Abstract Accumulating evidence indicates a critical role of myeloid cells in the pathophysiology of human cancers. In contrast to the well-characterized tumor-associated macrophages (TAMs), the ...significance of granulocytes in cancer has only recently begun to emerge. Increased numbers of neutrophil granulocytes have been observed both in the peripheral blood and in the tumor tissues of patients with different types of cancer. Importantly, these studies linked neutrophils to poor clinical outcome in cancer patients which suggests that these cells might have important tumor-promoting activities. Indeed, a number of functional in vitro and in vivo studies demonstrated that tumors stimulated neutrophils to promote angiogenesis and immunosuppression, as well as migration, invasion and metastasis of the tumor cells. Therefore, it became necessary to understand the mechanisms modulating the changes in the biology and functions of neutrophils in the context of the tumor microenvironment. In this review we will discuss several functions of neutrophils that might contribute to tumor progression. Furthermore, we will address in detail the cellular and molecular mechanisms that control modulation of neutrophils in the tumor microenvironment, such as recruitment to the tumor site (chemotaxis), prolonged survival and enhanced release of protumoral mediators.
Many-body QCD in leading high energy Regge asymptotics is described by the Balitsky–JIMWLK hierarchy of renormalization group equations for the x evolution of multi-point Wilson line correlators. ...These correlators are universal and ubiquitous in final states in deeply inelastic scattering and hadronic collisions. For instance, recently measured di-hadron correlations at forward rapidity in deuteron–gold collisions at the Relativistic Heavy Ion Collider (RHIC) are sensitive to four and six point correlators of Wilson lines in the small x color fields of the dense nuclear target. We evaluate these correlators numerically by solving the functional Langevin equation that describes the Balitsky–JIMWLK hierarchy. We compare the results to mean-field Gaussian and large Nc approximations used in previous phenomenological studies. We comment on the implications of our results for quantitative studies of multi-gluon final states in high energy QCD.
Accumulating evidence indicates that myeloid cells are critically involved in the pathophysiology of human cancers. In contrast to the well-characterized tumor-associated macrophages, the ...significance of granulocytes in cancer has only recently begun to emerge. A number of studies found increased numbers of neutrophil granulocytes and granulocytic myeloid-derived suppressor cells (GrMDSCs) both in the peripheral blood and in the tumor tissues of patients with different types of cancer. Most importantly, granulocytes have been linked to poor clinical outcome in cancer patients which suggests that these cells might have important tumor-promoting effects. In this review, we will address in detail the following major topics: (1) neutrophils and GrMDSCs in the peripheral blood of cancer patients—phenotype and functional changes; (2) neutrophils and GrMDSCs in the tumor tissue—potential mechanisms of tumor progression and (3) relevance of neutrophils and GrMDSCs for the clinical outcome of cancer patients. Furthermore, we will discuss the advantages and disadvantages of the current strategies used for identification and monitoring of human MDSCs. We propose a six-color immunophenotyping protocol that discriminates between monocytic MDSCs (MoMDSCs), two subsets of GrMDSCs and two subsets of immature myeloid cells in human cancer patients, thus, allowing for an improved characterization and understanding of these multifaceted cells.
Publicly available (own) transcriptomic data have been analyzed to quantify the alteration in functional pathways in thyroid cancer, establish the gene hierarchy, identify potential gene targets and ...predict the effects of their manipulation. The expression data have been generated by profiling one case of papillary thyroid carcinoma (PTC) and genetically manipulated BCPAP (papillary) and 8505C (anaplastic) human thyroid cancer cell lines. The study used the genomic fabric paradigm that considers the transcriptome as a multi-dimensional mathematical object based on the three independent characteristics that can be derived for each gene from the expression data. We found remarkable remodeling of the thyroid hormone synthesis, cell cycle, oxidative phosphorylation and apoptosis pathways. Serine peptidase inhibitor, Kunitz type, 2 (
) was identified as the Gene Master Regulator of the investigated PTC. The substantial increase in the expression synergism of
with apoptosis genes in the cancer nodule with respect to the surrounding normal tissue (NOR) suggests that
experimental overexpression may force the PTC cells into apoptosis with a negligible effect on the NOR cells. The predictive value of the expression coordination for the expression regulation was validated with data from 8505C and BCPAP cell lines before and after lentiviral transfection with
Low-salt diet (LSD) is a constant recommendation to hypertensive patients, but the genomic mechanisms through which it improves cardiac pathophysiology are still not fully understood. Our publicly ...accessible transcriptomic dataset of the left ventricle myocardium of adult male mice subjected to prolonged LSD or normal diet was analyzed from the perspective of the Genomic Fabric Paradigm. We found that LSD shifted the metabolic priorities by increasing the transcription control for fatty acids biosynthesis while decreasing it for steroid hormone biosynthesis. Moreover, LSD remodeled pathways responsible for cardiac muscle contraction (CMC), chronic Chagas (CHA), diabetic (DIA), dilated (DIL), and hypertrophic (HCM) cardiomyopathies, and their interplays with the glycolysis/glucogenesis (GLY), oxidative phosphorylation (OXP), and adrenergic signaling in cardiomyocytes (ASC). For instance, the statistically (
< 0.05) significant coupling between GLY and ASC was reduced by LSD from 13.82% to 2.91% (i.e., -4.75×), and that of ASC with HCM from 10.50% to 2.83% (-3.71×). The substantial up-regulation of the CMC, ASC, and OXP genes, and the significant weakening of the synchronization of the expression of the HCM, CHA, DIA, and DIL genes within their respective fabrics justify the benefits of the LSD recommendation.
