BACKGROUND: Pivotal studies with dupilumab demonstrated clinically relevant improvements in nasal polyp score, symptom score, and quality-of-life score in patients with chronic rhinosinusitis with nasal polyps (CRSwNP). OBJECTIVE: We evaluated the effectiveness of dupilumab in a large-scale CRSwNP cohort from 6 European tertiary-care centers. METHODOLOGY: Nasal polyp score, Sinonasal Outcome Test 22 score, visual analog scale for total sinus symptoms, loss of smell, and nasal blockage, and Asthma Control Test (ACT) score were collected from hospital records and assessed at baseline and again at 24 and 52 weeks' treatment with dupilumab in CRSwNP patients. Treatment effectiveness was evaluated in relation to demographic and lifestyle factors, sinus surgery history, presence of comorbidities, and blood eosinophil counts (BEC). Treatment response was evaluated according to European Forum for Research and Education in Allergy and Airway Diseases (EUFOREA) 2021 criteria. RESULTS: All patient outcomes improved at 24 and 52 weeks' treatment compared to baseline. Dupilumab showed effectiveness independent of age, sex, body mass index, smoking status, prior sinus surgery, presence of asthma, nonsteroidal anti-inflammatory drug-exacerbated respiratory disease, allergy, or baseline BEC. A total of 92.5% and 94.4% showed an improvement in at least 1 EUFOREA criterion at 24 and 52 weeks, respectively; 54.4% and 68.2% met all 4 of the more stringent EUFOREA criteria at 24 and 52 weeks, respectively. CONCLUSIONS: Real-world evaluation of dupilumab effectiveness demonstrates a robust and sustained response in at least two thirds of patients at 52 weeks' treatment. Favorable treatment response was independent of the number of sinus surgery procedures, major comorbidities, or baseline systemic levels of type 2 inflammation.
- MeSH
- Chronic Disease MeSH
- Adult MeSH
- Antibodies, Monoclonal, Humanized * therapeutic use MeSH
- Cohort Studies MeSH
- Quality of Life MeSH
- Middle Aged MeSH
- Humans MeSH
- Nasal Polyps * drug therapy immunology MeSH
- Rhinosinusitis MeSH
- Rhinitis * drug therapy MeSH
- Aged MeSH
- Sinusitis * drug therapy MeSH
- Treatment Outcome MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
- Geographicals
- Europe MeSH
While there is substantial research on what people want in their romantic and sexual partners, much of this work focuses on WEIRD, youthful samples, fails to consider the role of undesirable characteristics (i.e., things people do not want in partners) at all, or in conjunction with desirable characteristics (i.e., things people do want in partners), and may be overly reliant on psychometric approaches to pivotal variables in mating psychology like mate value and sociosexuality. In a nationally representative (online) sample of 2280 people from Czechia (aged between 18 and 50 years old), we examined linear and quadratic age, education, and self-perceived mate value (desirability) effects on the desired levels in mate choice of eight undesirable and seven desirable characteristics in men and women in relation to ostensible metrics of mate value. Self-perceived mate value alone explained little variance (men 1%, women 2%), while all mate value and mating strategy indicators together explained little variance of mate preferences and aversions (men 3%, women 5%). Desirable characteristics were better explained by mate value than undesirable ones. Our results are in line with evolutionary predictions suggesting that women are more demanding. Also, more qualities to offer correlate with more expectations in a partner.
- MeSH
- Adult MeSH
- Interpersonal Relations MeSH
- Middle Aged MeSH
- Humans MeSH
- Marriage psychology MeSH
- Adolescent MeSH
- Young Adult MeSH
- Surveys and Questionnaires MeSH
- Self Concept MeSH
- Sexual Behavior psychology MeSH
- Sexual Partners * psychology MeSH
- Choice Behavior MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Geographicals
- Czech Republic MeSH
CssRS is a two-component system that plays a pivotal role in mediating the secretion stress response in Bacillus subtilis. This system upregulates the synthesis of membrane-bound HtrA family proteases that cope with misfolded proteins that accumulate within the cell envelope as a result of overexpression or heat shock. Recent studies have shown the induction of CssRS-regulated genes in response to cell envelope stress. We investigated the induction of the CssRS-regulated htrA promoter in the presence of different cell wall- and membrane-active substances and observed induction of the CssRS-controlled genes by glycopeptides (vancomycin and teicoplanin), polymyxins B and E, certain β-lactams, and detergents. Teicoplanin was shown to elicit remarkably stronger induction than vancomycin and polymyxin B. Teicoplanin and polymyxin B induced the spxO gene expression in a CssRS-dependent fashion, resulting in increased activity of Spx, a master regulator of disulfide stress in Bacillus subtilis. The CssRS signaling pathway and Spx activity were demonstrated to be involved in Bacillus subtilis resistance to teicoplanin and polymyxin B.
