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Blood Reviews Jul 2024Patients with multiple myeloma (MM) were among the groups impacted more severely by the COVID-19 pandemic, with higher rates of severe disease and COVID-19-related... (Review)
Review
Endothelial injury and dysfunction with emerging immunotherapies in multiple myeloma, the impact of COVID-19, and endothelial protection with a focus on the evolving role of defibrotide.
Patients with multiple myeloma (MM) were among the groups impacted more severely by the COVID-19 pandemic, with higher rates of severe disease and COVID-19-related mortality. MM and COVID-19, plus post-acute sequelae of SARS-CoV-2 infection, are associated with endothelial dysfunction and injury, with overlapping inflammatory pathways and coagulopathies. Existing treatment options for MM, notably high-dose therapy with autologous stem cell transplantation and novel chimeric antigen receptor (CAR) T-cell therapies and bispecific T-cell engaging antibodies, are also associated with endothelial cell injury and mechanism-related toxicities. These pathologies include cytokine release syndrome (CRS) and neurotoxicity that may be exacerbated by underlying endotheliopathies. In the context of these overlapping risks, prophylaxis and treatment approaches mitigating the inflammatory and pro-coagulant effects of endothelial injury are important considerations for patient management, including cytokine receptor antagonists, thromboprophylaxis with low-molecular-weight heparin and direct oral anticoagulants, and direct endothelial protection with defibrotide in the appropriate clinical settings.
Topics: Humans; Multiple Myeloma; COVID-19; Polydeoxyribonucleotides; SARS-CoV-2; Immunotherapy; Cytokine Release Syndrome; Endothelium, Vascular
PubMed: 38852017
DOI: 10.1016/j.blre.2024.101218 -
BMC Pharmacology & Toxicology Jun 2024Antiplatelet therapy is an important factor influencing the postterm patency rate of carotid artery stenting (CAS). Clopidogrel is a platelet aggregation inhibitor...
Antiplatelet therapy is an important factor influencing the postterm patency rate of carotid artery stenting (CAS). Clopidogrel is a platelet aggregation inhibitor mediated by the adenosine diphosphate receptor and is affected by CYP2C19 gene polymorphisms in vivo. When the CYP2C19 gene has a nonfunctional mutation, the activity of the encoded enzyme will be weakened or lost, which directly affects the metabolism of clopidogrel and ultimately weakens its antiplatelet aggregation ability. Therefore, based on network pharmacology, analyzing the influence of CYP2C19 gene polymorphisms on the antiplatelet therapeutic effect of clopidogrel after CAS is highly important for the formulation of individualized clinical drug regimens. The effect of the CYP2C19 gene polymorphism on the antiplatelet aggregation of clopidogrel after CAS was analyzed based on network pharmacology. A total of 100 patients with ischemic cerebrovascular disease who were confirmed by the neurology department and required CAS treatment were studied. CYP2C19 genotyping was performed on all patients via a gene chip. All patients were classified into the wild-type (WT) group (*1/*1), heterozygous mutation (HTM) group (CYP2C19*1/*2, CYP2C19*1/*3), and homozygous mutation (HMM) group (CYP2C19*2/*2, CYP2C19*2/*3, and CYP2C19*3/*3). High-performance liquid chromatography (HPLC) with tandem mass spectrometry (MS/MS) was used to detect the blood concentration of clopidogrel and the plasma clopidogrel clearance (CL) rate in different groups of patients before and after clopidogrel treatment. The platelet aggregation rate of patients with different genotypes was measured by turbidimetry. The incidences of clopidogrel resistance (CR) and stent thrombosis in different groups after three months of treatment were analyzed. The results showed that among the different CYP2C19 genotypes, patients from the HTM group accounted for the most patients, while patients from the HTM group accounted for the least patients. Similarly, the clopidogrel CL of patients in the HMM group was lower than that of patients in the WT group and HTM group (P < 0.01). The platelet inhibition rate of patients in the HMM group was evidently inferior to that of patients in the WT group and HTM group (P < 0.01). The incidence of CR and stent thrombosis in the WT group was notably lower than that in the HTM and HMM groups (P < 0.01). These results indicate that the CYP2C19 gene can affect CR occurrence and stent thrombosis after CAS by influencing clopidogrel metabolism and platelet count.
