Manufacturing job losses in the recovery: the District outperforms the nation

This article examines job growth in the district's key manufacturing industries and in the seven district states. The article shows that while thousands of manufacturing jobs have been lost since the recovery began, the decline in the district has been less than in the nation. The primary strength of the region's manufacturing sector has been the food processing industry.Employment (Economic theory) ; Manufactures ; Federal Reserve District, 10th

An Analysis of Consumption and Expenditures for Lithuanian Households Using Budget Survey Data

Recent household budget survey data for Lithuania provide a profile of expenditure patterns for households by income level and living in either urban or rural areas. This paper provides an overview of expenditures and gives estimates of Engel functions and income elasticities for major expenditure groups and for food commodities. Food commodities are relatively important to households in both urban and rural areas and show relatively inelastic response to income levels. Based in an assumed reduction in income for 1991 of 41 percent, food shares are projected to increase by nearly 36 percent from 1989 levels. This is likely to be a lower bound for the anticipated changes

Remodulation of the tumor microenvironment by regulatory T cells

The tumor microenvironment is a complex system, which is composed of various types of non-tumor cells including stromal fibroblasts, the blood and lymphatic vascular networks, the extracellular matrix and notably, the infiltrating immune cells. Regulatory T cells (Treg cells) play a pivotal role in tumor malignant progression and contribute to the resistance of tumors to traditional anti-cancer therapies; however, the elimination of Treg cells is not a clinically viable approach, given their crucial role in maintaining immune homeostasis and preventing autoimmunity. Our laboratory has recently reported that Treg-restricted genetic disruption of Neuropilin-1 (Nrp1) selectively induced destabilization of Treg cells within the tumor microenvironment, leading to tumor clearance without inducing autoimmunity. Interestingly, despite of their dramatic tumor-suppressive function, Nrp1-deficient Treg cells are present in tumor in a comparable manner (number and kinetics) to their wild type counterparts, which provides an invaluable research tool to interrogate the function of intratumoral Treg cells without physically removing them and inducing systemic autoimmunity. In this study we aim to systematically investigate the cellular and molecular mediators as well as the underlying mechanisms of Treg-cell function within the tumor microenvironment using a systems biology approach. With the unique Treg-restrictive Nrp1-deficient mice tumor models combined with a multifaceted approach that consists of flow cytometry based immunophenotyping and large-scale transcriptomic profiling, our results indicated that Treg cells act as an early key regulator of tumor immune infiltration and actively induce the global remodulation of the tumor immune transcriptome. Computational deconvolution analysis of the gene profiling data derived from mixed populations further predicted a list of critically modified targets that are regulated at the single cell level. The functional validation of these targets may provide mechanism(s) by which Treg cells interplay with the tumor microenvironment to potentiate tumor growth. This may lead to the development of novel and selective cancer immunotherapies

The extent of metalloproteinase-mediated LAG3 cleavage limits the efficacy of PD1 blockade

Inhibitory receptors control immune responses preventing exacerbated T cell activation and the onset of autoimmunity; however, they also limit antitumor immunity. Enhanced co-expression of PD1 and LAG3 phenotypically mark functionally exhausted tumor-specific T cells, with dual PD1/LAG3 blockade synergistically limiting tumor growth in murine models. Like PD1, LAG3 expression is induced on activated T cells to negatively regulate T cell activation and proliferation and LAG3 is also required for maximal regulatory T (Treg) cell function. However, LAG3 expression and function is itself regulated by cell surface cleavage of the transmembrane domain connecting peptide by ADAM10 and ADAM17 metalloproteinase-disintegrins. This releases soluble LAG3, of which no biological function has been found to date. To investigate the impact of LAG3 cleavage on T cells within tumors, a non-cleavable LAG3 mouse (LAG3.NC) was generated in which exons 7 and 8 of Lag3, including the connecting peptide, is deleted in Cre-expressing cells. These exons are replaced and modified so that the connecting peptide is absent preventing LAG3 cleavage. LAG3.NC CD4Cre mice (with non-cleavable LAG3 expressed on all CD8+ and CD4+ T cells, including Tregs) and LAG3.NC E8ICre mice (restricted to CD8+ T cells only) exhibit enhanced expression of LAG3 on the respective T cell subsets in B16-F10 or MC38 tumors, co-expressing with PD1. Despite increased LAG3 expression, no difference in B16-F10 or MC38 tumor growth was observed in either LAG3.NC CD4Cre or LAG3.NC E8ICre mice compared with wild-type littermates. Upon therapeutic administration of anti-PD1 antibody (clone G4), MC38 tumor-bearing wild-type mice show significant tumor regression and 40% become tumor-free resulting in long-term survival. LAG3.NC CD4Cre mice were resistant to anti-PD1 therapy and succumb to tumor growth. However, anti-PD1 mediated tumor regression and long-term survival in LAG3.NC E8ICre mice. Analysis of re-stimulated CD8+ TILs isolated from LAG3.NC CD4Cre mice did not show enhanced IFN-gamma and TNF-alpha production following anti-PD1 therapy, which was observed with LAG3.NC E8ICre mice or wild-type littermates. Moreover, reduced proliferation was observed for all T cell subsets in LAG3.NC CD4Cre mice compared with LAG3.NC E8ICre and wild-type littermates following anti-PD1 treatment. As LAG3.NC CD4Cre, but not LAG3.NC E8ICre mice, are resistant to the favorable antitumor immune effects induced by anti-PD1, this suggests that enhanced LAG3 expression on CD4+ T cells or Tregs may act as a barrier to effective anti-PD1 immunotherapy. LAG3.NC mice crossed with Cre that restricts non-cleavable LAG3 to Tregs (Foxp3yfpiCre) or CD4+ T cells (ThPOKCre) are currently under analysis

