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Frontiers in Immunology 2024Increased levels of plasminogen activator inhibitor-1 (PAI-1) in tumors have been found to correlate with poor clinical outcomes in patients with cancer. Although...
BACKGROUND
Increased levels of plasminogen activator inhibitor-1 (PAI-1) in tumors have been found to correlate with poor clinical outcomes in patients with cancer. Although abundant data support the involvement of PAI-1 in cancer progression, whether PAI-1 contributes to tumor immune surveillance remains unclear. The purposes of this study are to determine whether PAI-1 regulates the expression of immune checkpoint molecules to suppresses the immune response to cancer and demonstrate the potential of PAI-1 inhibition for cancer therapy.
METHODS
The effects of PAI-1 on the expression of the immune checkpoint molecule programmed cell death ligand 1 (PD-L1) were investigated in several human and murine tumor cell lines. In addition, we generated tumor-bearing mice and evaluated the effects of a PAI-1 inhibitor on tumor progression or on the tumor infiltration of cells involved in tumor immunity either alone or in combination with immune checkpoint inhibitors.
RESULTS
PAI-1 induces PD-L1 expression through the JAK/STAT signaling pathway in several types of tumor cells and surrounding cells. Blockade of PAI-1 impedes PD-L1 induction in tumor cells, significantly reducing the abundance of immunosuppressive cells at the tumor site and increasing cytotoxic T-cell infiltration, ultimately leading to tumor regression. The anti-tumor effect elicited by the PAI-1 inhibitor is abolished in immunodeficient mice, suggesting that PAI-1 blockade induces tumor regression by stimulating the immune system. Moreover, combining a PAI-1 inhibitor with an immune checkpoint inhibitor significantly increases tumor regression.
CONCLUSIONS
PAI-1 protects tumors from immune surveillance by increasing PD-L1 expression; hence, therapeutic PAI-1 blockade may prove valuable in treating malignant tumors.
Topics: Animals; Humans; B7-H1 Antigen; Mice; Cell Line, Tumor; Plasminogen Activator Inhibitor 1; Tumor Escape; Neoplasms; Immune Checkpoint Inhibitors; Signal Transduction; Female; Gene Expression Regulation, Neoplastic; Tumor Microenvironment; Immune Evasion; Mice, Inbred C57BL
PubMed: 38779680
DOI: 10.3389/fimmu.2024.1365894 -
Ultrasound in Medicine & Biology Aug 2024Standard treatment for deep vein thrombosis (DVT) involves catheter-directed anticoagulants or thrombolytics, but the chronic thrombi present in many DVT cases are often...
OBJECTIVE
Standard treatment for deep vein thrombosis (DVT) involves catheter-directed anticoagulants or thrombolytics, but the chronic thrombi present in many DVT cases are often resistant to this therapy. Histotripsy has been found to be a promising adjuvant treatment, using the mechanical action of cavitating bubble clouds to enhance thrombolytic activity. The objective of this study was to determine if histotripsy enhanced recombinant tissue plasminogen activator (rt-PA) thrombolysis in highly retracted porcine clots in vitro in a flow model of occlusive DVT.
METHODS
Highly retracted porcine whole blood clots were treated for 1 h with either catheter-directed saline (negative control), rt-PA (lytic control), histotripsy, DEFINITY and histotripsy or the combination of rt-PA and histotripsy with or without DEFINITY. Five-cycle, 1.5 MHz histotripsy pulses with a peak negative pressure of 33.2 MPa and pulse repetition frequency of 40 Hz were applied along the clot. B-Mode and passive cavitation images were acquired during histotripsy insonation to monitor bubble activity.
RESULTS
Clots subjected to histotripsy with and without rt-PA exhibited greater thrombolytic efficacy than controls (7.0% flow recovery or lower), and histotripsy with rt-PA was more efficacious than histotripsy with saline (86.1 ± 10.2% compared with 61.7 ± 19.8% flow recovery). The addition of DEFINITY to histotripsy with or without rt-PA did not enhance either thrombolytic efficacy or cavitation dose. Cavitation dose generally did not correlate with thrombolytic efficacy.
