112 research outputs found
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
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
Extraction of ozone and chlorophyll-A distribution from AVIRIS data
The potential of airborne imaging spectrometry for assessing and monitoring natural resources is studied. Therefore, an AVIRIS scene of the NASA's MacEurope 1991 campaign - acquired in Central Switzerland - is used. The test site consists of an urban area, the Lake Zug with its surrounding fields, the Rigi mountain in the center of the test site, and the Lake of Four Cantons. The region is covered by the AVIRIS flight #910705, run 6 and 7 of the NASA ER-2 aircraft resulting in an average nominal pixel size of about 18 m. Simultaneous to the ER-2 overflight spectroradiometric measurements have been taken in various locations. Preselected reference targets were measured in the field with a GER Mark V spectroradiometer, and radiance measurements were taken to the lake using a Li-Cor LI 1800UW specroradiometer below and above the water surface. A comprehensive meteorological data set was obtained by joining the POLLUMET experiment which carried out measurements to investigate the summer smog in Switzerland on the same day. The quality assessment for the actual data set can be found in detail in Meyer et al. A parametric approach calculating the location of the airplane was used to simulate the observation geometry. This parametric preprocessing procedure, which takes care of effects of flight line and attitude variations as well as the pixel-by-pixel topographic corrections is described in Meyer
Simultaneous chronic rupture of quadriceps tendon and contra-lateral patellar tendon in a patient affected by tertiary hyperparatiroidism
Spontaneous ruptures of the extensor mechanism of the knee are very rare. They tend to increase considerably in patients with metabolic diseases such as chronic renal failure, hyperparathyroidism, diabetes, gout, and systemic lupus erythematosus. The reported case regards a 48-year-old man with chronic, spontaneous and simultaneous quadriceps, and contra-lateral patellar tendon rupture. The patient suffered from chronic renal failure and for the past year from tertiary hyperparathyroidism. Ruptured tendons were repaired and both knee were evaluated monthly for the next 12 months. Good functional recovery was achieved on both knees without relapse. This case emphasizes the importance of long-term high parathyroid hormone level in the etiology of tendons ruptures
Transcriptome of tumor-Infiltrating T cells in colorectal cancer patients uncovered a unique gene signature in CD4 + T cells associated with poor disease-specific survival
Colorectal cancer (CRC) is influenced by infiltration of immune cell populations in the tumor microenvironment. While elevated levels of cytotoxic T cells are associated with improved prognosis, limited studies have reported associations between CD4+ T cells and disease outcomes. We recently performed transcriptomic profiling and comparative analyses of sorted CD4+ and CD8+ tumor-infiltrating lymphocytes (TILs) from bulk tumors of CRC patients with varying disease stages. In this study, we compared the transcriptomes of CD4+ with CD8+ TILs. Functional annotation pathway analyses revealed the downregulation of inflammatory response-related genes, while T cell activation and angiogenesis-related genes were upregulated in CD4+ TILs. The top 200 deregulated genes in CD4+ TILs were aligned with the cancer genome atlas (TCGA) CRC dataset to identify a unique gene signature associated with poor prognosis. Moreover, 69 upregulated and 20 downregulated genes showed similar trends of up/downregulation in the TCGA dataset and were used to calculate “poor prognosis score” (ppScore), which was significantly associated with disease-specific survival. High ppScore patients showed lower expression of Treg-, Th1-, and Th17-related genes, and higher expression of Th2-related genes. Our data highlight the significance of T cells within the TME and identify a unique candidate prognostic gene signature for CD4+ TILs in CRC patients
Integrating institutional and behavioural measures of bribery
Bribery involves individuals exchanging material benefits for a service of a public institution. To understand the process of bribery we need to integrate measures of individual behaviour and institutional attributes rather than rely exclusively on surveys of individual perceptions and experience or macro-level corruption indexes national institutions. This paper integrates institutional and behavioural measures to show that where you live and who you are have independent influence on whether a person pays a bribe. The analysis of 76 nationwide Global Corruption Barometer surveys from six continents provides a date set in which both institutional and individual differences vary greatly. Multi-level multivariate logit analysis is used to test hypotheses about the influence of institutional context and individual contact with public services, socio-economic inequalities and roles, and conflicting behavioural and ethical norms. It finds that path-determined histories of early bureaucratization or colonialism have a major impact after controlling for individual differences. At the individual level, people who frequently make use of public services and perceive government as corrupt are more likely to pay bribes, while socio-economic inequality has no significant influence. While institutional history cannot be changed, changing the design of public services offers is something that contemporary governors could do to reduce the vulnerability of their citizens to bribery
Downregulation of TFPI in breast cancer cells induces tyrosine phosphorylation signaling and increases metastatic growth by stimulating cell motility
<p>Abstract</p> <p>Background</p> <p>Increased hemostatic activity is common in many cancer types and often causes additional complications and even death. Circumstantial evidence suggests that tissue factor pathway inhibitor-1 (TFPI) plays a role in cancer development. We recently reported that downregulation of TFPI inhibited apoptosis in a breast cancer cell line. In this study, we investigated the effects of TFPI on self-sustained growth and motility of these cells, and of another invasive breast cancer cell type (MDA-MB-231).</p> <p>Methods</p> <p>Stable cell lines with TFPI (both α and β) and only TFPIβ downregulated were created using RNA interference technology. We investigated the ability of the transduced cells to grow, when seeded at low densities, and to form colonies, along with metastatic characteristics such as adhesion, migration and invasion.</p> <p>Results</p> <p>Downregulation of TFPI was associated with increased self-sustained cell growth. An increase in cell attachment and spreading was observed to collagen type I, together with elevated levels of integrin α2. Downregulation of TFPI also stimulated migration and invasion of cells, and elevated MMP activity was involved in the increased invasion observed. Surprisingly, equivalent results were observed when TFPIβ was downregulated, revealing a novel function of this isoform in cancer metastasis.</p> <p>Conclusions</p> <p>Our results suggest an anti-metastatic effect of TFPI and may provide a novel therapeutic approach in cancer.</p
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Greasing the wheels? The impact of regulations and corruption on firm entry
This paper investigates the question of whether corruption might ‘grease the
wheels’ of an economy. We investigate whether and to what extent the impact of regulations
on entrepreneurship is dependent on corruption. We first test whether regulations robustly
deter firm entry into markets. Our results show that the existence of a larger number
of procedures required to start a business, as well as larger minimum capital requirements
are detrimental to entrepreneurship. Second, we test whether corruption reduces the negative
impact of regulations on entrepreneurship in highly regulated economies. Our empirical
analysis, covering a maximum of 43 countries over the 2003–2005 period, shows that corruption
facilitates firm entry in highly regulated economies. For example, the ‘greasing’
effect of corruption kicks in at around 50 days required to start a new business. Our results
thus provide support for the ‘grease the wheels’ hypothesis
Rumo a uma sociedade melhor: uma análise da agenda de reformas econômicas de J. S. Mill
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