MicroRNAs (miRNAs) have emerged as important regulators of gene expression in various biological processes, including cancer. miR-182-5p has gained attention for its potential implications in gynecologic cancers, including breast, ovarian, endometrial, and cervical cancers. miR-182-5p dysregulation has been associated with multiple facets of tumor biology in gynecologic cancers, including tumor initiation, progression, metastasis, and therapeutic response. Studies have highlighted its involvement in key signaling pathways and cellular processes that contribute to cancer development and progression. In addition, miR-182-5p has shown potential as a diagnostic and prognostic biomarker, with studies demonstrating its correlation with clinicopathological features and patient outcomes. Furthermore, the therapeutic potential of miR-182-5p is being explored in gynecologic cancers. Strategies such as miRNA mimics or inhibitors targeting miR-182-5p have shown promise in preclinical and early clinical studies. These approaches aim to modulate miR-182-5p expression, restoring normal cellular functions and potentially enhancing treatment responses. Understanding the biologic and clinical implications of miR-182-5p in gynecologic cancers is crucial for the development of targeted therapeutic strategies and personalized medicine approaches. Further investigations are needed to unravel the specific target genes and pathways regulated by miR-182-5p. It is important to consider the emerging biologic and clinical implications of miR-182-5p in gynecologic cancers.
- MeSH
- Humans MeSH
- MicroRNAs * genetics MeSH
- Biomarkers, Tumor genetics MeSH
- Genital Neoplasms, Female * genetics therapy MeSH
- Prognosis MeSH
- Gene Expression Regulation, Neoplastic MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
The extracellular matrix (ECM)-and its mechanobiology-regulates key cellular functions that drive tumor growth and development. Accordingly, mechanotherapy is emerging as an effective approach to treat fibrotic diseases such as cancer. Through restoring the ECM to healthy-like conditions, this treatment aims to improve tissue perfusion, facilitating the delivery of chemotherapies. In particular, the manipulation of ECM is gaining interest as a valuable strategy for developing innovative treatments based on nanoparticles (NPs). However, further progress is required; for instance, it is known that the presence of a dense ECM, which hampers the penetration of NPs, primarily impacts the efficacy of nanomedicines. Furthermore, most 2D in vitro studies fail to recapitulate the physiological deposition of matrix components. To address these issues, a comprehensive understanding of the interactions between the ECM and NPs is needed. This review focuses on the main features of the ECM and its complex interplay with NPs. Recent advances in mechanotherapy are discussed and insights are offered into how its combination with nanomedicine can help improve nanomaterials design and advance their clinical translation.
- MeSH
- Extracellular Matrix * metabolism MeSH
- Humans MeSH
- Neoplasms * therapy MeSH
- Nanoparticles * chemistry MeSH
- Nanomedicine * methods MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
OBJECTIVES: Decision-analytic models assessing the value of emerging Alzheimer's disease (AD) treatments are challenged by limited evidence on short-term trial outcomes and uncertainty in extrapolating long-term patient-relevant outcomes. To improve understanding and foster transparency and credibility in modeling methods, we cross-compared AD decision models in a hypothetical context of disease-modifying treatment for mild cognitive impairment (MCI) due to AD. METHODS: A benchmark scenario (US setting) was used with target population MCI due to AD and a set of synthetically generated hypothetical trial efficacy estimates. Treatment costs were excluded. Model predictions (10-year horizon) were assessed and discussed during a 2-day workshop. RESULTS: Nine modeling groups provided model predictions. Implementation of treatment effectiveness varied across models based on trial efficacy outcome selection (clinical dementia rating - sum of boxes, clinical dementia rating - global, mini-mental state examination, functional activities questionnaire) and analysis method (observed severity transitions, change from baseline, progression hazard ratio, or calibration to these). Predicted mean time in MCI ranged from 2.6 to 5.2 years for control strategy and from 0.1 to 1.0 years for difference between intervention and control strategies. Predicted quality-adjusted life-year gains ranged from 0.0 to 0.6 and incremental costs (excluding treatment costs) from -US$66 897 to US$11 896. CONCLUSIONS: Trial data can be implemented in different ways across health-economic models leading to large variation in model predictions. We recommend (1) addressing the choice of outcome measure and treatment effectiveness assumptions in sensitivity analysis, (2) a standardized reporting table for model predictions, and (3) exploring the use of registries for future AD treatments measuring long-term disease progression to reduce uncertainty of extrapolating short-term trial results by health-economic models.
