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Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, is a newly developed oral hypoglycemic agent. Sitagliptin increases the level of glucagon-like polypeptide (GLP)-1 that increases insulin secretion. In addition, GLP-1 decreases salt intake and increases urinary salt excretion. Therefore, the sitagliptin treatment might lower blood pressure in hypertensive patients with type 2 diabetes. It also remains to be examined whether the reduction in blood pressure with sitagliptin treatment is related to the blood glucose improvement and the body weight decrease. To identify beneficial effects of sitagliptin treatment, we administered sitagliptin (50 mg) on alternate days to seventeen type 2 diabetes outpatients with insufficient blood glucose control (8 males and 9 females; mean age of 67.1 years). The patients were also treated with oral hypoglycemic agents and antihypertensive drugs for six months before and during the sitagliptin administration. We measured the level of hemoglobin (Hb) A1c, systolic blood pressure (SBP), and body mass index (BMI) for up to six months thereafter. Their BMIs remained unchanged. The levels of HbA1c were dropped from 6.5 0.3% to 5.8 0.3%, while SBP was also dropped from 130.0 37.2 mmHg to 119.7 9.4 mmHg. However, the degree of the decrease in HbA1c levels was not significantly correlated with that of SBP (r = 0.24). In conclusion, the present findings suggest that sitagliptin lowers SBP without reducing BMI, independent of the blood glucose reduction. The hypotensive effect is apparent with the alternate-day regimen of sitagliptin at a lower dose compared to the everyday medication.

We previously reported that tumor endothelial cells (TECs) differ from normal endothelial cells (NECs) in characteristics such as cell proliferation, migration, gene profile, and responses to growth factors and several chemotherapeutic drugs.7, 8, 9, 10, 11, 12, 13, 14 As tumor blood vessels are reportedly heterogeneous15 and TECs play an important role in metastasis, we wished to investigate possible differences between TECs of tumors of differing malignancy.

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Open Access funding enabled and organized by Projekt DEAL. This project was conducted with data from the German National Cohort (NAKO) (www.nako.de). The NAKO is funded by the Federal Ministry of Education and Research (BMBF) [project funding reference numbers: 01ER1301A/B/C and 01ER1511D], the federal states and the Helmholtz Association, with additional financial support by the participating universities and the institutes of the Leibniz Association.

A large number of studies have investigated the relationship between blood pressure and tinnitus. Both studies utilizing clinical samples [5,6] and population-based studies [18,21,22,23,24,25] have suggested arterial hypertension to be associated with tinnitus and tinnitus handicap [26]. However, other studies could not confirm such an association [16,27,28]. In our study, we found a slightly increased RR syst and RR diast in patients with tinnitus, but no correlation with tinnitus handicap.

This project was conducted with data from the German National Cohort (NAKO) (www.nako.de, accessed 5 May 2023). The NAKO is funded by the Federal Ministry of Education and Research (BMBF) [project funding reference numbers: 01ER1301A/B/C and 01ER1511D], the federal states and the Helmholtz Association, with additional financial support by the participating universities and the institutes of the Leibniz Association.

Tumor endothelial cells (TEC) lining tumor blood vessels actively contribute to tumor progression and metastasis. In addition to tumor cells, TEC may develop drug resistance during cancer treatment, allowing the tumor cells to survive chemotherapy and metastasize. We previously reported that TECs resist paclitaxel treatment via upregulation of ABCB1. However, whether TEC phenotypes are altered by anticancer drugs remains to be clarified. Here, we show that ABCB1 expression increases after chemotherapy in urothelial carcinoma cases. The ratio of ABCB1-positive TEC before and after first-line chemotherapy in urothelial carcinoma tissues (n = 66) was analyzed by ABCB1 and CD31 immunostaining. In 42 cases (64%), this ratio increased after first-line chemotherapy. Chemotherapy elevated ABCB1 expression in endothelial cells by increasing tumor IL8 secretion. In clinical cases, ABCB1 expression in TEC correlated with IL8 expression in tumor cells after first-line chemotherapy, leading to poor prognosis. In vivo, the ABCB1 inhibitor combined with paclitaxel reduced tumor growth and metastasis compared with paclitaxel alone. Chemotherapy is suggested to cause inflammatory changes in tumors, inducing ABCB1 expression in TEC and conferring drug resistance. Overall, these findings indicate that TEC can survive during chemotherapy and provide a gateway for cancer metastasis. Targeting ABCB1 in TEC represents a novel strategy to overcome cancer drug resistance.

