T-Bet and Eomes Regulate the Balance between the Effector/Central Memory T Cells versus Memory Stem Like T Cells

Memory T cells are composed of effector, central, and memory stem cells. Previous studies have implicated that both T-bet and Eomes are involved in the generation of effector and central memory CD8 T cells. The exact role of these transcription factors in shaping the memory T cell pool is not well understood, particularly with memory stem T cells. Here, we demonstrate that both T-bet or Eomes are required for elimination of established tumors by adoptively transferred CD8 T cells. We also examined the role of T-bet and Eomes in the generation of tumor-specific memory T cell subsets upon adoptive transfer. We showed that combined T-bet and Eomes deficiency resulted in a severe reduction in the number of effector/central memory T cells but an increase in the percentage of CD62LhighCD44low Sca-1+ T cells which were similar to the phenotype of memory stem T cells. Despite preserving large numbers of phenotypic memory stem T cells, the lack of both of T-bet and Eomes resulted in a profound defect in antitumor memory responses, suggesting T-bet and Eomes are crucial for the antitumor function of these memory T cells. Our study establishes that T-bet and Eomes cooperate to promote the phenotype of effector/central memory CD8 T cell versus that of memory stem like T cells. © 2013 Li et al

Population pharmacokinetics of tigecycline in critically ill patients with severe infections

We sought to describe the population pharmacokinetics of tigecycline in critically ill patients and to determine optimized dosing regimens of tigecycline for different bacterial infections. This prospective study included 10 critically ill patients given a standard dose of tigecycline. Blood samples were collected during one dosing interval and were analyzed using validated chromatography. Population pharmacokinetics and Monte Carlo dosing simulations were undertaken using Pmetrics. Three target exposures, expressed as ratios of the 24-h area under the curve to MICs (AUC(0-24)/MIC), were evaluated (>= 17.9 for skin infections, >= 6.96 for intraabdominal infections, >= 4.5 for hospital-acquired pneumonia). The median age, total body weight, and body mass index (BMI) were 67 years, 69.1 kg, and 24.7 kg/m(2), respectively. A two-compartment linear model best described the time course of tigecycline concentrations. The parameter estimates (expressed as means +/- standard deviations [SD]) from the final model were as follows: clearance (CL), 7.50 +/- 1.11 liters/h; volume in the central compartment, 72.50 +/- 21.18 liters; rate constant for tigecycline distribution from the central to the peripheral compartment, 0.31 +/- 0.16 h(-1); and rate constant for tigecycline distribution from the peripheral to the central compartment, 0.29 +/- 0.30 h(-1). A larger BMI was associated with increased CL of tigecycline. Licensed doses were found to be sufficient for Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, and methicillin-resistant Staphylococcus aureus for an AUC(0- 24)/MIC target of 4.5 or 6.96. For a therapeutic target of 17.9, an increased tigecycline dose is required, especially for patients with higher BMI. The dosing requirements of tigecycline differ with the indication, with pathogen susceptibility, and potentially with patient BMI

Role of Granulocyte-Macrophage Colony-Stimulating Factor Production by T Cells during Mycobacterium tuberculosis Infection

ABSTRACT Mice deficient for granulocyte-macrophage colony-stimulating factor (GM-CSF−/−) are highly susceptible to infection with Mycobacterium tuberculosis, and clinical data have shown that anti-GM-CSF neutralizing antibodies can lead to increased susceptibility to tuberculosis in otherwise healthy people. GM-CSF activates human and murine macrophages to inhibit intracellular M. tuberculosis growth. We have previously shown that GM-CSF produced by iNKT cells inhibits growth of M. tuberculosis. However, the more general role of T cell-derived GM-CSF during infection has not been defined and how GM-CSF activates macrophages to inhibit bacterial growth is unknown. Here we demonstrate that, in addition to nonconventional T cells, conventional T cells also produce GM-CSF during M. tuberculosis infection. Early during infection, nonconventional iNKT cells and γδ T cells are the main source of GM-CSF, a role subsequently assumed by conventional CD4+ T cells as the infection progresses. M. tuberculosis-specific T cells producing GM-CSF are also detected in the peripheral blood of infected people. Under conditions where nonhematopoietic production of GM-CSF is deficient, T cell production of GM-CSF is protective and required for control of M. tuberculosis infection. However, GM-CSF is not required for T cell-mediated protection in settings where GM-CSF is produced by other cell types. Finally, using an in vitro macrophage infection model, we demonstrate that GM-CSF inhibition of M. tuberculosis growth requires the expression of peroxisome proliferator-activated receptor gamma (PPARγ). Thus, we identified GM-CSF production as a novel T cell effector function. These findings suggest that a strategy augmenting T cell production of GM-CSF could enhance host resistance against M. tuberculosis