- MeSH
- Alzheimer Disease * economics drug therapy MeSH
- Cost-Benefit Analysis * MeSH
- Models, Economic MeSH
- Cognitive Dysfunction * economics MeSH
- Quality-Adjusted Life Years MeSH
- Humans MeSH
- Decision Support Techniques MeSH
- Disease Progression MeSH
- Treatment Outcome MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Comparative Study MeSH
OBJECTIVES: Practice-based research (PBR) is an integral part of community pharmacy practice. The results obtained from PBR allow community pharmacists to gain the knowledge necessary to develop new patient services and acquire strategies to strengthen their role in the health system. The study aimed to assess pharmacists' attitudes and barriers towards PBR and investigate the factors that prevent or motivate community pharmacists from participating. METHODS: The cross-sectional study was conducted in May to Jun 2023 via an online structured pretested questionnaire. All licensed pharmacists registered in the Registry of Pharmacists of the Croatian Pharmaceutical Chamber, who listed community pharmacy as a place of work participated, i.e. 500 community pharmacists. The questionnaire consisted of two sections. Section A collected the respondents' sociodemographic characteristics. Section B contained two groups of relevant statements on a 5-point Likert scale divided into two sections: pharmacists' attitudes towards research in PBRs and barriers to participation in PBRs. KEY FINDINGS: The results showed that 97% of community pharmacists considered PBR important for developing new pharmacy services, and almost two-thirds considered participation in research to be part of pharmacy practice. The most often perceived barrier to research participation was the workload of daily tasks necessary for normal pharmacy functioning, recognized by 68% of community pharmacists. CONCLUSION: This study revealed community pharmacists' perception of the importance of PBR for the pharmacy profession. Involvement in PBR was important for the community pharmacists. The motivation for the PBR was present, despite the detected barriers. The results indicate the directions the community pharmacists should inspire.
- MeSH
- Adult MeSH
- Pharmacists * psychology statistics & numerical data organization & administration MeSH
- Middle Aged MeSH
- Humans MeSH
- Motivation MeSH
- Attitude of Health Personnel * MeSH
- Cross-Sectional Studies MeSH
- Surveys and Questionnaires MeSH
- Professional Role psychology MeSH
- Community Pharmacy Services * organization & administration MeSH
- Pharmacy Research * MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Geographicals
- Croatia MeSH
Myofascial pain syndrome (MPS) is a common musculoskeletal disorder that significantly affects quality of life. Conventional treatment approaches include pharmacological interventions, physical therapy, and procedures such as dry needling. Among these, ultrasound-guided injections (USGIs) have gained recognition for their precision and therapeutic benefits. Additionally, repetitive peripheral magnetic stimulation (rPMS) has emerged as a non-invasive neuromodulatory technique for pain management. This perspective article examines the physiological mechanisms and clinical applications of USGIs and rPMS, particularly in the lumbar multifidus muscle, and explores their potential synergistic effects. MPS is often associated with chronic muscle dysfunction due to energy depletion, leading to persistent pain and motor impairment. USGIs play a crucial role in restoring muscle perfusion, disrupting pain cycles, and providing diagnostic insights in real time. In parallel, rPMS modulates neuromuscular activation, enhances endogenous pain control, and promotes functional recovery. Ultrasound guidance enhances the precision and effectiveness of interventions, such as dry needling, interfascial plane blocks, and fascial hydrodissection, while rPMS complements these strategies by facilitating neuromuscular reconditioning and reducing pain via central and peripheral mechanisms. The preliminary findings suggest that combining multifidus USGIs with rPMS results in significant pain relief and functional improvements in patients with chronic low back pain. Integrating USGIs with rPMS represents a promising multimodal strategy for managing MPS. By combining targeted injections with non-invasive neuromodulation, clinicians may optimize therapeutic outcomes and provide sustained relief for patients with chronic musculoskeletal pain. Further research is needed to refine treatment protocols and assess the long-term efficacy.
