Perivascular Location Research Articles

Equine Mesenchymal Stromal Cells Retain a Pericyte-Like Phenotype.

Mesenchymal stem/stromal cells (MSCs) have been used in human and equine regenerative medicine, and interest in exploiting their potential has increased dramatically over the years. Despite significant effort to characterize equine MSCs, the actual origin of these cells and how much of their native phenotype is maintained in culture have not been determined. In this study, we investigated the relationship between MSCs, derived from adipose tissue (AT) and bone marrow (BM), and pericytes in the horse. Both pericyte (CD146, NG2, and αSMA) and MSC (CD29, CD90, and CD73) markers were detected in equine AT and colocalized around blood vessels. Importantly, as assessed by flow cytometry, both pericyte (CD146, NG2, and αSMA) and MSC (CD29, CD44, CD90, and CD105) markers were present in a majority (≥90%) of cells in cultures of AT-MSCs and BM-MSCs; however, levels of pericyte markers were variable within each of those populations. Moreover, the expression of pericyte markers was maintained for at least eight passages in both AT-MSCs and BM-MSCs. Hematopoietic (CD45) and endothelial (CD144) markers were also detected at low levels in MSCs by quantitative polymerase chain reaction (qPCR). Finally, in coculture experiments, AT-MSCs closely associated with networks produced by endothelial cells, resembling the natural perivascular location of pericytes in vivo. Our results indicate that equine MSCs originate from perivascular cells and moreover maintain a pericyte-like phenotype in culture. Therefore, we suggest that, in addition to classical MSC markers, pericyte markers such as CD146 could be used when assessing and characterizing equine MSCs.

A transcriptome-based assessment of the astrocytic dystrophin-associated complex in the developing human brain.

Astrocytes play a critical role in regulating the interface between the cerebral vasculature and the central nervous system. Contributing to this is the astrocytic endfoot domain, a specialized structure that ensheathes the entirety of the vasculature and mediates signaling between endothelial cells, pericytes, and neurons. The astrocytic endfoot has been implicated as a critical element of the glymphatic pathway, and changes in protein expression profiles in this cellular domain are linked to Alzheimer's disease pathology. Despite this, basic physiological properties of this structure remain poorly understood including the developmental timing of its formation, and the protein components that localize there to mediate its functions. Here we use human transcriptome data from male and female subjects across several developmental stages and brain regions to characterize the gene expression profile of the dystrophin-associated complex (DAC), a known structural component of the astrocytic endfoot that supports perivascular localization of the astroglial water channel aquaporin-4. Transcriptomic profiling is also used to define genes exhibiting parallel expression profiles to DAC elements, generating a pool of candidate genes that encode gene products that may contribute to the physiological function of the perivascular astrocytic endfoot domain. We found that several genes encoding transporter proteins are transcriptionally associated with DAC genes.

A mathematical model of histamine-mediated neural activation during acupuncture.

Acupoints (Xuewei) are the focus of acupuncture on the body in traditional Chinese medicine treatment. Mast and nerve cells share a perivascular location and are abundantly found at these acupoints. Both environmental factors and medical treatments (chemical and physical stimuli) can stimulate local mast cells (MCs) to degranulate and thus release histamine which then activates the nearby nerves and therefore contributes to a signal transmission from the peripheral to the central nervoussystem. In this paper, a mathematical model is constructed to describe the signaling pathways that originate from the cells located at an acupoint. We show that: (1) peripheral stimuli induce the release of histamine from MCs; (2) histamine excites receptors in primary sensory neurons and leads to membrane action potentials; (3) histamine released from MCs at an acupoint plays a key role in response to acupuncture. These results are consistent with experimental observations. Furthermore, this study may facilitate our understanding of the signal transmission process that occurs in response to peripheral stimuli as well as provide a useful modeling tool for quantitatively analyzing immune and acupuncture mechanisms that involve MCs.

A novel perivascular cell population in the zebrafish brain.

