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Cellular Reprogramming Jun 2024Mesenchymal stem cell (MSCs) therapy, as a rapidly developing area of medicine, holds great promise for the treatment of a variety of medical conditions. MSCs are... (Review)
Review
Mesenchymal stem cell (MSCs) therapy, as a rapidly developing area of medicine, holds great promise for the treatment of a variety of medical conditions. MSCs are multipotent stem cells that can be isolated from various tissues and could self-renew and differentiate. They secrete cytokines and trophic factors that create a regenerative microenvironment and have immunomodulatory properties. Although clinical trials have been conducted with MSCs in various diseases, concerns regarding the possibility of malignant transformation of these cells have been raised. The studies showed a higher rate of hematological malignancy and carcinogenesis in experimental models after MSC transplantation. The mechanisms underlying malignant transformation of MSCs are complex and not fully understood, but they are believed to involve the presence of special signaling molecules and alterations in cell behavior regulation pathways. Possible pathways that lead to MSCs' oncogenic transformation occur through two mechanisms: spontaneous and stimulated malignant transformation, including cell fusion, fusion proteins, and the tumor microenvironment. MSC-based therapies have the potential to revolutionize medicine, and addressing the issue of malignancy is crucial to ensure their safety and efficacy. Therefore, the purpose of the present review is to summarize the potential mechanisms of the malignant transformation of MSCs. [Figure: see text].
Topics: Mesenchymal Stem Cells; Humans; Cell Transformation, Neoplastic; Animals; Mesenchymal Stem Cell Transplantation; Tumor Microenvironment; Cell- and Tissue-Based Therapy
PubMed: 38917438
DOI: 10.1089/cell.2024.0026 -
Journal of Neuropathology and... Jun 2024Metabolic changes are observed in patients with both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although regulation of metabolic processes in...
Metabolic changes are observed in patients with both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although regulation of metabolic processes in the CNS is predominantly carried out within the hypothalamus, extra-hypothalamic CNS areas contain metabolic hormone receptors, including those for leptin (LEPR), insulin (INSR), and neuropeptide Y (NPY), indicating that they may play a role in biological processes underlying pathogenic disease processes. The status of these hormones within regions vulnerable in ALS/FTD is not well described. This study sought to determine whether the expression of these hormones and their receptors is altered in pathology-rich regions in cases of human FTD (superior frontal gyrus and insular cortex) and ALS (primary motor cortex and lumbar spinal cord) with TDP-43 pathology compared to matched healthy controls. LEPR mRNA was increased within the superior frontal gyrus of FTD cases and within primary motor cortex and lumbar spinal cord of ALS cases; INSR mRNA was increased in superior frontal gyrus and insular cortex of FTD cases. NPY protein was decreased in primary motor cortex and lumbar spinal cord of ALS cases. Our results demonstrate that metabolic hormones undergo complex alterations in ALS and FTD and suggest that these hormones could play critical roles in the pathogenesis of these diseases.
PubMed: 38917432
DOI: 10.1093/jnen/nlae054 -
Astrobiology Jun 2024The 21st century is likely to be the first century in which large-scale short- and long-term space missions become common. Accordingly, an ever-increasing body of...
The 21st century is likely to be the first century in which large-scale short- and long-term space missions become common. Accordingly, an ever-increasing body of research is focusing on understanding the effects of current and future space expeditions on human physiology in health and disease. Yet the complex experimental environment, the small number of participants, and the high cost of space missions are among the primary factors that hinder a better understanding of the impact of space missions on human physiology. The goal of our research was to develop a cost-effective, compact, and easy-to-manipulate system to address questions related to human health and disease in space. This initiative was part of the Ramon SpaceLab program, an annual research-based learning program designed to cultivate high school students' involvement in space exploration by facilitating experiments aboard the International Space Station (ISS). In the present study, we used the nematode (), a well-suited model organism, to investigate the effect of space missions on neurodegeneration-related processes. Our study specifically focused on the level of aggregation of Huntington's disease-causing polyglutamine stretch-containing (PolyQ) proteins in muscles, the canonical system for studying neurodegeneration in this organism. We compared animals expressing PolyQ proteins grown onboard the ISS with their genetically identical siblings grown on Earth and observed a significant difference in the number of aggregates between the two populations. Currently, it is challenging to determine whether this effect stems from developmental or morphological differences between the cultures or is a result of life in space. Nevertheless, our results serve as a proof of concept and open a new avenue for utilizing to address various open questions in space studies, including the effects of space conditions on the onset and development of neurodegenerative diseases.
