In atherosclerotic arteries, blood monocytes differentiate to macrophages in the presence of growth factors, such as macrophage colony-stimulation factor (M-CSF), and chemokines, such as platelet ...factor 4 (CXCL4). To compare the gene expression signature of CXCL4-induced macrophages with M-CSF-induced macrophages or macrophages polarized with IFN-gamma/LPS (M1) or IL-4 (M2), we cultured primary human peripheral blood monocytes for 6 d. mRNA expression was measured by Affymetrix gene chips, and differences were analyzed by local pooled error test, profile of complex functionality, and gene set enrichment analysis. Three hundred seventy-five genes were differentially expressed between M-CSF- and CXCL4-induced macrophages; 206 of them overexpressed in CXCL4 macrophages coding for genes implicated in the inflammatory/immune response, Ag processing and presentation, and lipid metabolism. CXCL4-induced macrophages overexpressed some M1 and M2 genes and the corresponding cytokines at the protein level; however, their transcriptome clustered with neither M1 nor M2 transcriptomes. They almost completely lost the ability to phagocytose zymosan beads. Genes linked to atherosclerosis were not consistently upregulated or downregulated. Scavenger receptors showed lower and cholesterol efflux transporters showed higher expression in CXCL4- than M-CSF-induced macrophages, resulting in lower low-density lipoprotein content. We conclude that CXCL4 induces a unique macrophage transcriptome distinct from known macrophage types, defining a new macrophage differentiation that we propose to call M4.
Pregnancy infections with Zika virus are associated with a spectrum of fetal brain injuries beyond microcephaly. Nonmicrocephalic children exposed to Zika virus in utero or early life should undergo ...neurodevelopmental testing to identify deficits and allow for early intervention. Additionally, long-term monitoring for higher order neurocognitive deficits should be implemented.
An ultrafast DNA sequence aligner (Isaac Genome Alignment Software) that takes advantage of high-memory hardware (>48 GB) and variant caller (Isaac Variant Caller) have been developed. We demonstrate ...that our combined pipeline (Isaac) is four to five times faster than BWA + GATK on equivalent hardware, with comparable accuracy as measured by trio conflict rates and sensitivity. We further show that Isaac is effective in the detection of disease-causing variants and can easily/economically be run on commodity hardware.
Isaac has an open source license and can be obtained at https://github.com/sequencing.
Zika virus (ZIKV) is a mosquito-transmitted flavivirus, recently linked to microcephaly and central nervous system anomalies following infection in pregnancy. Striking findings of disproportionate ...growth with a smaller than expected head relative to body length have been observed more commonly among fetuses with exposure to ZIKV in utero compared to pregnancies without ZIKV infection regardless of other signs of congenital infection including microcephaly. This study's objective was to determine the diagnostic accuracy of femur-sparing profile of intrauterine growth restriction for the identification of ZIKV-associated congenital injuries on postnatal testing. A retrospective cohort study of pregnant women with possible or confirmed ZIKV infection between January 1, 2016 and December 31, 2017 were included. Subjects were excluded if no prenatal ultrasound was available. A femur-sparing profile of growth restriction determined using INTERGROWTH-21st sonographic standard for head circumference to femur length (HC: FL). Congenital injuries were determined postnatally by imaging, comprehensive eye exam and standard newborn hearing screen. A total of 111 pregnant women diagnosed with ZIKV infection underwent fetal ultrasound and 95 neonates had complete postnatal evaluation. Prenatal microcephaly was detected in 5% of fetuses (6/111). Postnatal testing detected ZIKV-associated congenital injuries in 25% of neonates (24/95). A HC: FL Z-score ≤ -1.3 had a 52% specificity (95% CI 41-63%), 82% negative predictive value (NPV, 95% CI 73-88%) for the detection of ZIKV-associated congenital injuries in the neonatal period. A more stringent threshold with a Z-score ≤ -2 was associated with a 90% specificity (95% CI 81-95%), 81% NPV (95% CI 77-85%). Excluding cases of fetal microcephaly, HC: FL (Z-score ≤ -2) demonstrated a similar specificity (89%, 95% CI 81-95%) with superior NPV (87%, 95% CI 84-90%). The sonographic recognition of a normally proportioned fetus may be useful prenatally to exclude a wider spectrum of ZIKV-associated congenital injuries detected postnatally.
