CONTEXT: Exploration of the biological property of programmed death-ligand 1 (PD-L1) signaling that may impact bladder tumor growth in humanized animals and cell culture.
AIMS: The aim of this study ...is to evaluate how PD-L1 signaling involves bladder cancer growth and progression.
SETTINGS AND DESIGN: This study design involves experimental in vivo and in vivo study.
SUBJECTS AND METHODS: A role of PD-L1 signaling pathway inhibition for bladder cancer growth was assessed in humanized immunodeficient animals carried main molecular subtypes of bladder carcinoma patient-derived xenografts and provided with selective anti-PD-L1 treatment; bladder cancer cells invasiveness was evaluated in mixed RT112/84 cells + CD4+ cells culture incubated with PD-L1 blocker durvalumab. We used two-tailed Student's t-test to explore differences between main and control subgroups. Significance of intergroup comparison was measured with one-way ANOVA followed by the Tukey's or Newman-Keul's criterion. Survival curves were analyzed with Gehan's criterion with the Yate's correction. Differences were considered statistically significant at P < 0.05.
RESULTS: Anti-PD-L1 intervention increased survival of the animals carried both primary and relapsed luminal noninvasive, muscular invasive, and relapsed luminal bladder cancer xenografts. There was significant retardation of tumor volume duplication time in aforementioned subgroups correlated with PD-L1 expression. Durvalumab treatment in concentration-dependent manner inhibited tumor cells invasiveness of mixed RT112 + CD4+ culture cells with its maximum at the highest studied concentration (10 μM).
CONCLUSIONS: Obtained data constituted the pivotal role of programmed cell death-1/PD-L1 signaling pathway in bladder cancer development and progression. The results will have major implications for further clinical investigations.
Background: bladder cancer is one of the most common urinary tract malignancies. Establishment of robust predictors of disease progression and outcome is important for personalizing treatment of ...non-muscular invasive bladder carcinoma (NMIBC). In this study we evaluated association of PD-L1 expression with other prognostic biomarkers, such as expression of miRNA-145 and miRNA-200a, FGFR3 gene expression, and mutation status in tissue specimens of the luminal subtype of newly diagnosed high and low grade NMIBC. Methods: twenty patients with primary luminal NMIBC were enrolled in the study. Tumor grade and risk level were determined in accordance with European Organization for Research and Treatment of Cancer (EORTC) guidelines and World Health Organization (WHO) classification. Neoplasm molecular subtype and PD-L1 expression level were assessed by immunohistochemistry. We used real-time PCR to evaluate the expression of microRNAs and FGFR3. We detected FGFR3 hotspot mutations in codons 248 and 249 by Sanger sequencing. Results: high grade primary luminal NMIBC showed comparatively higher expression of PD-L1 and microRNA-145 than a low grade tumor, whereas the latter had a higher FGFR3 expression and hotspot mutation rate. The tumor grade (HR = 571.72 11.03–2.96 p = 0.002), PD-L1 expression (HR = 2.33 0.92–1.92 p = 0.012), and FGFR3 expression (HR = 0.08 0.17–0.42 p = 0.003) were associated with relapse-free survival. Conclusions: tumor grade in association with PD-L1 and FGFR3 expression can be considered as a complex predictor for primary luminal NMIBC progression.
Establishment of heterotopic patient-derived xenografts of primary and relapsed non-muscular invasive bladder cancer (NMIBC) to explore the biological property of PD-L1 signaling that may impact ...bladder tumor growth in humanized animals.
Tumor cells of luminal, basal, and p53 subtypes of primary and relapsed NMIBC were engrafted to irradiated (3.5 Gy) NOG/SCID female mice along with intraperitoneal transplantation of human lymphocytes (5 × 10
cells/mouse); a role of PD-L1 signaling pathway inhibition for bladder cancer growth was assessed in humanized animals that carried PD-L1-expressing main molecular subtypes of bladder carcinoma patient-derived xenografts (PDX) and provided with selective anti-PD-L1 treatment. We used two-tailed Student's
test to explore differences between main and control subgroups. Significance of intergroup comparison was measured with one-way ANOVA followed by the Tukey's or Newman-Keul's criterion. Survival curves were analyzed with the Gehan's criterion with the Yate's correction. The Spearman's correlation was used to assess the link between CD8
expression and sPD-L1 serum level. Differences were considered statistically significant at
< 0.05.
Heterotopic primary and relapsed luminal, basal, and p53 subtypes of NMIBC PDXs were established. More than 25% of counted tumor cells of all PDX specimens expressed PD-L1, so the tumors were ranged as PD-L1 positive. Anti-PD-L1 intervention increased survival of the animals that carried both primary and relapsed luminal noninvasive, muscular invasive, and relapsed luminal bladder cancer xenografts. There was significant retardation of tumor volume duplication time in aforementioned subgroups correlated with PD-L1 expression. Bad response of p53 mutant subtypes of NMIBC on specific anti-PD-L1 treatment may be associated with low CD8
cells representation into the tumors tissue.
Established PD-L1-positive NMIBC PDXs differently replied on anti-PD-L1 treatment due to both NMIBC molecular subtype and tumor T-suppressors population. The results may have major implications for further clinical investigations.
