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Journals 2018 EN

Performance Comparison of Mode Choice Optimization Algorithm with Simulated Discrete Choice Modeling

Hyuk-Jae Roh · Satish C. Sharma · Prasanta K. Sahu +1 more

Until recently, a majority of modeling tasks of transportation planning, especially in discrete choice modeling, is conducted with the help of commercial software and only concerned about the result of parameter estimates to get a policy-sensitive interpretation. This common practice prevents researchers from gaining a systematic knowledge involved in estimation mechanism. In this research, to shed a light on these limited modeling practices, a standard discrete choice model’s parameter is estimated using Quasi-Newton method, DFP, and BFGS. Two extended algorithms, called DFP-GSM and BFGS-GSM, are proposed for the first time to overcome the weakness of the Quasi-Newton method. The golden section method (GSM) incorporates a nonlinear programming technique to choose an optimal step size automatically. Partial derivatives of log-likelihood function are derived and coded using Visual Basic Application (VBA). Through extensive numerical evaluation, estimation capability of each proposed estimation algorithms is compared in terms of performance measures. The proposed algorithms show a stable estimation performance and the reasons were studied and discussed. Furthermore, useful insights educated in custom-built modeling are present.

Hindawi Publishing Corporation

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Journals 2018 EN

IL-6 Mediates Cross-Talk between Tumor Cells and Activated Fibroblasts in the Tumor Microenvironment

Tatiana A. Karakasheva · Eric W. Lin · Qiaosi Tang +19 more

The tumor microenvironment (TME) plays a major role in the pathogenesis of multiple cancer types, including upper-gastrointestinal (GI) cancers that currently lack effective therapeutic options. Cancer-associated fibroblasts (CAF) are an essential component of the TME, contributing to tumorigenesis by secreting growth factors, modifying the extracellular matrix, supporting angiogenesis, and suppressing antitumor immune responses. Through an unbiased approach, we have established that IL-6 mediates cross-talk between tumor cells and CAF not only by supporting tumor cell growth, but also by promoting fibroblast activation. As a result, IL-6 receptor (IL6Rα) and downstream effectors offer opportunities for targeted therapy in upper-GI cancers. IL-6 loss suppressed tumorigenesis in physiologically relevant three-dimensional (3D) organotypic and 3D tumoroid models and murine models of esophageal cancer. Tocilizumab, an anti-IL6Rα antibody, suppressed tumor growth in vivo in part via inhibition of STAT3 and MEK/ERK signaling. Analysis of a pan-cancer TCGA dataset revealed an inverse correlation between IL-6 and IL6Rα overexpression and patient survival. Therefore, we expanded evaluation of tocilizumab to head and neck squamous cell carcinoma patient-derived xenografts and gastric adenocarcinoma xenografts, demonstrating suppression of tumor growth and altered STAT3 and ERK1/2 gene signatures. We used small-molecule inhibitors of STAT3 and MEK1/2 signaling to suppress tumorigenesis in the 3D organotypic model of esophageal cancer. We demonstrate that IL6 is a major contributor to the dynamic cross-talk between tumor cells and CAF in the TME. Our findings provide a translational rationale for inhibition of IL6Rα and downstream signaling pathways as a novel targeted therapy in oral-upper-GI cancers. Significance: These findings demonstrate the interaction of esophageal cancer and cancer-associated fibroblasts through IL-6 signaling, providing rationale for a novel therapeutic approach to target these cancers. Cancer Res; 78(17); 4957-70. ©2018 AACR .

American Association for Cancer Research

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Journals 2018 EN

Sonidegib, a Novel Inhibitor of Suicidal Erythrocyte Death

Abdulla Al Mamun Bhuyan · Itishri Sahu · Hang Cao +1 more

Background/Aims: The Hedgehog pathway disrupting drug sonidegib is used in the treatment of basal cell carcinoma. Side effects of sonidegib include anemia, which could result either from impaired erythropoiesis or from loss of erythrocytes e.g. due to suicidal erythrocyte death or eryptosis, which is characterized by cell membrane scrambling with phosphatidylserine translocation to the cell surface and by cell shrinkage. Eryptosis is stimulated by cell stress, including energy depletion, hyperosmotic shock, oxidative stress and excessive increase of cytosolic Ca2+ activity ([Ca2+]i). The present study explored, whether sonidegib exerts an effect on eryptosis. Methods: Human erythrocytes have been treated with energy depletion (glucose withdrawal for 48 hours), hyperosmotic shock (addition of 550 mM sucrose for 6 hours), oxidative stress (addition of 0.3 mM tert-butylhydroperoxide [tBOOH] for 50 min) or Ca2+ ionophore ionomycin (1 µM for 60 min) in absence and presence of sonidegib (2-6 µg/ ml). After treatment flow cytometry was employed to quantify phosphatidylserine exposure at the cell surface from annexin-V-binding, and cell volume from forward scatter. Hemolysis was estimated from the hemoglobin concentration in the supernatant. Results: In the absence of cell stress exposure to sonidegib did not significantly modify annexin-V-binding or forward scatter, but triggered hemolysis. Energy depletion, hyperosmotic shock, oxidative stress and ionomycin, all markedly and significantly increased the percentage of annexin-V-binding erythrocytes, and decreased the forward scatter. Sonidegib significantly blunted the effect of energy depletion, hyperosmotic shock, and oxidative stress, but not of ionomycin on annexin-V-binding. Sonidegib further significantly blunted the effect of energy depletion, but not of hyperosmotic shock, oxidative stress, and ionomycin on forward scatter. Conclusions: Sonidegib is a novel inhibitor of erythrocyte cell membrane scrambling following energy depletion, hyperosmotic shock and oxidative stress.

