Cancer incidence in a chlorochemical plant in Isère, France: an occupational cohort study, 1979-2002.

Background: A major French chlorine chemical plant (chlor-alkali process with diaphragm cell and manufacturing of organochlorine chemicals) has used or produced known or suspected carcinogenic compounds.

Methods: A cohort study, based on the plant occupational health service and the regional cancer registry, analyzed the standardized incidence ratios of malignant tumors for the period 1979-2002. Individual exposures were estimated from workers' occupational histories in a dual division of jobs into 9 sectors and 115 workshops with known exposures.

CD8 T cell defect of TNF-α and IL-2 in DNAM-1 deficient mice delays clearance in vivo of a persistent virus infection.

DNAM-1 gene-deficient (-/-) mice take significantly longer to clear an acute and persistent LCMV infection in vivo than DNAM-1 +/+ mice. During acute LCMV priming, at the single cell level, DNAM-1 -/- mice made significantly less cytoplasmic CD8 TNF-α and IL-2 but not IFN-γ than their DNAM-1 +/+ counterparts. Restimulated immune memory CD8 T cells from DNAM-1 -/- and DNAM-1 +/+ mice were equivalent in cytolytic activity against LCMV-infected target cells but DNAM-1 -/- CD8 T cells had significant reductions in TNF-α and IL-2 that were associated on adoptive transfer with the inability to terminate the persistent viral infection.

AHR and the Transcriptional Regulation of Type-17/22 ILC.

Mucosal innate lymphoid cells (ILCs) are an emerging population of diverse and heterogeneous immune cells, all with the unique ability to mount a rapid response against invading pathogens. They are further divided into subsets based on their differing cell surface markers as well as in their functional specialization. In this review, we summarize recent reports describing the importance of the transcription factor aryl hydrocarbon receptor (AHR) in regulating the development of one of these subsets, the Type-17/22 ILCs, as well as in the organization of postnatal lymphoid structures.

Cutting edge: human FcRL4 and FcRL5 are receptors for IgA and IgG.

Fc receptor-like (FcRL) proteins are a family of cellular receptors homologous to FcγRI and are predominantly expressed by B cells. They function to costimulate or inhibit BCR signaling through consensus ITAMs and ITIMs; however, the extracellular ligands of these receptors remain unknown or controversial. In this study, we tested the ability of human FcRL proteins to bind Igs and found FcRL4 and FcRL5 to be bona fide Fc receptors.

Surface reactivity and cell responses to chrysotile asbestos nanofibers.

High aspect-ratio nanomaterials (HARNs) have recently attracted great attention from nanotoxicologists because of their similarity to asbestos. However, the actual risk associated with the exposure to nanosized asbestos, which escapes most regulations worldwide, is still unknown. Nanometric fibers of chrysotile asbestos have been prepared from two natural sources to investigate whether nanosize may modulate asbestos toxicity and gain insight on the hazard posed by naturally occurring asbestos, which may be defined as HARNs because of their dimensions.

Type I interferons: diversity of sources, production pathways and effects on immune responses.

Type I interferons (IFN-I) were first described over 50 years ago as factors produced by cells that interfere with virus replication and promote an antiviral state. Innate and adaptive immune responses to viruses are also greatly influenced by IFN-I. In this article we discuss the diversity of cellular sources of IFN-I and the pathways leading to IFN-I production during viral infections.

Spontaneous mutation of the Dock2 gene in Irf5-/- mice complicates interpretation of type I interferon production and antibody responses.

Genome-wide studies have identified associations between polymorphisms in the IFN regulatory factor-5 (Irf5) gene and a variety of human autoimmune diseases. Its functional role in disease pathogenesis, however, remains unclear, as studies in Irf5(-/-) mice have reached disparate conclusions regarding the importance of this transcription factor in type I IFN production and antibody responses. We identified a spontaneous genomic duplication and frameshift mutation in the guanine exchange factor dedicator of cytokinesis 2 (Dock2) that has arisen in at least a subset of circulating Irf5(-/-) mice and inadvertently been bred to homozygosity.

Biosimilar medicines in oncology: single-center experience with biosimilar G-CSF.

Aims: A biosimilar medicine is one with proven similarity to a reference biological product for which the patent has expired and whose active ingredient is produced or derived from a living organism. Recombinant granulocyte colony-stimulating growth factors (G-CSF) are used for the prophylaxis of febrile neutropenia.