The blood-brain barrier is essential for the proper homeostasis and function of the CNS, but its mechanism of function is poorly understood. Perivascular cells surrounding brain blood vessels are thought to be important for blood-brain barrier establishment, but their roles are not well defined. Here, we describe a novel perivascular cell population closely associated with blood vessels on the zebrafish brain. Based on similarities in their morphology, location, and scavenger behavior, these cells appear to be the zebrafish equivalent of cells variably characterized as Fluorescent Granular Perithelial cells (FGPs), perivascular macrophages, or 'Mato Cells' in mammals. Despite their macrophage-like morphology and perivascular location, zebrafish FGPs appear molecularly most similar to lymphatic endothelium, and our imaging studies suggest that these cells emerge by differentiation from endothelium of the optic choroidal vascular plexus. Our findings provide the first report of a perivascular cell population in the brain derived from vascular endothelium.

MRI-visible perivascular space location is associated with Alzheimer's disease independently of amyloid burden

Perivascular spaces that are visible on magnetic resonance imaging (MRI) are a neuroimaging marker of cerebral small vessel disease. Their location may relate to the type of underlying small vessel pathology: those in the white matter centrum semi-ovale have been associated with cerebral amyloid angiopathy, while those in the basal ganglia have been associated with deep perforating artery arteriolosclerosis. As cerebral amyloid angiopathy is an almost invariable pathological finding in Alzheimer's disease, we hypothesized that MRI-visible perivascular spaces in the centrum semi-ovale would be associated with a clinical diagnosis of Alzheimer's disease, whereas those in the basal ganglia would be associated with subcortical vascular cognitive impairment. We also hypothesized that MRI-visible perivascular spaces in the centrum semi-ovale would be associated with brain amyloid burden, as detected by amyloid positron emission tomography using 11C-Pittsburgh B compound (PiB-PET). Two hundred and twenty-six patients (Alzheimer's disease n = 110; subcortical vascular cognitive impairment n = 116) with standardized MRI and PiB-PET imaging were included. MRI-visible perivascular spaces were rated using a validated 4-point visual rating scale, and then categorized by severity ('none/mild', 'moderate' or 'frequent/severe'). Univariable and multivariable regression analyses were performed. Those with Alzheimer's disease-related cognitive impairment were younger, more likely to have a positive PiB-PET scan and carry at least one apolipoprotein E ɛ4 allele; those with subcortical vascular cognitive impairment were more likely to have hypertension, diabetes mellitus, hyperlipidaemia, prior stroke, lacunes, deep microbleeds, and carry the apolipoprotein E ɛ3 allele. In adjusted analyses, the severity of MRI-visible perivascular spaces in the centrum semi-ovale was independently associated with clinically diagnosed Alzheimer's disease (frequent/severe grade odds ratio 6.26, 95% confidence interval 1.66-23.58; P = 0.017, compared with none/mild grade), whereas the severity of MRI-visible perivascular spaces in the basal ganglia was associated with clinically diagnosed subcortical vascular cognitive impairment and negatively predicted Alzheimer's disease (frequent/severe grade odds ratio 0.03, 95% confidence interval 0.00-0.44; P = 0.009, compared with none/mild grade). MRI-visible perivascular space severity in either location did not predict PiB-PET. These findings provide further evidence that the anatomical distribution of MRI-visible perivascular spaces may reflect the underlying cerebral small vessel disease. Using MRI-visible perivascular space location and severity together with other imaging markers may improve the diagnostic value of neuroimaging in memory clinic populations, in particular in differentiating between clinically diagnosed Alzheimer's and subcortical vascular cognitive impairment.

Collision Metastasis of Chronic Lymphocytic Leukemia and Glioblastoma: A Case Report

Collision tumors or metastasis from an extracranial tumor to a primary brain neoplasm are rare but do occur. The majority involve metastases to meningiomas. This case presents the second documented collision of a systemic chronic lymphocytic leukemia (CLL) to a glioblastoma multiforme (GBM). Lymphomas tend to coalesce in perivascular locations, and the characteristic vascularity of glioblastomas may present a very inviting milieu for lymphoma cells.

Preferential Association of Lissencephaly-1 Gene Expression with CD133+ Glioblastoma Cells.