Topics: Caenorhabditis elegans; Animals; Space Flight; Peptides; Neurodegenerative Diseases; Humans
PubMed: 38917419
DOI: 10.1089/ast.2023.0096 -
Neurology(R) Neuroimmunology &... Sep 2024To report the association of zinc finger and SCAN domain containing 1 antibodies (ZSCAN1-abs) with rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and...
OBJECTIVES
To report the association of zinc finger and SCAN domain containing 1 antibodies (ZSCAN1-abs) with rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome in patients without tumor.
METHODS
Patients with symptoms compatible with ROHHAD syndrome but without an associated tumor were selected from our database. Serum and CSF samples were examined for the presence of ZSCAN1-abs by an in-house cell-based assay. In addition, samples from 149 patients with several inflammatory and noninflammatory disorders and 50 healthy participants served as controls.
RESULTS
Thirteen patients with ROHHAD syndrome were identified. Of these, we had paired serum/CSF samples from 6 patients and only serum from the other 7. Five of 6 patients (83.3%) with paired serum/CSF (4 children, 1 adult) had ZSCAN-abs only in CSF and 1 had antibodies in serum and CSF. ZSCAN1-abs were not detected in the remaining 7 patients with ROHHAD with only serum available or in any of the 199 control samples.
DISCUSSION
Patients with ROHHAD syndrome should be investigated for the presence of ZSCAN1-abs in CSF. The antibodies do not necessarily predict the presence of a tumor. The detection of ZSCAN1-abs in an adult patient suggests that this condition also occurs beyond the pediatric age.
Topics: Humans; Male; Adult; Female; Child; Autoantibodies; Hypothalamic Diseases; Adolescent; Transcription Factors; Hypoventilation; Autonomic Nervous System Diseases; Obesity; Young Adult; Middle Aged; Child, Preschool; Syndrome
PubMed: 38917381
DOI: 10.1212/NXI.0000000000200276 -
Neurology(R) Neuroimmunology &... Sep 2024To evaluate CSF inflammatory markers with accumulation of cortical damage as well as disease activity in patients with early relapsing-remitting MS (RRMS).
BACKGROUND AND OBJECTIVES
To evaluate CSF inflammatory markers with accumulation of cortical damage as well as disease activity in patients with early relapsing-remitting MS (RRMS).
METHODS
CSF levels of osteopontin (OPN) and 66 inflammatory markers were assessed using an immune-assay multiplex technique in 107 patients with RRMS (82 F/25 M, mean age 35.7 ± 11.8 years). All patients underwent regular clinical assessment and yearly 3T MRI scans for 2 years while 39 patients had a 4-year follow-up. White matter lesion number and volume, cortical lesions (CLs) and volume, and global cortical thickness (CTh) were evaluated together with the 'no evidence of disease activity' (NEDA-3) status, defined by no relapses, no disability worsening, and no MRI activity, including CLs.
RESULTS
The random forest algorithm selected OPN, CXCL13, TWEAK, TNF, IL19, sCD30, sTNFR1, IL35, IL16, and sCD163 as significantly associated with changes in global CTh. OPN and CXCL13 were most related to accumulation of atrophy after 2 and 4 years. In a multivariate linear regression model on CSF markers, OPN ( < 0.001), CXCL13 ( = 0.001), and sTNFR1 ( = 0.024) were increased in those patients with accumulating atrophy (adjusted R-squared 0.615). The 10 markers were added in a model that included all clinical, demographic, and MRI variables: OPN ( = 0.002) and IL19 ( = 0.022) levels were confirmed to be significantly increased in patients developing more CTh change over the follow-up (adjusted R-squared 0.619). CXCL13 and OPN also revealed the best association with NEDA-3 after 2 years, with OPN significantly linked to disability accumulation (OR 2.468 [1.46-5.034], = 0.004) at the multivariate logistic regression model.