CONCLUSION
Enhancement of thrombolytic efficacy was achieved using histotripsy, with and without catheter-directed rt-PA, in the presence of physiologic flow. This suggests these treatments may be effective as therapy for DVT.
Topics: Animals; Swine; Tissue Plasminogen Activator; Fibrinolytic Agents; Venous Thrombosis; Thrombolytic Therapy; In Vitro Techniques; Combined Modality Therapy; High-Intensity Focused Ultrasound Ablation; Treatment Outcome
PubMed: 38777639
DOI: 10.1016/j.ultrasmedbio.2024.04.002 -
Stroke and Vascular Neurology May 2024Racism contributes to higher comorbid risk factors and barriers to preventive measures for black Americans. Advancements in systems of care, tissue plasminogen activator...
BACKGROUND
Racism contributes to higher comorbid risk factors and barriers to preventive measures for black Americans. Advancements in systems of care, tissue plasminogen activator (tPA) availability and endovascular thrombectomy (ET) have impacted practice and outcomes while outpacing contemporary investigation into acute ischaemic stroke (AIS) care disparities. We examined whether recent data suggest ongoing disparity in AIS interventions and outcomes, and if hospital characteristics affect disparities.
METHODS
We examined 2016-2019 fee-for-service Medicare inpatient data. We ran unadjusted logistic regression models to calculate ORs and 95% CI for two interventions (tPA and ET) and four outcomes (inpatient mortality, 30-day mortality, discharge home and outpatient visit within 30 days), with the main predictor black versus white race, additionally adjusting for demographics, hospital characteristics, stroke severity and comorbidities.
RESULTS
805 181 AIS admissions were analysed (12.4% black, 87.6% white). Compared with white patients, black patients had reduced odds of receiving tPA (OR 0.71, 95% CI 0.69 to 0.74, p<0.0001) and ET (0.69, 95% CI 0.65 to 0.72, p<0.0001). After tPA, black patients had reduced odds of 30-day mortality (0.77, 95% CI 0.72 to 0.82, p<0.0001), discharge home (0.72, 95% CI 0.68 to 0.77, p<0.0001) and outpatient visit within 30 days (0.89, 95% CI 0.84 to 0.95, p=0.0002). After ET, black patients had reduced odds of 30-day mortality (0.71, 95% CI 0.63 to 0.79, p<0.0001) and discharge home (0.75, 95% CI 0.64 to 0.88, p=0.0005). Adjusted models showed little difference in the magnitude, direction or significance of the main effects.
CONCLUSIONS
Black patients were less likely to receive AIS treatments, and if treated had lower likelihood of 30-day mortality, discharge home and outpatient visits. Despite advancements in practice and therapies, racial disparities remain in the modern era of AIS care and are consistent with inequalities previously identified over the last 20 years. The impact of hospital attributes on AIS care disparities warrants further investigation.
PubMed: 38777349
DOI: 10.1136/svn-2023-003051 -
Clinical and Experimental Medicine May 2024Predicting the likelihood vascular events in patients with BCR/ABL1-negative myeloproliferative neoplasms (MPN) is essential for the treatment of the disease. However,...
