. Plasma EV concentration, size, and origin were analyzed by nanoparticle tracking analysis and flow cytometry. EVs were enriched by ultracentrifugation for proteomic analysis. RESULTS: The COMPASS regime fundamentally altered small (<200 nm) and large (200-1000 nm) EV concentration and size compared with aspirin alone. Crucially, levels of platelet-derived and myeloperoxidase-positive EVs became significantly decreased at follow-up. Comparative proteomic characterization further revealed a significant decrease in highly proinflammatory protein expression at follow-up. CONCLUSION: The observed changes in EV subpopulations, together with the differential protein expression profiles, suggest amelioration of an underlying proinflammatory and prothrombotic state upon dual therapy, which may be of clinical relevance toward understanding the fundamental mechanism underlying the reported superior cardiovascular outcomes associated with this antithrombotic regimen.

• MeSH
• Aspirin * administration & dosage   therapeutic use   adverse effects   MeSH
• Double-Blind Method MeSH
• Extracellular Vesicles * metabolism   drug effects   MeSH
• Platelet Aggregation Inhibitors * administration & dosage   adverse effects   therapeutic use   MeSH
• Factor Xa Inhibitors * administration & dosage   adverse effects   therapeutic use   MeSH
• Cardiovascular Diseases * blood   prevention & control   drug therapy   MeSH
• Drug Therapy, Combination * MeSH
• Middle Aged MeSH
• Humans MeSH
• Inflammation Mediators blood   MeSH
• Prospective Studies MeSH
• Proteomics methods   MeSH
• Rivaroxaban * administration & dosage   MeSH
• Aged MeSH
• Thrombosis blood   prevention & control   drug therapy   MeSH
• Treatment Outcome MeSH
• Inflammation blood   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Randomized Controlled Trial MeSH

Human migration is an increasingly common phenomenon and migrants are at risk of disadvantageous treatment. We reasoned that migrants may receive differential treatment by locals based on the closeness of their facial features to the host average. Residents of Türkiye, the country with the largest number of refugees currently, served as participants. Because many of these refugees are of Arabic origin, we created target facial stimuli varying along the axis connecting Turkish and Arabic morphological prototypes (excluding skin colour) computed using geometric morphometrics and available databases. Participants made judgements of two universal dimensions of social perception-warmth and competence-on these faces. We predicted that participants judging faces manipulated towards the Turkish average would provide higher warmth and competence ratings compared to judging the same faces manipulated towards the Arabic average. Bayesian statistical tools were employed to estimate parameter values in multilevel models with intercorrelated varying effects. The findings did not support the prediction and revealed raters (as well as target faces) to be an important source of variation in social judgements. In the absence of simple cues (e.g. skin colour, group labels), the effect of facial morphology on social judgements may be much more complex than previously assumed.

• MeSH
• Bayes Theorem MeSH
• Adult MeSH
• Humans MeSH
• Judgment * MeSH
• Adolescent MeSH
• Young Adult MeSH
• Face anatomy & histology   MeSH
• Facial Recognition physiology   MeSH
• Social Perception * MeSH
• Stereotyping * MeSH
• Refugees psychology   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Turkey MeSH

Alexander disease (AxD) is a rare and severe neurodegenerative disorder caused by mutations in glial fibrillary acidic protein (GFAP). While the exact disease mechanism remains unknown, previous studies suggest that mutant GFAP influences many cellular processes, including cytoskeleton stability, mechanosensing, metabolism, and proteasome function. While most studies have primarily focused on GFAP-expressing astrocytes, GFAP is also expressed by radial glia and neural progenitor cells, prompting questions about the impact of GFAP mutations on central nervous system (CNS) development. In this study, we observed impaired differentiation of astrocytes and neurons in co-cultures of astrocytes and neurons, as well as in neural organoids, both generated from AxD patient-derived induced pluripotent stem (iPS) cells with a GFAPR239C mutation. Leveraging single-cell RNA sequencing (scRNA-seq), we identified distinct cell populations and transcriptomic differences between the mutant GFAP cultures and a corrected isogenic control. These findings were supported by results obtained with immunocytochemistry and proteomics. In co-cultures, the GFAPR239C mutation resulted in an increased abundance of immature cells, while in unguided neural organoids and cortical organoids, we observed altered lineage commitment and reduced abundance of astrocytes. Gene expression analysis revealed increased stress susceptibility, cytoskeletal abnormalities, and altered extracellular matrix and cell-cell communication patterns in the AxD cultures, which also exhibited higher cell death after stress. Overall, our results point to altered cell differentiation in AxD patient-derived iPS-cell models, opening new avenues for AxD research.