Topics: Humans; Cytochrome P-450 CYP2C19; Clopidogrel; Platelet Aggregation Inhibitors; Stents; Male; Female; Platelet Aggregation; Aged; Middle Aged; Polymorphism, Genetic; Ticlopidine; Genotype; Carotid Arteries
PubMed: 38845014
DOI: 10.1186/s40360-024-00750-w -
BMC Medical Genomics Jun 2024Anesthetic drugs may alter exosomal microRNA (miRNA) contents and mediate cancer progression and tumor microenvironment remodeling. Our study aims to explore how the...
BACKGROUND
Anesthetic drugs may alter exosomal microRNA (miRNA) contents and mediate cancer progression and tumor microenvironment remodeling. Our study aims to explore how the anesthetics (sevoflurane and propofol) impact the miRNA makeup within exosomes in hepatocellular carcinoma (HCC), alongside the interconnected signaling pathways linked to the tumor immune microenvironment.
METHODS
In this prospective study, we collected plasma exosomes from two groups of HCC patients (n = 5 each) treated with either propofol or sevoflurane, both before anesthesia and after hepatectomy. Exosomal miRNA profiles were assessed using next-generation sequencing (NGS). Furthermore, the expression data from The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) was used to pinpoint the differentially expressed exosomal miRNAs (DEmiRNAs) attributed to the influence of propofol or sevoflurane in the context of HCC. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were used to dissect the signaling pathways and biological activities associated with the identified DEmiRNAs and their corresponding target genes.
RESULTS
A total of 35 distinct DEmiRNAs were exclusively regulated by either propofol (n = 9) or sevoflurane (n = 26). Through TCGA-LIHC database analysis, 8 DEmiRNAs were associated with HCC. These included propofol-triggered miR-452-5p and let-7c-5p, as well as sevoflurane-induced miR-24-1-5p, miR-122-5p, miR-200a-3p, miR-4686, miR-214-3p, and miR-511-5p. Analyses revealed that among these 8 DEmiRNAs, the upregulation of miR-24-1-5p consistently demonstrated a significant association with lower histological grades (p < 0.0001), early-stage tumors (p < 0.05) and higher survival (p = 0.029). Further analyses using GSEA and GSVA indicated that miR-24-1-5p, along with its target genes, were involved in governing the tumor immune microenvironment and potentially inhibiting tumor progression in HCC.
CONCLUSIONS
This study provided bioinformatics evidence suggesting that sevoflurane-induced plasma exosomal miRNAs may have a potential impact on the immune microenvironment of HCC. These findings established a foundation for future research into mechanistic outcomes in cancer patients.
Topics: Carcinoma, Hepatocellular; Humans; MicroRNAs; Liver Neoplasms; Exosomes; Computational Biology; Sevoflurane; Propofol; Disease Progression; Male; Anesthetics; Gene Expression Regulation, Neoplastic; Middle Aged; Female; Prospective Studies; Tumor Microenvironment
PubMed: 38840234
DOI: 10.1186/s12920-024-01922-7 -
Journal of Stroke May 2024Cancer can induce hypercoagulability, which may lead to stroke. This occurs when tumor cells activate platelets as part of their growth and metastasis. Tumor cells... (Review)
Review
Cancer can induce hypercoagulability, which may lead to stroke. This occurs when tumor cells activate platelets as part of their growth and metastasis. Tumor cells activate platelets by generating thrombin and expressing tissue factor, resulting in tumor cell-induced platelet aggregation. Histopathological studies of thrombi obtained during endovascular thrombectomy in patients with acute stroke and active cancer have shown a high proportion of platelets and thrombin. This underscores the crucial roles of platelets and thrombin in cancer-associated thrombosis. Cancer-associated stroke typically occurs in patients with active cancer and is characterized by distinctive features. These features include multiple infarctions across multiple vascular territories, markedly elevated blood D-dimer levels, and metastasis. The presence of cardiac vegetations on echocardiography is a robust indicator of cancer-associated stroke. Suspicion of cancer-associated stroke during endovascular thrombectomy arises when white thrombi are detected, particularly in patients with active cancer. Cancer-associated stroke is almost certain when histopathological examination of thrombi shows a very high platelet and a very low erythrocyte composition. Patients with cancer-associated stroke have high risks of mortality and recurrent stroke. However, limited data are available on the optimal treatment regimen for stroke prevention in these patients. Thrombosis mechanism in cancer is well understood, and distinct therapeutic targets involving thrombin and platelets have been identified. Therefore, direct thrombin inhibitors and/or antiplatelet agents may effectively prevent stroke recurrence. Additionally, this strategy has potential benefits in cancer treatment as accumulating evidence suggests that aspirin use reduces cancer progression, metastasis, and cancer-related mortality. However, clinical trials are necessary to assess the efficacy of this strategy involving the use of direct thrombin inhibitors and/or antiplatelet therapies.
