Interferon-gamma Inducible Protein 10 up-regulated by acute-phase graft injury induced late-phase cisplatin resistance after liver transplantation

published_or_final_versio

The significance of acute-phase small-for-size liver graft injury in mobilization of circulating EPCs/MDSCs/Tregs after LDLT for HCC patients

Oral Presentation - Session O40 HCC and Living Donor Transplantation: O40.06INTRODUCTION AND OBJECTIVE: Higher incidence of tumor recurrence is a major obstacle of living donor liver transplanatation (LDLT) for the patients with hepatocellular carcinoma (HCC). We have already demonstrated that acute phase small-for-size liver graft injury plays important role on late phase tumor recurrence and metastases in a serial animal studies. Understanding the molecular mechanism of acute phase small-for-size liver graft injury is essential for development of therapeutic strategy to reduce the likelihood of tumor recurrence after LDLT. In the current clinical study, we aim to investigate the impact of acute-phase small-for-size graft injury on mobilization of circulating endothelial progenitor cells (EPCs), myeloid-derived suppressive cells (MDSCs) and regulatory T cells (Tregs) in HCC patients after liver transplantation and to explore the molecular mechanism therein. METHODS: From May 2000 to November 2009, 115 adult HCC recipients were included in the current study. The intragraft microRNA profiles of the grafts greater (Group 1) and less than 60% (Group 2) of standard liver weight (SLW) were characterized by Low Density Array (LDA) analysis. Post-operative circulating EPCs (CD34+CD133+CD45-), MDSCs (CD34+CD13+CD33+) and Tregs (CD4+CD25+FOXP3+) were compared by FACS analysis. Intragraft hepatic stellate cell activation, macrophage infiltration and gene expression of Rac, Pyk2, Egr-1 and VEGF at the early phase after reperfusion were also detected by immunostaining and real-time RT-PCR, respectively. Clinical-pathological data including the incidence of tumor recurrence and metastasis were compared between the two groups. RESULTS: The patients were grouped into Group 1 (>= 60% SLW, n=37) and Group 2 (<60% SLW, n=78). The numbers of patients beyond Milan criteria [15/37(40.5%) vs 29/49(59.2%), p=0.838] or UCSF criteria [9/37(24.3%) vs 19/60(31.7%), p=1] were similar between the two groups. Much more patients in Group 2 developed tumor recurrence and lung metastasis [19/78(24.4%) vs 3/37(8%), p=0.04]. Level of circulating EPCs was significantly higher in Group 2 (Day 3: 0.09% vs 0.002%, p=0.019; Week 4: 0.12% vs 0.033%, p=0.037; Week 8: 0.0585% vs 0.025%, p=0.018; Week 12: 0.055% vs 0.028%, p=0.025). A tendency of larger populations of circulating MDSCs and Tregs was also found in Group 2. Most of the patients with tumor recurrence had hepatic sinusoidal injury at early phase after liver transplantation. Significant activation of hepatic stellate cells was found in Group 2 together with stronger intragraft protein expression of FAK and CAK compared to Group 1. Intragraft mRNA levels of Egr-1, RhoA, FAK and VEGF were also significantly higher in Group 2. microRNA LDA analysis demonstrated that mir-233, mir-141, mir-1308, mir-548 and mir-576 were differentially expressed between the two groups. These mirRNAs were predicted to regulate targeting genes linked to graft injury (MAPK, CCL4 and Egr-1), tumor invasiveness (STAT5, CDC2 and EGFR), angiogenesis (VEGF, FLT4 and ANGPTL5), and macrophage infiltration (MIP2). CONCLUSION: A significantly higher population of postoperative circulating EPCs, which are mobilized by small-for-size graft injury, may lead to a higher incidence of tumor recurrence and metastasis after LDLT. The distinct intragraft miRNA expression profile linked to acute-phase injury and angiogenesis may play a role in the mobilization of circulating EPCs, MDSCs, and Tregs.postprintThe 23rd International Congress of The Transplantation Society (TTS 2010), Vancouver, Canada, 15-19 August 2010. In Transplantation, 2010, v. 90 no. 2S, p. 268, abstract no. 51

