Bardet-Biedl syndrome (BBS) is a pleiotropic ciliopathy caused by dysfunction of the BBSome, a cargo adaptor essential for export of transmembrane receptors from cilia. Although actin-dependent ectocytosis has been proposed to compensate defective cargo retrieval, its molecular basis remains unclear, especially in relation to BBS pathology. In this study, we investigated how actin polymerization and ectocytosis are regulated within the cilium. Our findings reveal that ciliary CDC42, a RHO-family GTPase triggers in situ actin polymerization, ciliary ectocytosis, and cilia shortening in BBSome-deficient cells. Activation of the Sonic Hedgehog pathway further enhances CDC42 activity specifically in BBSome-deficient cilia. Inhibition of CDC42 in BBSome-deficient cells decreases the frequency and duration of ciliary actin polymerization events, causing buildup of G protein coupled receptor 161 (GPR161) in bulges along the axoneme during Sonic Hedgehog signaling. Overall, our study identifies CDC42 as a key trigger of ciliary ectocytosis. Hyperactive ciliary CDC42 and ectocytosis and the resulting loss of ciliary material might contribute to BBS disease severity.
- MeSH
- Actins * metabolism MeSH
- Bardet-Biedl Syndrome metabolism genetics pathology MeSH
- cdc42 GTP-Binding Protein * metabolism genetics MeSH
- Cilia * metabolism MeSH
- Humans MeSH
- Mice MeSH
- Hedgehog Proteins * metabolism MeSH
- Receptors, G-Protein-Coupled metabolism genetics MeSH
- Signal Transduction * MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
INTRODUCTION: The E3 ubiquitin ligase Cbl-b is a novel target in immune-oncology, with critical roles in regulating T-cell activation and signaling pathways. By facilitating the ubiquitination and degradation of key signaling proteins, Cbl-b modulates immune responses, maintaining immune homeostasis and preventing unwarranted T-cell proliferation. The therapeutic potential of Cbl-b as a cancer immunotherapy target is underscored by its contribution to an immunosuppressive tumor microenvironment, with efforts currently underway to develop small-molecule inhibitors. AREAS COVERED: We reviewed the small molecules, and antibody-drug conjugates targeting Cbl-b from 2018 to 2024. The patents were gathered through publicly available databases and analyzed with in-house developed cheminformatic workflow, described within the manuscript. EXPERT OPINION: Targeting Cbl-b presents a promising approach in immuno-oncology, offering a novel pathway to potentiate the immune system's ability to combat cancer beyond PDL1/PD1 inhibition. The development and clinical advancement of Cbl-b inhibitors, as evidenced by the ongoing trials, mark a significant step toward harnessing this target for therapeutic benefits. Overall, the strategic inhibition of Cbl-b holds substantial promise for improving cancer immunotherapy outcomes, heralding a new era in the fight against cancer.
- MeSH
- Adaptor Proteins, Signal Transducing MeSH
- Molecular Targeted Therapy * MeSH
- Immunoconjugates pharmacology MeSH
- Immunotherapy * methods MeSH
- Humans MeSH
- Tumor Microenvironment * immunology MeSH
- Neoplasms * immunology drug therapy MeSH
- Patents as Topic * MeSH
- Antineoplastic Agents pharmacology MeSH
- Proto-Oncogene Proteins c-cbl * immunology antagonists & inhibitors MeSH
- Signal Transduction drug effects MeSH
- T-Lymphocytes immunology drug effects MeSH
- Drug Development * MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
The presented guidelines are an update of the position paper, endorsed by the International Osteoporosis Foundation (IOF), on nomenclature of bone markers published over 2 decades ago. Novel insight into bone biology and pathophysiology of bone disorders has highlighted the increasing relevance of new and known mediators implicated in various aspects of bone metabolism. This updated guideline proposes the nomenclature Bone Status Indices (BSI) as the comprehensive classification rather than bone turnover markers, bone markers, metabolic markers of bone turnover or metabolic markers of bone turnover, that are currently in use for the implicated molecules. On behalf of the IFCC Committee on Bone Metabolism and the Joint IOF Working Group and IFCC Committee on Bone Metabolism, the authors propose standardized nomenclature, abbreviations and measurement units for the bone status indices.
