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OX40, a member of the tumor necrosis factor (TNF) receptor superfamily, is expressed on the surface of activated T cells. Upon interaction with its cognate ligand, OX40L, OX40 transmits costimulatory signals to antigen-primed T cells, promoting their activation, differentiation, and survival — processes essential for the establishment of adaptive immunity. Although the OX40-OX40L interaction has been extensively studied in the context of disease treatment, developing a substitute for the naturally expressed membrane-bound OX40L, particularly a multimerized OX40L trimers, that effectively regulates OX40-driven T cell responses remains a significant challenge. In this study, we successfully engineered soluble OX40L-fusion proteins capable of robustly activating OX40 on T cells. This was achieved by incorporating functional multimerization domains into the TNF homology domain of OX40L. These OX40L proteins bound to OX40, subsequently activated NF-κB signaling, and induced cytokine production by T cells in vitro . In vivo , mice treated with one of the OX40L-fusion proteins — comprising a single-chain OX40L trimer linked to the C-terminus of the human IgG1 Fc domain, forming a dimer of trimers — exhibited significantly enhanced clonal expansion of antigen-specific CD4 + T cells during the primary phase of the immune response. A comparable antibody-fusion single-chain TNF protein incorporating 4-1BBL, CD70 (CD27L), or GITRL in place of OX40L elicited similar in vivo T cell responses. Thus, we propose that optimizing the multimerization of OX40L proteins through innovative design strategies may facilitate the development of more effective agonists for targeted immunotherapies.

Background Cryptogenic stroke encompasses diverse emboligenic mechanisms and pathogeneses. Cerebral microbleeds (CMBs) occur differently among stroke subtypes. The association of CMBs with cryptogenic stroke is essentially unknown. Methods CHALLENGE ESUS/CS (Mechanisms of Embolic Stroke Clarified by Transesophageal Echocardiography for ESUS/CS) is a multicenter registry with comprehensive data including gradient-echo T2*-weighted magnetic resonance imaging of cryptogenic stroke patients who underwent transesophageal echocardiography. Patients’ clinical characteristics were compared according to the presence and location of CMBs. Results A total of 661 patients (68.7 ± 12.7 years; 445 males) were enrolled, and 209 (32%) had CMBs. Age (odds ratio [OR] 1.02, 95% confidence interval [CI] 1.00–1.04, p  = 0.020), male sex (OR 1.85, 95% CI 1.18–2.91, p  = 0.007), hypertension (OR 1.71, 95% CI 1.03–2.86, p  = 0.039), chronic kidney disease (OR 1.64, 95% CI 1.11–2.43, p  = 0.013), deep and subcortical white matter hyperintensity (OR 1.82, 95% CI 1.16–2.85, p  = 0.009), and periventricular hyperintensity (OR 2.18, 95% CI 1.37–3.46, p  = 0.001) were independently associated with the presence of CMBs. Aortic complicated lesions (OR 1.78, 95% CI 1.12–2.84, p  = 0.015) were associated with deep and diffuse CMBs, whereas prior anticoagulant therapy (OR 7.88, 95% CI, 1.83–33.9, p  = 0.006) was related to lobar CMBs. Conclusions CMBs were common, and age, male sex, hypertension, chronic kidney disease, and cerebral white matter diseases were related to CMBs in cryptogenic stroke. Aortic complicated lesions were associated with deep and diffuse CMBs, while prior anticoagulant therapy was related to lobar CMBs.

Purpose The acceleration time (AcT) ratio of the internal carotid artery (ICA) is increased in ICA stenosis. However, there are few reports that have directly compared the AcT ratio to digital subtraction angiography (DSA) findings. Methods We evaluated 177 vessels with DSA and carotid artery ultrasonography. The AcT ratio was calculated as AcT of the ICA (ICA–AcT)/AcT of the ipsilateral common carotid artery (CCA). We evaluated the correlation of DSA–NASCET stenosis with the origin of the ICA or the peak systolic velocity (ICApsv) in the stenotic region, ICApsv/peak systolic velocity of the CCA (CCApsv), ICA–AcT, and AcT ratio. Sensitivity and specificity for stenosis ≥ 70% were calculated based on the ICApsv, ICApsv/CCApsv, ICA–AcT, and AcT ratio. Results Using NASCET criteria, 34 vessels had 70% or greater stenosis. DSA–NASCET showed a significant positive correlation with ICApsv, ICApsv/CCApsv, ICA–AcT, and AcT ratio ( p  < 0.0001). When the cut-off value for ICApsv was set at 176 cm/s, ICApsv/CCApsv at 2.42, ICA–AcT at 0.095 s, and the AcT ratio at 1.35, the sensitivity was 97.1, 97.1, 82.4, and 97.1%, and the specificity was 94.4, 91.0, 83.2, and 83.2%, for DSA–NASCET ≥ 70%, respectively. Conclusion The AcT ratio is a beneficial parameter for evaluating ICA stenosis as well as ICApsv and ICApsv/CCApsv.

