Renin–angiotensin–aldosterone system inhibitors (RAASi) are associated with improved survival outcomes in patients receiving immune checkpoint inhibitors (ICIs), but the data on the response to ...treatment and tumour-based endpoints across different tumour types are unknown.
We carried out a retrospective study at two tertiary referral centres in Taiwan. All adult patients treated with ICIs between January 2015 and December 2021 were included. The primary outcome was overall survival and the secondary outcomes were progression-free survival (PFS) and clinical benefit rates.
In total, 734 patients were enrolled in our study, of which 171 were RAASi users and 563 were non-users. Compared with non-users, RAASi users had a longer median overall survival 26.8 (interquartile range 11.3–not reached) versus 15.2 (interquartile range 5.1–58.4) months, P < 0.001 and PFS 12.2 (interquartile range 3.9–34.5) versus 5.0 (interquartile range 2.2–15.2) months, P < 0.001. In univariate Cox proportional hazard analyses, the use of RAASi was associated with a 40% reduction in the risk of mortality hazard ratio 0.58 (95% confidence interval 0.44–0.76), P < 0.001 and disease progression hazard ratio 0.62 (95% confidence interval 0.50–0.77), P < 0.001. The association remained significant after adjusting for underlying comorbidities and cancer therapy in multivariate Cox analyses. A similar trend was observed for PFS. Furthermore, RAASi users experienced a greater clinical benefit rate than non-users (69% versus 57%, P = 0.006). Importantly, the use of RAASi before ICI initiation was not associated with improved overall survival and PFS. RAASi were not associated with an increased risk of adverse events.
The use of RAASi is associated with improved survival outcomes, treatment response and tumour-based endpoints in patients undergoing immunotherapy.
•RAASi were associated with improved clinical outcomes across a broad range of cancer patients receiving ICI.•Subgroup analysis showed that ARB were associated with improved clinical outcomes in patients undergoing immunotherapy.•The use of RAASi before immune checkpoint blockade was not associated with improved survival.•RAASi were not associated with increased risk of adverse events among cancer patients receiving ICI.
Diminished control of standing balance, traditionally indicated by greater postural sway magnitude and speed, is associated with falls in older adults. Tai Chi (TC) is a multisystem intervention that ...reduces fall risk, yet its impact on sway measures vary considerably. We hypothesized that TC improves the integrated function of multiple control systems influencing balance, quantifiable by the multi-scale "complexity" of postural sway fluctuations.
To evaluate both traditional and complexity-based measures of sway to characterize the short- and potential long-term effects of TC training on postural control and the relationships between sway measures and physical function in healthy older adults.
A cross-sectional comparison of standing postural sway in healthy TC-naïve and TC-expert (24.5±12 yrs experience) adults. TC-naïve participants then completed a 6-month, two-arm, wait-list randomized clinical trial of TC training. Postural sway was assessed before and after the training during standing on a force-plate with eyes-open (EO) and eyes-closed (EC). Anterior-posterior (AP) and medio-lateral (ML) sway speed, magnitude, and complexity (quantified by multiscale entropy) were calculated. Single-legged standing time and Timed-Up-and-Go tests characterized physical function.
At baseline, compared to TC-naïve adults (n = 60, age 64.5±7.5 yrs), TC-experts (n = 27, age 62.8±7.5 yrs) exhibited greater complexity of sway in the AP EC (P = 0.023), ML EO (P<0.001), and ML EC (P<0.001) conditions. Traditional measures of sway speed and magnitude were not significantly lower among TC-experts. Intention-to-treat analyses indicated no significant effects of short-term TC training; however, increases in AP EC and ML EC complexity amongst those randomized to TC were positively correlated with practice hours (P = 0.044, P = 0.018). Long- and short-term TC training were positively associated with physical function.
Multiscale entropy offers a complementary approach to traditional COP measures for characterizing sway during quiet standing, and may be more sensitive to the effects of TC in healthy adults.
ClinicalTrials.gov NCT01340365.
Chondrosarcoma is the second most common sarcoma in bone malignancy and is characterized by a high metastatic potential. Angiogenesis is essential for the cancer metastasis. Endothelin-1 (ET-1) has ...been implicated in tumor angiogenesis and metastasis. However, the relationship of ET-1 with vascular endothelial growth factor (VEGF) expression and angiogenesis in human chondrosarcoma cells is mostly unknown. Here, we found that the expression of ET-1 and VEGF were correlated with tumor stage and were significantly higher than that in the normal cartilage. Exogenous ET-1 with chondrosarcoma cells promoted VEGF expression and subsequently increased migration and tube formation in endothelial progenitor cells. ET-1 increased VEGF expression and angiogenesis through ETAR, integrin-linked kinase (ILK), Akt and hypoxia-inducible factor-1α (HIF-1α) signaling cascades. Knockdown of ET-1 decreased VEGF expression and also abolished chondrosarcoma conditional medium-mediated angiogenesis in vitro as well as angiogenesis effects in the chick chorioallantoic membrane and Matrigel plug nude mice model in vivo. In addition, in the xenograft tumor angiogenesis model, knockdown of ET-1 significantly reduced tumor growth and tumor-associated angiogenesis. Taken together, these results indicate that ET-1 occurs through ETAR, ILK and Akt, which in turn activates HIF-1α, resulting in the activation of VEGF expression and contributing to the angiogenesis and tumor growth of human chondrosarcoma cells.
