Abstract-Angiotensin II (Ang II) promotes vascular smooth muscle growth and may be involved in the initiation and progression of atherosclerosis. To examine whether Ang II receptor expression in vascular tissues is altered in atherosclerosis, male New Zealand White rabbits were fed a high-cholesterol diet (1% cholesterolϩ4% coconut oil mixed with regular chow; hypercholesterolemic group, nϭ12) or regular chow (control group, nϭ8) for 10 weeks. At the end of this period, the serum cholesterol level in the rabbits fed the high-cholesterol diet was higher than that in the control group (3616Ϯ144 versus 30Ϯ1 mg/dL, PϽ0.001). There was no atherosclerosis in the aortas of the control group, whereas 51Ϯ6% of the aorta was covered with atherosclerosis in the hypercholesterolemic group. Total Ang II receptor expression in the atherosclerotic aortic tissues was increased 5-fold in the hypercholesterolemic rabbits (292Ϯ28 versus 51Ϯ32 fmol/mg tissue, meanϮSE, PϽ0.001), and the increased Ang II receptor expression was entirely due to enhanced Ang II type 1 (AT 1 ) receptor expression (289Ϯ38 versus 38Ϯ18 fmol/mg, PϽ0.001), as Ang II type 2 receptor expression was unaltered (7Ϯ5 versus 3Ϯ2 fmol/mg, PϭNS). AT 1 receptors were localized primarily in the media and to some extent in the intima of the atherosclerotic aorta, as determined by immunohistochemistry with specific monoclonal and polyclonal AT 1 receptor antibodies. Increased synthesis of AT 1 receptor mRNA in atherosclerotic tissues was confirmed by reverse transcription-polymerase chain reaction. To evaluate the functional significance of increased AT 1 receptor expression, the constrictor response of aortic rings to Ang II was examined and found to be markedly enhanced in atherosclerotic aortic rings (PϽ0.01 versus control aortic rings). The endotheliumdependent relaxation of aortic rings from hypercholesterolemic rabbits was markedly attenuated (PϽ0.001). This study shows that hypercholesterolemia in rabbits results in atherosclerosis, loss of endothelium-dependent relaxation, and increased Ang II receptor (entirely AT 1 receptor) expression in aortic tissues, which may result in altered vasoreactivity.

Background/Aims: Pulmonary arterial endothelial plexiform lesions are a basic pathological change associated with pulmonary vascular remodeling and are characterized by the formation of tumorlets as a result of over-growth of endothelial cells. Accumulating evidence suggests that platelet-derived growth factor (PDGF) participates in regulating the progression of pulmonary arterial hypertension. However, whether PDGF promotes the survival of pulmonary arterial endothelial cells (PAECs), as well as the specific molecular mechanisms that underlie its actions, remains unknown. Methods: MTT assays, caspase-3 and caspase-9 activity assays and western blot analysis were performed. Results: We found that both the mRNA and protein expression of PDGF-B was induced by hypoxia and that the inhibitory effects exerted by hypoxia on apoptosis were attenuated by inhibitors of PDGF beta. Moreover, PDGF-B inhibited apoptosis in a dose-dependent manner by stimulating the phosphorylation of both Akt and Stat3, and the PI3K/AKT pathway serves as an up-stream participant in the Stat3 activation stimulated by PDGF-B. Additionally, the anti-apoptotic effects of PDGF-B were abolished when PAECs were treated with either an inhibitor or small interfering RNA targeting Stat3. Conclusions: These observations suggest that PDGF-B is induced by hypoxia and protects against apoptosis via the PI3K/Akt/Stat3 signaling pathway.

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This study aimed to evaluate treatment response, survival, safety profiles, and predictive factors to chimeric antigen receptor T cell (CAR-T) therapy in Chinese patients with relapsed or refractory B cell acute lymphoblast leukemia (R/R BALL). 39R/R BALL patients who underwent CART therapy were included. Baseline data were collected from patients' electronic medical records. Patients' peripheral bloods, bone marrow aspirates, and biopsies were obtained for routine examination, and treatment response and survival profiles as well as adverse events were evaluated. The rates of complete remission (CR), CR with minimal residual disease (MRD) negative/positive, and bridging to hematopoietic stem-cell transplantation (HSCT) were 92.3%, 76.9%, 15.4%, and 43.6%, respectively. The median event-free survival (EFS) was 11.6 months (95% confidence interval (CI): 4.0-19.2 months) and median overall survival (OS) was 14.0 months (95% CI: 10.9-17.1 months). Bridging to HSCT independently predicted better EFS and OS, while high bone marrow blasts level independently predicted worse EFS. The incidence of cytokine release syndrome (CRS) was 97.4%, and refractory disease as well as decreased white blood cell independently predicted higher risk of severe CRS. Other common adverse events included hematologic toxicities (grade I: 5.1%, grade II: 7.7%, grade III: 17.9%, grade IV: 69.2%), neurotoxicity (28.2%), infection (38.5%), and admission for intensive care unit (10.3%). In conclusion, CART therapy presents with promising treatment response, survival and safety profiles, and higher disease burden predicts worse survival as well as increased risk of severe CRS in Chinese R/R BALL patients.