The costimulatory signal regulated by the members of the tumor necrosis factor receptor (TNFR) superfamily expressed by T cells plays essential roles for T cell responses and has emerged as a promising target for cancer immunotherapy. However, it is unclear how the difference in TNFR costimulation contributes to T cell responses. In this study, to clarify the functional significance of four different TNFRs, OX40, 4-1BB, CD27 and GITR, we prepared corresponding single-chain TNF ligand proteins (scTNFLs) connected to IgG Fc domain with beneficial characteristics, i.e., Fc−scOX40L, Fc−sc4-1BBL, Fc−scCD27L (CD70) and Fc−scGITRL. Without intentional cross-linking, these soluble Fc−scTNFL proteins bound to corresponding TNFRs induced NF-kB signaling and promoted proliferative and cytokine responses in CD4+ and CD8+ T cells with different dose-dependencies in vitro. Mice injected with one of the Fc−scTNFL proteins displayed significantly augmented delayed-type hypersensitivity responses, showing in vivo activity. The results demonstrate that each individual Fc−scTNFL protein provides a critical costimulatory signal and exhibits quantitatively distinct activity toward T cells. Our findings provide important insights into the TNFR costimulation that would be valuable for investigators conducting basic research in cancer immunology and also have implications for T cell-mediated immune regulation by designer TNFL proteins.

Objective We investigated maximum intima-media thickness of the common carotid artery (IMT-C max ) in residents of Tochigi Prefecture, who have been reported to have high stroke mortality. Method Our study included 840 individuals. All participants underwent carotid ultrasonography and answered a questionnaire during participation in a health festival in Tochigi Prefecture. The questionnaire was designed to collect information on age, gender, and risk factors for stroke. IMT-C max was measured. Statistical analyses were performed to identify factors contributing to IMT-C max values ≥1.1 mm. Results In total, 117 subjects had an IMT-C max value ≥1.1 mm. IMT-C max correlated significantly with age, current smoking, hypertension, diabetes mellitus, heart disease, and previous symptomatic stroke ( p  < 0.05) in univariate analysis. Current smoking ( p  < 0.001, odds ratio 3.88) and hypertension ( p  = 0.0070, odds ratio 1.83) were seen as significant contributing factors to IMT-C max ≥1.1 mm in logistic regression analysis adjusted by age, gender, and previous symptomatic stroke. Conclusion We identified current smoking and hypertension as the most significant contributing factors to increased IMT-C max in residents of Tochigi Prefecture, emphasizing the importance of routine blood pressure monitoring and anti-smoking education in this population.

Background and purpose Although risk factors for acute coronary syndrome (ACS) and atherothrombotic cerebral infarction (ACI) are common, it is unknown if the risk factors for these two conditions are similar. The purpose of our study was to elucidate differences in carotid artery atherosclerotic features between ACS and ACI. Methods We measured carotid artery ultrasound-based atherosclerotic parameters in 61 ACS and 33 ACI patients. In the ACS patients, 31 had single-vessel coronary artery disease (SVD) and 30 had multivessel coronary artery disease (MVD). Results The maximum intima–media thickness (IMT) of the common carotid artery was higher in ACS patients with MVD than in ACS patients with SVD ( P  < 0.05), and tended to be higher than that in ACI patients ( P  = 0.085). The values in ACS patients with SVD and ACI patients were similar. The maximum IMT of the carotid artery bulb in ACS patients with MVD was similar to that in both ACS patients with SVD and ACI patients. The plaque score was higher in ACS patients with MVD than in ACS patients with SVD ( P  < 0.01), but similar to that in ACI patients. Conclusion ACS and ACI show common atherosclerotic features as assessed by carotid artery ultrasonography.

Background There may be a link between right-to-left shunt (RLs) and brain white matter lesions (WMLs) in patients with migraine. In this study, we assessed the relationship between WMLs and RLs in Japanese migraine patients. Methods A total of 107 consecutive patients with migraine with (MA) and without aura (MWOA) were included in this study. Contrast transcranial Doppler ultrasound was used to detect RLs. WMLs were graded using brain magnetic resonance imaging based on well-established criteria. Findings The prevalence of RLs was significantly increased in the WMLs positive group ( n  = 24) compared with the WMLs negative group ( n  = 83) (75.0% vs. 47.0%, p  = 0.015). In prevalence of WMLs between MA and MWOA patients, there were no statistical differences ( p  = 0.410). Logistic regression analysis adjusted by age and disease duration of migraine identified an RLs-positive status as the sole determinant for the presence of WMLs (OR = 6.15; 95% CI 1.82–20.8; p  = 0.003) Conclusion Our study suggests a possible link between RLs and WMLs in Japanese patients with migraine.