DISCUSSION
These data confirm and expand our knowledge on the prognostic role of the CSF inflammatory profile in predicting changes in cortical pathology and disease activity in early MS. The data emphasize a crucial role of OPN.
Topics: Humans; Osteopontin; Female; Male; Adult; Multiple Sclerosis, Relapsing-Remitting; Atrophy; Middle Aged; Cerebral Cortex; Magnetic Resonance Imaging; Biomarkers; Follow-Up Studies; Young Adult; Disease Progression
PubMed: 38917380
DOI: 10.1212/NXI.0000000000200265 -
Nucleic Acids Research Jun 2024From transcription to decay, RNA-binding proteins (RBPs) influence RNA metabolism. Using the RBP2GO database that combines proteome-wide RBP screens from 13 species, we...
From transcription to decay, RNA-binding proteins (RBPs) influence RNA metabolism. Using the RBP2GO database that combines proteome-wide RBP screens from 13 species, we investigated the RNA-binding features of 176 896 proteins. By compiling published lists of RNA-binding domains (RBDs) and RNA-related protein family (Rfam) IDs with lists from the InterPro database, we analyzed the distribution of the RBDs and Rfam IDs in RBPs and non-RBPs to select RBDs and Rfam IDs that were enriched in RBPs. We also explored proteins for their content in intrinsically disordered regions (IDRs) and low complexity regions (LCRs). We found a strong positive correlation between IDRs and RBDs and a co-occurrence of specific LCRs. Our bioinformatic analysis indicated that RBDs/Rfam IDs were strong indicators of the RNA-binding potential of proteins and helped predicting new RBP candidates, especially in less investigated species. By further analyzing RBPs without RBD, we predicted new RBDs that were validated by RNA-bound peptides. Finally, we created the RBP2GO composite score by combining the RBP2GO score with new quality factors linked to RBDs and Rfam IDs. Based on the RBP2GO composite score, we compiled a list of 2018 high-confidence human RBPs. The knowledge collected here was integrated into the RBP2GO database at https://RBP2GO-2-Beta.dkfz.de.
PubMed: 38917322
DOI: 10.1093/nar/gkae536 -
Science Signaling Jun 2024Palmitoylation of intact or cleaved gasdermin D causes plasma membrane pore formation.
Palmitoylation of intact or cleaved gasdermin D causes plasma membrane pore formation.
Topics: Lipoylation; Humans; Cell Membrane; Intracellular Signaling Peptides and Proteins; Animals; Gasdermins; Phosphate-Binding Proteins
PubMed: 38917221
DOI: 10.1126/scisignal.adr1306 -
Tweaking synaptic plasticity: Deciphering the role of WWC1 in memory opens new therapeutic horizons.Science Signaling Jun 2024WWC1 is a scaffolding protein in the evolutionarily conserved Hippo signaling network and is genetically linked to human memory and synaptic plasticity. In the archives... (Review)
Review
WWC1 is a scaffolding protein in the evolutionarily conserved Hippo signaling network and is genetically linked to human memory and synaptic plasticity. In the archives of , Stepan demonstrate the translational potential of modulating WWC1 through pharmacological inhibition of Hippo-pathway kinases to enhance cognition.
Topics: Humans; Neuronal Plasticity; Memory; Signal Transduction; Intracellular Signaling Peptides and Proteins; Animals; Protein Serine-Threonine Kinases; Proteins
PubMed: 38917220
DOI: 10.1126/scisignal.adp5354 -
Science Signaling Jun 2024The stabilization of different active conformations of G protein-coupled receptors is thought to underlie the varying efficacies of biased and balanced agonists. Here,...
