Anti-tumour immune activation by checkpoint inhibitors leads to durable responses in a variety of cancers, but combination approaches are required to extend this benefit beyond a subset of patients. In preclinical models tumour-derived VEGF limits immune cell activity while anti-VEGF augments intra-tumoral T-cell infiltration, potentially through vascular normalization and endothelial cell activation. This study investigates how VEGF blockade with bevacizumab could potentiate PD-L1 checkpoint inhibition with atezolizumab in mRCC. Tissue collections are before treatment, after bevacizumab and after the addition of atezolizumab. We discover that intra-tumoral CD8(+) T cells increase following combination treatment. A related increase is found in intra-tumoral MHC-I, Th1 and T-effector markers, and chemokines, most notably CX3CL1 (fractalkine). We also discover that the fractalkine receptor increases on peripheral CD8(+) T cells with treatment. Furthermore, trafficking lymphocyte increases are observed in tumors following bevacizumab and combination treatment. These data suggest that the anti-VEGF and anti-PD-L1 combination improves antigen-specific T-cell migration.

/pdf/atezolizumab-in-combination-with-bevacizumab-enhances-dsuu5atq7x.pdf

Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma

Predictive markers of anti-VEGF and emerging role of angiogenesis inhibitors as immunotherapeutics

Sirtuin is an essential factor that delays cellular senescence and extends the organismal lifespan through the regulation of diverse cellular processes. Suppression of cellular senescence by Sirtuin is mainly mediated through delaying the age-related telomere attrition, sustaining genome integrity and promotion of DNA damage repair. In addition, Sirtuin modulates the organismal lifespan by interacting with several lifespan regulating signaling pathways including insulin/IGF-1 signaling pathway, AMP-activated protein kinase, and forkhead box O. Although still controversial, it is suggested that the prolongevity effect of Sirtuin is dependent with the level of and with the tissue expression of Sirtuin. Since Sirtuin is also believed to mediate the prolongevity effect of calorie restriction, activators of Sirtuin have attracted the attention of researchers to develop therapeutics for age-related diseases. Resveratrol, a phytochemical rich in the skin of red grapes and wine, has been actively investigated to activate Sirtuin activity with consequent beneficial effects on aging. This article reviews the evidences and controversies regarding the roles of Sirtuin on cellular senescence and lifespan extension, and summarizes the activators of Sirtuin including Sirtuin-activating compounds and compounds that increase the cellular level of nicotinamide dinucleotide. [BMB Reports 2019; 52(1): 24-34].

Sirtuin signaling in cellular senescence and aging.

Cellular senescence is now considered an important driving mechanism for chronic lung diseases, particularly chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis. Cellular senescence is due to replicative and stress-related senescence with activation of p53 and p16INK4a, respectively, leading to activation of p21CIP1 and cell cycle arrest. Senescent cells secrete multiple inflammatory proteins known as the senescence-associated secretory phenotype, leading to low-grade chronic inflammation, which further drives senescence. Loss of key antiaging molecules sirtuin-1 and sirtuin-6 may be important in acceleration of aging and arises from oxidative stress reducing phosphatase PTEN (phosphatase tensin homolog), thereby activating PI3K (phosphoinositide-3-kinase) and mTOR (mammalian target of rapamycin). MicroRNA-34a (miR-34a), which is regulated by PI3K-mTOR signaling, plays a pivotal role in reducing sirtuin-1/6, and its inhibition with an antagomir results in their restoration, reducing markers of senescence, reducing senescence-associated secretory phenotype, and reversing cell cycle arrest in epithelial cells from peripheral airways of patients with COPD. miR-570 is also involved in reduction of sirtuin-1 and cellular senescence and is activated by p38 mitogen-activated protein kinase. These miRNAs may be released from cells in extracellular vesicles that are taken up by other cells, thereby spreading senescence locally within the lung but also outside the lung through the circulation; this may account for comorbidities of COPD and other lung diseases. Understanding the mechanisms of cellular senescence may result in new treatments for chronic lung disease, either by inhibiting PI3K-mTOR signaling, by inhibiting specific miRNAs, or by deletion of senescent cells with senolytic therapies, already shown to be effective in experimental lung fibrosis.