Materials & Methods: In this observational, single-center study, a total of 48 patients with solid tumors were treated with a new biosimilar G-CSF (Zarzio(®)) for 4-14 days from the day following the end of chemotherapy.

Chemotherapy and target therapy as neo-adjuvant approach for initially unresectable colorectal liver metastases.

Although surgery is the most effective treatment for liver metastases in colorectal cancer patients, only 15-20% of these patients are suitable for a radical surgical approach, and metastases recurrence may occur at follow up. In the last decade, the use of pre-operative chemotherapy in combination with new biological drugs has been introduced. We reviewed data of neo-adjuvant chemotherapy strategies aimed at increasing the resection rate of liver metastases in colorectal cancer patients who were initially considered unresectable.

Endoplasmic reticulum stress controls M2 macrophage differentiation and foam cell formation.

Macrophages are essential in atherosclerosis progression, but regulation of the M1 versus M2 phenotype and their role in cholesterol deposition are unclear. We demonstrate that endoplasmic reticulum (ER) stress is a key regulator of macrophage differentiation and cholesterol deposition. Macrophages from diabetic patients were classically or alternatively stimulated and then exposed to oxidized LDL.

Cutting edge: paradoxical roles of BST2/tetherin in promoting type I IFN response and viral infection.

Bone marrow stromal Ag 2 (BST2) is a transmembrane protein that prevents virus release from infected cells. It was also reported that BST2 inhibits type I IFN production by plasmacytoid dendritic cells. To determine BST2 impact on antiviral responses in vivo, we generated BST2(-/-) mice.

TREM2 and β-catenin regulate bone homeostasis by controlling the rate of osteoclastogenesis.

TREM2 is an immunoreceptor expressed on osteoclasts (OC) and microglia that transmits intracellular signals through the adaptor DAP12. Individuals with genetic mutations inactivating TREM2 or DAP12 develop the Nasu-Hakola disease (NHD) with cystic-like lesions of the bone and brain demyelination that lead to fractures and presenile dementia. The mechanisms of this disease are poorly understood.

Imiquimod clears tumors in mice independent of adaptive immunity by converting pDCs into tumor-killing effector cells.

Imiquimod is a synthetic compound with antitumor properties; a 5% cream formulation is successfully used to treat skin tumors. The antitumor effect of imiquimod is multifactorial, although its ability to modulate immune responses by triggering TLR7/8 is thought to be key. Among the immune cells suggested to be involved are plasmacytoid DCs (pDCs).

Joint use of epidemiological and hospital medico-administrative data to estimate prevalence. Application to French data on breast cancer.

Background: Estimate complete, limited-duration, and hospital prevalence of breast cancer in a French Département covered by a population-based cancer registry and in whole France using complementary information sources.

Methods: Incidence data from a cancer registry, national incidence estimations for France, mortality data, and hospital medico-administrative data were used to estimate the three prevalence indices. The methods included a modelling of epidemiological data and a specific process of data extraction from medico-administrative databases.

Leukocyte-associated Ig-like receptor-1-deficient mice have an altered immune cell phenotype.

Cross-linking of the collagen binding receptor leukocyte-associated Ig-like receptor-1 (LAIR-1) in vitro delivers an inhibitory signal that is able to downregulate activation-mediated signals. To study the in vivo function of LAIR-1, we generated LAIR-1(-/-) mice. They are healthy and fertile and have normal longevity; however, they show certain phenotypic characteristics distinct from wild-type mice, including increased numbers of splenic B, regulatory T, and dendritic cells.

Thickness of multiwalled carbon nanotubes affects their lung toxicity.

Two samples of highly pure multiwalled carbon nanotubes (MWCNTs) similar in hydrophobicity and surface reactivity were prepared with similar length, <5 μm, but markedly different diameter (9.4 vs 70 nm). The samples were compared for their cytotoxic activity, uptake, and ability to induce oxidative stress (ROS production and intracellular GSH depletion) in vitro in murine alveolar macrophages (MH-S).

Natural killer (NK) and NK-like cells at mucosal epithelia: Mediators of anti-microbial defense and maintenance of tissue integrity.

Natural killer (NK) cells are innate lymphocytes that play important roles in the defense against microbial pathogens through secretion of IFN-γ and recognition and lysis of virally or bacterially infected host cells. A recently identified population of NK-like cells that shares characteristics of both NK cells and lymphoid tissue inducer (LTi) cells promotes innate immune responses in epithelial tissue through the secretion of IL-22. In contrast to classical NK cells, NK-like cells are localized preferentially at mucosal sites, such as the intestinal mucosa.