Enabling Hyper-Personalisation: Automated Ad Creative Generation and Ranking for Fashion e-Commerce

Homepage is the first touch point in the customer's journey and is one of the prominent channels of revenue for many e-commerce companies. A user's attention is mostly captured by homepage banner images (also called Ads/Creatives). The set of banners shown and their design, influence the customer's interest and plays a key role in optimizing the click through rates of the banners. Presently, massive and repetitive effort is put in, to manually create aesthetically pleasing banner images. Due to the large amount of time and effort involved in this process, only a small set of banners are made live at any point. This reduces the number of banners created as well as the degree of personalization that can be achieved. This paper thus presents a method to generate creatives automatically on a large scale in a short duration. The availability of diverse banners generated helps in improving personalization as they can cater to the taste of larger audience. The focus of our paper is on generating wide variety of homepage banners that can be made as an input for user level personalization engine. Following are the main contributions of this paper: 1) We introduce and explain the need for large scale banner generation for e-commerce 2) We present on how we utilize existing deep learning based detectors which can automatically annotate the required objects/tags from the image. 3) We also propose a Genetic Algorithm based method to generate an optimal banner layout for the given image content, input components and other design constraints. 4) Further, to aid the process of picking the right set of banners, we designed a ranking method and evaluated multiple models. All our experiments have been performed on data from Myntra (http://www.myntra.com), one of the top fashion e-commerce players in India.Comment: Workshop on Recommender Systems in Fashion, 13th ACM Conference on Recommender Systems, 201

The clinical significance and potential therapeutic role of GPx3 in tumor recurrence after liver transplantation

published_or_final_versio

The Anti-Tumor Effects of M1 Macrophage-Loaded Poly (ethylene glycol) and Gelatin-Based Hydrogels on Hepatocellular Carcinoma

Background and Aims: Recently we reported that direct injection of M1 macrophages significantly caused tumor regression in vivo. Despite the promising result, a major limitation in translating this approach is the induction of acute inflammatory response. To improve the strategy, a biocompatible scaffold for cell presentation and support is essential to control cell fate. Here, we aimed to elucidate the anti-tumor effects of a poly(ethylene glycol) diacrylate (PEGdA) and thiolated gelatin poly(ethylene glycol) (Gel-PEG-Cys) cross-linked hydrogels capsulated with M1 macrophages in both in vitro and in vivo disease models. Methods: Hydrogels were made at 0.5% (w/v) Iragcure 2959 photoinitiator, 10% (w/v) PEGdA, and 10% (w/v) Gel-PEG-Cys. Monocytic THP-1 cells were loaded into hydrogels and differentiated into M1 macrophages with lipopolysaccharide (LPS) and interferon gamma (IFN-γ). The M1 hydrogels were then cocultivated with HCC cell-lines Hep3B and MHCC97L to investigate the anti-tumor capacities and the associated molecular profiles in vitro. A nude mice ectopic liver cancer model with dorsal window chamber (DWC) and a subcutaneous tumor model were both performed to validate the in vivo application of M1 hydrogels. Results: M1 hydrogels significantly decreased the viability of HCC cells (MHCC97L: -46%; Hep3B: -56.9%; P<0.05) compared to the control in vitro. In response to HCC cells, the hydrogel embedded M1 macrophages up-regulated nitrite and tumor necrosis factor alpha (TNF-α) activating caspase-3 induced apoptosis in the tumor cells. Increased tumor necrosis was observed in DWC filled with M1 hydrogels. In addition, mice treated with M1 hydrogels exhibited a significant 2.4-fold decrease in signal intensity of subcutaneous HCC tumor compared to control (P=0.036). Conclusion: M1 hydrogels induced apoptosis in HCC cells and tumor regression in vivo. Continuous development of the scaffold-based cancer immunotherapy may provide an alternative and innovative strategy against HCC.published_or_final_versio