- MeSH
- Biomarkers * metabolism analysis MeSH
- Bone and Bones * metabolism MeSH
- Humans MeSH
- Osteoporosis diagnosis metabolism MeSH
- Terminology as Topic * MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Guideline MeSH
OBJECTIVES: To prospectively validate the diagnostic performance of a non-invasive point-of-care tool (Rapid IAI System), including vaginal alpha-fetoprotein and interleukin-6, to predict the occurrence of intra-amniotic inflammation in a Spanish cohort of patients admitted with a diagnosis of preterm labor and intact membranes. METHODS: From 2017 to 2022, we prospectively evaluated a cohort of pregnant women diagnosed with preterm labor and intact membranes admitted below 34+0 weeks who underwent amniocentesis to rule-in/out intra-amniotic infection and/or inflammation. Vaginal sampling was performed at the time of amniocentesis or within 24-48 h. Amniotic fluid IL-6, vaginal alpha-fetoprotein and vaginal IL-6 concentrations were measured using a point-of-care tool provided by Hologic Inc., "Rapid IAI System". We defined intra-amniotic inflammation when amniotic fluid IL-6 values were greater than 11.3 ng/mL. During recruitment, clinicians were blinded to the results of the point-of-care tool. The original prediction model proposed by Hologic Inc. to predict intra-amniotic inflammation was validated in this cohort of patients. RESULTS: We included 151 patients diagnosed with preterm labor and intact membranes. Among these, 29 (19.2 %) had intra-amniotic inflammation. The algorithm including vaginal IL-6 and alpha-fetoprotein showed an area under curve to predict intra-amniotic inflammation of 80.3 % (±5.3 %) with a sensitivity of 72.4 %, specificity of 84.6 %, positive predictive valuve (PPV) of 52.5 %, negative predictive value (NPV) of 92.9 %, and a positive likelihood ratio (LR+) of 4.6 and negative likelihood ratio (LR-) of 0.33. CONCLUSIONS: External validation of a non-invasive rapid point-of-care tool, including vaginal alpha-fetoprotein and IL-6, showed very good diagnostic performance for predicting the absence of intra-amniotic inflammation in women with preterm labor and intact membranes.
- MeSH
- alpha-Fetoproteins * analysis metabolism MeSH
- Amniocentesis methods MeSH
- Chorioamnionitis * diagnosis MeSH
- Adult MeSH
- Risk Assessment methods MeSH
- Interleukin-6 * analysis blood metabolism MeSH
- Humans MeSH
- Amniotic Fluid * metabolism chemistry MeSH
- Point-of-Care Testing MeSH
- Obstetric Labor, Premature * diagnosis MeSH
- Predictive Value of Tests MeSH
- Prospective Studies MeSH
- Pregnancy MeSH
- Vagina metabolism MeSH
- Point-of-Care Systems MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Pregnancy MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Validation Study MeSH
AIMS: The left atrial appendage (LAA) produces natriuretic peptides and its removal or occlusion might increase the risk of heart failure (HF). We aimed to investigate the incidence of HF after LAA occlusion or removal (LAAO) in the Left Atrial Appendage Occlusion Study (LAAOS III). METHODS AND RESULTS: Patients (n = 4811) with atrial fibrillation (AF) and a CHA2DS2-VASc score ≥2, who were having cardiac surgery for another indication, were randomized to undergo surgical LAAO or not. We compared the composite outcome of HF-related hospitalizations and HF death between the two groups. HF assessment required clinical and radiographic evidence of HF. Analyses included a landmark analysis before and after 30 days and subgroups. Mean age was 71.2 years, 67.5% were male and 57.0% had prior HF. Over a mean follow-up of 3.8 years, 396 (8.3%) patients met the composite HF outcome: 209 (8.8%) with LAAO (n = 2379) and 187 (7.8%) without LAAO (n = 2391) (hazard ratio [HR] 1.12, 95% confidence interval [CI] 0.92-1.37, p = 0.25). There was no difference between the two groups in the first 30 days (1.6% vs. 1.1%; p = 0.12) and thereafter (7.6% vs. 7.1%; p = 0.57). Subgroups based on age, sex, body mass index, AF type, prior HF, cardiac rhythm or left ventricular ejection fraction showed consistent results. There was no difference in HF outcomes with LAAO between the cut-and-sew (HR 0.93, 95% CI 0.70-1.23, p = 0.62) versus other closure methods (HR 1.05, 95% CI 0.77-1.41, p = 0.77). CONCLUSIONS: Left atrial appendage occlusion or removal at the time of cardiac surgery does not appear to alter the risk of HF-related hospitalization or death. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01561651.