Optical mapping as a routine tool for bacterial genome sequence finishing

Background: In sequencing the genomes of two Xenorhabdus species, we encountered a large number of sequence repeats and assembly anomalies that stalled finishing efforts. This included a stretch of about 12 Kb that is over 99.9% identical between the plasmid and chromosome of X. nematophila. Results: Whole genome restriction maps of the sequenced strains were produced through optical mapping technology. These maps allowed rapid resolution of sequence assembly problems, permitted closing of the genome, and allowed correction of a large inversion in a genome assembly that we had considered finished. Conclusion: Our experience suggests that routine use of optical mapping in bacterial genome sequence finishing is warranted. When combined with data produced through 454 sequencing, an optical map can rapidly and inexpensively generate an ordered and oriented set of contigs to produce a nearly complete genome sequence assembly

Regulatory T Cells: Barriers of Immune Infiltration Into the Tumor Microenvironment

Regulatory T cells (Tregs) are key immunosuppressive cells that promote tumor growth by hindering the effector immune response. Tregs utilize multiple suppressive mechanisms to inhibit pro-inflammatory responses within the tumor microenvironment (TME) by inhibition of effector function and immune cell migration, secretion of inhibitory cytokines, metabolic disruption and promotion of metastasis. In turn, Tregs are being targeted in the clinic either alone or in combination with other immunotherapies, in efforts to overcome the immunosuppressive TME and increase anti-tumor effects. However, it is now appreciated that Tregs not only suppress cells intratumorally via direct engagement, but also serve as key interactors in the peritumor, stroma, vasculature and lymphatics to limit anti-tumor immune responses prior to tumor infiltration. We will review the suppressive mechanisms that Tregs utilize to alter immune and non-immune cells outside and within the TME and discuss how these mechanisms collectively allow Tregs to create and promote a physical and biological barrier, resulting in an immune-excluded or limited tumor microenvironment

Role of LAG-3 in Regulatory T Cells

AbstractRegulatory T cells (Tregs) limit autoimmunity but also attenuate the magnitude of antipathogen and antitumor immunity. Understanding the mechanism of Treg function and therapeutic manipulation of Tregs in vivo requires identification of Treg-selective receptors. A comparative analysis of gene expression arrays from antigen-specific CD4+ T cells differentiating to either an effector/memory or a regulatory phenotype revealed Treg-selective expression of LAG-3, a CD4-related molecule that binds MHC class II. Antibodies to LAG-3 inhibit suppression by induced Tregs both in vitro and in vivo. Natural CD4+CD25+ Tregs express LAG-3 upon activation, which is significantly enhanced in the presence of effector cells, whereas CD4+CD25+ Tregs from LAG-3−/− mice exhibit reduced regulatory activity. Lastly, ectopic expression of LAG-3 on CD4+ T cells significantly reduces their proliferative capacity and confers on them suppressor activity toward effector T cells. We propose that LAG-3 marks regulatory T cell populations and contributes to their suppressor activity

Central Nervous System Destruction Mediated by Glutamic Acid Decarboxylase-Specific CD4+ T Cells

High titers of autoantibodies against glutamic acid decarboxylase 65 (GAD65) are commonly observed in patients suffering from type 1 diabetes (T1D) as well as Stiff Person syndrome (SPS), a disorder that affects the central nervous system, and a variant of SPS, progressive encephalomyelitis with rigidity and myoclonus (PERM). While there is a considerable amount of data focusing on the role of GAD65-specific CD4+ T cells in T1D, little is known about their role in SPS. Here we show that mice possessing a monoclonal GAD65-specific CD4+ T cell population (4B5, PA19.9G11 or PA17.9G7) develop a lethal encephalomyelitis-like disease in the absence of any other T cells or B cells. GAD65-reactive CD4+ T cells were found throughout the CNS in direct concordance with GAD65 expression and activated microglia: proximal to the circumventricular organs at the interface between the brain parenchyma and the blood brain barrier. In the presence of B cells, high titer anti-GAD65 autoantibodies were generated but these had no effect on the incidence or severity of disease. In addition, GAD65-specific CD4+ T cells isolated from the brain were activated and produced IFN-γ. These findings suggest that GAD65-reactive CD4+ T cells alone mediate a lethal encephalomyelitis-like disease that may serve as a useful model to study GAD65-mediated diseases of the CNS