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International Journal of Molecular... Jun 2024Tissue biopsy remains the standard for diagnosing gastrointestinal stromal tumors (GISTs), although liquid biopsy is emerging as a promising alternative in oncology. In...
Tissue biopsy remains the standard for diagnosing gastrointestinal stromal tumors (GISTs), although liquid biopsy is emerging as a promising alternative in oncology. In this pilot study, we advocate for droplet digital PCR (ddPCR) to diagnose GIST in tissue samples and explore its potential for early diagnosis via liquid biopsy, focusing on the D842V mutation and hypermethylated gene. We utilized ddPCR to analyze the predominant mutation (D842V) in surgical tissue samples from 15 GIST patients, correlating with pathologists' diagnoses. We expanded our analysis to plasma samples to compare DNA alterations between tumor tissue and plasma, also investigating gene hypermethylation. We successfully detected the D842V mutation in GIST tissues by ddPCR. Despite various protocols to enhance mutation detection in early-stage disease, it remained challenging, likely due to the low concentration of DNA in plasma samples. Additionally, the results of Area Under the Curve (AUC) for the hypermethylated gene, analyzing concentration, ratio, and abundance were 0.74 (95% Confidence Interval (CI): 0.52 to 0.97), 0.77 (95% CI: 0.56 to 0.98), and 0.79 (95% CI: 0.59 to 0.99), respectively. As a rare disease, the early detection of GIST through such biomarkers is particularly crucial, offering significant potential to improve patient outcomes.
Topics: Humans; Septins; Gastrointestinal Stromal Tumors; DNA Methylation; Liquid Biopsy; Pilot Projects; Receptor, Platelet-Derived Growth Factor alpha; Female; Male; Middle Aged; Mutation; Polymerase Chain Reaction; Aged; Gastrointestinal Neoplasms; Biomarkers, Tumor; Adult
PubMed: 38928487
DOI: 10.3390/ijms25126783 -
International Journal of Molecular... Jun 2024Pericytes are multipotent cells embedded within the vascular system, primarily surrounding capillaries and microvessels where they closely interact with endothelial... (Review)
Review
Pericytes are multipotent cells embedded within the vascular system, primarily surrounding capillaries and microvessels where they closely interact with endothelial cells. These cells are known for their intriguing properties due to their heterogeneity in tissue distribution, origin, and multifunctional capabilities. Specifically, pericytes are essential in regulating blood flow, promoting angiogenesis, and supporting tissue homeostasis and regeneration. These multifaceted roles draw on pericytes' remarkable ability to respond to biochemical cues, interact with neighboring cells, and adapt to changing environmental conditions. This review aims to summarize existing knowledge on pericytes, emphasizing their versatility and involvement in vascular integrity and tissue health. In particular, a comprehensive view of the major signaling pathways, such as PDGFβ/ PDGFRβ, TGF-β, FOXO and VEGF, along with their downstream targets, which coordinate the behavior of pericytes in preserving vascular integrity and promoting tissue regeneration, will be discussed. In this light, a deeper understanding of the complex signaling networks defining the phenotype of pericytes in healthy tissues is crucial for the development of targeted therapies in vascular and degenerative diseases.
Topics: Pericytes; Humans; Signal Transduction; Homeostasis; Animals; Neovascularization, Physiologic; Receptor, Platelet-Derived Growth Factor beta
PubMed: 38928298
DOI: 10.3390/ijms25126592 -
International Journal of Molecular... Jun 2024Integrin αβ mediates platelet aggregation by binding the Arginyl-Glycyl-Aspartic acid (RGD) sequence of fibrinogen. RGD binding occurs at a site topographically...