Lissencephaly-1 (Lis1) protein is a dynein-binding protein involved in neural stem cell division, morphogenesis and motility. To determine whether Lis1 is a key factor in glioblastoma, we evaluated its expression and function in CD133+ glioblastoma cells. Global, Lis1 gene expression is similar in glioblastoma and normal samples. Interestingly, immunohistochemistry data indicate increased Lis1 expression colocalized with CD133 in a subset of glioma cells, including the tumor cells with perivascular localization. Lis1 gene expression is increased up to 60-fold in CD133 positive cells isolated from primary cultures of glioblastoma and U87 glioblastoma cell line as compared to CD133 negative cells. To investigate the potential role of Lis1 in CD133+ glioblastoma cells, we silenced Lis1 gene in U87 cell line obtaining shLis1-U87 cells. In shLis1-U87 cell culture we noticed a significant decrease of CD133+ cells fraction as compared with control cells and also, CD133+ cells isolated from shLis1-U87 were two times less adhesive, migratory and proliferative, as compared with control transfected U87 CD133+ cells. Moreover, Lis1 silencing decreased the proliferative capacity of irradiated U87 cells, an effect attributable to the lower percentage of CD133+ cells. This is the first report showing a preferential expression of Lis1 gene in CD133+ glioblastoma cells. Our data suggest a role of Lis1 in regulating CD133+ glioblastoma cells function.

β-amyloid can't go with the flow.

Reduced perivascular localization of aquaporin-4 channels is associated with Alzheimer’s disease pathology.

Association of Perivascular Localization of Aquaporin-4 With Cognition and Alzheimer Disease in Aging Brains

Cognitive impairment and dementia, including Alzheimer disease (AD), are common within the aging population, yet the factors that render the aging brain vulnerable to these processes are unknown. Perivascular localization of aquaporin-4 (AQP4) facilitates the clearance of interstitial solutes, including amyloid-β, through the brainwide network of perivascular pathways termed the glymphatic system, which may be compromised in the aging brain. To determine whether alterations in AQP4 expression or loss of perivascular AQP4 localization are features of the aging human brain and to define their association with AD pathology. Expression of AQP4 was analyzed in postmortem frontal cortex of cognitively healthy and histopathologically confirmed individuals with AD by Western blot or immunofluorescence for AQP4, amyloid-β 1-42, and glial fibrillary acidic protein. Postmortem tissue and clinical data were provided by the Oregon Health and Science University Layton Aging and Alzheimer Disease Center and Oregon Brain Bank. Postmortem tissue from 79 individuals was evaluated, including cognitively intact "young" individuals aged younger than 60 years (range, 33-57 years), cognitively intact "aged" individuals aged older than 60 years (range, 61-96 years) with no known neurological disease, and individuals older than 60 years (range, 61-105 years) of age with a clinical history of AD confirmed by histopathological evaluation. Forty-eight patient samples (10 young, 20 aged, and 18 with AD) underwent histological analysis. Sixty patient samples underwent Western blot analysis (15 young, 24 aged, and 21 with AD). Expression of AQP4 protein, AQP4 immunoreactivity, and perivascular AQP4 localization in the frontal cortex were evaluated. Expression of AQP4 was associated with advancing age among all individuals (R2 = 0.17; P = .003). Perivascular AQP4 localization was significantly associated with AD status independent of age (OR, 11.7 per 10% increase in localization; z = -2.89; P = .004) and was preserved among eldest individuals older than 85 years of age who remained cognitively intact. When controlling for age, loss of perivascular AQP4 localization was associated with increased amyloid-β burden (R2 = 0.15; P = .003) and increasing Braak stage (R2 = 0.14; P = .006). In this study, altered AQP4 expression was associated with aging brains. Loss of perivascular AQP4 localization may be a factor that renders the aging brain vulnerable to the misaggregation of proteins, such as amyloid-β, in neurodegenerative conditions such as AD.

Mesenchymal Stem Cells and Pericytes: To What Extent Are They Related?