Predicting the likelihood vascular events in patients with BCR/ABL1-negative myeloproliferative neoplasms (MPN) is essential for the treatment of the disease. However, effective assessment methods are lacking. Thrombin-antithrombin complex (TAT), plasmin-α- plasmininhibitor complex (PIC), thrombomodulin (TM), and tissue plasminogen activator-inhibitor complex (t-PAIC) are the new direct indicators for coagulation and fibrinolysis. The aim of this study was to investigate the changes of these four new indicators in thrombotic and hemorrhagic events in BCR/ABL1-negative MPN. The study cohort of 74 patients with BCR/ABL negative myeloproliferative disorders included essential thrombocythemia, polycythemia vera, and primary myelofibrosis (PMF). A panel of 4 biomarkers, including TAT, PIC, TM, and t-PAIC were determined using Sysmex HISCL5000 automated analyzers, whereas fibrin/fibrinogen degradation products (FDP), D-dimer and Antithrombin III (ATIII) were analyzed using Sysmex CS5100 coagulation analyzer. A total of 24 (32.4%) patients experienced thrombotic events and hemorrhagic events occurred in 8 patients (10.8%). Compared to patients without hemorrhagic-thrombotic events, patients with thrombotic events had higher fibrinogen (FIB) level, FDP level and lower ATIII activity, while patients with hemorrhagic events had lower white blood cell count and hemoglobin level, higher FDP level (P < 0.05). Patients with a JAK2V617F mutation were more likely to experience thrombotic events (P < 0.05). In addtion, patients with thrombotic events had higher TAT, PIC, TM, and t-PAIC levels than patients without hemorrhagic-thrombotic events (P < 0.05), whereas patients with hemorrhagic events had a lower median value in TAT and TM (no statistical difference, P > 0.05). Patients with higher TAT, TM and t-PAIC were more likely to experience thrombotic events (P < 0.05), and only TAT was positively correlated with thrombotic events (Spearman r =0.287, P = 0.019). TAT, PIC, TM, and t-PAIC combined with ATIII and FDP have a certain value for predicting thrombosis in patients with BCR/ABL1-negative MPN. These 6 parameters are worth further exploration as predictive factors and prognostic markers for early thrombotic events.
Topics: Humans; Male; Female; Middle Aged; Aged; Adult; Myeloproliferative Disorders; Fusion Proteins, bcr-abl; Thrombomodulin; Fibrinolysin; Aged, 80 and over; Biomarkers; Antithrombin III; Thrombosis; Hemorrhage; Clinical Relevance; alpha-2-Antiplasmin; Peptide Hydrolases
PubMed: 38776019
DOI: 10.1007/s10238-024-01371-7 -
Revista Da Associacao Medica Brasileira... 2024
Topics: Humans; Tissue Plasminogen Activator; Fibrinolytic Agents; Thrombolytic Therapy; Reperfusion; Recombinant Proteins
PubMed: 38775518
DOI: 10.1590/1806-9282.20240103 -
Heart Views : the Official Journal of... 2024A 40-year-old patient confirmed on computed tomography of the pulmonary arteries (CT/PAs) a large saddle pulmonary embolus in the main PA extending in both branches. He...
A 40-year-old patient confirmed on computed tomography of the pulmonary arteries (CT/PAs) a large saddle pulmonary embolus in the main PA extending in both branches. He was managed by ultrasound-supported catheter-directed (EkoSonic, Boston Scientific) intrapulmonary thrombolytic therapy using a recombinant tissue plasminogen activator prolonged infusion over 16 h with a total dose of 50 mg divided in both PAs simultaneously with intravenous unfractionated heparin. He showed clinical improvement with improved arterial oxygen (PaO2) with reduced oxygen therapy with a nasal cannula. Follow-up right heart catheterization showed a significant reduction of PA pressure from 96/32 (mean 64) to 47/27 (mean 39) mmHg. Repeat pulmonary angiography showed significant improvement in PA branch opacification, suggesting increased flow and successful therapy. The patient received oral anticoagulants for months. He had followed with CT/PA and echocardiogram after 4 weeks, both were normalized. He resumed his regular physical activities, including exercises in the gymnasium.
PubMed: 38774554
DOI: 10.4103/heartviews.heartviews_103_23 -
BMC Ophthalmology May 2024Comparing between the visual outcomes and post operative complications of two surgical treatments for sub macular hemorrhage, pars plana vitrectomy with tissue... (Comparative Study)
Comparative Study
Pneumatic displacement with intravitreal tPA injection versus vitrectomy with sub retinal tPA injection in small and medium sub macular hemorrhages- a multicenter comparative study.
PURPOSE
Comparing between the visual outcomes and post operative complications of two surgical treatments for sub macular hemorrhage, pars plana vitrectomy with tissue plasminogen activator (tPA) injection procedure, and pneumatic displacement of submacular hemorrhage with intravitreal tPA injection.