- MeSH
- Atrial Fibrillation * surgery complications epidemiology MeSH
- Incidence MeSH
- Cardiac Surgical Procedures methods MeSH
- Middle Aged MeSH
- Humans MeSH
- Follow-Up Studies MeSH
- Postoperative Complications epidemiology MeSH
- Aged MeSH
- Atrial Appendage * surgery MeSH
- Heart Failure * epidemiology etiology MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
- Randomized Controlled Trial MeSH
Rosette-forming glioneuronal tumors (RGNTs) with FGFR1 tyrosine kinase domain internal tandem duplication (FGFR1 ITD) is exceedingly rare, with only a few cases reported in the literature. Hereby we present a case of a tumor with RGNT morphology occurring in area of septum pellucidum of 43-year-old male. The tumor showed FGFR1 ITD, no PIK3CA, PIK3R1 or NF1 alterations and inconclusive methylation profile with match for class of "low-grade glial/glioneuronal/neuroepithelial tumors". No areas characteristic of dysembryoplastic neuroepithelial tumor were identified. A brief review of literature on discrepancies between morphological diagnosis of RGNT and molecular profile of the entity is provided.
- MeSH
- Adult MeSH
- Humans MeSH
- Brain Neoplasms * pathology genetics MeSH
- Neoplasms, Neuroepithelial * pathology genetics MeSH
- Receptor, Fibroblast Growth Factor, Type 1 * genetics MeSH
- Tandem Repeat Sequences MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Male MeSH
- Publication type
- Journal Article MeSH
- Case Reports MeSH
AIM: To assess the feasibility, safety and efficacy of using a high-flow nasal cannula (HFNC) for stabilising very preterm infants after birth. METHODS: A prospective observational study included preterm infants born at 28 + 0 to 31 + 6 weeks' gestation between February 2021 and December 2022 at the General University Hospital in Prague. Following delayed cord clamping, HFNC was administered at a flow rate of 8 L/min through the infants' nostrils. Criteria for switching to continuous positive airway pressure (CPAP) or positive pressure ventilation (PPV) included persistent bradycardia in the first few minutes or low saturation of oxygen (SpO2) after 5 min, respectively. RESULTS: Of the 65 infants enrolled in the study, 56 (86%) were successfully stabilised exclusively using HFNC while 7 (11%) required PPV. Additionally, 52 (80%) infants achieved SpO2 > 80% at 5 min, and 54 (83%) infants were successfully treated with HFNC within the first 3 h of life. CONCLUSION: The primary use of HFNC seems to be an appropriate alternative to CPAP for the stabilisation of very premature infants after birth and subsequent transfer to the NICU. A randomised trial comparing HFNC and CPAP in the delivery room will enable to answer the questions raised in this study.
- MeSH
- Cannula * MeSH
- Humans MeSH
- Infant, Extremely Premature * MeSH
- Infant, Premature MeSH
- Infant, Newborn MeSH
- Oxygen Inhalation Therapy * instrumentation methods MeSH
- Prospective Studies MeSH
- Feasibility Studies MeSH
- Continuous Positive Airway Pressure MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Infant, Newborn MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Observational Study 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
Treatment of gingival fibroblasts with PDL extracellular vesicles results in promotion of Wnt signalling pathway and osteogenic differentiation. PDL secretome shows selective wound healing and matrix remodelling which can have implications for future periodontal regenerative strategies.
- MeSH
- Cell Differentiation MeSH
- Extracellular Vesicles * physiology MeSH
- Fibroblasts physiology MeSH
- Gingiva cytology MeSH
- Wound Healing physiology MeSH
- Humans MeSH
- Osteogenesis physiology MeSH
- Periodontal Ligament * cytology physiology MeSH
- Regeneration * physiology MeSH
- Wnt Signaling Pathway physiology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