Karger Publishers

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Journals 2018 EN

Inhibition of Lithium Sensitive Orai1/ STIM1 Expression and Store Operated Ca2+ Entry in Chorea-Acanthocytosis Neurons by NF-κB Inhibitor Wogonin

Basma Sukkar · Stefan Hauser · Lisann Pelzl +8 more

Background/Aims: The neurodegenerative disease Chorea-Acanthocytosis (ChAc) is caused by loss-of-function-mutations of the chorein-encoding gene VPS13A. In ChAc neurons transcript levels and protein abundance of Ca2+ release activated channel moiety (CRAC) Orai1 as well as its regulator STIM1/2 are decreased, resulting in blunted store operated Ca2+-entry (SOCE) and enhanced suicidal cell death. SOCE is up-regulated and cell death decreased by lithium. The effects of lithium are paralleled by upregulation of serum & glucocorticoid inducible kinase SGK1 and abrogated by pharmacological SGK1 inhibition. In other cell types SGK1 has been shown to be partially effective by upregulation of NFκB, a transcription factor stimulating the expression of Orai1 and STIM. The present study explored whether pharmacological inhibition of NFκB interferes with Orai1/STIM1/2 expression and SOCE and their upregulation by lithium in ChAc neurons. Methods: Cortical neurons were differentiated from induced pluripotent stem cells generated from fibroblasts of ChAc patients and healthy volunteers. Orai1 and STIM1 transcript levels and protein abundance were estimated from qRT-PCR and Western blotting, respectively, cytosolic Ca2+-activity ([Ca2+]i) from Fura-2-fluorescence, SOCE from increase of [Ca2+]i following Ca2+ re-addition after Ca2+-store depletion with sarco-endoplasmatic Ca2+-ATPase inhibitor thapsigargin (1µM), as well as CRAC current utilizing whole cell patch clamp recording. Results: Orai1 and STIM1 transcript levels and protein abundance as well as SOCE and CRAC current were significantly enhanced by lithium treatment (2 mM, 24 hours). These effects were reversed by NFκB inhibitor wogonin (50 µM). Conclusion: The stimulation of expression and function of Orai1/STIM1/2 by lithium in ChAc neurons are disrupted by pharmacological NFκB inhibition.

Karger Publishers

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Journals 2018 EN

Graph Based Workload Driven Partitioning System by using MongoDB

Arvind Sahu · Swati Ahirrao

Received May 24, 2017 Revised Jan 18, 2018 Accepted Feb 11, 2018 The web applications and websites of the enterprises are accessed by a huge number of users with the expectation of reliability and high availability. Social networking sites are generating the data exponentially large amount of data. It is a challenging task to store data efficiently. SQL and NoSQL are mostly used to store data. As RDBMS cannot handle the unstructured data and huge volume of data, so NoSQL is better choice for web applications. Graph database is one of the efficient ways to store data in NoSQL. Graph database allows us to store data in the form of relation. In Graph representation each tuple is represented by node and the relationship is represented by edge. But, to handle the exponentially growth of data into a single server might decrease the performance and increases the response time. Data partitioning is a good choice to maintain a moderate performance even the workload increases. There are many data partitioning techniques like Range, Hash and Round robin but they are not efficient for the small transactions that access a less number of tuples. NoSQL data stores provide scalability and availability by using various partitioning methods. To access the Scalability, Graph partitioning is an efficient way that can be easily represent and process that data. To balance the load data are partitioned horizontally and allocate data across the geographical available data stores. If the partitions are not formed properly result becomes expensive distributed transactions in terms of response time. So the partitioning of the tuple should be based on relation. In proposed system, Schism technique is used for partitioning the Graph. Schism is a workload aware graph partitioning technique. After partitioning the related tuples should come into a single partition. The individual node from the graph is mapped to the unique partition. The overall aim of Graph partitioning is to maintain nodes onto different distributed partition so that related data come onto the same cluster.