METHODS
A retrospective chart review of patients with sub macular hemorrhage (SMH) was performed. Data was collected from 150 patients with sub macular hemorrhage. Patients were followed up from the day of admission and up to a year post surgery. Evaluation included visual acuity, optical coherence tomography (OCT), fundus examination and rates of complications.
RESULTS
Pars plana vitrectomy procedure has showed a better visual outcome in small SMH. Comparing complications between the two treatment modalities, no significant difference has been found in the study.
CONCLUSIONS
Pars plana vitrectomy and tPA showed a clear advantage with a trend of better visual acuity as well as a significant predictor to better visual acuity for small and medium sub macular hemorrhage.
Topics: Humans; Tissue Plasminogen Activator; Vitrectomy; Retinal Hemorrhage; Retrospective Studies; Male; Female; Visual Acuity; Intravitreal Injections; Aged; Tomography, Optical Coherence; Fibrinolytic Agents; Middle Aged; Aged, 80 and over
PubMed: 38773500
DOI: 10.1186/s12886-024-03468-9 -
Stroke Jul 2024The dramatic clinical improvement offered by mechanical thrombectomy raised questions about the relevance of prior intravenous thrombolysis in large-vessel occlusion... (Observational Study)
Observational Study
BACKGROUND
The dramatic clinical improvement offered by mechanical thrombectomy raised questions about the relevance of prior intravenous thrombolysis in large-vessel occlusion strokes. Hence, studying intravenous thrombolysis susceptibility and its dependence on thrombus composition is crucial. We used an observational proteomic study of whole thrombi retrieved by mechanical thrombectomy to identify factors associated with fibrin content and fibrinolytic activity (FA).
METHODS
In 104 stroke patients, the thrombi proteome was established by mass spectrometry coupled to liquid chromatography. FA was estimated in clots both outside (FA) by measuring D-dimer levels at the blood-thrombus interface and inside (FA) by evaluating the ratio of fibrinogen α to its plasmin-cleaved forms using proteomics coupled with protein electrophoresis. The factors associated with fibrin content, FA, and FA were determined by intravenous thrombolysis-adjusted linear regression.
RESULTS
FA (<0.0001) and FA (=0.0147) were driven by recombinant tissue-type plasminogen activator (r-tPA) administration (47/104) and thrombus composition. Indeed, FA was greater with fibrin-rich than erythrocyte-rich thrombi, presumably because of more (r)tPA substrates. Thus, FA was increased with cardioembolic thrombi (72/104), which are rich in fibrin (=0.0300). Opposite results were found inside the thrombus, suggesting that (r)tPA penetrability was hampered by the density of the fibrinous cap. Moreover, blood cells had a strong impact on thrombus structure and susceptibility to (r)tPA. Indeed, fibrin content was negatively associated with erythrocyte-specific proteins in the thrombus, admission hematocrit (=0.0139), and hemoglobin level (=0.0080), which underlines the key role of erythrocytes in thrombus composition. Also, an increased number of neutrophils impaired FA (=0.0225), which suggests that their aggregation around the thrombus prevented the (r)tPA attack. Only FA was significantly associated with reduced thrombus weight (=0.0310), increased recanalization rate (=0.0150), good clinical outcome (=0.0480), and reduced mortality (=0.0080).
CONCLUSIONS
Proteomics can offer new insights into the close relationship between thrombus composition and susceptibility to fibrinolysis, paving the way for new adjuvant therapies.
Topics: Humans; Male; Female; Fibrinolysis; Proteomics; Aged; Middle Aged; Intracranial Thrombosis; Stroke; Thrombectomy; Tissue Plasminogen Activator; Fibrin; Aged, 80 and over; Thrombolytic Therapy; Thrombosis
PubMed: 38771990
DOI: 10.1161/STROKEAHA.124.047156 -
Global Heart 2024There is growing evidence that concentrations of DNA methylation are associated with cardiovascular disease; however, it is unclear whether this association reflects a...