Mesenchymal stem cells (MSCs) were initially identified as progenitors of skeletal tissues within mammalian bone marrow and cells with similar properties were also obtained from other tissues such as adipose and dental pulp. Although MSCs have been extensively investigated, their native behavior and in vivo identity remain poorly defined. Uncovering the in vivo identity of MSCs has been challenging due to the lack of exclusive cell markers, cellular alterations caused by culture methods, and extensive focus on in vitro properties for characterization. Although MSC site of origin influences their functional properties, these mesenchymal progenitors can be found in the perivascular space in virtually all organs from where they were obtained. However, the precise identity of MSCs within the vascular wall is highly controversial. The recurrent concept that MSCs correspond to pericytes in vivo has been supported mainly by their perivascular localization and expression of some molecular markers. However, this view has been a subject of controversy, in part, due to the application of loose criteria to define pericytes and due to the lack of a marker able to unequivocally identify these cells. Furthermore, recent evidences indicate that subpopulations of MSCs can be found at extravascular sites such as the endosteum. In this opinion review, we bring together the advances and pitfalls on the search for the in vivo identity of MSCs and highlight the recent evidences that suggest that perivascular MSCs are adventitial cells, acting as precursors of pericytes and other stromal cells during tissue homeostasis.

Leydig cell stem cells: Identification, proliferation and differentiation

Adult Leydig cells develop from undifferentiated mesenchymal-like stem cells (stem Leydig cells, SLCs) present in the interstitial compartment of the early postnatal testis. Putative SLCs also have been identified in peritubular and perivascular locations of the adult testis. The latter cells, which normally are quiescent, are capable of regenerating new Leydig cells upon the loss of the adult cells. Recent studies have identified several protein markers to identify these cells, including nestin, PDGFRα, COUP-TFII, CD51 and CD90. We have shown that the proliferation of the SLCs is stimulated by DHH, FGF2, PDGFBB, activin and PDGFAA. Suppression of proliferation occurred with TGFβ, androgen and PKA signaling. The differentiation of the SLCs into testosterone-producing Leydig cells was found to be regulated positively by DHH (Desert hedgehog), lithium-induced signaling and activin; and negatively by TGFβ, PDGFBB, FGF2, Notch and Wnt signaling. DHH, by itself, was found to induce SLC differentiation into LH-responsive steroidogenic cells, suggesting that DHH plays a critical role in the commitment of SLC into the Leydig lineage. These studies, taken together, address the function and regulation of low turnover stem cells in a complex, adult organ, and also have potential application to the treatment of androgen deficiency.

Connective tissue growth factor (CTGF/CCN2) in haemophilic arthropathy and arthrofibrosis: a histological analysis.

Joint haemorrhage is the principal clinical manifestation of haemophilia frequently leading to advanced arthropathy and arthrofibrosis, resulting in severe disability. The degree and prevalence of arthrofibrosis in hemophilic arthropathy is more severe than in other forms of arthropathy. Expression of connective tissue growth factor (CTGF) has been linked to many fibrotic diseases, but has not been studied in the context of haemophilic arthropathy. We aim to compare synovial tissues histologically from haemophilia and osteoarthritis patients with advanced arthropathy in order to compare expression of proteins that are possibly aetiologic in the development of arthrofibrosis. Human synovial tissues were obtained from 10 haemophilia and 10 osteoarthritis patients undergoing joint surgery and processed for histology and immunohistochemistry. All samples from haemophilia patients had synovitis with hypertrophy and hyperplasia of synovial villi. Histologically, synovial tissues contained hyperplastic villi with increased cellularity and abundant haemosiderin- and ferritin-pigmented macrophage-like cells (HMCs), with a perivascular localization in the sub-surface layer. CTGF staining was observed in the surface layer and sub-surface layer in all haemophilia patients, exclusively co-localizing with HMCs. Quantification showed that the extent of CTGF-positive areas was correlated with the degree of detection of HMCs. CTGF was not observed in any of the samples from osteoarthritis patients. Using histological analysis, we showed that CTGF expression is elevated in haemophilia patients with arthrofibrosis and absent in patients with osteoarthritis. Additionally, we found that CTGF is always associated with haemosiderin-pigmented macrophage-like cells, which suggests that CTGF is produced by synovial A cells following the uptake of blood breakdown products.

Electronmicroscopic changes of the testes at the early stages after experimental thermal injury.