- Publication type
- Journal Article MeSH
Extracellular vesicles (EVs) are emerging as critical mediators of intercellular communication in the tumor microenvironment (TME), profoundly influencing cancer progression. These nano-sized vesicles, released by both tumor and stromal cells, carry a diverse cargo of proteins, nucleic acids, and lipids, reflecting the dynamic cellular landscape and mediating intricate interactions between cells. This review provides a comprehensive overview of the biogenesis, composition, and functional roles of EVs in cancer, highlighting their significance in both basic research and clinical applications. We discuss how cancer cells manipulate EV biogenesis pathways to produce vesicles enriched with pro-tumorigenic molecules, explore the specific contributions of EVs to key hallmarks of cancer, such as angiogenesis, metastasis, and immune evasion, emphasizing their role in shaping TME and driving therapeutic resistance. Concurrently, we submit recent knowledge on how the cargo of EVs can serve as a valuable source of biomarkers for minimally invasive liquid biopsies, and its therapeutic potential, particularly as targeted drug delivery vehicles and immunomodulatory agents, showcasing their promise for enhancing the efficacy and safety of cancer treatments. By deciphering the intricate messages carried by EVs, we can gain a deeper understanding of cancer biology and develop more effective strategies for early detection, targeted therapy, and immunotherapy, paving the way for a new era of personalized and precise cancer medicine with the potential to significantly improve patient outcomes.
An organism is considered "alive" if it can grow, reproduce, respond to external stimuli, metabolize nutrients, and maintain stability. By this definition, both mitochondria and viruses exhibit the key characteristics of independent life. In addition to their capacity for self-replication under specifically defined conditions, both mitochondria and viruses can communicate via shared biochemical elements, alter cellular energy metabolism, and adapt to their local environment. To explain this phenomenon, we hypothesize that early viral prototype species evolved from ubiquitous environmental DNA and gained the capacity for self-replication within coacervate-like liquid droplets. The high mutation rates experienced in this environment streamlined their acquisition of standard genetic codes and adaptation to a diverse set of host environments. Similarly, mitochondria, eukaryotic intracellular organelles that generate energy and resolve oxygen toxicity, originally evolved from an infectious bacterial species and maintain their capacity for active functionality within the extracellular space. Thus, while mitochondria contribute profoundly to eukaryotic cellular homeostasis, their capacity for freestanding existence may lead to functional disruptions over time, notably, the overproduction of reactive oxygen species, a phenomenon strongly linked to aging-related disorders. Overall, a more in-depth understanding of the full extent of the evolution of both viruses and mitochondria from primordial precursors may lead to novel insights and therapeutic strategies to address neurodegenerative processes and promote healthy aging.
- MeSH
- Energy Metabolism MeSH
- Humans MeSH
- Mitochondria * metabolism MeSH
- Origin of Life * MeSH
- Viruses * metabolism genetics MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
The necessity of oxygen for metabolic processes means that hypoxia can lead to serious cell and tissue damage. On the other hand, in some situations, hypoxia occurs under physiological conditions and serves as an important regulation factor. The airway epithelium is specific in that it gains oxygen not only from the blood supply but also directly from the luminal air. Many respiratory diseases are associated with airway obstruction or excessive mucus production thus leading to luminal hypoxia. The main goal of this review is to point out how the airway epithelium reacts to hypoxic conditions. Cells detect low oxygen levels using molecular mechanisms involving hypoxia-inducible factors (HIFs). In addition, the cells of the airway epithelium appear to overexpress HIFs in hypoxic conditions. HIFs then regulate many aspects of epithelial cell functions. The effects of hypoxia include secretory cell stimulation and hyperplasia, epithelial barrier changes, and ciliogenesis impairment. All the changes can impair mucociliary clearance, exacerbate infection, and promote inflammation leading to damage of airway epithelium and subsequent airway wall remodeling. The modulation of hypoxia regulatory mechanisms may be one of the strategies for the treatment of obstructive respiratory diseases or diseases with mucus hyperproduction. Keywords: Secretory cells, Motile cilia, Epithelial barrier, Oxygenation, Obstructive respiratory diseases.