- MeSH
- Anti-Bacterial Agents * pharmacology MeSH
- Bacillus subtilis * genetics drug effects metabolism MeSH
- Bacterial Proteins * genetics metabolism MeSH
- Polymyxin B * pharmacology MeSH
- Promoter Regions, Genetic MeSH
- Gene Expression Regulation, Bacterial * drug effects MeSH
- Signal Transduction MeSH
- Teicoplanin * pharmacology MeSH
- Publication type
- Journal Article MeSH
Considering the growing role of ultrasound-guided procedures in musculoskeletal medicine, training as regards these interventions is pivotal. While hands-on training on cadavers can be considered optimal, it has several drawbacks, e.g., high cost, poor availability, and technical challenges regarding preservation. Apart from cadavers, different approaches to practicing needle guidance are taught in ultrasound workshops whereby phantoms from meat (e.g., chicken breast), cheese or gelatin are used. Likewise, this article aims to provide a detailed description as to how different gelatin-based phantoms can be prepared. In line with the EURO-MUSCULUS/USPRM (European Musculoskeletal Ultrasound Study Group/Ultrasound Study Group of the International Society of Physical and Rehabilitation Medicine) protocols/background, the authors describe particular basic and advanced phantoms to be used for practicing different technical/manual skills pertaining to common ultrasound-guided procedures. The present manuscript can be considered a practical and ready-to-use "recipe book" for readers who are interested in the wide spectrum of interventional ultrasound.
- MeSH
- Phantoms, Imaging * MeSH
- Ultrasonography, Interventional * MeSH
- Clinical Competence MeSH
- Humans MeSH
- Musculoskeletal Diseases diagnostic imaging rehabilitation MeSH
- Physical and Rehabilitation Medicine * education MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Geographicals
- Europe MeSH
INTRODUCTION: Mitochondrial dysfunction stands as a pivotal feature in neurodegenerative disorders, spurring the quest for targeted therapeutic interventions. This review examines Ubiquitin-Specific Protease 30 (USP30) as a master regulator of mitophagy with therapeutic promise in Alzheimer's disease (AD) and Parkinson's disease (PD). USP30's orchestration of mitophagy pathways, encompassing PINK1-dependent and PINK1-independent mechanisms, forms the crux of this exploration. METHOD: A systematic literature search was conducted in PubMed, Scopus, and Web of Science, selecting studies that investigated USP's function, inhibitor design, or therapeutic efficacy in AD and PD. Inclusion criteria encompassed mechanistic and preclinical/clinical data, while irrelevant or duplicate references were excluded. Extracted findings were synthesized narratively. RESULTS: USP30 modulates interactions with translocase of outer mitochondrial membrane (TOM) 20, mitochondrial E3 ubiquitin protein ligase 1 (MUL1), and Parkin, thus harmonizing mitochondrial quality control. Emerging novel USP30 inhibitors, racemic phenylalanine derivatives, N-cyano pyrrolidine, and notably, benzosulphonamide class compounds, restore mitophagy, and reduce neurodegenerative phenotypes across diverse models with minimal off-target effects. Modulation of other USPs also influences neurodegenerative disease pathways, offering additional therapeutic avenues. CONCLUSIONS: In highlighting the nuanced regulation of mitophagy by USP30, this work heralds a shift toward more precise and effective treatments, paving the way for a new era in the clinical management of neurodegenerative disorders.
