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Biomedicines May 2024Acute hypoxemic respiratory failure (AHRF) is defined as acute and progressive, and patients are at a greater risk of developing acute respiratory distress syndrome...
Acute hypoxemic respiratory failure (AHRF) is defined as acute and progressive, and patients are at a greater risk of developing acute respiratory distress syndrome (ARDS). Until now, most studies have focused on prognostic and diagnostic biomarkers in ARDS. Since there is evidence supporting a connection between dysregulated coagulant and fibrinolytic pathways in ARDS progression, it is plausible that this dysregulation also exists in AHRF. The aim of this study was to explore whether levels of soluble endothelial protein C receptor (sEPCR) and plasminogen differentiate patients admitted to the emergency department (ED) with AHRF. sEPCR and plasminogen levels were measured in 130 AHRF patients upon ED presentation by ELISA. Our results demonstrated that patients presenting to the ED with AHRF had elevated levels of sEPCR and plasminogen. It seems that dysregulation of coagulation and fibrinolysis occur in the early stages of respiratory failure requiring hospitalisation. Further research is needed to fully comprehend the contribution of sEPCR and plasminogen in AHRF.
PubMed: 38791043
DOI: 10.3390/biomedicines12051081 -
Biomedicines May 2024The aim of the present study is to investigate the prognostic utility of point-of-care (POC)-measured proenkephalin (PENK), a novel biomarker, in terms of predicting...
BACKGROUND
The aim of the present study is to investigate the prognostic utility of point-of-care (POC)-measured proenkephalin (PENK), a novel biomarker, in terms of predicting in-hospital mortality in patients presenting to the emergency department (ED) with septic shock.
METHODS
Bedside PENK was measured in consecutive patients presenting to the ED with septic shock according to the Sepsis-3 clinical criteria. The association of PENK with inflammatory and routine biomarkers, and its role as a predictor of in-hospital mortality, was examined.
RESULTS
Sixty-one patients with septic shock [53% females, median age 83 years (IQR 71-88)] were evaluated. Median (IQR) values of creatinine, plasma lactate, soluble urokinase plasminogen activator receptor (SuPAR), procalcitonin and PENK were 1.7 (1.0-2.9) mg/dL, 3.6 (2.1-6.8) mmol/L, 13.1 (10.0-21.4) ng/mL, 2.06 (0.84-3.49) ng/mL, and 205 (129-425) pmol/L, respectively. LogPENK significantly correlated with LogLactate (rho = 0.369, = 0.004), LogCreatinine (rho = 0.537, < 0.001), LogProcalcitonin (rho = 0.557, < 0.001), and LogSuPAR (rho = 0.327, = 0.011). During hospitalization, 39/61 (64%) patients died. In a multivariable logistic regression model, logPENK was an independent predictor of in-hospital mortality (OR 11.9, 95% CI: 1.7-84.6, = 0.013).
CONCLUSION
POC PENK levels measured upon presentation to the ED strongly correlated with metabolic, renal and inflammatory biomarkers, and may serve as a predictor of in-hospital mortality in patients with septic shock.
PubMed: 38790966
DOI: 10.3390/biomedicines12051004 -
Cells May 2024A heterogenous population of inflammatory elements, other immune and nonimmune cells and cancer-associated fibroblasts (CAFs) are evident in solid malignancies where... (Review)
Review
A heterogenous population of inflammatory elements, other immune and nonimmune cells and cancer-associated fibroblasts (CAFs) are evident in solid malignancies where they coexist with the growing tumor mass. In highly desmoplastic malignancies, CAFs are the prominent mesenchymal cell type in the tumor microenvironment (TME), where their presence and abundance signal a poor prognosis. CAFs play a major role in the progression of various cancers by remodeling the supporting stroma into a dense, fibrotic matrix while secreting factors that promote the maintenance of cancer stem-like characteristics, tumor cell survival, aggressive growth and metastasis and reduced sensitivity to chemotherapeutics. Tumors with high stromal fibrotic signatures are more likely to be associated with drug resistance and eventual relapse. Identifying the molecular underpinnings for such multidirectional crosstalk among the various normal and neoplastic cell types in the TME may provide new targets and novel opportunities for therapeutic intervention. This review highlights recent concepts regarding the complexity of CAF biology in cholangiocarcinoma, a highly desmoplastic cancer. The discussion focuses on CAF heterogeneity, functionality in drug resistance, contributions to a progressively fibrotic tumor stroma, the involved signaling pathways and the participating genes.
Topics: Humans; Tumor Microenvironment; Cholangiocarcinoma; Cancer-Associated Fibroblasts; Disease Progression; Bile Duct Neoplasms; Animals; Signal Transduction; Drug Resistance, Neoplasm
PubMed: 38786020
DOI: 10.3390/cells13100796 -
Journal of Education and Health... 2024The benefits of using Alteplase are time-dependent. This study aimed to evaluate delays between the onset of symptoms and the administration of Alteplase and related...
BACKGROUND
The benefits of using Alteplase are time-dependent. This study aimed to evaluate delays between the onset of symptoms and the administration of Alteplase and related factors in patients with acute ischemic stroke (AIS).
