Immunohistological analysis of B7-H4, IDO1, and PD-L1 expression and tumor immune microenvironment based on triple-negative breast cancer subtypes.

BACKGROUND: B7 homolog 4 (B7-H4) and indoleamine 2,3-dioxygenase (IDO1) are factors involved in the inhibition of antitumor activity and are new therapeutic targets for immune checkpoint therapy. Our study aimed to simultaneously investigate the interrelationship among B7-H4, IDO1 and programmed cell death ligand 1 (PD-L1) expression in triple-negative breast cancer (TNBC), including tumor immune microenvironment (TIME) and TNBC subtypes. METHODS: Immunostaining for PD-L1, B7-H4, and IDO1 was performed on whole-slide sections of 119 cases of TNBC. The TIME was evaluated based on stromal tumor infiltrating lymphocytes (sTILs; %), pattern classification of TILs, tumor-stroma ratio (TSR), and tertiary lymphoid structure (TLS). TNBC subtypes were also determined by immunohistochemistry analysis of cytokeratin 5/6 and androgen receptor (AR) expression. RESULTS: B7-H4 expression was significantly higher in cases with a combined positive score cutoff of 5 for PD-L1 (clone 28-8; p = 0.021), inflamed TIL pattern (p = 0.007), and TLS ≥ 4 (p = 0.006). B7-H4 expression was higher in case of CK5/6 ≥ 10 (p = 0.035). The H-scores of AR and B7-H4 were inversely correlated (ρ = - 0.509, p < 0.001). B7-H4 and IDO1 expression levels were inversely correlated in cases with AR < 10 (ρ = - 0.354, p < 0.001). CONCLUSIONS: These results suggest that considering the TIL pattern and TLS and identifying the expression of PD-L1 and the basal-like type are useful for estimating B7-H4 expression. In addition, luminal androgen receptor (LAR)-type is frequently deficient in B7-H4 expression. In non-LAR types, B7-H4 and IDO1 expression are exclusive.

A Newly Developed Method-Based Xanthine Oxidoreductase Activities in Various Human Liver Diseases.

Studies evaluating xanthine oxidoreductase (XOR) activities in comprehensive liver diseases are scarce, and different etiologies have previously been combined in groups for comparison. To accurately evaluate XOR activities in liver diseases, the plasma XOR activities in etiology-based comprehensive liver diseases were measured using a novel, sensitive, and accurate assay that is a combination of liquid chromatography and triple quadrupole mass spectrometry to detect [13C2, 15N2]uric acid using [13C2, 15N2]xanthine as a substrate. We also mainly evaluated the association between the plasma XOR activities and parameters of liver tests, purine metabolism-associated markers, oxidative stress markers, and an inflammation marker. In total, 329 patients and 32 controls were enrolled in our study. Plasma XOR activities were generally increased in liver diseases, especially in the active phase, such as in patients with hepatitis C virus RNA positivity, those with abnormal alanine transaminase (ALT) levels in autoimmune liver diseases, and uncured hepatocellular carcinoma patients. Plasma XOR activities were numerically highest in patients with acute hepatitis B. Plasma XOR activities were closely correlated with parameters of liver tests, especially serum ALT levels, regardless of etiology and plasma xanthine levels. Our results indicated that plasma XOR activity might reflect the active phase in various liver diseases.

Pathological Study on the Expression of Vasohibins in Peripheral Artery Disease.

Vasohibin-2 (VASH2) is a gene that promotes local angiogenesis. The tubulin carboxypeptidase activity of vasohibin causes detyrosination of alpha-tubulin and may play an important role in the regulation of various phenomena. Pathological and therapeutic angiogenesis are involved in atherosclerotic lesions. This study aimed to investigate whether the expression of VASH2 is associated with peripheral artery disease (PAD) in relation to angiogenesis, tubulin detyrosination, and severity of atherosclerotic lesions. An analysis of femoral and tibial arteries obtained from 86 patients with PAD or abdominal aortic aneurysm (AAA) was performed. The expressions of cluster of differentiation 31, VASH1, VASH2, and detyrosinated alpha-tubulin (DT-tubulin) were examined by immunohistochemistry, and their association with PAD was analyzed. The counts of VASH2 in the tunica media and adventitia in the tibial artery were significantly higher than those in the femoral artery in the PAD (P = 0.005 and P = 0.008, respectively) and AAA (P = 0.002 and P < 0.001, respectively) groups. In the tunica media and adventitia, VASH2 was significantly correlated with DT-tubulin. There was no significant difference in the expression of VASH2 and DT-tubulin in medial smooth muscle cells (McNemar test, P > 0.999). This study revealed the possible involvements of VASH2 in atherosclerosis by two methods-one maybe related to the progression of atherosclerosis by inducing angiogenesis and the second may be related to the decrease in arterial elasticity by increasing DT-tubulin in medial smooth muscle cells.