Immune checkpoints in circulating and tumor-Infiltrating CD4 + T Cell Subsets in Colorectal cancer patients

Blockade of inhibitory immune checkpoints (ICs) is a promising therapeutic approach; however, it has shown limited success in some cancers including colorectal cancer (CRC). The tumor microenvironment (TME) is largely responsible for response to therapy, and its constituents may provide robust biomarkers for successful immunotherapeutic approaches. In this study, we performed phenotypical characterization and critical analyses of key inhibitory ICs and T regulatory cell (Treg)-related markers on CD4+ T cell subsets in CRC patients, and compared with normal colon tissues and peripheral blood from the same patients. We also investigated correlations between the levels of different CD4+ T cell subsets and the clinicopathologic features including disease stage and tumor budding. We found a significant increase in the levels of CD4+FoxP3+Helios+ T cells, which represent potentially highly immunosuppressive Tregs, in the CRC TME. Additionally, tumor-infiltrating CD4+ T cells upregulated programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), T cell immunoglobulin and mucin domain-3 (TIM-3) and lymphocyte-activation gene 3 (LAG-3). We also characterized the expression of PD-1, CTLA-4, TIM-3, and LAG-3 on different CD4+FoxP3−/+Helios−/+ T cell subsets. Interestingly, we found that CTLA-4, TIM-3, and LAG-3 were mainly co-expressed on FoxP3+Helios+ Tregs in the TME. Additionally, FoxP3high Tregs expressed higher levels of Helios, CTLA-4 and TIM-3 than FoxP3low T cells. These results highlight the significance of Tregs in the CRC TME and suggest that Tregs may hamper response to IC blockade in CRC patients, but effects of different IC inhibition regimes on Treg levels or activity warrants further investigations. We also found that CD4+CTLA-4+ T cells in circulation are increased in patients with advanced disease stage. This study simultaneously provides important insights into the differential levels of CD4+ T cell subpopulations and IC expression in CRC TME, compared to periphery and associations with clinicopathologic features, which could be used as potential biomarkers for CRC progression and response to therapy

A Survey on Wireless Network Simulators

The Network simulator helps the developer to create and simulate new models on an arbitrary network by specifying both the behavior of the network nodes and the communication channels. It provides a virtual environment for an assortment of desirable features such as modeling a network based on a specific criteria and analyzing its performance under different scenarios. This saves cost and time required for testing the functionality and the execution of network. This paper has surveyed various Wireless Network Simulators and compared them

A Survey on Wireless Network Simulators

The Network simulator helps the developer to create and simulate new models on an arbitrary network by specifying both the behavior of the network nodes and the communication channels. It provides a virtual environment for an assortment of desirable features such as modeling a network based on a specific criteria and analyzing its performance under different scenarios. This saves cost and time required for testing the functionality and the execution of network. This paper has surveyed various Wireless Network Simulators and compared them

Kinetics of the Esterification Reaction between Pentanoic Acid and Methanol Catalyzed by Noncorrosive Cation Exchange Resin

Methyl pentanoate, commonly known as methyl valerate, is the methyl ester of pentanoic acid (valeric acid) with a fruity odour. Methyl pentanoate is commonly used in fragrances, beauty care, soap, laundry detergents at levels of 0.1 – 1 %. In its very pure form (purity 99.5 %) it is used as a plasticizer in the manufacture of plastics. In the present investigation, kinetics of esterification of pentanoic acid with methanol catalyzed by heterogeneous catalyst in a batch-type reactor is reported. The effect of reaction conditions such as temperature, molar ratio, catalyst loading, and initial concentration of pentanoic acid and methanol, and the inhibiting effect of water on the kinetics has been studied. The pentanoic acid conversion reached 93 % at 333.15 K at a methanol to pentanoic acid molar ratio of 10:1 with 7 % (g L–1) Amberlyst 15 as catalyst. Mass transfer effects were found to be negligible. Observed reaction rate data was fitted to the regression technique. Estimated Eley-Rideal kinetic model reaction rate constants were fitted to the Arrhenius type equation with activation energy EA 39.5 kJ mol–1 and pre exponential factor ko 1.8 · 103 L2 g–1 mol–1 h–1

Transcriptomic profiling of tumor-infiltrating CD4 + TIM-3 + T Cells reveals their suppressive, exhausted, and metastatic characteristics in colorectal cancer patients

T cell immunoglobulin mucin-3 (TIM-3) is an immune checkpoint identified as one of the key players in regulating T-cell responses. Studies have shown that TIM-3 is upregulated in the tumor microenvironment (TME). However, the precise role of TIM-3 in colorectal cancer (CRC) TME is yet to be elucidated. We performed phenotypic and molecular characterization of TIM-3+ T cells in the TME and circulation of CRC patients by analyzing tumor tissues (TT, TILs), normal tissues (NT, NILs), and peripheral blood mononuclear cells (PBMC). TIM-3 was upregulated on both CD4+ and CD3+CD4− (CD8+) TILs. CD4+TIM-3+ TILs expressed higher levels of T regulatory cell (Tregs)-signature genes, including FoxP3 and Helios, compared with their TIM-3− counterparts. Transcriptomic and ingenuity pathway analyses showed that TIM-3 potentially activates inflammatory and tumor metastatic pathways. Moreover, NF-κB-mediated transcription factors were upregulated in CD4+TIM-3+ TILs, which could favor proliferation/invasion and induce inflammatory and T-cell exhaustion pathways. In addition, we found that CD4+TIM-3+ TILs potentially support tumor invasion and metastasis, compared with conventional CD4+CD25+ Tregs in the CRC TME. However, functional studies are warranted to support these findings. In conclusion, this study discloses some of the functional pathways of TIM-3+ TILs, which could improve their targeting in more specific therapeutic approaches in CRC patients