- MeSH
- Precision Medicine methods MeSH
- Humans MeSH
- Mitochondrial Proteins MeSH
- Mitophagy * physiology drug effects MeSH
- Neurodegenerative Diseases * drug therapy metabolism MeSH
- Ubiquitin-Specific Proteases metabolism antagonists & inhibitors MeSH
- Thiolester Hydrolases metabolism MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting women of reproductive age, characterized by a spectrum of reproductive, endocrine, and metabolic disturbances. The etiology of PCOS encompasses a complex interplay of genetic, metabolic, inflammatory, and oxidative factors, though the precise pathological mechanisms remain inadequately understood. Despite considerable variability in the clinical characteristics and biochemical profiles among individuals with PCOS, abnormalities in follicular development are a hallmark of the condition. Granulosa cells, integral to follicular development, play a pivotal role in follicle maturation. Recent studies have established a strong correlation between granulosa cell programmed cell death and follicular atresia in PCOS. This review provides a comprehensive analysis of the current understanding of granulosa cell programmed cell death and its contribution to follicular atresia within the pathophysiology of PCOS, providing a foundation for future research endeavors. Key words Follicular atresia, Hyperandrogenism, Insulin resistance, Polycystic ovary syndrome, Programmed cell death of granulosa cells.
- MeSH
- Apoptosis * MeSH
- Follicular Atresia * metabolism MeSH
- Granulosa Cells * metabolism pathology MeSH
- Humans MeSH
- Ovarian Follicle metabolism pathology MeSH
- Polycystic Ovary Syndrome * pathology metabolism MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
The cross-section measurement of Antimony (Sb) is pivotal to modify or stagnate the rate of neutron flux in nuclear reactors. Neutron induced reaction cross-section data for isotopes of Sb is meagre as per reported in EXFOR. A comprehensive attempt has been made to analyse the reaction cross-section of 121Sb and 123Sb at monoenergetic neutron energy of 14.96 ± 0.03 MeV. The experiment was performed at the Neutron and Ion Irradiation Facility, Institute for Plasma Research (IPR), Gujarat (India). The 27Al(n,α)24Na reaction is used to monitor the flux and to estimate the cross-section of (n,2n), (n,p) reactions using neutron activation technique. Monoenergetic neutrons generated by D-T fusion reaction were bombarded on the natural sample of Sb to induce radioactivity. A High Purity Germanium detector (HPGe) with a resolution of 2.1 keV at 1.33 MeV γ-ray energy of 60Co based on GENIE software was used for the counting of emitted gamma photo peaks. Calculated results are compared with the existing studies from EXFOR. The cross-section values are estimated using TALYS-2.0 statistical code by employing different input parameters, along with the latest Evaluated Nuclear data libraries (ENDF/B-VIII.0, JEFF-3.3). To obtain more precise data, uncertainties from various parameters are propagated using the correlation coefficients among all the parameters. This systematic detailed covariance analysis helps to reduce the present discrepancies and to refine the nuclear data.
- Publication type
- Journal Article MeSH
PURPOSE: Tumor Treating Fields (TTFields) are electric fields that disrupt processes critical for cancer cell viability and tumor progression. The pivotal, phase 3 ENGOT-ov50/GOG-3029/INNOVATE-3 study evaluated efficacy and safety of TTFields therapy with paclitaxel (PTX) vs PTX in patients with platinum-resistant ovarian cancer (PROC). PATIENTS AND METHODS: Adult patients with PROC with ≤ 5 total prior lines of therapy (LOT), including ≤ 2 prior LOT for platinum-resistant disease, and ECOG PS of 0-1 were randomized 1:1 to receive TTFields (200 kHz; ≥ 18 h/day) + PTX (80 mg/m2 weekly) or PTX. Primary endpoint was overall survival (OS). Exploratory post-hoc analyses assessed OS in pegylated liposomal doxorubicin (PLD)-naive patients. RESULTS: Between March 2019 and November 2021, 558 patients (ECOG PS 0, 60.2 %; median [range] age, 62 [22-91] years) were assigned TTFields+PTX (n = 280) or PTX (n = 278). 24.4 % had 4 + prior LOT. Median OS was 12.2 months with TTFields+PTX vs 11.9 months with PTX (HR, 1.01; 95 % CI, 0.83-1.24; p = 0.89). Grade ≥ 3 adverse events (AEs) were similar between treatment groups. Grade 1/2 device-related skin AEs occurred in 83.6 % of patients receiving TTFields therapy. In exploratory post-hoc analysis in PLD-naive patients, median OS was 16 months with TTFields+PTX (n = 113) vs 11.7 months with PTX (n = 88; nominal HR, 0.67; 95 % CI, 0.49-0.94; p = 0.03). CONCLUSIONS: No new safety signals were identified. TTFields+PTX did not significantly improve OS compared with PTX in the intent-to-treat population. An exploratory post-hoc analysis suggests a potentially favorable benefit-risk profile for TTFields therapy in PLD-naive patients.
