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Jernej Mlakar

Bio: Jernej Mlakar is an academic researcher from University of Ljubljana. The author has contributed to research in topics: Glioma & Cancer research. The author has an hindex of 8, co-authored 18 publications receiving 2558 citations.

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TL;DR: The case of an expectant mother who had a febrile illness with rash at the end of the first trimester of pregnancy while she was living in Brazil and revealed microcephaly with calcifications in the fetal brain and placenta is described.
Abstract: Summary A widespread epidemic of Zika virus (ZIKV) infection was reported in 2015 in South and Central America and the Caribbean. A major concern associated with this infection is the apparent increased incidence of microcephaly in fetuses born to mothers infected with ZIKV. In this report, we describe the case of an expectant mother who had a febrile illness with rash at the end of the first trimester of pregnancy while she was living in Brazil. Ultrasonography performed at 29 weeks of gestation revealed microcephaly with calcifications in the fetal brain and placenta. After the mother requested termination of the pregnancy, a fetal autopsy was performed. Micrencephaly (an abnormally small brain) was observed, with almost complete agyria, hydrocephalus, and multifocal dystrophic calcifications in the cortex and subcortical white matter, with associated cortical displacement and mild focal inflammation. ZIKV was found in the fetal brain tissue on reversetranscriptase–polymerase-chain-reaction (RT-PCR) assay, with consistent findings on electron microscopy. The complete genome of ZIKV was recovered from the fetal brain.

2,403 citations

Journal ArticleDOI
TL;DR: It is shown that ZIKV infects both neocortical and spinal cord neuroepithelial stem cells as well as their fetal homolog, radial glial cells (RGCs), causing disrupted mitoses, supernumerary centrosomes, structural disorganization, and cell death.

241 citations

Journal ArticleDOI
TL;DR: The findings are in agreement with neuroimaging of Zika virus-associated fetal and infant micrencephalic brains and, to some extent, with neuroIMaging of other intrauterine infections causing microcephaly.
Abstract: Context.—The 2015 outbreak of Zika virus in Brazil resulted in a 20-times increased prevalence of congenital microcephaly in stillborns and neonates and was instrumental in raising the suspicion of a causal association between Zika virus and microcephaly. Objective.—To provide a comprehensive description of the neuropathologic features of congenital Zika virus infection. Design.—Autopsy evaluation of the brain from a fetus of 32 weeks and 6 days of gestation, with a prenatal diagnosis of microcephaly associated with polymerase chain reaction–confirmed, fetal, Zika virus infection. Results.—Multiple severe pathology findings were present. These included lissencephaly, except for the occipital lobes, where some pachygyria was observed. Also present was reduction and thinning of white matter, ventriculomegaly of the lateral ventricles, and coalescent calcifications in the cortical-subcortical white matter border associated with glioneuronal outbursting into the subarachnoid space above and heterotopias below...

45 citations

Journal ArticleDOI
TL;DR: Meningioma grade, size and number of tissue blocks were independent predictors of brain invasion assessability and can be improved by extensive sampling of meningioma surgical.
Abstract: Aims Despite the important prognostic value of brain invasion in meningiomas, little attention has been paid to its massessment, and the parameters associated with brain invasion assessability (identification of brain tissue in the surgical specimen) are not well characterized. The aim of our study was to determine the parameters that are associated with brain invasion assessability and brain invasion in meningiomas. Material and methods By binary logistic regression analysis, we studied the association of various clinical and pathologic parameters with brain invasion assessabilitym and brain invasion in 294 meningiomas: 149 unselected consecutive meningiomas with extensive sampling, diagnosed in 2009 and 2010, collected prospectively, and 145 meningiomas diagnosed in 1999 and 2000 when little attention was paid to brain invasion assessment. Results Meningioma grade, size and number of tissue blocks were independent predictors of brain invasion assessability. Brain tissue was identified in 78 of 233 (33%) benign, 33 of 51 (65%) atypical, and 10 of 10 (100%) malignant meningiomas. In univariate analysis, group (prospective vs.retrospective), type (recurrent vs. primary), cleavability, meningioma grade and mitotic count were predictors of brain invasion, while only meningioma grade, and group retained predictive value in multivariate analysis. Brain invasion, when assessable, was identified in 22 of 78 (28%) benign, 21 of 33 (64%) atypical, and 10 of 10 (100%) malignant meningiomas. Conclusions Brain invasion assessability is related to meningioma grade and size and can be improved by extensive sampling of meningioma surgical.

42 citations

Journal ArticleDOI
TL;DR: Autocrine and paracrine cross-talk in glioblastoma and, in particular, gli oblastoma stem cells with its stromal microenvironment, involves CCR5 and CCL5, contributing to gliOBlastoma invasion, suggesting the CCL 5/CCR5 axis as a potential therapeutic target that can be targeted with repositioned drug maraviroc.
Abstract: The chemokine CCL5/RANTES is a versatile inflammatory mediator, which interacts with the receptor CCR5, promoting cancer cell interactions within the tumor microenvironment. Glioblastoma is a highly invasive tumor, in which CCL5 expression correlates with shorter patient survival. Using immunohistochemistry, we identified CCL5 and CCR5 in a series of glioblastoma samples and cells, including glioblastoma stem cells. CCL5 and CCR5 gene expression were significantly higher in a cohort of 38 glioblastoma samples, compared to low-grade glioma and non-cancerous tissues. The in vitro invasion of patients-derived primary glioblastoma cells and glioblastoma stem cells was dependent on CCL5-induced CCR5 signaling and is strongly inhibited by the small molecule CCR5 antagonist maraviroc. Invasion of these cells, which was enhanced when co-cultured with mesenchymal stem cells (MSCs), was inhibited by maraviroc, suggesting that MSCs release CCR5 ligands. In support of this model, we detected CCL5 and CCR5 in MSC monocultures and glioblastoma-associated MSC in tissue sections. We also found CCR5 expressing macrophages were in close proximity to glioblastoma cells. In conclusion, autocrine and paracrine cross-talk in glioblastoma and, in particular, glioblastoma stem cells with its stromal microenvironment, involves CCR5 and CCL5, contributing to glioblastoma invasion, suggesting the CCL5/CCR5 axis as a potential therapeutic target that can be targeted with repositioned drug maraviroc.

