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Abstract The plasminogen activator inhibitor-1 (PAI-1)→mature brain-derived neurotrophic factor (mBDNF) pathway plays a pivotal role in the conversion of probrain-BDNF (ProBDNF) to mBDNF, but its clinical relevance in patients with alcohol use disorder (AUD) remains unknown. Enzyme-linked immunosorbent assays were used to examine the relevant protein levels of components of the PAI-1→mBDNF pathway in plasma samples from three groups of subjects, and statistical analysis was performed using analysis of variance (ANOVA) and one-way repeated-measures ANOVA. Our findings revealed significant alterations induced by alcohol. (1) AUD was associated with significant decreases in tissue plasminogen activator (tPA), mBDNF, and tropomyosin receptor kinase B (TrkB); significant increases in PAI-1, ProBDNF, and P75 neurotrophin receptor (P75NTR); and inhibited conversion of ProBDNF to mBDNF. (2) Following abstinence, the levels of tPA, mBDNF, and TrkB in the AUD group significantly increased, whereas the levels of PAI-1, ProBDNF, and P75NTR significantly decreased, promoting the conversion of ProBDNF to mBDNF. These clinical outcomes collectively suggest that AUD inhibits the conversion of ProBDNF to mBDNF and that abstinence reverses this process. The PAI-1→mBDNF cleavage pathway is hypothesized to be associated with AUD and abstinence treatment.

Bleeding within the pleural space may result in persistent clot formation called retained hemothorax (RH). RH is prone to organization, which compromises effective drainage, leading to lung restriction and dyspnea. Intrapleural fibrinolytic therapy is used to clear the persistent organizing clot in lieu of surgery, but fibrinolysin selection, delivery strategies, and dosing have yet to be identified. We used a recently established rabbit model of RH to test whether intrapleural delivery of single-chain urokinase (scuPA) can most effectively clear RH. scuPA, or single-chain tissue plasminogen activator (sctPA), was delivered via thoracostomy tube on day 7 as either one or two doses 8 h apart. Pleural clot dissolution was assessed using transthoracic ultrasonography, chest computed tomography, two-dimensional and clot displacement measurements, and gross analysis. Two doses of scuPA (1 mg/kg) were more effective than a bolus dose of 2 mg/kg in resolving RH and facilitating drainage of pleural fluids (PF). Red blood cell counts in the PF of scuPA, or sctPA-treated rabbits were comparable, and no gross intrapleural hemorrhage was observed. Both fibrinolysins were equally effective in clearing clots and promoting pleural drainage. Biomarkers of inflammation and organization were likewise comparable in PF from both groups. The findings suggest that single-agent therapy may be effective in clearing RH; however, the clinical advantage of intrapleural scuPA remains to be established by future clinical trials. [ABSTRACT FROM AUTHOR]

Background: A cluster of metabolic indicators responsible to elevate the risk of high blood sugar, heart diseases along with stroke is called metabolic syndrome (MetS). Adipokines play critical roles in the formation and progression of these clusters of diseases. Adiponectin enhances fatty acid oxidation, prevents foam cell formation and improves lipid metabolism. In contrast, plasminogen activator inhibitor-1 (PAI-1) possesses pro-atherogenic properties. Carotid intima-media thickness (CIMT) is directly associated with an increased risk of myocardial infarction and stroke. Complete information about the association related to adipokines and CIMT in MetS of Indian population is lacking. Objective: To evaluate the association of adipokine levels and PAI-1 with CIMT in MetS patients, including its components. Materials and methods: We performed a cross-sectional study and IDF criteria were used for the screening of MetS. A total of 164 subjects with MetS (88 males and 76 females) and 100 controls (54 males and 46 females) were enrolled. Serum levels of adiponectin and PAI-1 were measured using ELISA. A CIMT measurement of carotid arteries was also done. The relationship between various parameters was assessed by the Pearson correlation coefficient test. Results: The levels of adiponectin were lower (p < 0.001), while those of PAI-1 and CIMT were higher (p < 0.001) when we compared patients with controls. When the number of metabolic abnormalities increased, the levels of adiponectin decreased and those of PAI-1 increased. There was a strong negative association between PAI-1 levels and those of adiponectin (p <0.001). Conclusion: Our findings indicate that elevated PAI-1 levels are associated with a higher probability of having MetS and negatively impact MetS-related components. [ABSTRACT FROM AUTHOR]

Background: Burns represent a serious health problem, associated with multiple-organ failure, prolonged hospitalization, septic complications, and increased rate of mortality. The main aim of our study was to evaluate the levels of various circulating molecules in children with severe burns (more than 25% TBSA), in three different moments: 48 h, day 10, and day 21 post-burn. Materials and Methods: This study included 32 children with burns produced by flame, hot liquid, and electric arc and 21 controls. Serum plasminogen activator inhibitor-1 (PAI-1), α 1-acid glycoprotein (AGP), C-reactive protein (CRP), and platelet factor 4 (PF4) were detected using the Multiplex technique. Several parameters, such as fibrinogen, leucocyte count, thrombocyte count, triiodothyronine, thyroxine, and thyroid-stimulating hormone were also determined for each patient during hospitalization. Results: Significant statistical differences were obtained for CRP, AGP, and PF4 compared to the control group, in different moments of measurements. Negative correlations between CRP, AGP, and PF4 serum levels and burned body surface, and also the hospitalization period, were observed. Discussions: CRP levels increased in the first 10 days after burn trauma and then decreased after day 21. Serum PAI-1 levels were higher immediately after the burn and started decreasing only after day 10 post-burn. AGP had elevated levels 48 h after the burn, then decreased at 7–10 days afterwards, and once again increased levels after 21 days. PF4 serum levels increased after day 10 since the burning event. Conclusions: Serum CRP, AGP, PAI-1, and PF4 seem to be promising molecules in monitoring patients with a burn within the first 21 days. [ABSTRACT FROM AUTHOR]

Abstract Background Upon cellular injury, damage-associated molecular patterns (DAMPs) are released into the extracellular space and evoke proinflammatory and prothrombotic responses in animal models of sterile inflammation. However, in clinical settings, the dynamics of DAMP levels after trauma and links between DAMPs and trauma-associated coagulopathy remain largely undetermined. Methods Thirty-one patients with severe trauma, who were transferred to Kagoshima City Hospital between June 2018 and December 2019, were consecutively enrolled in this study. Blood samples were taken at the time of delivery, and 6 and 12 h after the injury, and once daily thereafter. The time-dependent changes of coagulation/fibrinolysis markers, including thrombin-antithrombin complex, α2-plasmin inhibitor (α2-PI), plasmin-α2-PI complex, and plasminogen activator inhibitor-1 (PAI-1), and DAMPs, including high mobility group box 1 and histone H3, were analyzed. The relationship between coagulation/fibrinolysis markers, DAMPs, Injury Severity Score, in-hospital death, and amount of blood transfusion were analyzed. Results The activation of coagulation/fibrinolysis pathways was evident at the time of delivery. In contrast, PAI-1 levels remained low at the time of delivery, and then were elevated at 6–12 h after traumatic injury. Histone H3 and high mobility group box 1 levels were elevated at admission, and gradually subsided over time. PAI-1 levels at 6 h were associated with serum histone H3 levels at admission. Increased histone H3 levels and plasmin-α2-PI complex levels were associated with in-hospital mortality. α2-PI levels at admission showed the strongest negative correlation with the amount of blood transfusion. Conclusion The elevation of histone H3 levels and fibrinolysis perturbation are associated with fatal outcomes in patients with traumatic injury. Patients with low α2-PI levels at admission tend to require blood transfusion.

Background: Platelet “Microvesicles” (MVs) are studied for their role in blood coagulation and inflammation. The study aimed to establish if MVs are related to age, plasma levels of inflammation, coagulation, and fibrinolysis markers in healthy individuals. Methods: We prospectively enrolled volunteers aged over 18 years. MVs, plasma levels of C-reactive protein (CRP), Interleukin 6 (IL-6), Interleukin 10 (IL-10), Interleukin 17 (IL-17), and transforming growth factor β (TGF-β), fibrinogen, plasminogen activator inhibitor-1 (PAI-1), von Willebrand factor (VWF), homocysteine, factor VII (FVII), thrombin activatable fibrinolysis inhibitor (TAFI), and Protein S were tested. Results: A total of 246 individuals (median age 65 years (“IQR”54–72)) were evaluated. Both univariate analysis and logistic regression models showed that MVs positively correlate with age, CRP, IL-6, IL-10, IL-17, TGF-β, fibrinogen, PAI-1, VWF, FVII, and homocysteine, while inversely correlating with TAFI and Protein S. The ROC curve analysis performed to identify a cut off for MV values (700 kMP) showed a good accuracy with over-range cytokines fibrinolysis factor and coagulation markers. Conclusions: To the best of our knowledge, this study is the first to correlate MVs with an entire panel of cardiovascular risk factors in healthy individuals. A future possible role of MVs in screening exams is suggested. [ABSTRACT FROM AUTHOR]

Simple Summary: Hyper-angiogenesis is a characteristic of glioblastoma (GBM), and anti-angio-genesis is a crucial strategy to interfere with tumor progression in GBM therapy. We previously found a high expression of ALDH1A3 in proliferating vasculature in GBM patients, which was associated with poor prognosis. The present study generated two ALDH1A3-overexpressing GBM cells (oxGBMs) and demonstrated a potent pro-angiogenesis function of ALDH1A3 under the different conditions of co-culturing oxGBMs with endothelial cells in vitro and in an angiogenesis model in vivo. Moreover, we identified a mechanism underlying the oxALDH1A3-mediated pro-angiogenic effect involving the paracrine PAI-1 and IL-8 derived from oxGBMs. Blockage of PAI-1 or IL-8 hindered the hyper-angiogenesis phenotype resulting from oxALDH1A3. These findings defined a novel function of ALDH1A3 as an angiogenesis promoter in GBM, beyond its role as a well-known cancer stem cell marker, and highlighted ALDH1A3-PAI-1/IL-8 as a novel targeting signaling for future anti-angiogenesis therapy in GBM. Hyper-angiogenesis is a typical feature of glioblastoma (GBM), the most aggressive brain tumor. We have reported the expression of aldehyde dehydrogenase 1A3 (ALDH1A3) in proliferating vasculature in GBM patients. We hypothesized that ALDH1A3 may act as an angiogenesis promoter in GBM. Two GBM cell lines were lentivirally transduced with either ALDH1A3 (ox) or an empty vector (ev). The angiogenesis phenotype was studied in indirect and direct co-culture of endothelial cells (ECs) with oxGBM cells (oxGBMs) and in an angiogenesis model in vivo. Angiogenesis array was performed in oxGBMs. RT2-PCR, Western blot, and double-immunofluorescence staining were performed to confirm the expression of targets identified from the array. A significantly activated angiogenesis phenotype was observed in ECs indirectly and directly co-cultured with oxGBMs and in vivo. Overexpression of ALDH1A3 (oxALDH1A3) led to a marked upregulation of PAI-1 and IL-8 mRNA and protein and a consequential increased release of both proteins. Moreover, oxALDH1A3-induced angiogenesis was abolished by the treatment of the specific inhibitors, respectively, of PAI-1 and IL-8 receptors, CXCR1/2. This study defined ALDH1A3 as a novel angiogenesis promoter. oxALDH1A3 in GBM cells stimulated EC angiogenesis via paracrine upregulation of PAI-1 and IL-8, suggesting ALDH1A3-PAI-1/IL-8 as a novel signaling for future anti-angiogenesis therapy in GBM. [ABSTRACT FROM AUTHOR]

Background: Upon cellular injury, damage-associated molecular patterns (DAMPs) are released into the extracellular space and evoke proinflammatory and prothrombotic responses in animal models of sterile inflammation. However, in clinical settings, the dynamics of DAMP levels after trauma and links between DAMPs and trauma-associated coagulopathy remain largely undetermined. Methods: Thirty-one patients with severe trauma, who were transferred to Kagoshima City Hospital between June 2018 and December 2019, were consecutively enrolled in this study. Blood samples were taken at the time of delivery, and 6 and 12 h after the injury, and once daily thereafter. The time-dependent changes of coagulation/fibrinolysis markers, including thrombin-antithrombin complex, α2-plasmin inhibitor (α2-PI), plasmin-α2-PI complex, and plasminogen activator inhibitor-1 (PAI-1), and DAMPs, including high mobility group box 1 and histone H3, were analyzed. The relationship between coagulation/fibrinolysis markers, DAMPs, Injury Severity Score, in-hospital death, and amount of blood transfusion were analyzed. Results: The activation of coagulation/fibrinolysis pathways was evident at the time of delivery. In contrast, PAI-1 levels remained low at the time of delivery, and then were elevated at 6–12 h after traumatic injury. Histone H3 and high mobility group box 1 levels were elevated at admission, and gradually subsided over time. PAI-1 levels at 6 h were associated with serum histone H3 levels at admission. Increased histone H3 levels and plasmin-α2-PI complex levels were associated with in-hospital mortality. α2-PI levels at admission showed the strongest negative correlation with the amount of blood transfusion. Conclusion: The elevation of histone H3 levels and fibrinolysis perturbation are associated with fatal outcomes in patients with traumatic injury. Patients with low α2-PI levels at admission tend to require blood transfusion. [ABSTRACT FROM AUTHOR]

Abstract Background Diabetic retinopathy (DR) is a serious complication of longstanding type 2 diabetes mellitus (T2DM), a leading cause of blindness and visual disability in the world. The aim of this study is to compare the activity of tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) in tears and serum of patients with DR and those without DR. Method Among the T2DM patients enrolled in this study, 26 patients had DR (n = 26) while 29 were without DR (n = 29). The blood and tear samples were obtained from all participants. The level of PAI-1 and tPA were measured in both the serum and tears. Anthropometric measurements, HbA1c, renal and lipid profile were also obtained. Results Patients with DR had significantly longer disease duration and higher systolic blood pressure compared to those without DR. Serum PAI-1 level was significantly higher in patients with DR compared to those without DR, 32.72 (IQR 32.52) vs 21.37 (IQR 14.93) ng/mL, respectively (p 0.05). Among patients with DR, there were no significant correlations between tear and serum of both biomarkers. Patients without DR showed a moderate positive correlation between serum and tear tPA levels with a coefficient of 0.363, albeit no statistical significance. Patients with DR demonstrated a significant positive correlation between levels of tears PAI-1 and BMI (r = 0.555, p = 0.026). In the group without DR, there was a statistically significant positive correlation between serum level of PAI-1 with urine albumin creatinine ratio (UACR) (r = 0.501, p = 0.013). Conclusion The present study demonstrated a significantly greater serum PAI-1 levels in patients with DR compared to those without DR. No significant correlations between tears and serum PAI-1 and tPA were observed. Thus, the role of tear biomarkers remains relevant for further investigations.

Purpose: To validate the prognostic role of urokinase-type plasminogen-activator (uPA) and plasminogen activator inhibitor type-1 (PAI-1) protein expression in FFPE archived tumor samples when assessed by immunohistochemistry. Patients and methods: Fresh-frozen, paraffin-embedded (FFPE) samples from 303 postmenopausal women with hormone receptor-positive, early breast cancer were investigated. The patients had received 5 years of endocrine therapy in the prospectively randomized ABCSG-8 trial. Immunohistochemistry for stromal uPA and PAI-1 protein expression was correlated with distant recurrence-free survival (DRFS) and overall survival (OS). Results: We detected stromal uPA in 132 of 297 tumors (44.4%) and stromal PAI-1 expression in 74 out of 299 samples (24.7%). Co-expression of uPA and PAI-1 was present in 48 of 294 (16.3%) cases. Neither uPA nor PAI-1 expression was associated with tumor size, age, nodal status, grading, or quantitative receptor status. Patients whose tumor stroma expressed uPA protein had a significantly shorter DRFS (adjusted HR for relapse: 2.78; 95% CI 1.31–5.93; p = 0.008 Cox regression analysis) than women without uPA expression. No such association was seen for PAI-1 and the uPA/PAI1 ratio. After a median follow-up of 5.6 years, women with uPA-positive tumors demonstrated significantly shorter DRFS (93.3% vs. 84.8%; p

Stressful events trigger a set of complex biological responses which follow a bell-shaped pattern. Low-stress conditions have been shown to elicit beneficial effects, notably on synaptic plasticity together with an increase in cognitive processes. In contrast, overly intense stress can have deleterious behavioral effects leading to several stress-related pathologies such as anxiety, depression, substance use, obsessive-compulsive and stressor- and trauma-related disorders (e.g., post-traumatic stress disorder or PTSD in the case of traumatic events). Over a number of years, we have demonstrated that in response to stress, glucocorticoid hormones (GCs) in the hippocampus mediate a molecular shift in the balance between the expression of the tissue plasminogen activator (tPA) and its own inhibitor plasminogen activator inhibitor-1 (PAI-1) proteins. Interestingly, a shift in favor of PAI-1 was responsible for PTSD-like memory induction. In this review, after describing the biological system involving GCs, we highlight the key role of tPA/PAI-1 imbalance observed in preclinical and clinical studies associated with the emergence of stress-related pathological conditions. Thus, tPA/PAI-1 protein levels could be predictive biomarkers of the subsequent onset of stress-related disorders, and pharmacological modulation of their activity could be a potential new therapeutic approach for these debilitating conditions. [ABSTRACT FROM AUTHOR]

Background: Diabetic retinopathy (DR) is a serious complication of longstanding type 2 diabetes mellitus (T2DM), a leading cause of blindness and visual disability in the world. The aim of this study is to compare the activity of tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) in tears and serum of patients with DR and those without DR.Method: Among the T2DM patients enrolled in this study, 26 patients had DR (n = 26) while 29 were without DR (n = 29). The blood and tear samples were obtained from all participants. The level of PAI-1 and tPA were measured in both the serum and tears. Anthropometric measurements, HbA1c, renal and lipid profile were also obtained.Results: Patients with DR had significantly longer disease duration and higher systolic blood pressure compared to those without DR. Serum PAI-1 level was significantly higher in patients with DR compared to those without DR, 32.72 (IQR 32.52) vs 21.37 (IQR 14.93) ng/mL, respectively (p < 0.05). However, tear PAI-1 were comparable in both groups. Serum and tear tPA levels in both groups were also comparable (p > 0.05). Among patients with DR, there were no significant correlations between tear and serum of both biomarkers. Patients without DR showed a moderate positive correlation between serum and tear tPA levels with a coefficient of 0.363, albeit no statistical significance. Patients with DR demonstrated a significant positive correlation between levels of tears PAI-1 and BMI (r = 0.555, p = 0.026). In the group without DR, there was a statistically significant positive correlation between serum level of PAI-1 with urine albumin creatinine ratio (UACR) (r = 0.501, p = 0.013).Conclusion: The present study demonstrated a significantly greater serum PAI-1 levels in patients with DR compared to those without DR. No significant correlations between tears and serum PAI-1 and tPA were observed. Thus, the role of tear biomarkers remains relevant for further investigations. [ABSTRACT FROM AUTHOR]

To validate the prognostic role of urokinase-type plasminogen-activator (uPA) and plasminogen activator inhibitor type-1 (PAI-1) protein expression in FFPE archived tumor samples when assessed by immunohistochemistry. Fresh-frozen, paraffin-embedded (FFPE) samples from 303 postmenopausal women with hormone receptor-positive, early breast cancer were investigated. The patients had received 5 years of endocrine therapy in the prospectively randomized ABCSG-8 trial. Immunohistochemistry for stromal uPA and PAI-1 protein expression was correlated with distant recurrence-free survival (DRFS) and overall survival (OS). We detected stromal uPA in 132 of 297 tumors (44.4%) and stromal PAI-1 expression in 74 out of 299 samples (24.7%). Co-expression of uPA and PAI-1 was present in 48 of 294 (16.3%) cases. Neither uPA nor PAI-1 expression was associated with tumor size, age, nodal status, grading, or quantitative receptor status. Patients whose tumor stroma expressed uPA protein had a significantly shorter DRFS (adjusted HR for relapse: 2.78; 95% CI 1.31–5.93; p = 0.008 Cox regression analysis) than women without uPA expression. No such association was seen for PAI-1 and the uPA/PAI1 ratio. After a median follow-up of 5.6 years, women with uPA-positive tumors demonstrated significantly shorter DRFS (93.3% vs. 84.8%; p < 0.013 log-rank test), and tended to have a worse OS (83.0% vs. 77.3%; p = 0.106) compared to women with uPA negative tumors. This independent validation in archived tumor samples from a large prospective randomized trial confirms the clinical utility of stromal uPA evaluation by immunohistochemistry. This provides level 1b evidence for the prognostic role of stromal uPA in women with endocrine-responsive early breast cancer. • Prospective trial provides level 1b evidence. • UPA expression associated with better DDFS and OS. [ABSTRACT FROM AUTHOR]

Although ischemia increases the abundance of plasminogen activator inhibitor-1 (PAI-1), its source and role in the ischemic brain remain unclear. We detected PAI-1-immunoreactive cells with morphological features of reactive astrocytes in the peri-ischemic cortex of mice after an experimentally-induced ischemic lesion, and of a chimpanzee that suffered a naturally-occurring stroke. We found that although the abundance of PAI-1 increases 24 hours after the onset of the ischemic injury in a non-reperfusion murine model of ischemic stroke, at that time-point there is no difference in astrocytic reactivity and the volume of the ischemic lesion between wild-type (Wt) animals and in mice either genetically deficient (PAI-1−/−) or overexpressing PAI-1 (PAI-1Tg). In contrast, 72 hours later astrocytic reactivity and the volume of the ischemic lesion were decreased in PAI-1−/− mice and increased in PAI-1Tg animals. Our immunoblottings and fractal analysis studies show that the abundance of astrocytic PAI-1 rises during the recovery phase from a hypoxic injury, which in turn increases the abundance of glial fibrillary acidic protein (GFAP) and triggers morphological features of reactive astrocytes. These studies indicate that cerebral ischemia-induced release of astrocytic PAI-1 triggers astrocytic reactivity associated with enlargement of the necrotic core. [ABSTRACT FROM AUTHOR]

Irritable bowel syndrome (IBS) is characterized by gastrointestinal symptoms. Overweight and increased risk of metabolic syndromes/diabetes are observed in IBS, conditions associated with plasminogen activator inhibitor-1 (PAI-1) and visfatin. The aim of this study was to measure blood levels of AXIN1, cholecystokinin (CCK), enkephalin, ghrelin, neuropeptide Y (NPY), PAI-1, and visfatin before and after a 4-week intervention with a starch- and sucrose-reduced diet (SSRD). A total of 105 IBS patients were randomized to either SSRD (n = 80) or ordinary diet (n = 25). Questionnaires were completed, and blood was analyzed for AXIN1 and hormones. AXIN1 (p = 0.001) and active ghrelin levels (p = 0.025) were lower in IBS than in healthy volunteers at baseline, whereas CCK and enkephalin levels were higher (p < 0.001). In the intervention group, total IBS-symptom severity score (IBS-SSS), specific gastrointestinal symptoms, psychological well-being, and the influence of intestinal symptoms on daily life were improved during the study, and weight decreased (p < 0.001 for all), whereas only constipation (p = 0.045) and bloating (p = 0.001) were improved in the control group. PAI-1 levels tended to be decreased in the intervention group (p = 0.066), with a difference in the decrease between groups (p = 0.022). Visfatin levels were decreased in the intervention group (p = 0.007). There were few correlations between hormonal levels and symptoms. Thus, this diet not only improves IBS symptoms but also seems to have a general health-promoting effect. [ABSTRACT FROM AUTHOR]

Owing to advances in treatment modalities and supportive care, overall survival rates have reached up to 90% among children with acute lymphoblastic leukemia (ALL). However, due to the underlying illness and therapy, they are at a greater risk of developing lifestyle diseases. Hence, special attention is paid to early detection of the components of metabolic syndrome (MetS). This study aimed at investigating the association of plasma levels of nine diabetes markers with being overweight and components of MetS in ALL survivors. The study included 56 subjects with mean age of 12.36 ± 5.15 years. The commercially available Bio-Plex Pro Human Diabetes 10-Plex Panel kit was used to evaluate levels of diabetes biomarkers. ALL survivors presented statistically higher concentrations of GIP (p = 0.026), glucagon (p = 0.001), leptin (p = 0.022), and PAI-1 (p = 0.047), whereas the concentration of ghrelin was lower (p < 0.001) compared to the control group. Moreover, subjects within normal BMI range showed higher GIP (p = 0.005) and lower ghrelin concentration (p < 0.001) compared to healthy peers. At least one risk factor of MetS was present in 58.9% of participants, who showed significantly higher levels of C-peptide (p = 0.028), leptin (p = 0.003), and PAI-1 (p = 0.034) than survivors who did not meet any MetS criteria. In conclusion, ALL survivors are at greater risk of disturbances in carbohydrate metabolism. Understanding the pathogenesis and applicability of diabetes markers is crucial for developing strategies to prevent metabolic syndrome in ALL survivors. [ABSTRACT FROM AUTHOR]

The aim of the present study was to determine whether adipokines monocyte chemoattractant protein-1 (MCP-1) and plasminogen activator inhibitor-1 (PAI-1) can affect the functions of ovarian cells in cats. The addition of either MCP-1 or PAI-1 increased viability; promoted the accumulation of proliferation markers and progesterone and estradiol release; and decreased the accumulation of apoptosis markers in cultured feline granulosa cells. The present observations suggest that MCP-1 or PAI-1 can be physiological stimulators of ovarian granulosa cell functions., Competing Interests: Declaration of Competing Interest We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome., (Copyright © 2024 Society for Biology of Reproduction & the Institute of Animal Reproduction and Food Research of Polish Academy of Sciences in Olsztyn. Published by Elsevier B.V. All rights reserved.)

Background: There is no established standard 3 rd line treatment for patients with advanced non-small cell lung cancer (NSCLC). Although cytotoxic chemotherapeutic agents that are not used as 1 st or 2 nd line treatment are administrated as 3 rd line treatment, their anti-tumor efficacy is insufficient. Anti-programmed death ligand-1 (PD-L1)/programmed death-1 (PD1) treatment is more effective and less toxic than chemotherapy in anti-PD-L1/PD-1 treatment-naïve patients with NSCLC. Therefore, anti-PD-L1/PD-1 therapy is considered an appropriate 3 rd line treatment. However, the anti-tumor efficacy is limited in patients previously treated with anti-PD-L1/PD-1 antibody. Today, new drugs are needed to increase the efficacy of anti-PD-L1/PD-1 antibodies., Methods: This open-label, single-arm, investigator-initiated phase II study is designed to evaluate combination treatment of nivolumab and TM5614, a plasminogen activator inhibitor (PAI-1) inhibitor as 3 rd or more line treatment in NSCLC patients who underwent standard treatment. The primary endpoint is the objective response rate and the secondary endpoints are progression-free survival (PFS), overall survival (OS), duration of response (DOR) and safety. Recruitment began in September 2023 and is expected to continue for approximately three years., Discussion: Currently, there is no standard 3 rd line treatment for advanced NSCLC, and we hope that the findings of this study will facilitate more effective treatments in this setting. Ethics and dissemination: the study protocol conformed to the ethical principles outlined in the Declaration of Helsinki. All patients will provide written informed consent prior to enrollment. Results will be published in a peer-reviewed publication., Trial Registration: This study is registered to Japan Registry of Clinical Trials with number: jRCT2061230039 (19/July/2023)., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-1858/coif). T.M. reports honoraria from Chugai Pharmaceutical Co. Ltd., AstraZeneca K.K., Eli Lilly Japan K.K., MSD K.K., Taiho Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Bristol-Myers Squibb Co. Ltd. and Kyowa Kirin Co., Ltd. outside the submitted work. T.S. reports honoraria from Chugai Pharmaceutical Co. Ltd., AstraZeneca K.K., Eli Lilly Japan K.K., MSD K.K., Taiho Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Novartis Pharma K.K., Merck Biopharma Co., Ltd., Janssen Pharmaceutical K.K., Amgen Inc., Daiichi-Sankyo Co., Ltd., Takeda Pharmaceutical Co., Ltd., Hisamitsu Pharmaceutical Co., Inc. and Illumina, Inc. outside the submitted work. Y.T. reports honoraria from Daiichi Sankyo Co. Ltd., AstraZeneca K.K., Chugai Pharmaceutical Co. Ltd., Kyowa Kirin Co., Ltd., TAIHO PHARMACEUTICAL Co., Ltd. and Bristol-Myers Squibb K.K. outside the submitted work, in addition to grants from Pfizer Health Research Foundation outside the submitted work. E.I. reports grants from Janssen Pharmaceutical K.K., Pfizer Japan Inc., Bristol-Myers Squibb Co. Ltd., Ono Pharmaceutical Co., Ltd. and Takeda Pharmaceutical Co., Ltd., outside the submitted work and honoraria from Chugai Pharmaceutical Co. Ltd., AstraZeneca K.K., Eli Lilly Japan K.K., Ono Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co., Ltd., Bristol-Myers Squibb Co. Ltd., Pfizer Japan Inc., Janssen Pharmaceutical K.K., Novartis Pharma K.K. and Boehringer-Ingelheim Japan Inc., outside the submitted work and research material from AstraZeneca K.K. and Janssen Pharmaceutical K.K. outside the submitted work. T.K. reports honoraria from Chugai Pharmaceutical Co. Ltd., AstraZeneca K.K., Eli Lilly Japan K.K., Ono Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co., Ltd., Bristol-Myers Squibb Co. Ltd., Pfizer Japan Inc., Novartis Pharma K.K., Taiho Pharmaceutical Co., Ltd., MSD K.K., Kyowa Kirin Co., Ltd., Boehringer-Ingelheim Japan Inc., Nippon Kayaku Co., Ltd., Daiichi-Sankyo Co., Ltd., Amgen Inc., Eisai Co. Ltd., Merck Biopharma Co., Ltd., Bayer Holding Ltd., Sawai Pharmaceutical Co., Ltd. outside the submitted work and grants from Chugai Pharmaceutical Co. Ltd., AstraZeneca K.K., Eli Lilly Japan K.K., Ono Pharmaceutical Co. Ltd., Bristol-Myers Squibb Co. Ltd., Pfizer Japan Inc., Taiho Pharmaceutical Co., Ltd., MSD K.K., Kyowa Kirin Co., Ltd., Daiichi-Sankyo Co., Ltd., Amgen Inc., Eisai Co. Ltd., Merck Biopharma Co., Ltd., Bayer Holding Ltd., Pfizer Japan Inc., AbbVie GK., LabCorp Japan, G.K., IQVIA Inc., Gilead Sciences, Inc. outside the submitted work, and consulting fee from Chugai Pharmaceutical Co. Ltd., AstraZeneca K.K., Ono Pharmaceutical Co. Ltd., Pfizer Japan Inc., Daiichi-Sankyo Co., Ltd., Bayer Holding Ltd., AbbVie GK. outside the submitted work. S.H. reports honoraria from Bristol-Myers Squibb Co. Ltd. outside submitted work. Y.O. reports consulting fee from Kitasato University Hospital and Association of Medical Education and Ethics outside submitted work, and honoraria for lectures of biostatistics from Tokai University, Graduate School of Medicine outside submitted work and is Data Monitoring Committee member of EVA-001-02 study sponsored by Evastem Co., Ltd., and Certified Committee member for Regenerative Medicine, Tokai University outside the submitted work. T.M. declares research grants from Astellas Pharma Inc., Daiichi Sankyo Co., Ltd., and KOWA DENTAL HEALTH K.K. and Renascience Inc. outside the submitted work, and honoraria from Renascience Inc. outside the submitted work, and stocks of Renascience Inc. N.H. reports honoraria from Chugai Pharmaceutical Co. Ltd., AstraZeneca K.K., MSD K.K., Ono Pharmaceutical Co., Ltd. and Bristol-Myers Squibb Co. Ltd. outside the submitted work. N.H. reports that this study is supported by Renascience Inc. (to Hiroshima University Hospital). The other authors have no conflicts of interest to declare., (2024 Journal of Thoracic Disease. All rights reserved.)

A systemic inflammatory response leads to widespread organ dysfunction, such as kidney dysfunction. Plasminogen activator inhibitor-1 (PAI-1) is involved in the pathogenesis of inflammatory kidney injury; however, the regulatory mechanism of PAI-1 in injured kidneys remains unclear. PAI-1 is induced by interleukin (IL)-6 in patients with sepsis. In addition, the stabilization of IL-6 is regulated by the adenine-thymine-rich interactive domain-containing protein 5a (Arid5a). Therefore, the aim of the present study was to examine the involvement of Arid5a/IL-6/PAI-1 signaling in lipopolysaccharide (LPS)-induced inflammatory kidney injury. LPS treatment to C57BL/6J mice upregulated Pai-1 mRNA in the kidneys. Enzyme-linked immunosorbent assay (ELISA) revealed that PAI-1 expression was induced in the culture supernatants of LPS-treated human umbilical vein endothelial cells, but not in those of LPS-treated human kidney 2 (HK-2) cells, a tubular cell line. Combined with single-cell analysis, endothelial cells were found to be responsible for PAI-1 elevation in LPS-treated kidneys. Administration of TM5441, a PAI-1 inhibitor, reduced the urinary albumin/creatinine ratio, concomitant with downregulation of Il-6 and Arid5a mRNA expressions. IL-6 treatment in LPS model mice further upregulated Pai-1 mRNA expression compared with LPS alone, accompanied by renal impairment. Furthermore, the expression of Il-6 and Pai-1 mRNA was lower in Arid5a knockout mice than in wild-type mice after LPS treatment. Taken together, the vicious cycle of Arid5a/IL-6/PAI-1 signaling is involved in LPS-induced kidney injury.