PubMed: 38836266
DOI: 10.5853/jos.2023.03279 -
Saudi Medical Journal Jun 2024
Topics: Humans; Colorectal Neoplasms; Aspirin; Disease Progression; Anti-Inflammatory Agents, Non-Steroidal
PubMed: 38830654
DOI: No ID Found -
Archives of Razi Institute Dec 2023Pentoxifylline (PTXF) is a vasoactive agent that plays a significant role in the treatment of thin-layer endometrium cases. The PTXF, also identified as oxpentifylline,...
Pentoxifylline (PTXF) is a vasoactive agent that plays a significant role in the treatment of thin-layer endometrium cases. The PTXF, also identified as oxpentifylline, is a member of xanthine derivatives and a competitive nonselective phosphodiesterase inhibitor leading to the elevation of intracellular cAMP, inhibition of tumor necrosis factor and leukotriene synthesis, activation of protein kinase A, and reduction of inflammation and innate immunity. Moreover, it is used as an agent to relieve muscle pain in people with peripheral artery disease (vascular irregularities). It is also an acceptable choice for the treatment of radiation-induced fibrosis. Therefore, the present study aimed to determine the advantageous impact of PTXF and PTXF-loaded poly lactic-co-glycolic acid (PLGA) on female rats after being exposed to ethanol to create a thin layer of the endometrium. For this purpose, 50 female rats were selected and divided into five groups (G1: negative normal control, G2: positive control, G3: PLGA only, G4: preference PTXF, and G5: PLGA-PTXF groups) for a 20-day treatment period. In this study, the histopathological section revealed a perfect improvement in the tissues of the uterine horn of female rats that induced endometria and were treated with PLGA-PTXF. In this group of rats, clear healing was achieved and there was an increase in the thickness of endometrium and myometrium, compared to the ordinary PTXF-treated group which had the lowest recovery characteristics. However, the positive control group underwent a significant decrease in terms of endometrium and myometrium thickness as well as vascular and glandular density. This study showed that the PTXF-loaded PLGA had the capacity to heal the thin layer of the endometrium by improving the levels of histopathological changes, especially regarding the thickness of the endometrium and myometrium more than the ordinary PTXF.
Topics: Pentoxifylline; Animals; Female; Rats; Endometrium; Polylactic Acid-Polyglycolic Acid Copolymer; Rats, Wistar
PubMed: 38828173
DOI: 10.32592/ARI.2023.78.6.1762 -
Drug Design, Development and Therapy 2024Mechanistic studies showed that morphine may impair the antiplatelet effect of P2Y12 inhibitors. However, Several clinical studies with cardiovascular events as an...
PURPOSE
Mechanistic studies showed that morphine may impair the antiplatelet effect of P2Y12 inhibitors. However, Several clinical studies with cardiovascular events as an outcome are contradictory, and the broader impact of this drug interaction on additional organ systems remains uncertain. With multisource data, this study sought to determine the effects of morphine interaction with P2Y12 inhibitors on major adverse outcomes comprehensively, and identify the warning indicators.