Background. Severe thermal injuries accompanied by the development of endogenous intoxication, causing severe structural and metabolic disorders not only of the skin, but of all organs and body systems of burned organism. But lesser known submicroscopic changes of testis – the central organ of male reproductive system in dynamics after burn injury. Objective. The aim of this work was to established ultrastructural reorganization of the testes at early stages after experimental thermal injury. Methods. Experiment has been carried out on 20 mature white rats-males. Burn applied under ketamin anesthesia for 18-20% of hairless body surface of animals. Histological studies indicate the development of third-degree burn of skin. Experimental animals were decapitated on the 1st, 3th and 7th days of the experiment (early stage of shock and toxemia). Collecting the material for electronmicroscopic research conducted under the conventional method. Results. Electronmicroscopic research of the testes on the 1st day after thermal injury (stage of shock) detected adaptive-compensatory reorganization of the structural components of organ. Arterioles, venules and hemocapillaries have expanded lumens filled with blood cells, mainly erythrocytes. Vessel walls are irregularly thickened due to swelling of the endothelial cytoplasm and basement membrane. There are degranulation and mitochondrial hypertrophy in the cytoplasm of a part of Leydig cells that have perivascular location. There are also signs of reorganization of spermatogenic epithelium. Small amount of spermatogonia with signs of mitosis are available. Sertoli cells are moderately changed. Primary and secondary spermatocytes include round nucleus that have euchromatin and small clumps of heterochromatin in carioplasm, and small amount of organelles in the cytoplasm. Some spermatids and spermatozoa have damage structure of acrosome, observed high electron density of nucleus. At the early stage of toxemia (3th, 7th day of experiment) detected signs of destructive changes in the blood capillaries of the stroma and structural components of convoluted seminiferous tubules of the testes of experimental animals. Conclusion. Under burn shock ultrastructural reorganization of microcirculatory bed, walls of convoluted tubules and spermatogenic epithelium has adaptive-compensatory character. At the early stage of toxemia thermal lesions of animals skin lead to destructive changes in the blood capillaries, endocrinocytes, submicroscopic organization of structural components of the convoluted seminiferous tubules.

MWA Versus RFA for Perivascular and Peribiliary CRLM: A Retrospective Patient- and Lesion-Based Analysis of Two Historical Cohorts

PurposeTo retrospectively analyse the safety and efficacy of radiofrequency ablation (RFA) versus microwave ablation (MWA) in the treatment of unresectable colorectal liver metastases (CRLM) in proximity to large vessels and/or major bile ducts.Method and MaterialsA database search was performed to include patients with unresectable histologically proven and/or 18F–FDG–PET avid CRLM who were treated with RFA or MWA between January 2001 and September 2014 in a single centre. All lesions that were considered to have a peribiliary and/or perivascular location were included. Univariate logistic regression analysis was performed to assess the distribution of patient, tumour and procedure characteristics. Multivariate logistic regression was used to correct for potential confounders.ResultsTwo hundred and forty-three patients with 774 unresectable CRLM were ablated. One hundred and twenty-two patients (78 males; 44 females) had at least one perivascular or peribiliary lesion (n = 199). Primary efficacy rate of RFA was superior to MWA after 3 and 12 months of follow-up (P = 0.010 and P = 0.022); however, after multivariate analysis this difference was non-significant at 12 months (P = 0.078) and vanished after repeat ablations (P = 0.39). More CTCAE grade III complications occurred after MWA versus RFA (18.8 vs. 7.9 %; P = 0.094); biliary complications were especially common after peribiliary MWA (P = 0.002).ConclusionFor perivascular CRLM, RFA and MWA are both safe treatment options that appear equally effective. For peribiliary CRLM, MWA has a higher complication rate than RFA, with similar efficacy. Based on these results, it is advised to use RFA for lesions in the proximity of major bile ducts.

Identification and Characterization of Human Endometrial Mesenchymal Stem/Stromal Cells and Their Potential for Cellular Therapy.