Zika virus is a mosquito-transmitted flavivirus and was first linked to congenital microcephaly caused by a large outbreak in northeastern Brazil. Although the Zika virus epidemic is now in decline, ...pregnancies in large parts of the Americas remain at risk because of ongoing transmission and the potential for new outbreaks. This review presents why Zika virus is still a complex and worrisome public health problem with an expanding spectrum of birth defects and how Zika virus and related viruses evade the immune response to injure the fetus. Recent reports indicate that the spectrum of fetal brain and other anomalies associated with Zika virus exposure is broader and more complex than microcephaly alone and includes subtle fetal brain and ocular injuries; thus, the ability to prenatally diagnose fetal injury associated with Zika virus infection remains limited. New studies indicate that Zika virus imparts disproportionate effects on fetal growth with an unusual femur-sparing profile, potentially providing a new approach to identify viral injury to the fetus. Studies to determine the limitations of prenatal and postnatal testing for detection of Zika virus–associated birth defects and long-term neurocognitive deficits are needed to better guide women with a possible infectious exposure. It is also imperative that we investigate why the Zika virus is so adept at infecting the placenta and the fetal brain to better predict other viruses with similar capabilities that may give rise to new epidemics. The efficiency with which the Zika virus evades the early immune response to enable infection of the mother, placenta, and fetus is likely critical for understanding why the infection may either be fulminant or limited. Furthermore, studies suggest that several emerging and related viruses may also cause birth defects, including West Nile virus, which is endemic in many parts of the United States. With mosquito-borne diseases increasing worldwide, there remains an urgent need to better understand the pathogenesis of the Zika virus and related viruses to protect pregnancies and child health.
Atherosclerosis is a chronic inflammatory disease. Lesion progression is primarily mediated by cells of the monocyte/macrophage lineage. IL-17A is a proinflammatory cytokine, which modulates immune ...cell trafficking and is involved inflammation in (auto)immune and infectious diseases. But the role of IL-17A still remains controversial. In the current study, we investigated effects of IL-17A on advanced murine and human atherosclerosis, the common disease phenotype in clinical care. The 26-wk-old apolipoprotein E-deficient mice were fed a standard chow diet and treated either with IL-17A mAb (n = 15) or irrelevant Ig (n = 10) for 16 wk. Furthermore, essential mechanisms of IL-17A in atherogenesis were studied in vitro. Inhibition of IL-17A markedly prevented atherosclerotic lesion progression (p = 0.001) by reducing inflammatory burden and cellular infiltration (p = 0.01) and improved lesion stability (p = 0.01). In vitro experiments showed that IL-17A plays a role in chemoattractance, monocyte adhesion, and sensitization of APCs toward pathogen-derived TLR4 ligands. Also, IL-17A induced a unique transcriptome pattern in monocyte-derived macrophages distinct from known macrophage types. Stimulation of human carotid plaque tissue ex vivo with IL-17A induced a proinflammatory milieu and upregulation of molecules expressed by the IL-17A-induced macrophage subtype. In this study, we show that functional blockade of IL-17A prevents atherosclerotic lesion progression and induces plaque stabilization in advanced lesions in apolipoprotein E-deficient mice. The underlying mechanisms involve reduced inflammation and distinct effects of IL-17A on monocyte/macrophage lineage. In addition, translational experiments underline the relevance for the human system.
The controversy continues over the clinical utility of preoperative embolization for reducing tumor vascularity of intracranial meningiomas prior to resection. Previous studies comparing embolization ...and nonembolization patients have not controlled for detailed tumor parameters before assessing outcomes.
The authors reviewed the cases of all patients who underwent resection of a WHO grade I intracranial meningioma at their institution from 2008 to 2016. Propensity score matching was used to generate embolization and nonembolization cohorts of 52 patients each, and a retrospective review of clinical and radiological outcomes was performed.