Transactional customer embeddings have become one of the most popular methods for businesses to solve customer-related challenges. Despite the high quality, embeddings may lack interpretability, ...which makes it difficult to understand and extract the meaningful information from the received representations. To address this limitation, we propose an embedding framework that make use of users’ geographical transactional activity, which captures individuals’ spatial patterns and preferences. Our framework consists of three steps: calculating custom client geographic activity feature vectors, clustering these vectors, and calculating the resulting user low-dimensional vectors where each value represents the distance between the user geographic activity vector and the cluster center. Experiments on the partner bank dataset demonstrate the effectiveness of proposed method. Our approach achieves comparable performance to the existing methods in purchase category forecasting, task of missing category prediction and that of campaign targeting. Furthermore, the obtained model results can be visualized and interpreted, which makes it possible to understand the user behavior
On 21 of November 2012 at the department of comparative politics of the PFUR was held the round table: “Soft power in global politics: regional and functional dimensions”.
Activated ghrelin receptor GHS-R1α triggers cell signalling pathways that modulate energy homeostasis and biosynthetic processes. However, the effects of ghrelin on mRNA translation are unknown. ...Using various reporter assays, here we demonstrate a rapid elevation of protein synthesis in cells within 15–30 min upon stimulation of GHS-R1α by ghrelin. We further show that ghrelin-induced activation of translation is mediated, at least in part, through the de-phosphorylation (de-suppression) of elongation factor 2 (eEF2). The levels of eEF2 phosphorylation at Thr56 decrease due to the reduced activity of eEF2 kinase, which is inhibited via Ser366 phosphorylation by rpS6 kinases. Being stress-susceptible, the ghrelin-mediated decrease in eEF2 phosphorylation can be abolished by glucose deprivation and mitochondrial uncoupling. We believe that the observed burst of translation benefits rapid restocking of neuropeptides, which are released upon GHS-R1α activation, and represents the most time- and energy-efficient way of prompt recharging the orexigenic neuronal circuitry.
Oxygen and glucose metabolism play pivotal roles in many (patho)physiological conditions. In particular, oxygen and glucose deprivation (OGD) during ischemia and stroke results in extensive tissue ...injury and cell death.
Using time-resolved ribosome profiling, we assess gene expression levels in a neural cell line, PC12, during the first hour of OGD. The most substantial alterations are seen to occur within the first 20 minutes of OGD. While transcription of only 100 genes is significantly altered during one hour of OGD, the translation response affects approximately 3,000 genes. This response involves reprogramming of initiation and elongation rates, as well as the stringency of start codon recognition. Genes involved in oxidative phosphorylation are most affected. Detailed analysis of ribosome profiles reveals salient alterations of ribosome densities on individual mRNAs. The mRNA-specific alterations include increased translation of upstream open reading frames, site-specific ribosome pauses, and production of alternative protein isoforms with amino-terminal extensions. Detailed analysis of ribosomal profiles also reveals six mRNAs with translated ORFs occurring downstream of annotated coding regions and two examples of dual coding mRNAs, where two protein products are translated from the same long segment of mRNA, but in two different frames.
These findings uncover novel regulatory mechanisms of translational response to OGD in mammalian cells that are different from the classical pathways such as hypoxia inducible factor (HIF) signaling, while also revealing sophisticated organization of protein coding information in certain genes.
Mutations in genes encoding cytochrome c oxidase (mitochondrial complex IV) subunits and assembly factors e.g., synthesis of cytochrome c oxidase 2 (SCO2) are linked to severe metabolic syndromes. ...Notwithstanding that SCO2 is under transcriptional control of tumor suppressor p53, the role of mitochondrial complex IV dysfunction in cancer metabolism remains obscure. Herein, we demonstrate that the loss of SCO2 in HCT116 colorectal cancer cells leads to significant metabolic and signaling perturbations. Specifically, abrogation of SCO2 increased NAD+ regenerating reactions and decreased glucose oxidation through citric acid cycle while enhancing pyruvate carboxylation. This was accompanied by a reduction in amino acid levels and the accumulation of lipid droplets. In addition, SCO2 loss resulted in hyperactivation of the insulin‐like growth factor 1 receptor (IGF1R)/AKT axis with paradoxical downregulation of mTOR signaling, which was accompanied by increased AMP‐activated kinase activity. Accordingly, abrogation of SCO2 expression appears to increase the sensitivity of cells to IGF1R and AKT, but not mTOR inhibitors. Finally, the loss of SCO2 was associated with reduced proliferation and enhanced migration of HCT116 cells. Collectively, herein we describe potential adaptive signaling and metabolic perturbations triggered by mitochondrial complex IV dysfunction.
In this study, we provide evidence suggesting potential adaptive mechanisms that are activated in response to dysfunction of mitochondrial complex IV in HCT116 colon cancer cell line. These mechanisms involve dramatic metabolic reprogramming to compensate for the disruption of mitochondrial functions that is accompanied by the activation of the IGF1R/AKT axis, increased AMPK activity, and paradoxical downregulation of mTORC1 signaling.
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