The stabilization of different active conformations of G protein-coupled receptors is thought to underlie the varying efficacies of biased and balanced agonists. Here, profiling the activation of signal transducers by angiotensin II type 1 receptor (ATR) agonists revealed that the extent and kinetics of β-arrestin binding exhibited substantial ligand-dependent differences, which were lost when receptor internalization was inhibited. When ATR endocytosis was prevented, even weak partial agonists of the β-arrestin pathway acted as full or near-full agonists, suggesting that receptor conformation did not exclusively determine β-arrestin recruitment. The ligand-dependent variance in β-arrestin translocation was much larger at endosomes than at the plasma membrane, showing that ligand efficacy in the β-arrestin pathway was spatiotemporally determined. Experimental investigations and mathematical modeling demonstrated how multiple factors concurrently shaped the effects of agonists on endosomal receptor-β-arrestin binding and thus determined the extent of functional selectivity. Ligand dissociation rate and G protein activity had particularly strong, internalization-dependent effects on the receptor-β-arrestin interaction. We also showed that endocytosis regulated the agonist efficacies of two other receptors with sustained β-arrestin binding: the V vasopressin receptor and a mutant β-adrenergic receptor. In the absence of endocytosis, the agonist-dependent variance in β-arrestin2 binding was markedly diminished. Our results suggest that endocytosis determines the spatiotemporal bias in GPCR signaling and can aid in the development of more efficacious, functionally selective compounds.
Topics: Endocytosis; Humans; Signal Transduction; Receptor, Angiotensin, Type 1; beta-Arrestins; HEK293 Cells; Receptors, Vasopressin; Receptors, Adrenergic, beta-2; Endosomes; Receptors, G-Protein-Coupled; Animals; Ligands; Protein Binding; Protein Transport
PubMed: 38917219
DOI: 10.1126/scisignal.adi0934 -
PloS One 2024Acute ischemic stroke (AIS) is a significant global health issue, directly impacting mortality and disability. The Totaled Health Risks in Vascular Events (THRIVE) score...
Prognostic value of combining 24-hour ASPECTS and hemoglobin to red cell distribution width ratio to the THRIVE score in predicting in-hospital mortality among ischemic stroke patients treated with intravenous thrombolysis.
BACKGROUND
Acute ischemic stroke (AIS) is a significant global health issue, directly impacting mortality and disability. The Totaled Health Risks in Vascular Events (THRIVE) score is appreciated for its simplicity and ease of use to predict stroke clinical outcomes; however, it lacks laboratory and neuroimaging data, which limits its ability to predict outcomes precisely. Our study evaluates the impact of integrating the 24-hour Alberta Stroke Program Early CT Score (ASPECTS) and hemoglobin-to-red cell distribution width (HB/RDW) ratio into the THRIVE score using the multivariable fractional polynomial (MFP) method (combined THRIVE-MFP model) compared to the THRIVE-c model. We aim to assess their added value in predicting in-hospital mortality (IHM) prognosis.
MATERIALS AND METHODS
A retrospective study from January 2015 to July 2022 examined consecutive AIS patients receiving intravenous thrombolysis. Data on THRIVE scores, 24-hour ASPECTS, and HB/RDW levels were collected upon admission. The model was constructed using logistic regression and the MFP method. The prognostic value was determined using the area under the receiver operating characteristic curve (AuROC). Ischemic cerebral lesions within the middle cerebral artery territory were evaluated with non-contrast computed tomography (NCCT) after completing 24 hours of intravenous thrombolysis (24-hour ASPECTS).
RESULTS
Among a cohort of 345 patients diagnosed with AIS who received intravenous thrombolysis, 65 individuals (18.8%) experienced IHM. The combined THRIVE-MFP model was significantly superior to the THRIVE-c model in predicting IHM (AuROC 0.980 vs. 0.876, p<0.001), 3-month mortality (AuROC 0.947 vs. 0.892, p<0.001), and 3-month poor functional outcome (AuROC 0.910 vs. 0.853, p<0.001).
CONCLUSION
The combined THRIVE-MFP model showed excellent predictive performance, enhancing physicians' ability to stratify patient selection for intensive neurological monitoring and guiding treatment decisions. Incorporating 24-hour ASPECTS on NCCT and HB/RDW proved valuable in mortality prediction, particularly for hospitals with limited access to advanced neuroimaging resources.
Topics: Humans; Female; Ischemic Stroke; Male; Aged; Hospital Mortality; Prognosis; Hemoglobins; Retrospective Studies; Erythrocyte Indices; Middle Aged; Thrombolytic Therapy; Aged, 80 and over; ROC Curve
PubMed: 38917218
DOI: 10.1371/journal.pone.0304765