Identification of lymph node metastasis-related genes and patterns of immune infiltration in colon adenocarcinoma

BackgroundsColon adenocarcinoma(COAD) is one of the most common tumors of the digestive tract. Lymph node metastasis (LNM) is a well-established prognostic factor for COAD. The mechanism of COAD lymph node metastasis in immunology remains unknown. The identification of LNM-related biomarkers of COAD could help in its treatment. Thus, the current study was aimed to identify key genes and construct a prognostic signature.MethodsGene expression and clinical data were obtained from The Cancer Genome Atlas (TCGA) database. Differentially expressed genes were calculated by using R software. GO functional and KEGG pathway enrichment analysis were processed. The CIBERSORT algorithm was used to assess immune cell infiltration. STRING database was used to screen key genes and constructed a protein-protein interaction network (PPI network). The LASSO-Cox regression analysis was performed based on the components of the PPI network. The correlation analysis between LNM-related signature and immune infiltrating cells was then investigated. TISIDB was used to explore the correlation between the abundance of immunomodulators and the expression of the inquired gene.ResultsIn total, 394 differentially expressed genes were identified. After constructing and analyzing the PPI network, 180 genes were entered into the LASSO-Cox regression model, constructing a gene signature. Five genes(PMCH, LRP2, NAT1, NKAIN4, and CD1B) were identified as LNM-related genes of clinical value. Correlation analysis revealed that LRP2 and T follicular helper cells (R=0.34, P=0.0019) and NKAIN4 and T follicular helper cells (R=0.23, P=0.041) had significant correlations. Immunologic analysis revealed that LRP2 and NKAIN4 are potential coregulators of immune checkpoints in COAD.ConclusionIn general, this study revealed the key genes related to lymph node metastasis and prognostic signature. Several potential mechanisms and therapeutic and prognostic targets of lymph node metastasis were also demonstrated in COAD

Automatic Portmanteau tests with applications to market risk management

This article reviews some recent advances in testing for serial correlation, provides Stata code for implementation and illustrates its application to market risk forecast evaluation. The classical and widely used Portamenteau tests and their data-driven versions are the focus of this article. These tests are simple to implement for two reasons: First, the researcher does not need to specify the order of the autocorrelation tested, since the test automatically chooses this number; second, its asymptotic none distribution is chi-square with one degree of freedom, so there is no need of using a bootstrap procedure to estimate the critical values. We illustrate the wide applicability of the methodology with applications to forecast evaluation for market risk measures, such as Value-at-Risk and Expected Shortfall.Zaichao Du. Research funded by the National Science Foundation of China, 71401140. Juan Carlos Escanciano. Research funded by the Spanish Plan Nacional de I+D+I, reference number ECO2014-55858-P. Guangwei Zhu. Research funded by the Excellent Doctoral Dissertation Foundation of SWUFE

A Distributed Approach to Efficient Model Predictive Control of Building HVAC Systems

Model based predictive control (MPC) is increasingly being seen as an attractive approach in controlling building HVAC systems. One advantage of the MPC approach is the ability to integrate weather forecast, occupancy information and utility price variations in determining the optimal HVAC operation. However, application to largescale building HVAC systems is limited by the large number of controllable variables to be optimized at every time instance. This paper explores techniques to reduce the computational complexity arising in applying MPC to the control of large-scale buildings. We formulate the task of optimal control as a distributed optimization problem within the MPC framework. A distributed optimization approach alleviates computational costs by simultaneously solving reduced dimensional optimization problems at the subsystem level and integrating the resulting solutions to obtain a global control law. Additional computational efficiency can be achieved by utilizing the occupancy and utility price profiles to restrict the control laws to a piecewise constant function. Alternatively, under certain assumptions, the optimal control laws can be found analytically using a dynamic programming based approach without resorting to numerical optimization routines leading to massive computational savings. Initial results of simulations on case studies are presented to compare the proposed algorithms

Temozolomide and Pazopanib Combined with FOLFOX Regressed a Primary Colorectal Cancer in a Patient-derived Orthotopic Xenograft Mouse Model.

PurposeThe goal of the present study was to determine the efficacy of temozolomide (TEM) and pazopanib (PAZ) combined with FOLFOX (oxaliplatin, leucovorin and 5-fluorouracil) on a colorectal cancer patient-derived orthotopic xenograft (PDOX) mouse model.Materials and methodsA colorectal cancer tumor from a patient previously established in non-transgenic nude mice was implanted subcutaneously in transgenic green fluorescence protein (GFP)-expressing nude mice in order to label the tumor stromal cells with GFP. Then labeled tumors were orthotopically implanted into the cecum of nude mice. Mice were randomized into four groups: Group 1, untreated control; group 2, TEM + PAZ; group 3, FOLFOX; group 4, TEM + PAZ plus FOLFOX. Tumor width, length, and mouse body weight were measured weekly. The Fluor Vivo imaging System was used to image the GFP-lableled tumor stromal cells in vivo. H&E staining and immunohistochemical staining were used for histological analysis.ResultsAll three treatments inhibited tumor growth as compared to the untreated control group. The combination of TEM + PAZ + FOLFOX regressed tumor growth significantly more effectively than TEM + PAZ or FOLFOX. Only the combination of TEM + PAZ + FOLFOX group caused a decrease in body weight. PAZ suppressed lymph vessels density in the colorectal cancer PDOX mouse model suggesting inhibition of lymphangiogenesis.ConclusionOur results suggest that the combination of TEM + PAZ + FOLFOX has clinical potential for colorectal cancer patient