PATIENTS AND METHODS
Interaction signals were sought in 187,919 safety reports from the FDA Adverse Event Reporting System (FAERS) database, utilizing reporting odds ratios (repOR). In a cohort of 5240 acute coronary syndrome patients, the analyses were validated, and the biological effects of warning indicators were further studied with Mendelian randomization and mediation analysis.
RESULTS
Potential risk of renal system adverse events in patients cotreated with morphine is significantly higher in FAERS (repOR 4.83, 95% CI 4.42-5.28, false discovery rate adjusted- =3.55*10). The analysis of in-house patient cohorts validated these results with an increased risk of acute kidney injury (adjusted OR: 1.65; 95% CI: 1.20 to 2.26), and we also found a risk of myocardial infarction in patients treated with morphine (adjusted OR: 1.55; 95% CI: 1.14 to 2.11). The Morphine group exhibited diminished Plateletcrit (PCT) levels post-surgery and lower PCT levels were associated with an increased risk of AKI.
CONCLUSION
The administration of morphine in patients treated with P2Y12 receptor inhibitors should be carefully evaluated. PCT may serve as a potential warning indicator for morphine-related renal injury.
Topics: Humans; Morphine; Purinergic P2Y Receptor Antagonists; Acute Coronary Syndrome; Male; Female; Middle Aged; Aged; Platelet Aggregation Inhibitors; Analgesics, Opioid
PubMed: 38828024
DOI: 10.2147/DDDT.S458299 -
International Heart Journal 2024This study aimed to investigate the molecular mechanisms underlying the protective effects of cyclooxygenase (cox) inhibitors against myocardial hypertrophy.Rat H9c2...
This study aimed to investigate the molecular mechanisms underlying the protective effects of cyclooxygenase (cox) inhibitors against myocardial hypertrophy.Rat H9c2 cardiomyocytes were induced by mechanical stretching. SD rats underwent transverse aortic constriction to induce pressure overload myocardial hypertrophy. Rats were subjected to echocardiography and tail arterial pressure in 12W. qPCR and western blot were used to detect the expression of Notch-related signaling. The inflammatory factors were tested by ELISA in serum, heart tissue, and cell culture supernatant.Compared with control, levels of pro-inflammatory cytokines IL-6, TNF-α, and IL-1β were increased and anti-inflammatory cytokine IL-10 was reduced in myocardial tissues and serum of rat models. Levels of Notch1 and Hes1 were reduced in myocardial tissues. However, cox inhibitor treatment (aspirin and celecoxib), the improvement of exacerbated myocardial hypertrophy, fibrosis, dysfunction, and inflammation was parallel to the activation of Notch1/Hes1 pathway. Moreover, in vitro experiments showed that, in cardiomyocyte H9c2 cells, application of ~20% mechanical stretching activated inflammatory mediators (IL-6, TNF-α, and IL-1β) and hypertrophic markers (ANP and BNP). Moreover, expression levels of Notch1 and Hes1 were decreased. These changes were effectively alleviated by aspirin and celecoxib.Cox inhibitors may protect heart from hypertrophy and inflammation possibly via the Notch1/Hes1 signaling pathway.
Topics: Animals; Receptor, Notch1; Rats; Transcription Factor HES-1; Rats, Sprague-Dawley; Signal Transduction; Celecoxib; Aspirin; Male; Myocytes, Cardiac; Cyclooxygenase Inhibitors; Cardiomegaly; Disease Models, Animal
PubMed: 38825493
DOI: 10.1536/ihj.23-614 -
Food Research International (Ottawa,... Jul 2024Several scientific studies have warned that the ingestion of dietary lipid oxidation products (LOPs) may initiate or exacerbate the development of several chronic...