- MeSH
- Hypoxia * metabolism MeSH
- Oxygen metabolism MeSH
- Humans MeSH
- Respiratory Mucosa * metabolism MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
Resistance to glucocorticoids (GC), the common agents for remission induction in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL), poses a significant therapeutic hurdle. Therefore, dissecting the mechanisms shaping GC resistance could lead to new treatment modalities. Here, we showed that CD9- BCP-ALL cells were preferentially resistant to prednisone and dexamethasone over other standard cytotoxic agents. Concordantly, we identified significantly more poor responders to the prednisone prephase among BCP-ALL patients with a CD9- phenotype, especially for those with adverse presenting features including older age, higher white cell count and BCR-ABL1. Furthermore, gain- and loss-offunction experiments dictated a definitive functional linkage between CD9 expression and GC susceptibility, as demonstrated by the reversal and acquisition of relative GC resistance in CD9low and CD9high BCP-ALL cells, respectively. Despite physical binding to the GC receptor NR3C1, CD9 did not alter its expression, phosphorylation or nuclear translocation but potentiated the induction of GC-responsive genes in GC-resistant cells. Importantly, the MEK inhibitor trametinib exhibited higher synergy with GC against CD9- than CD9+ lymphoblasts to reverse drug resistance in vitro and in vivo. Collectively, our results elucidate a previously unrecognized regulatory function of CD9 in GC sensitivity, and inform new strategies for management of children with resistant BCP-ALL.
- MeSH
- Tetraspanin 29 * metabolism genetics MeSH
- Drug Resistance, Neoplasm * genetics MeSH
- Dexamethasone pharmacology MeSH
- Child MeSH
- Glucocorticoids * pharmacology therapeutic use MeSH
- Humans MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Precursor B-Cell Lymphoblastic Leukemia-Lymphoma * drug therapy metabolism genetics pathology MeSH
- Child, Preschool MeSH
- Receptors, Glucocorticoid metabolism genetics MeSH
- Animals MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Male MeSH
- Mice MeSH
- Child, Preschool MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Deficit alfa-1-antitrypsinu (AATD) je jedním z nejčastějších genetických onemocnění. Většina osob nese dvě kopie divoké alely M genu SERPINA1, který kóduje alfa-1-antitrypsin (AAT), a má normální AAT v krvi. Devadesát pět procent případů těžkého deficitu AAT je důsledkem homozygotní záměny Glu342Lys (alela Z), která je přítomna u 1 z 25 osob evropského původu. Mírný nedostatek AAT je obvykle důsledkem mutace Glu264Val (alela S). AAT je syntetizován v játrech a vylučován do krve, kde je jeho hlavní úlohou chránit plicní tkáň před působením neutrofilní elastázy. Bodové mutace mohou vést k precipitaci AAT v játrech, což vede k jaterní fibróze a cirhóze vlivem proteotoxického stresu („gain of function“). Naopak nedostatek cirkulujícího AAT predisponuje homozygoty s těžkým deficitem k časnému vzniku plicního emfyzému („loss of function“). Článek podává přehled současných poznatků o patofyziologii deficitu AAT, možnostech jeho diagnostiky a diskutuje možnosti léčby plicního onemocnění i nové možnosti léčby jaterního onemocnění.
Alpha-1-antitrypsin (AAT) deficiency (AATD) is one of the most common genetic disorders. Most people carry two copies of the wild-type M allele of the SERPINA1 gene, which encodes AAT, and have normal blood concentrations of AAT. Ninety-five percent of cases of severe AAT deficiency result from the homozygous Glu342Lys substitution (Z allele), which is present in 1 in 25 persons of European descent. Mild AAT deficiency is usually due to the Glu264Val mutation (S allele). AAT is synthesized in the liver and secreted into the blood. Its primary role is to protect lung tissue from neutrophil elastase attack. Point mutations can lead to the retention of AAT in the liver, leading to liver fibrosis and cirrhosis due to proteotoxic stress ("gain of function"), whereas the lack of circulating AAT predisposes homozygotes with severe deficiency to early onset of pulmonary emphysema ("loss of function"). This article reviews current knowledge of the pathophysiology of AAT deficiency, and its diagnostic options and discusses treatment options for pulmonary and novel treatment strategies in liver disease.