BACKGROUND
There is growing evidence that concentrations of DNA methylation are associated with cardiovascular disease; however, it is unclear whether this association reflects a causal relationship.
METHODS
We utilized a two-sample Mendelian randomization (MR) approach to investigate whether DNA methylation can affect the risk of developing cardiovascular disease in human life. We primarily performed the inverse variance weighted (IVW) method to analyze the causal effect of DNA methylation on multiple cardiovascular diseases. Additionally, to ensure the robustness of our findings, we conducted several sensitivity analyses using alternative methodologies. These analysis methods included maximum likelihood, MR-Egger regression, weighted median method, and weighted model methods.
RESULTS
Inverse variance weighted estimates suggested that an SD increase in DNA methylation Hannum age acceleration exposure increased the risk of cardiac arrhythmias (OR = 1.03, 95% CI 1.00-1.05, = 0.0290) and atrial fibrillation (OR = 1.03, 95% CI 1.00-1.05, = 0.0022). We also found that an SD increase in DNA methylation PhenoAge acceleration exposure increased the risk of heart failure (OR = 1.01, 95% CI 1.00-1.03, = 0.0362). Exposure to DNA methylation-estimated granulocyte proportions was found to increase the risk of hypertension (OR = 1.00, 95% CI 1.00-1.0001, p = 0.0291). Exposure to DNA methylation-estimated plasminogen activator inhibitor-1 levels was found to increase the risk of heart failure (OR = 1.00, 95% CI 1.00-1.00, = 0.0215).
CONCLUSION
This study reveals a causal relationship between DNA methylation and CVD. Exposed to high levels of DNA methylation Hannum age acceleration inhabitants with an increased risk of cardiac arrhythmias and atrial fibrillation. DNA methylation PhenoAge acceleration levels exposure levels were positively associated with the increased risk of developing heart failure. This has important implications for the prevention of cardiovascular diseases.
Topics: Humans; DNA Methylation; Mendelian Randomization Analysis; Cardiovascular Diseases; Risk Factors
PubMed: 38765775
DOI: 10.5334/gh.1324 -
PloS One 2024Mechanisms underlying primary and acquired resistance to MET tyrosine kinase inhibitors (TKIs) in managing non-small cell lung cancer remain unclear. In this study, we...
Mechanisms underlying primary and acquired resistance to MET tyrosine kinase inhibitors (TKIs) in managing non-small cell lung cancer remain unclear. In this study, we investigated the possible mechanisms acquired for crizotinib in MET-amplified lung carcinoma cell lines. Two MET-amplified lung cancer cell lines, EBC-1 and H1993, were established for acquired resistance to MET-TKI crizotinib and were functionally elucidated. Genomic and transcriptomic data were used to assess the factors contributing to the resistance mechanism, and the alterations hypothesized to confer resistance were validated. Multiple mechanisms underlie acquired resistance to crizotinib in MET-amplified lung cancer cell lines. In EBC-1-derived resistant cells, the overexpression of SERPINE1, the gene encoding plasminogen activator inhibitor-1 (PAI-1), mediated the drug resistance mechanism. Crizotinib resistance was addressed by combination therapy with a PAI-1 inhibitor and PAI-1 knockdown. Another mechanism of resistance in different subline cells of EBC-1 was evaluated as epithelial-to-mesenchymal transition with the upregulation of antiapoptotic proteins. In H1993-derived resistant cells, MEK inhibitors could be a potential therapeutic strategy for overcoming resistance with downstream mitogen-activated protein kinase pathway activation. In this study, we revealed the different mechanisms of acquired resistance to the MET inhibitor crizotinib with potential therapeutic application in patients with MET-amplified lung carcinoma.
Topics: Humans; Plasminogen Activator Inhibitor 1; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; Proto-Oncogene Proteins c-met; Crizotinib; Lung Neoplasms; Cell Line, Tumor; Protein Kinase Inhibitors; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic
PubMed: 38758826
DOI: 10.1371/journal.pone.0300644