/pdf/cellular-senescence-as-a-mechanism-and-target-in-chronic-45pini4gex.pdf

Cellular Senescence as a Mechanism and Target in Chronic Lung Diseases

Modulation of angiogenesis during adipose tissue development in murine models of obesity

Sirtuins, epigenetics and longevity.

Chemokine CX3CL1 is unique, possessing the ability to act as a dual agent: chemoattractant and adhesive compound. Acting via its sole receptor CX3CR1, CX3CL1 participates in many processes in human placental tissue, including inflammation and angiogenesis. Strongly upregulated by hypoxia and/or inflammation-induced inflammatory cytokines secretion, CX3CL1 may act locally as a key angiogenic factor. Both clinical observations and histopathological studies of the diabetic placenta have confirmed an increased incidence of hypoxia and inflammatory reactions with defective angiogenesis. In this study we examined comparatively (diabetes class C complicated versus normal pregnancy) the correlation between CX3CL1 content in placental tissue, the mean CX3CR1 expression, and density of the network of placental microvessels. A sandwich enzyme immunoassay was applied for CX3CL1 measurement in placental tissue homogenates, whereas quantitative immunohistochemical techniques were used for the assessment of CX3CR1 expression and the microvascular density. Significant differences have been observed for all analyzed parameters between the groups. The mean concentration of CX3CL1 in diabetes was increased and accompanied by augmented placental microvessel density as well as a higher expression of CX3CR1. In conclusion, we suggest involvement of CX3CL1/CX3CR1 signaling pathway in the pathomechanism of placental microvasculature remodeling in diabetes class C.

/pdf/fractalkine-cx3cl1-and-its-receptor-cx3cr1-may-contribute-to-43ci7m6qw3.pdf

Fractalkine (CX3CL1) and Its Receptor CX3CR1 May Contribute to Increased Angiogenesis in Diabetic Placenta

Objective: Vasculogenesis and angiogenesis are crucial for maintaining proper placental perfusion and optimal fetal development. Among other physical and chemical factors, hypoxia is known to stimulate angiogenic processes. Preplacental type of hypoxia is often associated with maternal anemia and is thought to enhance vascularization within the fetoplacental unit. The goal of this study was to establish the correlation between the local expression of vascular endothelial growth factor (VEGF) and placenta growth factor (PlGF) receptors (flt-1, flk-1) with maternal hemoglobin (Hb) concentration, hematocrit (Ht) values and the infant birthweight.Methods: In total, 43 specimens of term placentas obtained from normal course pregnancies delivered at term were included in the study. The expression of flt-1 and flk-1 receptors was analyzed by immunohistochemical staining. Vascular/extravascular tissular index (V/EVTI) was measured by assessing a total vascular area. Nonparametric Mann–Whitney U-test and S...

Maternal hemoglobin concentration and hematocrit values may affect fetus development by influencing placental angiogenesis.

Oxytocin (OXT) acts through its specific receptor (OXTR) and increased density of OXTR and/or augmented sensitivity to OXT were postulated as prerequisites of normal onset of labor. Expression of OXTR in the placental term trophoblast cells has not yet been analyzed in the context of contractile activity of the uterus. Here we examine comparatively OXT contents in the placental tissue adjacent to the uterine wall and expressions of OXTR in this tissue and corresponding isolated placental trophoblast cells.

/pdf/myometrial-contractility-influences-oxytocin-receptor-oxtr-hix9t47d85.pdf

Myometrial contractility influences oxytocin receptor (OXTR) expression in term trophoblast cells obtained from the maternal surface of the human placenta.

Aleksandra Stangret

Papers

Sirtuins, epigenetics and longevity.

Fractalkine (CX3CL1) and Its Receptor CX3CR1 May Contribute to Increased Angiogenesis in Diabetic Placenta

Maternal hemoglobin concentration and hematocrit values may affect fetus development by influencing placental angiogenesis.

Myometrial contractility influences oxytocin receptor (OXTR) expression in term trophoblast cells obtained from the maternal surface of the human placenta.

Fractalkine and placental growth factor: A duet of inflammation and angiogenesis in cardiovascular disorders.