Transcriptomic profiling disclosed the role of DNA methylation and histone modifications in tumor-infiltrating myeloid-derived suppressor cell subsets in colorectal cancer

Increased numbers of myeloid-derived suppressor cells (MDSCs) are positively correlated with poor prognosis and reduced survivals of cancer patients. They play central roles in tumor immune evasion and tumor metastasis. However, limited data are available on phenotypic/transcriptomic characteristics of the different MDSCs subsets in cancer. These cells include immature (I-MDSCs), monocytic (M-MDSCs), and polymorphonuclear/granulocytic (PMN-MDSCs). Phenotypic characterization of myeloid subsets from 27 colorectal cancer (CRC) patients was assessed by flow cytometric analyses. RNA-sequencing of sorted I-MDSCs, PMN-MDSCs, and antigen-presenting cells (APCs) was also performed. We found that the levels of I-MDSCs and PMN-MDSCs were increased in tumor tissues (TT), compared with normal tissues (NT) in colorectal cancer. Our functional annotation analyses showed that genes associated with histone deacetylase (HDAC) activation- and DNA methylation-mediated transcriptional silencing were upregulated, and histone acetyl transferase (HAT)-related genes were downregulated in tumor-infiltrating I-MDSCs. Moreover, pathways implicated in cell trafficking and immune suppression, including Wnt, interleukin-6 (IL-6), and mitogen-activated protein kinase (MAPK) signaling, were upregulated in I-MDSCs. Notably, PMN-MDSCs showed downregulation in genes related to DNA methylation and HDAC binding. Using an ex vivo model, we found that inhibition of HDAC activation or neutralization of IL-6 in CRC tumor tissues downregulates the expression of genes associated with immunosuppression and myeloid cell chemotaxis, confirming the importance of HDAC activation and IL-6 signaling pathway in MDSC function and chemotaxis. This study provides novel insights into the epigenetic regulations and other molecular pathways in different myeloid cell subsets within the CRC tumor microenvironment (TME), giving opportunities to potential targets for therapeutic benefits

A pedagogical framework for enhancing skills of references and citations

References and citations form a basis for scientific research and creation/discovery of knowledge. However literature reviews had indicated that many errors are present in scholarly papers published in journals and conferences as well as in books and articles. Furthermore, course works of students studying in higher education institutions contain mistakes in references lists and in-text citations. Problems that stem from these inaccuracies are multifarious and range from the act of plagiarism, not acknowledging the source, problems in information access and retrieval as well as causing inaccuracies in ranking articles and journals, thus hindering the growth of knowledge. Based on the importance of this global issue this research was initiated. The first objective of our research was to determine root causes for the presence of mistakes and inadequacies in references and citations within the academic arena. We chose the academic arena because they are the training grounds for education and scientific research. Furthermore, through this research we sought a unique practical solution for this issue. In order to conduct a thorough and comprehensive investigation into the above mentioned problems, and to achieve the aim of proposing a suitable solution, we divided our research work into three main phases. First phase was the investigative phase. During this phase a thorough literature review was conducted. As a result of this review, research questions were formed. Both quantitative and qualitative methods were adopted to investigate the causes of erroneous references and citations. Triangulation research methodology was used to get reliable and comprehensive information. Data received through these methods were analyzed and core issues such as inadequate feedback and training in referencing task were highlighted. In the second phase, termed as solution phase, a pedagogical framework was proposed to resolve issues that were reported during the investigative phase. A conceptual framework was built on the principles of Learning theories and spaced repetition theory. To evaluate this framework experiments were conducted. This was done in the third and final phase of the research which was termed as evaluation phase. Two types of experiments were conducted, first type was in a traditional classroom environment and the second type of experiment was with students who chose to work independently (without tutors). Data were collected and analyzed from these experiments using both quantitative methods and qualitative methods and were analyzed. This research provides insight into causes of errors within referencing tasks of students in higher education. It Indicates that reform in the pedagogy for teaching this skill is needed. Furthermore a unique pedagogy is presented. Results from experiments have indicated that through the proposed operational model improvements of referencing skills have been seen

Quantum Games with Correlated Noise

We analyze quantum game with correlated noise through generalized quantization scheme. Four different combinations on the basis of entanglement of initial quantum state and the measurement basis are analyzed. It is shown that the advantage that a quantum player can get by exploiting quantum strategies is only valid when both the initial quantum state and the measurement basis are in entangled form. Furthermore, it is shown that for maximum correlation the effects of decoherence diminish and it behaves as a noiseless game.Comment: 12 page