In total, 52 consecutive patients who underwent embolization (mean follow-up 34.8 ± 31.5 months) were compared to 52 patients who did not undergo embolization (mean follow-up 32.8 ± 28.7 months; p = 0.63). Variables controlled for included patient age (p = 0.82), tumor laterality (p > 0.99), tumor location (p > 0.99), tumor diameter (p = 0.07), tumor invasion into a major dural sinus (p > 0.99), and tumor encasement around the internal carotid artery or middle cerebral artery (p > 0.99). The embolization and nonembolization cohorts did not differ in terms of estimated blood loss during surgery (660.4 ± 637.1 ml vs 509.2 ± 422.0 ml; p = 0.17), Simpson grade IV resection (32.7% vs 25.0%; p = 0.39), perioperative procedural complications (26.9% vs 19.2%; p = 0.35), development of permanent new neurological deficits (5.8% vs 7.7%; p = 0.70), or favorable modified Rankin Scale (mRS) score (a score of 0-2) at last follow-up (96.0% vs 92.3%; p = 0.43), respectively. When comparing the final mRS score to the preoperative mRS score, patients in the embolization group were more likely than patients in the nonembolization group to have an improvement in mRS score (50.0% vs 28.8%; p = 0.03).
After controlling for patient age, tumor size, tumor laterality, tumor location, tumor invasion into a major dural sinus, and tumor encasement of the internal carotid artery or middle cerebral artery, preoperative meningioma embolization intended to decrease tumor vascularity did not improve the surgical outcomes of patients with WHO grade I intracranial meningiomas, but it did lead to a greater chance of clinical improvement compared to patients not treated with embolization.
The inducible costimulator (ICOS) plays a key role in the development of Th17 cells, but its role in the development and antitumor activity of IL-17-producing CD8(+) T cells (Tc17) remains unknown. ...We found that ICOS costimulation was important for the functional maintenance, but not differentiation, of Tc17 cells in vitro. Blocking the ICOS pathway using an antagonist mAb or by using recipient mice genetically deficient in the ICOS ligand reduced the antitumor activity of adoptively transferred Tc17 cells. Conversely, activating Tc17 cells with an ICOS agonist in vitro enhanced their capacity to eradicate melanoma and induce autoimmune vitiligo when infused into mice. However, ICOS stimulation did not augment the antitumor activity of IL-2 expanded T cells. Additional investigation revealed that ICOS stimulation not only increased IL-2Rα, CXCR3, and IL-23R expression on Tc17 cells, but also dampened their expression of suppressive molecule CD39. Although Tc17 cells activated with an ICOS agonist cosecreted heightened IL-17A, IL-9, and IFN-γ, their therapeutic effectiveness was critically dependent on IFN-γ production. Depletion of IL-17A and IL-9 had little impact on antitumor Tc17 cells activated with an ICOS agonist. Collectively, our work reveals that the ICOS pathway potentiates the antitumor activity of adoptively transferred Tc17 cells. This work has major implications for the design of vaccine, Ab and cell-based therapies for autoimmunity, infectious disease, and cancer.
The plasma microparticle proteome Little, Kristina M; Smalley, David M; Harthun, Nancy L ...
Seminars in thrombosis and hemostasis,
11/2010, Letnik:
36, Številka:
8
Journal Article
Recenzirano
All cell types shed ectosomes and exosomes, collectively known as microparticles (MP; 0.1 to 1.5 μm in diameter), when activated or stressed; normal human plasma contains ~2 μg MP protein/mL. The ...cellular composition of plasma MP is altered in many diseases, including acute coronary syndrome, diabetes mellitus, sepsis, and sickle cell disease. We measured the plasma MP protein composition of 42 patients (median age 69.5 years, most with cardiovascular disease) by label-free liquid chromatography coupled to tandem mass spectrometry. Among 458 proteins detected with high confidence (identified by at least two unique peptides with SEQUEST XCor (Thermo Electron Corp., San Jose, CA) ≥ 2.0, 2.2, and 3.3 for charge states +1, +2, and +3, respectively), 130 were present in most patients, representing a "core" set of plasma MP proteins. This core is enriched in cytoskeletal, integrin complex, and hemostasis proteins, and spectral counts of several proteins correlate with patient age and gender. We conclude that the MP proteome may be a useful and reliable source of biologically relevant disease biomarkers.
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