Reconstructing the evolution of sea level during past warmer epochs such as the Pliocene provides insight into the response of sea level and ice sheets to prolonged warming
. Although estimates of ...the global mean sea level (GMSL) during this time do exist, they vary by several tens of metres
, hindering the assessment of past and future ice-sheet stability. Here we show that during the mid-Piacenzian Warm Period, which was on average two to three degrees Celsius warmer than the pre-industrial period
, the GMSL was about 16.2 metres higher than today owing to global ice-volume changes, and around 17.4 metres when thermal expansion of the oceans is included. During the even warmer Pliocene Climatic Optimum (about four degrees Celsius warmer than pre-industrial levels)
, our results show that the GMSL was 23.5 metres above the present level, with an additional 1.6 metres from thermal expansion. We provide six GMSL data points, ranging from 4.39 to 3.27 million years ago, that are based on phreatic overgrowths on speleothems from the western Mediterranean (Mallorca, Spain). This record is unique owing to its clear relationship to sea level, its reliable U-Pb ages and its long timespan, which allows us to quantify uncertainties on potential uplift. Our data indicate that ice sheets are very sensitive to warming and provide important calibration targets for future ice-sheet models
.
Myocardium transcriptomes of left and right atria and ventricles from four adult male C57Bl/6j mice were profiled with Agilent microarrays to identify the differences responsible for the distinct ...functional roles of the four heart chambers. Female mice were not investigated owing to their transcriptome dependence on the estrous cycle phase. Out of the quantified 16,886 unigenes, 15.76% on the left side and 16.5% on the right side exhibited differential expression between the atrium and the ventricle, while 5.8% of genes were differently expressed between the two atria and only 1.2% between the two ventricles. The study revealed also chamber differences in gene expression control and coordination. We analyzed ion channels and transporters, and genes within the cardiac muscle contraction, oxidative phosphorylation, glycolysis/gluconeogenesis, calcium and adrenergic signaling pathways. Interestingly, while expression of Ank2 oscillates in phase with all 27 quantified binding partners in the left ventricle, the percentage of in-phase oscillating partners of Ank2 is 15% and 37% in the left and right atria and 74% in the right ventricle. The analysis indicated high interventricular synchrony of the ion channels expressions and the substantially lower synchrony between the two atria and between the atrium and the ventricle from the same side.
Glioblastoma (GBM) is the most malignant brain tumor and one of the deadliest types of solid cancer overall. Despite aggressive therapeutic approaches consisting of maximum safe surgical resection ...and radio-chemotherapy, more than 95% of GBM patients die within 5 years after diagnosis. Thus, there is still an urgent need to develop novel therapeutic strategies against this disease. Accumulating evidence indicates that cannabinoids have potent anti-tumor functions and might be used successfully in the treatment of GBM. This review article summarizes the latest findings on the molecular effects of cannabinoids on GBM, both
and in (pre-) clinical studies in animal models and patients. The therapeutic effect of cannabinoids is based on reduction of tumor growth via inhibition of tumor proliferation and angiogenesis but also via induction of tumor cell death. Additionally, cannabinoids were shown to inhibit the invasiveness and the stem cell-like properties of GBM tumors. Recent phase II clinical trials indicated positive results regarding the survival of GBM patients upon cannabinoid treatment. Taken together these findings underline the importance of elucidating the full pharmacological effectiveness and the molecular mechanisms of the cannabinoid system in GBM pathophysiology.
We have previously shown that activation of the acid sphingomyelinase (ASM), the release of ceramide and the formation of ceramide-enriched membrane domains are central for the induction of apoptosis ...by CD95. Here, we demonstrate that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and CD95 activate the ASM via a redox mechanism resulting in release of ceramide and formation of ceramide-enriched membrane platforms. Ceramide-enriched membrane platforms serve to cluster DR5 upon stimulation. Antioxidants prevent TRAIL-mediated stimulation of ASM, the release of ceramide, the formation of ceramide-enriched membrane platforms and the induction of apoptosis by TRAIL. Further, ASM-deficient splenocytes fail to cluster DR5 in ceramide-enriched membrane domains upon TRAIL stimulation and resist TRAIL-induced apoptosis, events that were restored by addition of natural C(16)-ceramide. A dose-response analysis indicates that ceramide-enriched membrane platforms greatly sensitized tumor cells to TRAIL-induced apoptosis. Our data indicate that ceramide-enriched membrane platforms are required for the signaling of TRAIL-DR5 complexes under physiological conditions.
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