SummaryHuman endometrium is a highly regenerative tissue, undergoing more than 400 cycles of proliferation, differentiation, and shedding during a woman's reproductive life. Adult stem cells, including mesenchymal stem/stromal cells (MSCs), are likely responsible for the immense cellular turnover in human endometrium. The unique properties of MSCs, including high proliferative ability, self-renewal, differentiation to mesodermal lineages, secretion of angiogenic factors, and many other growth-promoting factors make them useful candidates for cellular therapy and tissue engineering. In this review, we summarize the identification and characterization of newly discovered MSCs from the human endometrium: their properties, the surface markers used for their prospective isolation, their perivascular location in the endometrium, and their potential application in cellular therapies. The endometrium, or the lining of uterus, has recently been identified as a new and accessible source of mesenchymal stem cells, which can be obtained without anesthesia. Endometrial mesenchymal stem cells have comparable properties to bone marrow and adipose tissue mesenchymal stem cells. Endometrial mesenchymal stem cells are purified with known and novel perivascular surface markers and are currently under investigation for their potential use in cellular therapy for several clinical conditions with significant burden of disease.

JAK2V617F-mutant megakaryocytes contribute to hematopoietic stem/progenitor cell expansion in a model of murine myeloproliferation.

The myeloproliferative neoplasms (MPNs) are characterized by hematopoietic stem/progenitor cell (HSPC) expansion and overproduction of mature blood cells. The JAK2V617F mutation is present in hematopoietic cells in a majority of patients with MPNs, but the mechanism(s) responsible for MPN stem cell expansion remain incomplete. One hallmark feature of the marrow in patients with MPNs is megakaryocyte (MK) hyperplasia. We report here that mice bearing a human JAK2V617F gene restricted exclusively to the MK lineage develop many of the features of a MPN. Specifically, these mice exhibit thrombocytosis, splenomegaly, increased numbers of marrow and splenic hematopoietic progenitors and a substantial expansion of HSPCs. In addition, wild-type mice transplanted with cells from JAK2V617F-bearing MK marrow develop a myeloproliferative syndrome with thrombocytosis and erythrocytosis as well as pan-hematopoietic progenitor and stem cell expansion. As marrow histology in this murine model of myeloproliferation reveals a preferentially perivascular localization of JAK2V617F-mutant MKs and an increased marrow sinusoid vascular density, it adds to accumulating data that MKs are an important component of the marrow HSPC niche, and that MK expansion might indirectly contribute to the critical role of the thrombopoietin/c-Mpl signaling pathway in HSPC maintenance and expansion.

Pericytic mimicry in well-differentiated liposarcoma/atypical lipomatous tumor

Pericytes are modified smooth muscle cells that closely enwrap small blood vessels, regulating and supporting the microvasculature through direct endothelial contact. Pericytes demonstrate a distinct immunohistochemical profile, including expression of smooth muscle actin, CD146, platelet-derived growth factor receptor β, and regulator of G-protein signaling 5. Previously, pericyte-related antigens have been observed to be present among a group of soft tissue tumors with a perivascular growth pattern, including glomus tumor, myopericytoma, and angioleiomyoma. Similarly, malignant tumor cells have been shown to have a pericyte-like immunoprofile when present in a perivascular location, seen in malignant melanoma, glioblastoma, and adenocarcinoma. Here, we examine well-differentiated liposarcoma specimens, which showed some element of perivascular areas with the appearance of smooth muscle (n = 7 tumors). Immunohistochemical staining was performed for pericyte antigens, including smooth muscle actin, CD146, platelet-derived growth factor receptor β, and regulator of G-protein signaling 5. Results showed consistent pericytic marker expression among liposarcoma tumor cells within a perivascular distribution. MDM2 immunohistochemistry and fluorescence in situ hybridization for MDM2 revealed that these perivascular cells were of tumor origin (7/7 tumors), whereas double immunohistochemical detection for CD31/CD146 ruled out an endothelial cell contribution. These findings further support the concept of pericytic mimicry, already established in diverse malignancies, and its presence in well-differentiated liposarcoma. The extent to which pericytic mimicry has prognostic significance in liposarcoma is as yet unknown.

Nestin+cells forming spheroids aggregates resembling tumorspheres in experimental ENU-induced gliomas.