TIM-3 Expression Characterizes Regulatory T Cells in Tumor Tissues and Is Associated with Lung Cancer Progression

Background: T cell immunoglobulin-3 (TIM-3) has been established as a negative regulatory molecule and plays a critical role in immune tolerance. TIM-3 is upregulated in exhausted CD8 + T cells in both chronic infection and tumor. However, the nature of TIM-3 +CD4 + T cells in the tumor microenvironment is unclear. This study is to characterize TIM-3 expressing lymphocytes within human lung cancer tissues and establish clinical significance of TIM-3 expression in lung cancer progression. Methodology: A total of 51 human lung cancer tissue specimens were obtained from pathologically confirmed and newly diagnosed non-small cell lung cancer (NSCLC) patients. Leukocytes from tumor tissues, distal normal lung tissues, and peripheral blood mononuclear cells (PBMC) were analyzed for TIM-3 surface expression by flow cytometry. TIM-3 expression on tumor-infiltrating lymphocytes (TILs) was correlated with clinicopathological parameters. Conclusions: TIM-3 is highly upregulated on both CD4 + and CD8 + TILs from human lung cancer tissues but negligibly expressed on T cells from patients' peripheral blood. Frequencies of IFN-γ + cells were reduced in TIM-3 +CD8 + TILs compared to TIM-3 -CD8 + TILs. However, the level of TIM-3 expression on CD8 + TILs failed to associate with any clinical pathological parameter. Interestingly, we found that approximately 70% of TIM-3 +CD4 + TILs expressed FOXP3 and about 60% of FOXP3 + TILs were TIM-3 +. Importantly, TIM-3 expression on CD4 + T cells correlated with poor clinicopathological parameters of NSCLC such as nodal metastasis and advanced cancer stages. Our study reveals a new role of TIM-3 as an important immune regulator in the tumor microenvironment via its predominant expression in regulatory T cells. © 2012 Gao et al

Increased Levels of BAFF and APRIL Related to Human Active Pulmonary Tuberculosis

BACKGROUND: Despite great efforts to improve diagnosis and treatment, tuberculosis (TB) remains a major health problem worldwide, especially in developing countries. Lack of concrete immune markers is still the obstacle to properly evaluate active TB. Therefore, identification of more validated biomarkers and phenotypic signatures is imperative. In particular, T cell-related biomarkers are more significant. METHODOLOGY: To understand the nature of CD4(+) T cell-derived signatures involved in infection and disease development, we examined and analyzed whole genome expression profiles of purified CD4(+) T cells from healthy individuals (HD), two distinct populations with latent infection (with low or high IFN-γ levels, LTB(L)/LTB(H)) and untreated TB patients. Following, we validated the expression profiles of genes in the peripheral CD4(+) T cells from each group and examined secretion levels of distinct cytokines in serum and pleural effusion. PRINCIPAL FINDINGS: Our bio-informatic analyses indicate that the two latent populations and clinical TB patients possess distinct CD4(+) T cell gene expression profiles. Furthermore, The mRNA and protein expression levels of B cell activating factor (BAFF), which belongs to the TNF family, and a proliferation-inducing ligand (APRIL) were markedly up-regulated at the disease stage. In particular, the dramatic enhancement of BAFF and APRIL in the pleural effusion of patients with tuberculosis pleurisy suggests that these proteins may present disease status. In addition, we found that the BAFF/APRIL system was closely related to the Th1 immune response. Our study delineates previously unreported roles of BAFF and APRIL in the development of tuberculosis, and these findings have implications for the diagnosis of the disease. Our study also identifies a number of transcriptional signatures in CD4(+) T cells that have the potential to be utilized as diagnostic and prognostic tools to combat the tuberculosis epidemic

Comparison of the sensory properties of fragrant and non-fragrant rice (Oryza sativa), focusing on the role of the popcorn-like aroma compound 2-acetyl-1-pyrroline

2-Acetyl-1-pyrroline (2-AP) has been widely reported as a key contributor to the popcorn-like aroma of fragrant rice (Oryza sativa). To gain a greater understanding of its contribution to the aroma in both fragrant and non-fragrant rice, sensory profiling was conducted with a trained panel to examine the sensory properties of six boiled rice samples, three fragrant and three non-fragrant varieties. The intensity of the popcorn note as an orthonasal odour, a retronasal flavour and as an after-effect was significantly higher in fragrant rice than in non-fragrant rice. However, panellists could not differentiate these popcorn attributes between the three different fragrant rice varieties. 2-AP was extracted from the boiled rice samples by headspace solid-phase microextraction and quantified by gas chromatography–mass spectrometry. 2-AP was below the limits of quantitation in non-fragrant varieties; however, gas chromatography–olfactometry of samples indicated the presence of 2-AP in both raw fragrant and non-fragrant rice varieties