Integrin αβ mediates platelet aggregation by binding the Arginyl-Glycyl-Aspartic acid (RGD) sequence of fibrinogen. RGD binding occurs at a site topographically proximal to the α and β subunits, promoting the conformational activation of the receptor from bent to extended states. While several experimental approaches have characterized RGD binding to αβ integrin, applying computational methods has been significantly more challenging due to limited sampling and the need for a priori information regarding the interactions between the RGD peptide and integrin. In this study, we employed all-atom simulations using funnel metadynamics (FM) to evaluate the interactions of an RGD peptide with the α and β subunits of integrin. FM incorporates an external history-dependent potential on selected degrees of freedom while applying a funnel-shaped restraint potential to limit RGD exploration of the unbound state. Furthermore, it does not require a priori information about the interactions, enhancing the sampling at a low computational cost. Our FM simulations reveal significant molecular changes in the β subunit of integrin upon RGD binding and provide a free-energy landscape with a low-energy binding mode surrounded by higher-energy prebinding states. The strong agreement between previous experimental and computational data and our results highlights the reliability of FM as a method for studying dynamic interactions of complex systems such as integrin.
Topics: Oligopeptides; Platelet Glycoprotein GPIIb-IIIa Complex; Protein Binding; Humans; Molecular Dynamics Simulation; Blood Platelets; Binding Sites; Integrin beta3
PubMed: 38928286
DOI: 10.3390/ijms25126580 -
International Journal of Molecular... Jun 2024Eastern Diamondback Rattlesnake () envenomation is a medical emergency encountered in the Southeastern United States. The venom contains a snake venom thrombin-like...
Eastern Diamondback Rattlesnake () envenomation is a medical emergency encountered in the Southeastern United States. The venom contains a snake venom thrombin-like enzyme (SVTLE) that is defibrinogenating, causing coagulopathy without effects on platelets in humans. This investigation utilized thrombelastographic methods to document this coagulopathy kinetically on the molecular level in a rabbit model of envenomation via the analyses of whole blood samples without and with platelet inhibition. Subsequently, the administration of a novel ruthenium compound containing site-directed antivenom abrogated the coagulopathic effects of envenomation in whole blood without platelet inhibition and significantly diminished loss of coagulation in platelet-inhibited samples. This investigation provides coagulation kinetic insights into the molecular interactions and results of SVTLE on fibrinogen-dependent coagulation and confirmation of the efficacy of a ruthenium antivenom. These results serve as a rationale to investigate the coagulopathic effects of other venoms with this model and assess the efficacy of this site-directed antivenom.
Topics: Animals; Rabbits; Antivenins; Crotalus; Crotalid Venoms; Blood Coagulation; Thrombelastography; Ruthenium; Snake Bites; Male; Venomous Snakes
PubMed: 38928044
DOI: 10.3390/ijms25126334 -
International Journal of Molecular... Jun 2024The gold standard in the non-surgical treatment of periodontitis is scaling and root planing (SRP). In recent years, the use of autogenous platelet concentrates has... (Review)
Review
The gold standard in the non-surgical treatment of periodontitis is scaling and root planing (SRP). In recent years, the use of autogenous platelet concentrates has spread over many specialties in dentistry and, thus, has also been gaining popularity in periodontal treatment. Its two main fractions are platelet-rich plasma (PRP) and platelet-rich fibrin (PRF), which, since 2014, can also be used via injection as injectable platelet-rich fibrin (i-PRF). The authors conducted a comprehensive systematic review in accordance with the PRISMA 2020 guidelines. It involved searching PubMed, Embase, Scopus, and Google Scholar databases using the phrases ("Root Planing" OR "Subgingival Curettage" OR "Periodontal Debridement") AND ("Platelet-Rich Plasma"). Based on the authors' inclusion and exclusion criteria, 12 results were included in the review, out of 1170 total results. The objective of this review was to ascertain the impact of utilizing PRP and i-PRF in SRP. The results revealed that both the incorporation of PRP and i-PRF were found to be significantly associated with are duction in gingival pocket depth and again in clinical attachment level; however, i-PRF demonstrated superiority in improving clinical parameters. Furthermore, i-PRF demonstrated notable bactericidal efficacy against . On the other hand, PRP proved inferior to an Nd:YAG laser in clinical parameter improvement; however, it demonstrated significant efficiency as well. This literature review led the authors to the conclusion that autologous platelet concentrates might be competent agents for improving the therapeutic outcomes of SRP.