Nestin+cells from spheroid aggregates display typical histopathological features compatible with cell stemness. Nestin and CD133+cells found in glioblastomas, distributed frequently around aberrant vessels, are considered as potential cancer stem cells. They are possible targets for antitumoral therapy because they lead the tumorigenesis, invasiveness and angiogenesis. However, little is known about their role and presence in low-grade gliomas. The aim of this work is to localize and characterize the distribution of these cells inside tumors during the development of experimental endogenous glioma. For this study, a single dose of Ethyl-nitrosourea was injected into pregnant rats. Double immunofluorescences were performed in order to identify stem-like and differentiated cells. Low-grade gliomas display Nestin+cells distributed throughout the tumor. More malignant gliomas show, in addition to that, a perivascular location with some Nestin+cells co-expressing CD133 or VEGF, and the intratumoral spheroid aggregates of Nestin/CD133+cells. These structures are encapsulated by well-differentiated VEGF/GFAP+cells. Spheroid aggregates increase in size in the most malignant stages. Spheroid aggregates have morphological and phenotypic similarities to in vitro neurospheres and could be an in vivo analogue of them. These arrangements could be a reservoir of undifferentiated cells formed to escape adverse microenvironments.

Preliminary Outcome of Microwave Ablation of Hepatocellular Carcinoma: Breaking the 3-cm Barrier?

PurposeTo evaluate preliminary outcomes after microwave ablation (MWA) of hepatocellular carcinoma (HCC) up to 5 cm and to determine the influence of tumor size. Materials and MethodsElectronic records were searched for HCC and MWA. Between January 2011 and September 2014, 173 HCCs up to 5 cm were treated by MWA in 129 consecutive patients (89 men, 40 women; mean age, 66.9 y ± 9.5). Tumor characteristics related to local tumor progression and primary and secondary treatment efficacy were evaluated by univariate analysis. Outcomes were compared between tumors ≤ 3 cm and tumors > 3 cm. ResultsTechnical success, primary efficacy, and secondary efficacy were 96.5%, 99.4%, and 94.2% at a mean follow-up period of 11.8 months ± 9.8 (range, 0.8–40.6 mo). Analysis of tumor characteristics showed no significant risk factor for local tumor progression, including subcapsular location (P = .176), tumor size (P = .402), and perivascular tumor location (P = .323). The 1-year and 2-year secondary or overall treatment efficacy rates for tumors measuring ≤ 3 cm were 91.2% and 82.1% and for tumors 3.1–5 cm were 92.3% and 83.9% (P = .773). The number of sessions to achieve secondary efficacy was higher in the larger tumor group (1.13 vs 1.06, P = .005). There were three major complications in 134 procedures (2.2%). ConclusionsWith use of current-generation MWA devices, percutaneous ablation of HCCs up to 5 cm can be achieved with high efficacy.

Pivotal Role for CD16+ Monocytes in Immune Surveillance of the Central Nervous System.

Monocytes represent a heterogeneous population of primary immune effector cells. At least three different subsets can be distinguished based on expression of the low-affinity FcγRIII: CD14(++)CD16 -: classical monocytes, CD14(++)CD16(+) intermediate monocytes, and CD14(+)CD16 ++: non-classical monocytes. Whereas CD16 -: classical monocytes are considered key players in multiple sclerosis (MS), little is known on CD16(+) monocytes and how they contribute to the disease. In this study, we examined the frequency and phenotype of monocyte subpopulations in peripheral blood, cerebrospinal fluid (CSF), and brain biopsy material derived from MS patients and controls. Furthermore, we addressed a possible monocyte dysfunction in MS and analyzed migratory properties of monocyte subsets using human brain microvascular endothelial cells. Our ex vivo studies demonstrated that CD16(+) monocyte subpopulations are functional but numerically reduced in the peripheral blood of MS patients. CD16(+) monocytes with an intermediate-like phenotype were found to be enriched in CSF and dominated the CSF monocyte population under noninflammatory conditions. In contrast, an inversed CD16(+) to CD16 -: CSF monocyte ratio was observed in MS patients with relapsing-remitting disease. Newly infiltrating, hematogenous CD16(+) monocytes were detected in a perivascular location within active MS lesions, and CD16(+) monocytes facilitated CD4(+) T cell trafficking in a blood -: brain barrier model. Our findings support an important role of CD16(+) monocytes in the steady-state immune surveillance of the CNS and suggest that CD16(+) monocytes shift to sites of inflammation and contribute to the breakdown of the blood-brain barrier in CNS autoimmune diseases.