• MeSH
• Alexander Disease * genetics   pathology   metabolism   MeSH
• Astrocytes * metabolism   pathology   MeSH
• Cell Differentiation * physiology   MeSH
• Glial Fibrillary Acidic Protein * metabolism   genetics   MeSH
• Induced Pluripotent Stem Cells * metabolism   MeSH
• Coculture Techniques MeSH
• Cells, Cultured MeSH
• Humans MeSH
• Mutation MeSH
• Neural Stem Cells metabolism   MeSH
• Neurons metabolism   pathology   MeSH
• Organoids metabolism   pathology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

The forskolin-induced swelling assay (FIS) in patient-derived intestinal organoids (PDIOs), used to determine in vitro responsiveness to elexacaftor/tezacaftor/ivacaftor (ETI), showed variability in swelling among PDIOs obtained from people with CF (pwCF) carrying the same F508del/F508del CFTR genotype. We aimed to characterise the effect of ETI on the transcriptional activity of PDIOs-derived cells to understand the intracellular processes triggered by ETI and the differences in treatment response. Six high- and six low-responding PDIOs to ETI, derived from F508del/F508del pwCF, were incubated with or without ETI for 2 to 6 h. Gene expression was assessed using 3'-mRNA sequencing and modelled using negative binomial models. Incubation with ETI resulted in a significant upregulation of several biological processes: mostly related to chemokines and signalling, chemotaxis, and tissue development processes. No changes were observed in abundance of the CFTR transcripts or in CFTR-related gene sets and pathways. The genes and pathways associated with ETI did not overlap with those whose expression changed with time only. PDIOs with a high FIS response did not significantly differ in any interpretable gene from the FIS-low organoids. The changes in the PDIOs gene expression upon the exposure to ETI cannot explain differences in the magnitude of PDIOs FIS-measured response to ETI. In conclusion, on incubation with ETI, genes of the CFTR-related pathways do not change their transcriptional activity; instead, overexpression was observed in genes of inflammatory-like cytokine response and receptor activation pathways.

• MeSH
• Chloride Channel Agonists therapeutic use   pharmacology   MeSH
• Aminophenols * therapeutic use   pharmacology   MeSH
• Benzodioxoles * therapeutic use   pharmacology   MeSH
• Quinolones * pharmacology   therapeutic use   MeSH
• Cystic Fibrosis * genetics   drug therapy   MeSH
• Drug Combinations MeSH
• Indoles * pharmacology   MeSH
• Humans MeSH
• Organoids * metabolism   MeSH
• Cystic Fibrosis Transmembrane Conductance Regulator genetics   MeSH
• Pyrazoles * pharmacology   MeSH
• Pyridines pharmacology   MeSH
• Pyrrolidines pharmacology   MeSH
• Pyrroles pharmacology   MeSH
• Gene Expression Profiling methods   MeSH
• Intestines drug effects   MeSH
• Transcriptome MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

Clear-cell renal cell carcinoma (ccRCC) is a common urological malignancy with an increasing incidence. The development of molecular biomarkers that can predict the response to treatment and guide personalized therapy selection would substantially improve patient outcomes. Dysregulation of non-coding RNA (ncRNA) has been shown to have a role in the pathogenesis of ccRCC. Thus, an increasing number of studies are being carried out with a focus on the identification of ncRNA biomarkers in ccRCC tissue samples and the connection of these markers with patients' prognosis, pathological stage and grade (including metastatic potential), and therapy outcome. RNA sequencing analysis led to the identification of several ncRNA biomarkers that are dysregulated in ccRCC and might have a role in ccRCC development. These ncRNAs have the potential to be prognostic and predictive biomarkers for ccRCC, with prospective applications in personalized treatment selection. Research on ncRNA biomarkers in ccRCC is advancing, but clinical implementation remains preliminary owing to challenges in validation, standardization and reproducibility. Comprehensive studies and integration of ncRNAs into clinical trials are essential to accelerate the clinical use of these biomarkers.

• MeSH
• Carcinoma, Renal Cell * genetics   diagnosis   MeSH
• Humans MeSH
• Biomarkers, Tumor * genetics   MeSH
• Kidney Neoplasms * genetics   diagnosis   MeSH
• RNA, Untranslated * genetics   MeSH
• Prognosis MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Gene Expression Profiling MeSH
• Transcriptome * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Our aim is to determine the number of leukocytes, T lymphocytes and B lymphocytes and the expression of activation markers CD200 and CD23 on B lymphocytes in atopic dermatitis (AD) patients (treated and not treated with dupilumab) during the pollen season. We examined 29 patients not treated with dupilumab, 24 patients treated with dupilumab and 40 healthy subjects as a control group. The count of T and B lymphocytes and their subsets were assessed by flow cytometry. The non-parametric Kruskal-Wallis one-factor analysis of variance with post hoc by Dunn's test with Bonferroni's modification was used for statistical processing. Although there was a significant improvement in skin findings in patients treated with dupilumab, the changes in immunological profile show a persistent altered immune response characterized by dysregulation and overactivation of B lymphocytes. Dupilumab therapy leads to normalization of relative T regulatory lymphocytes and total memory B lymphocytes and to decreased count of absolute CD8+ T lymphocytes. Why carry out this study?Studies investigating the immunological profile of atopic dermatitis (AD) patients during the pollen season are rare. There are no studies investigating the count of B lymphocytes (CD5+, CD22+ and CD73+ B lymphocytes) and the expression of activation markers CD23 and CD200 on B lymphocytes and on their subsets during pollen season in AD patients treated and non-treated with dupilumab therapy.What was learned from the study?In atopic dermatitis (AD) patients with and without dupilumab therapy, we confirmed the significantly higher count of absolute neutrophils, absolute monocytes, absolute eosinophils, absolute basophils, non-switched B lymphocytes, transitional B lymphocytes, CD23 memory, naive, non-switched, switched and total CD23 B lymphocytes, the relative count of CD200 memory and CD200 switched B lymphocytes.In dupilumab treated patients, we confirmed the significantly higher count of relative eosinophils, relative CD16+ eosinophils, relative CD200 non-switched B lymphocytes and lower count of absolute CD8+ T lymphocytes. Further studies should focus on investigating the effect of dupilumab on CD8+ T lymphocytes and their subpopulations.In patients without dupilumab therapy, we confirmed the significantly higher count of relative neutrophils, relative T regulatory lymphocytes and total memory B lymphocytes.The changes in the count of CD5+, CD22+ and CD73+ B lymphocytes were not observed during pollen season in both groups of AD patients.