To assess the changes of ABCB1 expression in tumor cells during chemotherapy, immunostaining was performed using an anti-ABCB1 antibody in urothelial carcinoma specimens before and after first-line chemotherapy (Fig. 1A; Table 1). We confirmed tumor cells with cytokeratin staining (Supplementary Fig. S1A). ABCB1 expression in tumor cells varied among the cases. There were no significant differences in ABCB1 expression in the tumor cells before and after first-line chemotherapy (Fig. 1B). Next, we analyzed ABCB1 expression in tumor blood vessels, which were visualized with an anti-CD31 antibody (Fig. 1C). Only a few TECs were stained with the anti-ABCB1 antibody in the most tumor tissues collected before first-line chemotherapy. However, interestingly, there were more ABCB1-positive TECs in the tumor tissue after first-line chemotherapy (Fig. 1C). Quantitative analysis showed that the ratio of ABCB1-positive TECs was significantly increased after first-line chemotherapy (Fig. 1D). Conversely, in noncancerous areas, the blood vessels were hardly stained with anti-ABCB1 in both before and after first-line chemotherapy (Fig. 1E; Supplementary Fig. S1B). The ABCB1 expression change in tumor cells by chemotherapy has no tendency. Alternatively, it was suggested that chemotherapy induced ABCB1 expression in TECs.

ABCB1-positive blood vessels increased after first-line chemotherapy in urothelial carcinoma. A, Representative immunostaining of ABCB1 (brown) in clinical urothelial carcinoma tissues before and after first-line chemotherapy. Scale bar, 100 m. B, Quantitative analysis of ABCB1 expression in tumor cells between, before, and after chemotherapy (P = 0.8920, Wilcoxon signed rank test; n = 66). C, Representative immunostaining of CD31 (left) or ABCB1 (right) in serial sections of urothelial carcinoma specimens. Scale bar, 100 m. Black arrowheads, CD31-positive blood vessels. White and red arrowheads indicate ABCB1-negative and -positive blood vessels, respectively. D, Quantitative analysis of the ABCB1-positive ratio of tumor blood vessels between, before, and after chemotherapy (*, P < 0.0001, Wilcoxon signed rank test; n = 66). E, Quantitative analysis of the ABCB1-positive ratio of blood vessels in noncancerous part before and after chemotherapy (P = 0.0565, Wilcoxon signed rank test; n = 61). N.S., not significant.

ABCB1 upregulation in TECs was correlated with poor prognosis in patients with urothelial carcinoma. A, Association between IL8 expression in tumor tissues and prognosis in patients with bladder cancer was evaluated using the PrognoScan database. Overall (left) and disease-specific (right) survival (*, P = 0.013409 or 0.000607, log-rank test; n = 165). B, Representative immunostaining of IL8 (brown) in clinical urothelial carcinoma tissues before and after first-line chemotherapy. Scale bar, 100 m. C, Correlation between IL8 expression in tumor tissues and the ABCB1-positive ratio of tumor blood vessels after first-line chemotherapy (Spearman rank correlation test, r = 0.3913; P = 0.0012). D, Association between IL8 expression in tumor tissues during chemotherapy and the ABCB1-positive ratio of tumor blood vessels. Notably, the ABCB1-high group (right; n = 24) showed an increased IL8 staining score after first-line chemotherapy, but not the ABCB1-low group (left, n = 42; *, P < 0.05, Wilcoxon signed rank test; N.S., not significant). The cut-off point of ABCB1-positive ratio was 7% (Supplementary Fig. S4). E, Association between the ABCB1-positive ratio of tumor blood vessels and overall or disease-specific survival of patients with urothelial carcinoma (*, P = 0.0111 or 0.0438, log-rank test; n = 66). 2351a5e196