Topics: Humans; Platelet-Rich Plasma; Platelet-Rich Fibrin; Periodontitis; Root Planing; Injections
PubMed: 38928026
DOI: 10.3390/ijms25126319 -
International Journal of Molecular... Jun 2024Platelets have a fundamental role in mediating hemostasis and thrombosis. However, more recently, a new idea is making headway, highlighting the importance of platelets... (Review)
Review
Platelets have a fundamental role in mediating hemostasis and thrombosis. However, more recently, a new idea is making headway, highlighting the importance of platelets as significant actors in modulating immune and inflammatory responses. In particular, platelets have an important role in the development of vascular amyloid-b-peptide(ab) deposits, known to play a relevant role in Alzheimer's disease (AD) through accumulation and deposition within the frontal cortex and hippocampus in the brain. The involvement of platelets in the pathogenesis of AD opens up the highly attractive possibility of applying antiplatelet therapy for the treatment and/or prevention of AD, but conclusive results are scarce. Even less is known about the potential role of platelets in mild cognitive impairment (MCI). The aim to this brief review is to summarize current knowledge on this topic and to introduce the new perspectives on the possible role of platelet activation as therapeutic target both in AD and MCI.
Topics: Humans; Blood Platelets; Alzheimer Disease; Platelet Activation; Neurodegenerative Diseases; Cognitive Dysfunction; Animals; Amyloid beta-Peptides; Platelet Aggregation Inhibitors
PubMed: 38927999
DOI: 10.3390/ijms25126292 -
Bioengineering (Basel, Switzerland) Jun 2024Scaffold-guided breast tissue regeneration (SGBTR) can transform both reconstructive and cosmetic breast surgery. Implant-based surgery is the most common method....
Scaffold-guided breast tissue regeneration (SGBTR) can transform both reconstructive and cosmetic breast surgery. Implant-based surgery is the most common method. However, there are inherent limitations, as it involves replacement of tissue rather than regeneration. Regenerating autologous soft tissue has the potential to provide a more like-for-like reconstruction with minimal morbidity. Our SGBTR approach regenerates soft tissue by implanting additively manufactured bioresorbable scaffolds filled with autologous fat graft. A pre-clinical large animal study was conducted by implanting 100 mL breast scaffolds ( = 55) made from medical-grade polycaprolactone into 11 minipigs for 12 months. Various treatment groups were investigated where immediate or delayed autologous fat graft, as well as platelet rich plasma, were added to the scaffolds. Computed tomography and magnetic resonance imaging were performed on explanted scaffolds to determine the volume and distribution of the regenerated tissue. Histological analysis was performed to confirm the tissue type. At 12 months, we were able to regenerate and sustain a mean soft tissue volume of 60.9 ± 4.5 mL (95% CI) across all treatment groups. There was no evidence of capsule formation. There were no immediate or long-term post-operative complications. In conclusion, we were able to regenerate clinically relevant soft tissue volumes utilizing SGBTR in a pre-clinical large animal model.