• MeSH
• Dermatitis, Atopic * drug therapy   immunology   MeSH
• B-Lymphocytes immunology   MeSH
• Antigens, CD MeSH
• Adult MeSH
• Antibodies, Monoclonal, Humanized * therapeutic use   MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Pollen immunology   MeSH
• Receptors, IgE MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

INTRODUCTION: Breast cancer comprises the leading cause of cancer-related death in women. MicroRNAs (miRNAs) have emerged as important factors with concern to carcinogenesis and have potential for use as biomarkers. METHODS: This study provides a comprehensive evaluation of the microRNA expression in invasive breast carcinoma of no special type tissues compared with benign tissues via large-scale screening and the candidate-specific validation of 15 miRNAs and U6 snRNA applying qPCR and the examination of clinicopathological data. RESULTS: Of the six downregulated miRNAs, let-7c was identified as the most promising miRNA biomarker and its lower expression was linked with Ki-67 positivity, luminal B versus luminal A samples, multifocality, lymph node metastasis, and inferior PFS. Of the 9 upregulated sncRNAs, the data on U6 snRNA, miR-493 and miR-454 highlighted their potential oncogenic functions. An elevated U6 snRNA expression was associated with the tumor grade, Ki-67 positivity, luminal B versus A samples, lymph node metastasis, and worsened PFS (and OS) outcomes. An elevated miR-454 expression was detected in higher grades, Ki-67 positive and luminal B versus A samples. Higher miR-493 levels were noted for the tumor stage (and grade) and worse patient outcomes (PFS, OS). The data also suggested that miR-451a and miR-328 may have tumor suppressor roles, and miR-182 and miR-200c pro-oncogenic functions, while the remaining sncRNAs did not evince any significant associations. CONCLUSION: We showed particular microRNAs and U6 snRNA as differentially expressed between tumors and benign tissues and associated with clinicopathological parameters, thus potentially corresponding with important roles in breast carcinogenesis. Their importance should be further investigated and evaluated in follow-up studies to reveal their potential in clinical practice. INTRODUCTION: Breast cancer comprises the leading cause of cancer-related death in women. MicroRNAs (miRNAs) have emerged as important factors with concern to carcinogenesis and have potential for use as biomarkers. METHODS: This study provides a comprehensive evaluation of the microRNA expression in invasive breast carcinoma of no special type tissues compared with benign tissues via large-scale screening and the candidate-specific validation of 15 miRNAs and U6 snRNA applying qPCR and the examination of clinicopathological data. RESULTS: Of the six downregulated miRNAs, let-7c was identified as the most promising miRNA biomarker and its lower expression was linked with Ki-67 positivity, luminal B versus luminal A samples, multifocality, lymph node metastasis, and inferior PFS. Of the 9 upregulated sncRNAs, the data on U6 snRNA, miR-493 and miR-454 highlighted their potential oncogenic functions. An elevated U6 snRNA expression was associated with the tumor grade, Ki-67 positivity, luminal B versus A samples, lymph node metastasis, and worsened PFS (and OS) outcomes. An elevated miR-454 expression was detected in higher grades, Ki-67 positive and luminal B versus A samples. Higher miR-493 levels were noted for the tumor stage (and grade) and worse patient outcomes (PFS, OS). The data also suggested that miR-451a and miR-328 may have tumor suppressor roles, and miR-182 and miR-200c pro-oncogenic functions, while the remaining sncRNAs did not evince any significant associations. CONCLUSION: We showed particular microRNAs and U6 snRNA as differentially expressed between tumors and benign tissues and associated with clinicopathological parameters, thus potentially corresponding with important roles in breast carcinogenesis. Their importance should be further investigated and evaluated in follow-up studies to reveal their potential in clinical practice.

• MeSH
• Adult MeSH
• Neoplasm Invasiveness MeSH
• Middle Aged MeSH
• Humans MeSH
• Lymphatic Metastasis MeSH
• MicroRNAs * genetics   metabolism   MeSH
• Biomarkers, Tumor * genetics   metabolism   MeSH
• Breast Neoplasms * pathology   genetics   metabolism   mortality   MeSH
• Gene Expression Regulation, Neoplastic * MeSH
• RNA, Small Nuclear * genetics   metabolism   MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH