FKBP5 regulation on anti-PD-1 therapy

Background. Antitumor therapies targeting programmed cell death-1 (PD-1) or its ligand-1 (PD-L1) are used in various cancers. However, in glioblastoma (GBM), the expression of PD-L1 varies between patients, and the relationship between this variation and the efficacy of anti-PD-1 antibody therapy remains unclear. High expression levels of PD-L1 affect the proliferation and invasiveness of GBM cells. As COX-2 modulates PD-L1 expression in cancer cells, we tested the hypothesis that the COX-2 inhibitor celecoxib potentiates anti-PD-1 antibody treatment via the downregulation of PD-L1. Methods. Six-week-old male C57BL/6 mice injected with murine glioma stem cells (GSCs) were randomly divided into four groups treated with vehicle, celecoxib, anti-PD-1 antibody, or celecoxib plus anti-PD-1 antibody and the antitumor effects of these treatments were assessed. To verify the mechanisms underlying these effects, murine GSCs and human GBM cells were studied in vitro. Results. Compared with that with each single treatment, the combination of celecoxib and anti-PD-1 antibody treatment significantly decreased tumor volume and prolonged survival. The high expression of PD-L1 was decreased by celecoxib in the glioma model injected with murine GSCs, cultured murine GSCs, and cultured human GBM cells. This reduction was associated with post-transcriptional regulation of the co-chaperone FK506-binding protein 5 (FKBP5). Conclusions. Combination therapy with anti-PD-1 antibody plus celecoxib might be a promising therapeutic strategy to target PD-L1 in glioblastoma. The downregulation of highly-expressed PD-L1 via FKBP5, induced by celecoxib, could play a role in its antitumor effects

Could clazosentan, first approved in Japan, improve neurological prognosis after subarachnoid hemorrhage in combination with modified water-electrolyte management?

An aneurysmal subarachnoid hemorrhage (aSAH) is a devastating event associated with a high mortality and morbidity rate. Though numerous medications are used to prevent cerebral vasospasm and vasospasm-related cerebral infarction after aSAH, no effective pharmacological treatment has been established. Clazosentan, a highly selective endothelin receptor type A antagonist, was approved for use in Japan in April 2022 based on results of two pivotal randomized, placebo-controlled phase 3 studies (JapicCTI-163369, JapicCTI-163368). These studies indicated that clazosentan significantly reduced the incidence of vasospasm-related morbidity and all-cause mortality after aneurysm coiling and clipping. Clazosentan is thus expected to become a “game changer” for improving the neurological prognosis after aSAH. However, other reports indicate that even when clazosentan or nimodipine are administered for prophylaxis against delayed neurological decline, patients treated with increased colloid administration or hypertonic saline (3% sodium chloride) load exhibit poor functional outcome and higher mortality, suggesting that extra fluid and sodium derived from prophylactic colloid administration contribute to negative outcomes after aSAH. Pharmacological treatments such as clazosentan in addition to perioperative management involving delivery of less water and sodium might be crucial for achieving better outcomes than conventional therapy. Based on a literature review, we present here the future perspectives regarding clazosentan and the necessity for modifying management of the water-electrolyte balance by focusing on endothelin-1 and blood–brain barrier disruption

Time-dependent and site-dependent morphological changes in rupture-prone arteries : ovariectomized rat intracranial aneurysm model

OBJECTIVE The pathogenesis of intracranial aneurysm rupture remains unclear. Because it is difficult to study the time course of human aneurysms and most unruptured aneurysms are stable, animal models are used to investigate the characteristics of intracranial aneurysms. The authors have newly established a rat intracranial aneurysm rupture model that features site-specific ruptured and unruptured aneurysms. In the present study the authors examined the time course of changes in the vascular morphology to clarify the mechanisms leading to rupture. METHODS Ten-week-old female Sprague-Dawley rats were subjected to hemodynamic changes, hypertension, and ovariectomy. Morphological changes in rupture-prone intracranial arteries were examined under a scanning electron microscope and the association with vascular degradation molecules was investigated. RESULTS At 2–6 weeks after aneurysm induction, morphological changes and rupture were mainly observed at the posterior cerebral artery; at 7–12 weeks they were seen at the anterior Willis circle including the anterior communicating artery. No aneurysms at the anterior cerebral artery–olfactory artery bifurcation ruptured, suggesting that the inception of morphological changes is site dependent. On week 6, the messenger RNA level of matrix metalloproteinase–9, interleukin-1β, and the ratio of matrix metalloproteinase–9 to the tissue inhibitor of metalloproteinase–2 was significantly higher at the posterior cerebral artery, but not at the anterior communicating artery, of rats with aneurysms than in sham-operated rats. These findings suggest that aneurysm rupture is attributable to significant morphological changes and an increase in degradation molecules. CONCLUSIONS Time-dependent and site-dependent morphological changes and the level of degradation molecules may be indicative of the vulnerability of aneurysms to rupture

Progression to In-Hospital Ischemic Stroke

Background and Purpose: Little attention has been paid to the pathogenesis of in-hospital stroke, despite poor outcomes and a longer time from stroke onset to treatment. We studied the pathophysiology and biomarkers for detecting patients who progress to in-hospital ischemic stroke (IHS). Methods: Seventy-nine patients with IHS were sequentially recruited in the period 2011–2017. Their characteristics, care, and outcomes were compared with 933 patients who had an out-of-hospital ischemic stroke (OHS) using a prospectively collected database of the Tokushima University Stroke Registry. Results: Active cancer and coronary artery disease were more prevalent in patients with IHS than in those with OHS (53.2 and 27.8% vs. 2.0 and 10.9%, respectively; p < 0.001), the median onset-to-evaluation time was longer (300 vs. 240 min; p = 0.015), and the undetermined etiology was significantly higher (36.7 vs. 2.4%; p < 0.001). Although there was no significant difference in stroke severity at onset between the groups, patients with IHS had higher modified Rankin Scale (mRS) scores (3–6) at discharge (67.1 vs. 50.3%; p = 0.004) and rates of death during hospitalization (16.5 vs. 2.9%; p < 0.001). D-dimer (5.8 vs. 0.8 µg/mL; p < 0.001) and fibrinogen (532 vs. 430 mg/dL; p = 0.014) plasma levels at the time of onset were significantly higher in patients with IHS after propensity score matching. Multivariate logistic regression analysis revealed that active cancer (odds ratio [OR] 2.30; 95% confidence interval [CI] 1.26–4.20), prestroke mRS scores 3–5 (OR 6.78; 95% CI 3.96–11.61), female sex (OR 1.57; 95% CI 1.19–2.08), and age ≥75 years (OR 2.36; 95% CI 1.80–3.08) were associated with poor outcomes. Conclusions: Patients with IHS had poorer outcomes than those with OHS because of a higher prevalence of active cancer and functional dependence before stroke onset. Elevated plasma levels of D-dimer and fibrinogen, especially with active cancer, can help identify patients who are at a higher risk of progression to IHS

RUPTURED CEREBRAL ANEURYSMS AND SEVERE PD

BACKGROUND: The pathophysiology of subarachnoid hemorrhages (SAHs) due to ruptured intracranial aneurysms (IAs) remains unclear.Although a relationship between SAHs and periodontal disease (PD) has been suggested, the mechanism requires clarification. OBJECTIVE: To evaluate the relationship between PD and SAHs and to identify periodontal pathogens associated with SAHs. METHODS: This prospective study included consecutive patients with ruptured (n = 11) and unruptured (n = 14) IAs and healthy controls (n = 8). The plasma and plaque subgingival bacterial deoxyribonucleic acid (DNA) levels in PD were evaluated by a dentist using the Community Periodontal Index of Treatment Needs (CPITN). Plasma levels of matrix metalloproteinase (MMP-9), tissue inhibitors of matrix metalloproteinase (TIMP2), and procollagen I were analyzed. RESULTS: Patients with ruptured IAs, had significantly higher CPITN scores than the controls, suggesting that ruptured IAs were associated with severe PD. Although no rupture-specific bacteria were identified, the positive rate of plaque subgingival bacterial DNA was significantly higher in patients with severe PD than in those without severe PD. Multivariate logistic regression analysis indicated that bleeding on probing (BOP)was associated with ruptured IAs (odds ratio, 1.10; 95% confidence interval 1.04–1.20; P = .0001). BOP was positively associated with plasma MMP-9 levels and a disequilibrium in the MMP-9/TIMP2 ratio. BOP was negatively correlated with plasma procollagen I levels (P < .05, for each). This suggested that local inflammation with severe PD might have systemic effects and lead to ruptured IAs. CONCLUSION: Disequilibrium of plasma protease/anti-protease associated with a high BOP rate in severe PD may be attributable to IA rupture

The association of C-reactive protein with an oxidative metabolite of LDL and its implication in atherosclerosis

C-reactive protein (CRP) is one of the strongest independent predictors of cardiovascular disease. We have previously reported that oxidized LDL (oxLDL) interacts with beta 2-glycoprotein I (beta 2GPI), implicating oxLDL/P2GPI complexes as putative autoantigens in autoimmune-mediated atherosclerotic vascular disease. In this study, we investigated the interaction of CRP with oxLDL/beta 2GPI complexes and its association with atherosclerosis in patients with diabetes mellitus (DM). CRP/oxLDL/R2GPI complexes were predominantly found in sera of DM patients with atherosclerosis. In contrast, noncomplexed CRP isoforms were present in sera of patients with acute/chronic inflammation, i.e., various pyrogenic diseases, rheumatoid arthritis (RA), and DM. Immunohistochemistry staining colocalized CRP and beta 2GPI together with oxLDL in carotid artery plaques but not in synovial tissue from RA patients, strongly suggesting that complex formation occurs during the development of adierosclerosis. Serum levels of CRP correlated with soluble forms of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, and oxLDL/beta 2GPI complexes correlated with total cholesterol and hemoglobin Al c. Thus, the generation of CRP/oxLDL/beta 2GPI complexes seems to be associated with arterial inflammation, hyperglycemia, and hypercholesterolemia. CRP/oxLDL/R2GPI complexes can be distinguished from pyrogenic noncomplexed CRP isoforms and may represent a more specific and predictive marker for atherosclerosis

Vocabulary Size in Speech May Be an Early Indicator of Cognitive Impairment.

Little is known about the relationship between mild cognitive impairment (MCI) and changes to language abilities. Here, we used the revised Hasegawa Dementia Scale (HDS-R) to identify suspected MCI in elderly individuals. We then analyzed written and spoken narratives to compare the language abilities between study participants with and without MCI in order to explore the relationship between cognitive and language abilities, and to identify a possible indicator for the early detection of MCI and dementia. We recruited 22 people aged 74 to 86 years (mean: 78.32 years; standard deviation: 3.36). The participants were requested to write and talk about one of the happiest events in their lives. Based on HDS-R scores, we divided the participants into 2 groups: the MCI Group comprised 8 participants with a score of 26 or lower, while the Healthy Group comprised 14 participants with a score of 27 or higher. The transcriptions of both written and spoken samples for each participant were used in the measurement of NLP-based language ability scores. Our analysis showed no significant differences in writing abilities between the 2 groups in any of the language ability scores. However, analysis of the spoken narrative showed that the MCI Group had a significantly larger vocabulary size. In addition, analysis of a metric that signified the gap in content between the spoken and written narratives also revealed a larger vocabulary size in the MCI Group. Individuals with early-stage MCI may be engaging in behavior to conceal their deteriorating cognition, thereby leading to a temporary increase in their active spoken vocabulary. These results indicate the possible detection of early stages of reduced cognition before dementia onset through the analysis of spoken narratives

Dependency distance.

<p>Dependency distance.</p

Yngve score.

<p>Yngve score.</p