Many antidepressants stimulate adult hippocampal neurogenesis, but the mechanisms by which they increase neurogenesis and modulate behavior are incompletely understood. Here we show that hippocampal ...bone morphogenetic protein (BMP) signaling is modulated by antidepressant treatment, and that the changes in BMP signaling mediate effects of antidepressant treatment on neural progenitor cell proliferation and behavior. Treatment with the selective serotonin reuptake inhibitor fluoxetine suppressed BMP signaling in the adult mouse hippocampus both by decreasing levels of BMP4 ligand and increasing production of the BMP inhibitor noggin. Increasing BMP signaling in the hippocampus via viral overexpression of BMP4 blocked the effects of fluoxetine on proliferation in the dentate gyrus and on depressive behavior. Conversely, inhibiting BMP signaling via viral overexpression of noggin in the hippocampus or infusion of noggin into the ventricles exerted antidepressant and anxiolytic activity along with an increase in hippocampal neurogenesis. Similarly, conditional genetic deletion of the type II BMP receptor in Ascl1-expressing cells promoted neurogenesis and reduced anxiety- and depression-like behaviors, suggesting that neural progenitor cells contribute to the effects of BMP signaling on affective behavior. These observations indicate that BMP signaling in the hippocampus regulates depressive behavior, and that decreasing BMP signaling may be required for the effects of some antidepressants. Thus BMP signaling is a new and powerful potential target for the treatment of depression.
Anthocyanins and nonphotochemical quenching (NPQ) are two important tools that provide photoprotection in plant leaves. In order to understand how plants use these tools for acclimation to changing ...seasonal conditions, we investigated pigments, antioxidative capacity, and photosynthesis in leaves of an evergreen tree (
Acmena acuminatissima
) in two contrasting seasons. Young leaves of
A. acuminatissima
appeared in distinct colors, being light green in summer and red in winter due to the presence of anthocyanins. In the winter young leaves, anthocyanins contributed less than 2% to the antioxidant pool. In the summer, young leaves had higher NPQ than that of mature leaves, but in the winter, they did not derive any NPQ-related advantage over mature leaves. These results suggest that the accumulation of anthocyanins in young leaves in the winter may compensate for the insufficient photoprotection afforded by NPQ and that anthocyanins function as a light attenuator to protect the photochemical apparatus against excess light.
It has been reported that the miR-106b∼25 cluster, a paralog of the miR-17∼92 cluster, possesses oncogenic activities. However, the precise role of each microRNA (miRNA) in the miR-106b∼25 cluster is ...not yet known. In this study, we examined the function of miR-93, one of the microRNAs within the miR-106b∼25 cluster, in angiogenesis and tumor formation. We found that miR-93 enhanced cell survival, promoted sphere formation and augmented tumor growth. Most strikingly, when miR-93-overexpressing U87 cells were co-cultured with endothelial cells, they supported endothelial cell spreading, growth, migration and tube formation. In vivo studies revealed that miR-93-expressing cells induced blood vessel formation, allowing blood vessels to extend to tumor tissues in high densities. Angiogenesis promoted by miR-93 in return facilitated cell survival, resulting in enhanced tumor growth. We further showed that integrin-β8 is a target of miR-93. Higher levels of integrin-β8 are associated with cell death in tumor mass and in human glioblastoma. Silencing of integrin-β8 expression using small interfering RNA promoted cell proliferation, whereas ectopic expression of integrin-β8 decreased cell growth. These findings showed that miR-93 promotes tumor growth and angiogenesis by suppressing, at least in part, integrin-β8 expression. Our results suggest that inhibition of miR-93 function may be a feasible approach to suppress angiogenesis and tumor growth.
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. Despite progress in diagnostics and treatment of HCC, its prognosis remains poor. Emerging studies ...showed that long noncoding RNAs (lncRNAs) have crucial regulatory roles in cancer biology. In the current study, differentially expressed lncRNAs between HCC and paired non-tumor tissues were identified using microarrays. The effects of a specific differentially expressed lncRNA (termed ZEB1-AS1) on tumor progression were investigated in vitro and in vivo. We found that ZEB1-AS1 is frequently upregulated in HCC samples, especially in metastatic tumor tissues. DNA methylation analysis shows a tumor-specific ZEB1-AS1 promoter hypomethylation. Aberrant methylation is tightly correlated with overexpression of ZEB1-AS1 in HCC. Patients with ZEB1-AS1 hypomethylation or with high ZEB1-AS1 expression have poor recurrence-free survival. Functionally, ZEB1-AS1 promotes tumor growth and metastasis, acts as an oncogene in HCC. The ZEB1-AS1 gene is located in physical contiguity with ZEB1 and positively regulates the ZEB1 expression. ZEB1 inhibition partially abrogates ZEB1-AS1-induced epithelial to mesenchymal transition (EMT) and cancer metastasis. Our results provide novel insights into the function of lncRNA-driven hepatocarcinogenesis, highlight the important role of ZEB1-AS1 and ZEB1 in HCC progression, and indicate that ZEB1-AS1 may be served as a valuable prognostic biomarker for HCC.
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