Overdiagnosis from non-progressive cancer detected by screening mammography: stochastic simulation study with calibration to population based registry data.

Objective: To quantify the magnitude of overdiagnosis from non-progressive disease detected by screening mammography, after adjustment for the potential for lead time bias, secular trend in the underlying risk of breast cancer, and opportunistic screening.

Design: Approximate bayesian computation analysis with a stochastic simulation model designed to replicate standardised incidence rates of breast cancer. The model components included the lifetime probability of breast cancer, the natural course of breast cancer, and participation in organised and opportunistic mammography screening.

AHR drives the development of gut ILC22 cells and postnatal lymphoid tissues via pathways dependent on and independent of Notch.

Innate lymphoid cells (ILCs) of the ILC22 type protect the intestinal mucosa from infection by secreting interleukin 22 (IL-22). ILC22 cells include NKp46(+) and lymphoid tissue-inducer (LTi)-like subsets that express the aryl hydrocarbon receptor (AHR). Here we found that Ahr(-/-) mice had a considerable deficit in ILC22 cells that resulted in less secretion of IL-22 and inadequate protection against intestinal bacterial infection.

Melanoma differentiation-associated gene 5 is critical for protection against Theiler's virus-induced demyelinating disease.

Infection of dendritic and glial cells with Theiler's murine encephalomyelitis virus (TMEV) induces various cytokines via Toll-like receptor- and melanoma differentiation-associated gene 5 (MDA5)-dependent pathways. However, the involvement and role of MDA5 in cytokine gene activation and the pathogenesis of TMEV-induced demyelinating disease are largely unknown. In this study, we demonstrate that MDA5 plays a critical role in the production of TMEV-induced alpha interferon (IFN-α) during early viral infection and in protection against the development of virus-induced demyelinating disease.

Type I interferon negatively controls plasmacytoid dendritic cell numbers in vivo.

Plasmacytoid dendritic cells (pDCs) specialize in the secretion of type I interferons (IFN-I) and thus are considered critical mediators of antiviral responses. We recently reported that pDCs have a very early but limited and transient capacity to curtail viral infections. Additionally, pDC numbers are not sustained in human infections caused by Hepatitis B or C viruses (HBV and HCV) and HIV.

Effects of pH, ionic strength, and applied voltage on migration of dental monomers in an organic matrix.

Objectives: The application of an electric field has been shown to positively influence the bonding of dentin bonding systems (DBS) by improving adhesive impregnation into dentin. However, the mechanism responsible for this phenomenon has not been completely elucidated. The aim of this study was to clarify the effects of pH, matrix ionic strength, and applied voltage on the migration of commonly used DBS monomers in a model matrix (agarose gel).

dsRNA sensors and plasmacytoid dendritic cells in host defense and autoimmunity.

The innate immune system detects viruses through molecular sensors that trigger the production of type I interferons (IFN-I) and inflammatory cytokines. As viruses vary tremendously in size, structure, genomic composition, and tissue tropism, multiple sensors are required to detect their presence in various cell types and tissues. In this review, we summarize current knowledge of the diversity, specificity, and signaling pathways downstream of viral sensors and ask whether two distinct sensors that recognize the same viral component are complementary, compensatory, or simply redundant.

Human C-type lectin domain family 4, member C (CLEC4C/BDCA-2/CD303) is a receptor for asialo-galactosyl-oligosaccharides.

Plasmacytoid dendritic cells are specialized in the production of type I interferon (type I IFN), which promotes antiviral and antitumor responses, as well as autoimmune disorders. Activation of type I IFN secretion depends on the pattern recognition receptors TLR7 and TLR9, which sense microbial RNA and DNA, respectively. Type I IFN production is modulated by several receptors, including the type II C-type lectin domain family 4, member C (CLEC4C).

TLR7/9 versus TLR3/MDA5 signaling during virus infections and diabetes.

IFN-I are pleiotropic cytokines that impact innate and adaptive immune responses. In this article, we discuss TLR7/9 versus TLR3/MDA5 signaling in antiviral responses and diabetes. pDCs are thought to have a critical role in antiviral defense because of their ability to rapidly secrete large amounts of IFN-I through TLR7/9 signaling.