ABSTRACT
Molecular diagnostics of inherited platelet disorders (IPD) has been revolutionized by the implementation of high-throughput sequencing (HTS) approaches. A conclusive diagnosis using HTS tests can be obtained quickly and cost-effectively in many, but not all patients. The expanding use of HTS tests has raised concerns regarding complex variant interpretation and the ethical implications of detecting unsolicited findings such as variants in IPD genes RUNX1, ETV6, and ANKRD26, which are associated with increased leukemic risk. This guidance document has been developed and written by a multidisciplinary team of researchers and clinicians, with expertise in hematology, clinical and molecular genetics, and bioethics, alongside a RUNX1 patient advocacy representative. We recommend that for clinical diagnostics, HTS for IPD should use a multigene panel of curated diagnostic-grade genes. Critically, we advise that an HTS test for clinical diagnostics should only be ordered by a clinical expert that is: (a) fully aware of the complexity of genotype-phenotype correlations for IPD; (b) able to discuss these complexities with a patient and family members before the test is initiated; and (c) able to interpret and appropriately communicate the results of a HTS diagnostic report, including the implication of variants of uncertain clinical significance. Each patient should know what an HTS test could mean for his or her clinical management before initiating a test. We hereby propose an exemplified informed consent document that includes information on these ethical concerns and can be used by the community for implementation of HTS of IPD in a clinical diagnostic setting. This paper does not include recommendations for HTS of IPD in a research setting.
Subject(s)
Blood Platelet Disorders , High-Throughput Nucleotide Sequencing , Blood Platelet Disorders/diagnosis , Blood Platelet Disorders/genetics , Communication , Female , Genetic Association Studies , Humans , Informed ConsentABSTRACT
The most abundant immune cell type is the neutrophil, a key first responder after pathogen invasion. Neutrophil numbers in the periphery are tightly regulated to prevent opportunistic infections and aberrant inflammation. In healthy individuals, more than 1 × 109 neutrophils per kilogram body weight are released from the bone marrow every 24 hours. To maintain homeostatic levels, an equivalent number of senescent cells must be cleared from circulation. Recent studies indicate that clearance of senescent neutrophils by resident tissue macrophages and DCs helps to set homeostatic levels of neutrophils via effects on the IL-23/IL-17/G-CSF cytokine axis, which stimulates neutrophil production in the bone marrow. However, the molecular events in phagocytes underlying this feedback loop have remained indeterminate. Liver X receptors (LXRs) are members of the nuclear receptor superfamily that regulate both lipid metabolic and inflammatory gene expression. Here, we demonstrate that LXRs contribute to the control of neutrophil homeostasis. Using gain- and loss-of-function models, we found that LXR signaling regulated the efficient clearance of senescent neutrophils by peripheral tissue APCs in a Mer-dependent manner. Furthermore, activation of LXR by engulfed neutrophils directly repressed the IL-23/IL-17/G-CSF granulopoietic cytokine cascade. These results provide mechanistic insight into the molecular events orchestrating neutrophil homeostasis and advance our understanding of LXRs as integrators of phagocyte function, lipid metabolism, and cytokine gene expression.
Subject(s)
Neutrophils/immunology , Neutrophils/metabolism , Orphan Nuclear Receptors/metabolism , Animals , Apoptosis , Cellular Senescence , Cytokines/genetics , Feedback, Physiological , Gene Expression , Homeostasis , Interleukin-17/genetics , Interleukin-17/metabolism , Interleukin-23 Subunit p19/genetics , Interleukin-23 Subunit p19/metabolism , Lipid Metabolism , Liver/cytology , Liver/immunology , Liver/metabolism , Liver X Receptors , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Orphan Nuclear Receptors/deficiency , Orphan Nuclear Receptors/genetics , Phagocytosis , Signal Transduction , Spleen/cytology , Spleen/immunology , Spleen/metabolismABSTRACT
Annually the Prostate Cancer Foundation (PCF) organizes a scientific retreat to assemble the premier prostate cancer researchers from around the world to share and review the latest progress made in the field and to evaluate future directions. This report highlights some of the most significant advances made in prostate cancer research in 2010 that were presented at the 17th Annual PCF Scientific Retreat.