PubMed: 38927829
DOI: 10.3390/bioengineering11060593 -
Bioengineering (Basel, Switzerland) Jun 2024Degenerative disc disease (DDD) is a pervasive condition that limits quality of life and burdens economies worldwide. Conventional pharmacological treatments primarily... (Review)
Review
Degenerative disc disease (DDD) is a pervasive condition that limits quality of life and burdens economies worldwide. Conventional pharmacological treatments primarily aimed at slowing the progression of degeneration have demonstrated limited long-term efficacy and often do not address the underlying causes of the disease. On the other hand, orthobiologics are regenerative agents derived from the patient's own tissue and represent a promising emerging therapy for degenerative disc disease. This review comprehensively outlines the pathophysiology of DDD, highlighting the inadequacies of existing pharmacological therapies and detailing the potential of orthobiologic approaches. It explores advanced tools such as platelet-rich plasma and mesenchymal stem cells, providing a historical overview of their development within regenerative medicine, from foundational in vitro studies to preclinical animal models. Moreover, the manuscript delves into clinical trials that assess the effectiveness of these therapies in managing DDD. While the current clinical evidence is promising, it remains insufficient for routine clinical adoption due to limitations in study designs. The review emphasizes the need for further research to optimize these therapies for consistent and effective clinical outcomes, potentially revolutionizing the management of DDD and offering renewed hope for patients.
PubMed: 38927827
DOI: 10.3390/bioengineering11060591 -
Bioengineering (Basel, Switzerland) Jun 2024Over time, numerous surgical procedures and biomaterials have been proposed for the reconstruction of post-extraction bone defects, each with their advantages and...
BACKGROUND
Over time, numerous surgical procedures and biomaterials have been proposed for the reconstruction of post-extraction bone defects, each with their advantages and disadvantages. The main objective of this study was to evaluate dimensional changes in the alveolar bone 3 months after tooth extraction, before implant planning, comparing alveolar ridge preservation (ARP) with spontaneous healing.
METHODS
A total of 84 patients with non-restorable molars were included in the study. Forty-two patients received ARP with advanced platelet-rich fibrin (A-PRF) and spontaneous healing was evaluated in these patients. Cone beam computed tomography (CBCT) analysis performed before and after surgical intervention was used to determine the changes in vertical and horizontal bone dimensions produced after tooth extraction.
RESULTS
CBCT measurements showed reduction in both vertical and horizontal alveolar bone size in both groups. For the study group, the alveolar parameters (height, width) were higher compared to the control group. The percentage variations between dimensional differences from the two groups were 38.58% for height, and for width were 36.88% at 0 mm, 35.56% at 3 mm, 36.61% at 5 mm, and 38.73% at 7 mm. The differences were statistically significant ( ˂ 0.0005).
CONCLUSIONS
The results obtained after ARP with A-PRF showed a reduced loss of bone volume compared to spontaneous healing.
PubMed: 38927802
DOI: 10.3390/bioengineering11060566 -
Genes Jun 2024Lipedema and lymphedema are physically similar yet distinct diseases that are commonly misdiagnosed. We previously reported that lipedema and lymphedema are associated...
Lipedema and lymphedema are physically similar yet distinct diseases that are commonly misdiagnosed. We previously reported that lipedema and lymphedema are associated with increased risk for venous thromboembolism (VTE). The underlying etiology of the prothrombotic profile observed in lipedema and lymphedema is unclear, but may be related to alterations in platelets. Our objective was to analyze the platelet transcriptome to identify biological pathways that may provide insight into platelet activation and thrombosis. The platelet transcriptome was evaluated in patients with lymphedema and lipedema, then compared to control subjects with obesity. Patients with lipedema were found to have a divergent transcriptome from patients with lymphedema. The platelet transcriptome and impacted biological pathways in lipedema were surprisingly similar to weight-matched comparators, yet different when compared to overweight individuals with a lower body mass index (BMI). Differences in the platelet transcriptome for patients with lipedema and lymphedema were found in biological pathways required for protein synthesis and degradation, as well as metabolism. Key differences in the platelet transcriptome for patients with lipedema compared to BMI-matched subjects involved metabolism and glycosaminoglycan processing. These inherent differences in the platelet transcriptome warrant further investigation, and may contribute to the increased risk of thrombosis in patients with lipedema and lymphedema.
Topics: Humans; Lymphedema; Lipedema; Female; Transcriptome; Middle Aged; Blood Platelets; Male; Adult; Body Mass Index; Platelet Activation; Obesity; Case-Control Studies
PubMed: 38927673
DOI: 10.3390/genes15060737