Identifying Systemically Important Banks and Firms Based on a Multilayer DebtRank Model

The stability of the financial system plays a crucial role in the sustainable economic development. Hence, to identify systemically important banks and firms, we take lending relationships with different loan terms and common asset relationships with different investment cycles into consideration to present a multilayer DebtRank model of the bank-firm system. In the light of simulation research, we can obtain the following results. First, the bank-firm system constructed displays a significant core-periphery structure, which exists in the actual financial system. Then, only very few banks and firms show systemically important characteristics, where “important” subjects hold very high net assets and profits, while "fragile" subjects possess negative net assets and serious losses. Furthermore, the bank-firm multilayer DebtRank model presents a great stability to a certain extent. Overall, the multilayer DebtRank model constructed in this paper has certain theoretical reference value for the supervisory authorities to extract the internal characteristics of systemically important banks and firms and identify them effectively

Experimental study on the transporting and crushing effect of gas on coal powder during the develop stage of coal and gas outburst in roadway

Abstract In recent years, coal and gas outburst disasters are still occurring and difficult to prevent, seriously endangering the safety of coal mine production. It is well known that the transporting and crushing of outburst coal is the main pathway of energy dissipation during the coal and gas outburst process. However, a consensus regarding how much gas involves in outburst and affects energy dissipation is still lacking. Quantitative study on the gas effect on migration and fragmentation characteristics of outburst coal in restricted roadway space can improve the energy model and guide the prevention and control of gas outburst. In this paper, an improved visual coal and gas outburst dynamic effect simulation experiment system was used to conduct outburst simulation experiments at different gas pressure conditions. The results showed that the movement of outburst coal in the roadway has experienced various flow patterns. In the initial stage of the outburst, under low gas pressure condition, the motion of the outburst coal was dominated by stratified flow. However, as the gas pressure increases, the initial acceleration increases, and the outburst coal mainly move forward rapidly in the form of plug flow. The average velocity at 0.3, 0.5, and 0.8 MPa gas pressure condition were 6.75, 22.22 and 35.81 m/s, respectively. Gas also has a crushing effect on outburst coal. With increasing gas pressure, the number of coal powder particles of the same mass increased significantly, and the range of the particle size distribution of the particles decreaed, and the median particle size decreased. As the gas pressure increases, the outburst intensity gradually increases, and the total energy involved in the outburst work also increases. However, the energy dissipation pathways are different. At 0.3 MPa, the energy dissipation is dominated by crushing energy, which is about six times the ejection energy. As the gas pressure increased to 0.8 MPa, the proportion of the ejection energy gradually increases to about twice that of the crushing energy. Under the experimental conditions, 2.71–13.43% of the adsorbed gas involves in the outburst (AGIO) through rapid desorption, and the proportion increases with increasing gas pressure. This paper improves the energy model of coal and gas outburst, which is applicable to risk assessment and prevention of outburst disasters

Procalcitonin-guided antibiotic therapy in critically ill adults: a meta-analysis

Abstract Background As a novel biomarker of inflammation, procalcitonin (PCT) has proven useful to guide antibiotic therapy in intensive care unit (ICU). However, there are controversial on mortality. The aim of this study was to evaluate the utility of PCT-guided antibiotic therapy in critically ill adults and determine whether studies are sufficient. Methods A systematic search in PubMed, Embase and Cochrane was performed. We included only randomized controlled trials which compared the safety and efficacy between PCT-guided or standard antibiotic therapy groups in ICU adults. Trial sequential analysis and GARDE approach were performed. Results Fifteen studies met our criteria for inclusion finally, with a cumulative number of 5486 ICU patients. There was no difference in 28-day mortality between two compared groups (P = 0.626), but significant decreases were observed in the duration of antibiotic therapy for the first episode of infection (P < 0.001) and length of hospitalization (P = 0.049). No significant deference was found in secondary endpoints except total duration of antibiotic therapy (P < 0.001). TSA revealed that the pooled sample sizes of 28-day mortality and the duration of antibiotic therapy for the first episode of infection exceeded the estimated required information size, but not the length of hospitalization. Conclusions PCT-guided therapy is a better and safer algorithm to be applied into ICU patients, which appears no effect on 28-day mortality while performing preferable utility in reducing the duration of antibiotic therapy for the first episode of infection. More studies on these endpoints were not recommended