- MeSH
- Drug Resistance, Neoplasm * MeSH
- Adult MeSH
- Electric Stimulation Therapy methods adverse effects MeSH
- Middle Aged MeSH
- Humans MeSH
- Young Adult MeSH
- Ovarian Neoplasms * drug therapy therapy mortality pathology MeSH
- Paclitaxel * therapeutic use MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Young Adult MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase III MeSH
- Multicenter Study MeSH
- Randomized Controlled Trial MeSH
In the complex network of cellular physiology, the maintenance of cellular proteostasis emerges as a critical factor for cell survival, particularly under stress conditions. This homeostasis is largely governed by a sophisticated network of molecular chaperones and co-chaperones, among which Bcl-2-associated athanogene 3 (BAG3), able to interact with the ATPase domain of Heat Shock Protein 70 (HSP70), plays a pivotal role. The BAG3-HSP70 functional module is not only essential for cellular homeostasis but is also involved in the pathogenesis of various diseases, including cancer, neurodegenerative disorders, and cardiac dysfunction, making it an attractive target for therapeutic intervention. Inspired by our continuous interest in the development of new chemical platforms able to interfere with BAG3 protein, herein we report the discovery of compound 16, the first-in-class BAG3/HSP70 dual modulator, obtained by combining the multicomponent Ugi reaction with the alkyne-azide Huisgen procedure in a sequential tandem reaction approach. Through a combination of biophysical analysis, biochemical assays, and cell-based studies, we elucidated the mechanism of action of this inhibitor and assessed its potential as a therapeutic agent. Hence, this study can open new avenues for the development of novel anticancer strategies that leverage the simultaneous disruption of multiple chaperone pathways.
- MeSH
- Adaptor Proteins, Signal Transducing * metabolism antagonists & inhibitors MeSH
- Humans MeSH
- Molecular Chaperones metabolism antagonists & inhibitors chemistry MeSH
- Molecular Structure MeSH
- Cell Line, Tumor MeSH
- Cell Proliferation drug effects MeSH
- Apoptosis Regulatory Proteins * metabolism antagonists & inhibitors MeSH
- HSP70 Heat-Shock Proteins * antagonists & inhibitors metabolism MeSH
- Antineoplastic Agents * pharmacology chemistry chemical synthesis MeSH
- Drug Screening Assays, Antitumor MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
The intestine hosts the largest immune system and peripheral nervous system in the human body. The gut‒brain axis orchestrates communication between the central and enteric nervous systems, playing a pivotal role in regulating overall body function and intestinal homeostasis. Here, using a human three-dimensional in vitro culture model, we investigated the effects of serotonin, a neuromodulator produced in the gut, on immune cell and intestinal tissue interactions. Serotonin attenuated the tumor necrosis factor-induced proinflammatory response, mostly by affecting the expression of chemokines. Serotonin affected the phenotype and distribution of tissue-migrating monocytes, without direct contact with the cells, by remodeling the intestinal tissue. Collectively, our results show that serotonin plays a crucial role in communication among gut-brain axis components and regulates monocyte migration and plasticity, thereby contributing to gut homeostasis and the progression of inflammation. In vivo studies focused on the role of neuromodulators in gut inflammation have shown controversial results, highlighting the importance of human experimental models. Moreover, our results emphasize the importance of human health research in human cell-based models and suggest that the serotonin signaling pathway is a new therapeutic target for inflammatory bowel disease.
- MeSH
- Humans MeSH
- Monocytes metabolism immunology MeSH
- Cell Movement MeSH
- Serotonin * metabolism MeSH
- Signal Transduction MeSH
- Intestinal Mucosa * metabolism pathology MeSH
- Tumor Necrosis Factor-alpha metabolism MeSH
- Inflammation metabolism pathology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
