Notch signaling defects in NK cells in patients with cancer.

Altered expressions of proto-oncogenes have been reported during normal lymphocytes mitogenesis and in T and B lymphocytes in patients with autoimmune diseases. We have recently demonstrated a significantly decreased expression of c-kit and c-Myc in NK cells isolated from patients with cancer, which might be related to the functional deficiency of NK cells in the tumor environment. Here, focusing on the regulatory mechanisms of this new clinical phenomenon, we determined expression of c-Myc, Notch1, Notch2, p-53, Cdk6, Rb and phosphorylated Rb in NK cells isolated from the healthy donors and cancer patients. The results of our study revealed a significant down-regulation of expression of Notch receptors and up-regulation of Cdk6 expression in NK cells in cancer, while no significant changes in the expression of p53 and Rb proteins were seen. These data revealed novel signaling pathways altered in NK cells in the tumor environment and support further investigation of the origin of deregulated expression of proto-oncogenes in NK cells patients with different types of cancer.

State-Resolved Dissociation and Exchange Reactions in CO2 Flows.

State-resolved chemical reactions in CO2 are studied by taking into account excitation of all vibrational modes and preferential reaction mechanisms. The effect of several parameters on the reaction rate coefficients is discussed; it is shown that the nonequilibrium factor in the expression for the rate coefficients of exchange reactions is much less sensitive to the number of accounted vibrational states and model parameters than that of dissociation. On the other hand, the choice of thermal equilibrium Arrhenius law parameters is crucial for the correct prediction of rate coefficients for both reactions. Developed models are implemented to the one-dimensional boundary layer code for coupled state-to-state simulations of nonequilibrium CO2 flows under Mars entry conditions. Vibrational distributions, mixture composition, flow variables, and heat flux are studied for several kinetic schemes and different models of chemical reactions. Whereas including the exchange reactions weakly affects the flow, switching between the Park and McKenzie sets of parameters results in significant modification of the kinetic mechanisms; for the McKenzie model, recombination near the wall is a dominating reaction, whereas for the Park model, chemical reactions are frozen. Different contributions to the heat flux are evaluated and a satisfactory agreement with experiments is shown.

Abnormal Expression of c-Myc Oncogene in NK Cells in Patients with Cancer.

Natural killer (NK) cells have received a lot of attention in recent years for the roles they play in immunity and particularly in antitumor immune responses. Although defects in NK cell functions are recognized as important mechanisms for immune evasion of malignant cells, molecular pathways regulating NK cell dysfunction and exhaustion in cancer are largely unknown. Here we tested whether the c-myc proto-oncogene, known to promote cell proliferation, growth, differentiation, and apoptosis by regulating the expression of numerous target genes, may be involved in the mechanism of NK cell abnormalities in patients with lung and gastric cancer. Analysis of c-myc mRNA and protein expression in peripheral blood NK cells, mitogen-activated protein kinase (MAPK) activity, cell cycle, and cell longevity revealed a significantly decreased expression of c-myc mRNA and protein and mitotic arrest of NK cells in different phases of cell cycle. In addition, a significant decrease of NK cell death was also detected. These data allow the suggestion that defects of NK cell-mediated tumor surveillance may be associated with disturbed c-myc expression in NK cells in cancer patients. A better understanding of the mechanisms of NK cell dysfunction in cancer will help in the NK cell-mediated therapeutic eradication of primary and metastatic cancer cells and prolong patient survival.

Effect of Asymmetric Mode on CO2 State-to-State Vibrational-Chemical Kinetics.

Coupled state-to-state vibrational-chemical kinetics, gas dynamics, and heat transfer in the five-component mixture of dissociated CO2 are studied using the complete three-mode kinetic model and the reduced scheme involving mainly the vibrational states of the asymmetric mode. The emphasis is on the effect of asymmetric vibrations on the rate of dissociation, fluid dynamic variables, and heat flux. It is shown that intermode vibrational energy transitions between CO and CO2 asymmetric mode may considerably decrease the rate of dissociation; the presence of CO in the mixture quickly depletes high vibrational states and thus inhibits dissociation at low temperatures. The reduced model overpredicts populations of highly located states of the asymmetric mode, especially when intermode VV transitions are neglected; therefore, using the simplified model in flows with dominating dissociation may yield overestimated dissociation rate. In the hypersonic flow along the stagnation line, the influence of asymmetric vibrations on the fluid dynamics and heat transfer is weak; the main role belongs to chemical reactions and VT transitions in the bending mode. In this case, the computationally efficient simplified model can be used to predict macroscopic variables and heat flux without significant loss of accuracy.

Mechanisms of Coupled Vibrational Relaxation and Dissociation in Carbon Dioxide.