MATERIALS AND METHODS
In this cross-sectional study, 60 AIS patients receiving Alteplase were selected by census sampling from July 2020 to July 2021 from the eligible patients referred to Shahid Beheshti Hospital in Kashan, Iran. The data collection tool was a researcher-made questionnaire containing demographic information, time periods from the onset of symptoms to the injection of Alteplase, and associated factors. The required information was collected from the patients, their relatives, their health records, and Kashan Emergency Medical Service (EMS) information system. Data were analyzed in SPSS-16.
RESULTS
Eighty-five percent of the 60 patients participating in the study were transferred to the hospital by EMS ambulances. The mean time intervals between different phases were as follows: Onset-To-Door (OTD) time 81.35 ± 33.76 minutes; Door-To-CT (DTC) scan time 16.12 ± 17.46 minutes; Door-To-Needle (DNT) time 51.30 ± 26.14 minutes; and the overall Onset-To-Needle (ONT) time 133.75 ± 39.17 minutes. Also, the mean ONT in people transferred by EMS was about 129 minutes, and the longest prehospital delay in these patients was related to the time between the arrival of the EMS ambulance to the hospital. Marital status and geographical location where the stroke had occurred showed a significant relationship with prehospital delay and pre-hospital notification (PHN) by EMS But there was no relationship between underlying diseases or economic status and prehospital delays; also, the patient's diastolic blood pressure at the time of receiving Alteplase showed a significant relationship with in-hospital delay.
CONCLUSION
The findings of the study showed that the majority of people trust and use EMS ambulances to transfer to the hospital and the time spent in different stages, from the onset of symptoms to the injection of the thrombolytic drug, was in an acceptable range in the patients.
PubMed: 38784291
DOI: 10.4103/jehp.jehp_1685_22 -
Biochemistry Jun 2024The active form of the murine urokinase-type plasminogen activator (muPA) is formed by a 27-residue disordered light chain connecting the amino-terminal fragment (ATF)...
The active form of the murine urokinase-type plasminogen activator (muPA) is formed by a 27-residue disordered light chain connecting the amino-terminal fragment (ATF) with the serine protease domain. The two chains are tethered by a disulfide bond between C1 in the disordered light chain and C122 in the protease domain. Previous work showed that the presence of the disordered light chain affected the inhibition of the protease domain by antibodies. Here we show that the disordered light chain induced a 3.7-fold increase in of the protease domain of muPA. In addition, hydrogen-deuterium exchange mass spectrometry (HDX-MS) and accelerated molecular dynamics (AMD) were performed to identify the interactions between the disordered light chain and the protease domain. HDX-MS revealed that the light chain is contacting the 110s, the turn between the β10- and β11-strand, and the β7-strand. A reduction in deuterium uptake was also observed in the activation loop, the 140s loop and the 220s loop, which forms the S1-specificty pocket where the substrate binds. These loops are further away from where the light chain seems to be interacting with the protease domain. Our results suggest that the light chain most likely increases the activity of muPA by allosterically favoring conformations in which the specificity pocket is formed. We propose a model by which the allostery would be transmitted through the β-strands of the β-barrels to the loops on the other side of the protease domain.
Topics: Animals; Mice; Urokinase-Type Plasminogen Activator; Allosteric Regulation; Molecular Dynamics Simulation; Hydrogen Deuterium Exchange-Mass Spectrometry; Kinetics
PubMed: 38780522
DOI: 10.1021/acs.biochem.4c00071 -
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 -
Molecular Therapy. Methods & Clinical... Jun 2024Genetic manipulation of animal models is a fundamental research tool in biology and medicine but is challenging in large animals. In rodents, models can be readily...
Genetic manipulation of animal models is a fundamental research tool in biology and medicine but is challenging in large animals. In rodents, models can be readily developed by knocking out genes in embryonic stem cells or by knocking down genes through delivery of nucleic acids. Swine are a preferred animal model for studying the cardiovascular and immune systems, but there are limited strategies for genetic manipulation. Lipid nanoparticles (LNPs) efficiently deliver small interfering RNA (siRNA) to knock down circulating proteins, but swine are sensitive to LNP-induced complement activation-related pseudoallergy (CARPA). We hypothesized that appropriately administering optimized siRNA-LNPs could knock down circulating levels of plasminogen, a blood protein synthesized in the liver. siRNA-LNPs against plasminogen (siPLG) reduced plasma plasminogen protein and hepatic plasminogen mRNA levels to below 5% of baseline values. Functional assays showed that reducing plasminogen levels modulated systemic blood coagulation. Clinical signs of CARPA were not observed, and occasional mild and transient hepatotoxicity was present in siPLG-treated animals at 5 h post-infusion, which returned to baseline by 7 days. These findings advance siRNA-LNPs in swine models, enabling genetic engineering of blood and hepatic proteins, which can likely expand to proteins in other tissues in the future.
PubMed: 38779336
DOI: 10.1016/j.omtm.2024.101258 -
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