Robust estimation of lake metabolism by coupling high frequency dissolved oxygen and chlorophyll fluorescence data in a Bayesian framework

Gross primary production (GPP) and community respiration (R) are increasingly calculated from high-frequency measurements of dissolved oxygen (DO) by fitting dynamic metabolic models to the observed DO time series. Because different combinations of metabolic components result in nearly the same DO time series, theoretical problems burden this inverse modeling approach. Bayesian parameter inference could improve identification of processes by including independent knowledge in the estimation procedure. This method, however, requires model development because parameters of existing metabolic models are too abstract to achieve a significant improvement. Because algal biomass is a key determinant of GPP and R, and high-frequency data on phytoplankton biomass are increasingly available, coupling DO and biomass time series within a Bayesian framework has a high potential to support identification of individual metabolic components. We demonstrate this potential in 3 lakes. Phytoplankton data were simulated via a sequential Bayesian learning procedure coupled with an error model that accounted for systematic errors caused by structural deficiencies of the metabolic model. This method provided ecologically coherent, and therefore presumably robust, estimates for biomass-specific metabolic rates and contributes to a better understanding of metabolic responses to natural and anthropogenic disturbances

The Global Lake Ecological Observatory Network (GLEON): the evolution of grassroots network science

Nine years later, with over 380 members from 40 countries, and 50 publications to its credit, GLEON is growing at a rapid pace and pushing the boundaries of the practice of network science. GLEON is really three networks: a network of lakes, data, and peopl

A Global lake ecological observatory network (GLEON) for synthesising high-frequency sensor data for validation of deterministic ecological models

A Global Lake Ecological Observatory Network (GLEON; www.gleon.org) has formed to provide a coordinated response to the need for scientific understanding of lake processes, utilising technological advances available from autonomous sensors. The organisation embraces a grassroots approach to engage researchers from varying disciplines, sites spanning geographic and ecological gradients, and novel sensor and cyberinfrastructure to synthesise high-frequency lake data at scales ranging from local to global. The high-frequency data provide a platform to rigorously validate processbased ecological models because model simulation time steps are better aligned with sensor measurements than with lower-frequency, manual samples. Two case studies from Trout Bog, Wisconsin, USA, and Lake Rotoehu, North Island, New Zealand, are presented to demonstrate that in the past, ecological model outputs (e.g., temperature, chlorophyll) have been relatively poorly validated based on a limited number of directly comparable measurements, both in time and space. The case studies demonstrate some of the difficulties of mapping sensor measurements directly to model state variable outputs as well as the opportunities to use deviations between sensor measurements and model simulations to better inform process understanding. Well-validated ecological models provide a mechanism to extrapolate high-frequency sensor data in space and time, thereby potentially creating a fully 3-dimensional simulation of key variables of interest

Intestinal epithelial cell-derived IL-15 determines local maintenance and maturation of intraepithelial lymphocytes in the intestine

Interleukin-15 (IL-15) is a cytokine critical for maintenance of intestinal intraepithelial lymphocytes (IELs), especially CD8αα+ IELs (CD8αα IELs). In the intestine, IL-15 is produced by intestinal epithelial cells (IECs), blood vascular endothelial cells (BECs) and hematopoietic cells. However, the precise role of intestinal IL-15 on IELs is still unknown. To address the question, we generated two kinds of IL-15 conditional knockout (IL-15cKO) mice: villin-Cre (Vil-Cre) and Tie2-Cre IL-15cKO mice. IEC-derived IL-15 was specifically deleted in Vil-Cre IL-15cKO mice, whereas IL-15 produced by BECs and hematopoietic cells is deleted in Tie2-Cre IL-15cKO mice. The cell number and frequency of CD8αα IELs and NK IELs were significantly reduced in Vil-Cre IL-15cKO mice. By contrast, CD8αα IELs were unchanged in Tie2-Cre IL-15cKO mice, indicating that IL-15 produced by BECs and hematopoietic cells is dispensable for CD8αα IELs. Expression of an anti-apoptotic factor, Bcl-2, was decreased, whereas Fas expression was increased in CD8αα IELs of Vil-Cre IL-15cKO mice. Forced expression of Bcl-2 by a Bcl-2 transgene partially restored CD8αα IELs in Vil-Cre IL-15cKO mice, suggesting that some IL-15 signal other than Bcl-2 is required for maintenance of CD8αα IELs. Furthermore, granzyme B production was reduced, whereas PD-1 expression was increased in CD8αα IELs of Vil-Cre IL-15cKO mice. These results collectively suggested that IEC-derived IL-15 is essential for homeostasis of IELs by promoting their survival and functional maturation