Several scientific studies have warned that the ingestion of dietary lipid oxidation products (LOPs) may initiate or exacerbate the development of several chronic non-communicable diseases in humans. Indeed, the constantly increasing consumption of culinary oils by larger global populations indicates the need for scientific techniques to suppress the evolution of LOPs in thermo-oxidised oils. This study employed a 600.13 MHz frequency NMR spectrometer in evaluating the effect of 10, 50, and 100 ppm concentrations of chemical compounds reported to have antioxidant properties in continuously-stirred and thermally stressed polyunsaturated fatty acid (PUFA)-rich hemp seed oil at a frying temperature of 180℃ for 180 min. Research data acquired showed that the antioxidants α- and γ-tocopherol, γ-oryzanol, β-carotene, eugenol, resveratrol, ascorbyl palmitate, gentisic acid, and L-ascorbic acid all played a vital role in suppressing the evolution of secondary aldehydic lipid oxidation products in hemp seed oil. However, the most ineffective LOP-suppressing agent was L-lysine, an observation which may be accountable by its poor oil solubility. Nonetheless, trends deduced for compounds acting as antioxidants were mainly unique for each class of agent tested. Conversely, the antioxidant capacity of resveratrol was consistently higher, and this effect was found to be independent of its added amounts. This report provides a direct approach in developing scientific methods for the suppression of LOPs in thermo-oxidatively susceptible PUFA-rich cooking oils.
Topics: Antioxidants; Plant Oils; Hot Temperature; Cannabis; Lipid Peroxidation; Cooking; Seeds; Resveratrol; Fatty Acids, Unsaturated; Magnetic Resonance Spectroscopy; Ascorbic Acid; Plant Extracts
PubMed: 38823855
DOI: 10.1016/j.foodres.2024.114415 -
International Journal of Cardiology Sep 2024The comparative efficacy and safety of adjusted- and standard-dose prasugrel in East Asian patients with acute myocardial infarction (AMI) undergoing percutaneous... (Comparative Study)
Comparative Study
BACKGROUND
The comparative efficacy and safety of adjusted- and standard-dose prasugrel in East Asian patients with acute myocardial infarction (AMI) undergoing percutaneous coronary intervention (PCI) remain unclear. This study aimed to comparatively assess the ischaemic and bleeding outcomes of adjusted-dose (maintenance dose: 3.75 mg) and standard-dose (maintenance dose: 10 mg) prasugrel in East Asian patients with AMI undergoing PCI.
METHODS
From a combined dataset sourced from nationwide AMI registries in Japan and South Korea (n = 17,118), patients treated with either adjusted- or standard-dose prasugrel were identified. Patients who did not undergo emergent PCI, those on oral anticoagulants, and those meeting the criteria of contraindication of prasugrel in South Korea (age ≥ 75 years, body weight < 60 kg, or history of stroke) were excluded. Major adverse cardiovascular events (MACE) and Thrombolysis in Myocardial Infarction (TIMI) major bleeding events were compared between the adjusted-dose (n = 1160) and standard-dose (n = 1086) prasugrel groups.
RESULTS
Within the propensity-matched cohort (n = 702 in each group), no significant difference was observed in the in-hospital MACE between the adjusted- and standard-dose prasugrel groups (1.85% vs. 2.71%, odds ratio [OR] 0.68, 95% confidence interval [CI] 0.33-1.38, p = 0.286). However, the incidence of in-hospital major bleeding was significantly lower in the adjusted-dose prasugrel group than in the standard-dose group (0.43% vs. 1.71%, OR 0.25, 95% CI 0.07-0.88, p = 0.031). The cumulative 12-month incidence of MACE was equivalent in both groups (4.70% vs. 4.70%, OR 1.00, 95% CI 0.61-1.64, p = 1.000).
CONCLUSIONS
Among East Asian patients with AMI undergoing PCI, those administered adjusted-dose prasugrel exhibited a lower risk of in-hospital bleeding events than those administered standard-dose prasugrel, while maintaining a comparable 1-year incidence of MACE.
Topics: Aged; Female; Humans; Male; Middle Aged; Cohort Studies; Dose-Response Relationship, Drug; East Asian People; Hemorrhage; Japan; Myocardial Infarction; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Registries; Republic of Korea; Treatment Outcome
PubMed: 38823533
DOI: 10.1016/j.ijcard.2024.132197