Tumor immune microenvironment of cutaneous angiosarcoma with cancer testis antigens and the formation of tertiary lymphoid structures

Cutaneous angiosarcoma (CAS) is a highly malignant tumor with few effective treatments. Although the indication for immune checkpoint inhibitors such as anti-PD-1 antibodies is expected to expand, there are many unknowns regarding the tumor immune microenvironment in CAS, which is generally considered an immunologically “cold” tumor. Our previous study demonstrated that tertiary lymphoid structures (TLSs) were associated with a favorable prognosis in CAS. However, we still don’t know what the difference is between cases of TLS-rich and TLS-poor. Furthermore, the number of TLSs can vary significantly between lesions in the same case, for example, between primary and recurrence. To analyze the changes in the tumor immune microenvironment in CAS in more detail, we performed comprehensive RNA sequencing using a Next-generation sequencer (NGS). Sixty-two samples from 31 cases of CAS treated at Nagoya City University were collected. NGS and gene set enrichment analysis (GSEA) were performed on 15 samples among them. Immunohistochemistry and prognostic analysis by Kaplan-Meier method were performed on all 62 samples. NGS results showed that NY-ESO-1 (CTAG1B) was significantly upregulated in the TLS-positive cases. Immune checkpoint molecules including programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) were upregulated in TLS-negative or TLS-low cases and seemed to associate with the suppression of TLS formation. In a comparison of primary and recurrent lesions, other cancer-testis antigens (CTAs) including XAGE-1B were significantly upregulated in recurrent lesions. The number of infiltrating CD8-positive cells and TLSs showed no significant trend between primary and recurrent lesions. However, the PD-L1 expression of tumor cells was significantly lower in recurrent than in primary lesions. Chemokines correlated with NY-ESO-1 expression were CCL21 and CXCL8, and only CCL21 correlated with the number of TLS. There was no chemokine associated with XAGE-1. NY-ESO-1 and XAGE-1 are detectable by immunohistochemistry. Although each cannot be a prognostic marker by itself, they can be a helpful marker in combination with the number of TLSs. CTAs play an essential role in forming the tumor immune microenvironment in CAS. These findings are evidence that CAS is an immunologically “hot” tumor and provides us with potential therapeutic targets and encourages the expansion of immunotherapy indications

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Investigation of Age-Associated Cognitive Functional Homophily in Community-Dwelling Older Adults&rsquo; Confidant Social Networks Using Exponential Random Graph Model

One of the prominent interventions to tackle loneliness and social isolation in older adults is social facilitation. The present study investigated whether similarities in cognitive functions that are sensitive to age play a role in confidant social networks among older adults. We analyzed the data of 252 community-dwelling older adults in Wakuya City, Miyagi Prefecture, Japan, who responded to a self-administered questionnaire and cognitive health checkups provided by the city in 2017. We performed Exponential Random Graph Model and investigated educational attainment, orientation, word registration, clock drawing, delayed recall, verbal fluency and logical memory homophily while adjusting for density, reciprocity, age, sex living arrangement, presence of disability in instrumental activities of daily living, educational attainment and cognitive impairment status. The probability of a confidant tie with an older adult was significantly reduced by 6% (odds ratio (OR): 0.94, 95% confidence interval (CI): 0.90&ndash;0.99) for one score difference in logical memory, and marginally increased by 5% (OR: 1.05; 95% CI: 1.00&ndash;1.11) for one score difference in delayed recall. There was no significant association between educational attainment and other age-associated cognitive functional scores. Our findings suggest that similar logical memory functions play a role in strong social network building among community-dwelling older adults in Japan

Directivity-Dependency-Reduced Blind Source Separation Integrating ICA, Beamforming and Binary Masking

IROS2007: IEEE International Conference on Intelligent Robots and Systems, October 29 - November 2, 2007, San Diego, CA, USA.A real-time two-stage blind source separation (BSS) method for convolutive mixtures of speech is now being studied by the authors, in which a single-input multiple-output (SIMO)-model-based independent component analysis (ICA) and an SIMO-model-based binary masking are combined. However because of using humanoid robot head or directional microphones to observe the sounds and adopting binary masking in the 2nd stage, the previous two-stage BSS method has directivity dependency for sound source layout. In this paper, we introduce an improved BSS method which uses omni-directional microphones and creates flexible directivity internally instead of the fixed directional microphones while keeping the separation performance. The experimental results reveal that the separation performance can be considerably improved by using the proposed method compared with the conventional BSS methods