Antigen spreading-induced CD8+T cells confer protection against the lethal challenge of wild-type malignant mesothelioma by eliminating myeloid-derived suppressor cells

published_or_final_versio

The role of regulatory B cells on hepatocellular carcinoma progression

Poster PresentationCongress Theme: Translating Discoveries into Prevention and CuresPURPOSE: Regulatory B cells (Bregs) play important roles in autoimmune diseases, but their function in hepatocellular carcinoma (HCC) progression remains unclear. This study attempted to unveil the role of Bregs on HCC progression. EXPERIMENTAL DESIGN: This study examined the distribution of intrahepatic B cells and circulating Bregs population at the level of phenotypes as well as functionality in HCC patients. The mechanisms of Bregs regulating liver tumor cells were further explored in a series of in vitro and in vivo functional studies. RESULTS: The percentage of B cells at tumor margin region was significantly higher than that in tumor or non-tumor region. Increased intrahepatic B cells at tumor margin were positively associated with tumor invasive features and more tumor recurrence. Besides, HCC patients had a significant higher percentage of circulating Bregs than healthy people. Increased circulating Bregs were positively correlated with advanced tumor staging, tumor multiplicity and venous infiltration. Next, our in vivo study firstly revealed that human Bregs promoted HCC tumor growth independent of Tregs in SCID mice. The migration of Bregs into tumor in mice was further confirmed by in vivo imaging and histology. Finally, the molecular mechanism of Bregs promoted proliferation and migration of HCC cells was proved by direct cell-cell interaction via CD40/CD154 signaling in vitro. Coculture of Bregs and HCC cells induced CD40/CD154-dependent cytokines secretion. CONCLUSION: Human Bregs promoted HCC growth and invasiveness by interacting with HCC tumor cells through CD40/CD154 signaling pathway. Bregs might be both a prognostic marker and a therapeutic target for HCC.published_or_final_versio

CircRNA expression profiles in human dental pulp stromal cells undergoing oxidative stress

Background: Oxidative stress has a determinantal effect on human dental pulp stromal cells (hDPSCs), including affecting their longevity and functionality. Circular RNAs (circRNAs) play an essential role in stromal cell behavior; however, the exact mechanism in which circRNAs functions within hDPSCs were undergoing oxidative stress remains unclear. The purpose of this study is to assess the global changes and characteristics of circRNAs in hDPSCs undergoing oxidative stress. Methods: Using an oxidative stress model of hDPSCs, we applied microarray analysis to examine the circRNAs profiles. We confirmed the changes in circRNAs by quantitative Real-Time PCR (qRT-PCR). Furthermore, bioinformatics tools, including a miRcode map, TargetScan, gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, were reconstructed for further assessment. SIRT1 gene and protein expression were tested by qRT-PCR and In Cell-Western analysis. Results: We revealed 330 upregulated, and 533 downregulated circRNAs undergoing oxidative stress in hDPSCs and confirmed three circRNAs distinct expressions (hsa_circ_0000257, hsa_circ_0087354, and hsa_circ_0001946) in hDPSCs undergoing oxidative stress by qRT-PCR. GO, and KEGG pathway enrichment revealed the differentially expressed circRNAs might participate in p53 and cell cycle signaling networks associated with oxidative stress. SIRT1 gene and protein expression was reduced in the oxidatively stressed cells (OSC) group compared to untreated cells (UC). Conclusions: The findings of this study has provided new insights into circRNAs and a basis for further studies assessing the potential functions of hsa_circ_0000257, hsa_circ_0087354, and hsa_circ_0001946 in oxidatively stressed hDPSCs

Entanglement control in one-dimensional s=1/2s=1/2 random XY spin chain

The entanglement in one-dimensional random XY spin systems where the impurities of exchange couplings and the external magnetic fields are considered as random variables is investigated by solving the different spin-spin correlation functions and the average magnetization per spin. The entanglement dynamics near particular locations of the system is also studied when the exchange couplings (or the external magnetic fields) satisfy three different distributions(the Gaussian distribution, double-Gaussian distribution, and bimodal distribution). We find that the entanglement can be controlled by varying the strength of external magnetic field and the different distributions of impurities. Moreover, the entanglement of some nearest-neighboring qubits can be increased for certain parameter values of the three different distributions.Comment: 13 pages, 4 figure