A complete vibrational state-specific kinetic scheme describing dissociating carbon dioxide mixtures is proposed. CO2 symmetric, bending and asymmetric vibrations and dissociation-recombination are strongly coupled through intermode vibrational energy transfers. Comparative study of state-resolved rate coefficients is carried out; the effect of different transitions may vary considerably with temperature. A nonequilibrium 1-D boundary layer flow typical to hypersonic planetary entry is studied in the state-to-state approach. To assess the sensitivity of fluid-dynamic variables and heat transfer to various vibrational transitions and chemical reactions, corresponding processes are successively included to the kinetic scheme. It is shown that vibrational-translational (VT) transitions in the symmetric and asymmetric modes do not alter the flow and can be neglected whereas the VT2 exchange in the bending mode is the main channel of vibrational relaxation. Intermode vibrational exchanges affect the flow implicitly, through energy redistribution enhancing VT relaxation; the dominating role belongs to near-resonant transitions between symmetric and bending modes as well as between CO molecules and CO2 asymmetric mode. Strong coupling between VT2 relaxation and chemical reactions is emphasized. While vibrational distributions and average vibrational energy show strong dependence on the kinetic scheme, the heat flux is more sensitive to chemical reactions.

Functional heterogeneity of circulating T regulatory cell subsets in breast cancer patients.

BACKGROUND: Regulatory T cells (Tregs) play a major role in tumor escape from immunosurveillance by suppressing effector cells. The number of Tregs is increased in tumor sites and peripheral blood of breast cancer patients. However, the data regarding phenotypic and functional heterogeneity of Treg subpopulations in breast cancer are limited. The present study aimed to investigate the number and suppressive potential of Tregs that possess natural naïve-(N nTregs), effector/memory-like (EM nTregs), and Tr1-like phenotypes in breast cancer patients and healthy women. METHODS: The study included 10 HW and 17 primary breast cancer patients. Numbers of CD4+CD25+FoxP3+CD45RA+ N nTregs, CD4+CD25+FoxP3+CD45RA- EM nTregs, and CD4+IL-4-IL-10+ Tr1 subsets and the expression of CTLA-4, CD39, GITR, LAP, and IL-35 by these Treg subsets were measured in freshly obtained peripheral blood by flow cytometry. RESULTS: Herein, we demonstrate that the percentages of N nTregs, EM nTregs, CD25+ and FoxP3+ Tr1 cells are elevated in the peripheral blood of breast cancer patients, but do not correlate with cancer stages. Nevertheless, the frequency of CD25+ Tr1 cells was associated with nodal involvement, while the number of EM nTregs correlated with clinical outcome. The expression of CTLA-4 and IL-35 by all assessed Treg subsets was increased throughout all tumor stages (I-III). CONCLUSIONS: Collectively, the current study shows phenotypic alterations in suppressive receptors of Treg subsets, suggesting that breast cancer patients have increased activity of N nTregs, EM nTregs and Tr1 cells; and EM nTregs and CD25+ Tr1 cells represent prospective markers for assessing disease prognosis.

Alterations of oncogenes expression in NK cells in patients with cancer.

INTRODUCTION: C-kit/SCF signaling plays a key role in regulating NK cell homeostasis, maturation, proliferation, and cytotoxicity. C-kit-deficiency in NK cells results in significant reduction of their number, suggesting an imperative role for c-kit signaling in NK cell biology. We have recently showed that human NK cells express not only c-kit-receptor, but also both membrane-bound and soluble forms of c-kit ligand-Stem cell factor. The goal of this study was to characterize the c-kit/SCF autocrine loop in peripheral blood NK cells obtained from patients with cancer. METHODS: Using Smart Flare and qRT-PCR, we have characterized expression of c-kit and two forms of SCF in patients' NK cells and correlated these results with the expression of c-myc and STAT3. RESULTS: Our results demonstrated that the expression of proto-oncogenes c-myc and c-kit was significantly decreased in NK cells from all cancer patients. Expression of membrane-bound SCF in NK cells correlated with the presence of remote metastases. CONCLUSIONS: We suggest that the abnormal signaling and expression of c-kit/SCF, c-myc, and STAT3 in NK cells is responsible for the defect in their cytolytic activity in cancer and these defects at the gene expression level may be the cause rather than the result of tumor progression.

Elemental transport coefficients in viscous plasma flows near local thermodynamic equilibrium.

We propose a convenient formulation of elemental transport coefficients in chemically reacting and plasma flows locally approaching thermodynamic equilibrium. A set of transport coefficients for elemental diffusion velocities, heat flux, and electric current is introduced. These coefficients relate the transport fluxes with the electric field and with the spatial gradients of elemental fractions, pressure, and temperature. The proposed formalism based on chemical elements and fully symmetric with the classical transport theory based on chemical species, is particularly suitable to model mixing and demixing phenomena due to diffusion of chemical elements. The aim of this work is threefold: to define a simple and rigorous framework suitable for numerical implementation, to allow order of magnitude estimations and qualitative predictions of elemental transport phenomena, and to gain a deeper insight into the physics of chemically reacting flows near local equilibrium.