38 citations


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TL;DR: The in situ immune response profile and mechanisms of neuronal cell damage in fatal Zika microcephaly cases were investigated and changes found were mainly calcification, necrosis, neuronophagy, gliosis, microglial nodules, and inflammatory infiltration of mononuclear cells.
Abstract: Zika virus (ZIKV) has recently caused a pandemic disease, and many cases of ZIKV infection in pregnant women resulted in abortion, stillbirth, deaths and congenital defects including microcephaly, which now has been proposed as ZIKV congenital syndrome. This study aimed to investigate the in situ immune response profile and mechanisms of neuronal cell damage in fatal Zika microcephaly cases. Brain tissue samples were collected from 15 cases, including 10 microcephalic ZIKV-positive neonates with fatal outcome and five neonatal control flavivirus-negative neonates that died due to other causes, but with preserved central nervous system (CNS) architecture. In microcephaly cases, the histopathological features of the tissue samples were characterized in three CNS areas (meninges, perivascular space, and parenchyma). The changes found were mainly calcification, necrosis, neuronophagy, gliosis, microglial nodules, and inflammatory infiltration of mononuclear cells. The in situ immune response against ZIKV in the CNS of newborns is complex. Despite the predominant expression of Th2 cytokines, other cytokines such as Th1, Th17, Treg, Th9, and Th22 are involved to a lesser extent, but are still likely to participate in the immunopathogenic mechanisms of neural disease in fatal cases of microcephaly caused by ZIKV.

3,514 citations

Journal ArticleDOI
TL;DR: Despite mild clinical symptoms in the mother, ZIKV infection during pregnancy is deleterious to the fetus and is associated with fetal death, fetal growth restriction, and a spectrum of central nervous system abnormalities.
Abstract: BackgroundZika virus (ZIKV) has been linked to central nervous system malformations in fetuses. To characterize the spectrum of ZIKV disease in pregnant women and infants, we followed patients in Rio de Janeiro to describe clinical manifestations in mothers and repercussions of acute ZIKV infection in infants. MethodsWe enrolled pregnant women in whom a rash had developed within the previous 5 days and tested blood and urine specimens for ZIKV by reverse-transcriptase–polymerase-chain-reaction assays. We followed women prospectively to obtain data on pregnancy and infant outcomes. ResultsA total of 345 women were enrolled from September 2015 through May 2016; of these, 182 women (53%) tested positive for ZIKV in blood, urine, or both. The timing of acute ZIKV infection ranged from 6 to 39 weeks of gestation. Predominant maternal clinical features included a pruritic descending macular or maculopapular rash, arthralgias, conjunctival injection, and headache; 27% had fever (short-term and low-grade). By Jul...

1,711 citations

Journal ArticleDOI
TL;DR: It is concluded that a causal relationship exists between prenatal Zika virus infection and microcephaly and other serious brain anomalies and needs to intensify efforts toward the prevention of adverse outcomes caused by congenital Zika virus infections.
Abstract: Summary The Zika virus has spread rapidly in the Americas since its first identification in Brazil in early 2015. Prenatal Zika virus infection has been linked to adverse pregnancy and birth outcomes, most notably microcephaly and other serious brain anomalies. To determine whether Zika virus infection during pregnancy causes these adverse outcomes, we evaluated available data using criteria that have been proposed for the assessment of potential teratogens. On the basis of this review, we conclude that a causal relationship exists between prenatal Zika virus infection and microcephaly and other serious brain anomalies. Evidence that was used to support this causal relationship included Zika virus infection at times during prenatal development that were consistent with the defects observed; a specific, rare phenotype involving microcephaly and associated brain anomalies in fetuses or infants with presumed or confirmed congenital Zika virus infection; and data that strongly support biologic plausibility, including the identification of Zika virus in the brain tissue of affected fetuses and infants. Given the recognition of this causal relationship, we need to intensify our efforts toward the prevention of adverse outcomes caused by congenital Zika virus infection. However, many questions that are critical to our prevention efforts remain, including the spectrum of defects caused by prenatal Zika virus infection, the degree of relative and absolute risks of adverse outcomes among fetuses whose mothers were infected at different times during pregnancy, and factors that might affect a woman’s risk of adverse pregnancy or birth outcomes. Addressing these questions will improve our ability to reduce the burden of the effects of Zika virus infection during pregnancy.

1,692 citations

Journal ArticleDOI
19 May 2016-Cell
TL;DR: A miniaturized spinning bioreactor (SpinΩ) is developed to generate forebrain-specific organoids from human iPSCs that recapitulate key features of human cortical development, including progenitor zone organization, neurogenesis, gene expression, and, notably, a distinct human-specific outer radial glia cell layer.

1,526 citations

Journal ArticleDOI
TL;DR: It is shown that a strain of the ZIKV, MR766, serially passaged in monkey and mosquito cells efficiently infects human neural progenitor cells (hNPCs) derived from induced pluripotent stem cells, identified as a direct ZikV target, and reveals transcriptional dysregulation, notably of cell-cycle-related pathways.

1,122 citations