Cerebral Microangiopathy in Leukoencephalopathy With Cerebral Calcifications and Cysts: A Pathological Description

2020 ◽  
Vol 36 (2) ◽  
pp. 133-140
Author(s):  
Guy Helman ◽  
Angela N. Viaene ◽  
Asako Takanohashi ◽  
Marjolein Breur ◽  
Rebecca Berger ◽  
...  
Keyword(s):  
White Matter ◽  
Vascular Malformations ◽  
Proteolipid Protein ◽  
Lymphocytic Infiltration ◽  
Cystic Degeneration ◽  
Small Vessels ◽  
Pathogenic Variants ◽  
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Foamy Macrophages

Leukoencephalopathy with calcifications and cysts (LCC) is a neurological syndrome recently associated with pathogenic variants in SNORD118. We report autopsy neuropathological findings from an individual with genetically confirmed LCC. Histologic studies included staining of formalin-fixed paraffin-embedded tissue sections by hematoxylin and eosin, elastic van Gieson, and luxol fast blue. Immunohistochemistry stains against glial fibrillary acidic protein, proteolipid protein, phosphorylated neurofilament, CD31, alpha-interferon, LN3, and inflammatory markers were performed. Gross examination revealed dark tan/gray appearing white matter with widespread calcifications. Microscopy revealed a diffuse destructive process due to a vasculopathy with secondary ischemic lesions and mineralization. The vasculopathy involved clustered small vessels, resembling vascular malformations, and sporadic lymphocytic infiltration of vessel walls. The white matter was also diffusely abnormal, with concurrent loss of myelin and axons, tissue rarefaction with multifocal cystic degeneration, and the presence of foamy macrophages, secondary calcifications, and astrogliosis. The midbrain, pons, and cerebellum were diffusely involved. It is not understood why variants in SNORD118 result in a disorder that predominantly causes neurological disease and significantly disrupts the cerebral vasculature. Clinical and radiological benefit was recently reported in an LCC patient treated with Bevacizumab; it is important that these patients are rapidly diagnosed and trial of this treatment modality is considered in appropriate circumstances.

scholarly journals Aquaporin-4 protein expression in normal canine brains

2021 ◽  
Vol 17 (1) ◽  
Author(s):  
Patricia Álvarez ◽  
Ester Blasco ◽  
Martí Pumarola ◽  
Annette Wessmann
Keyword(s):  
White Matter ◽  
Cancer Progression ◽  
Aquaporin 4 ◽  
Histopathological Study ◽  
White Matter Tracts ◽  
Aqp4 Expression ◽  
Canine Brain ◽  
Potential Marker ◽  
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Abstract Background Aquaporin-4 (AQP4) is in growing recognition as potential marker for cancer progression, differentiation and therapeutic intervention. No information is available about AQP4 expression in the normal canine brain. The aim of this histopathological study is to confirm the presence of AQP4 by immunohistochemistry technique in a group of non-pathological canine brains and to describe its expression and distribution across the brain. Results Twelve non-pathological canine brains of various ages (ranging from 21 days to 17 years) and breeds were included in the study. Immunohistochemical expression of AQP4 was analyzed using formalin-fixed paraffin-embedded brain tissue sections. The findings were correlated between AQP4 expressing cells and astrocytes using glial fibrillary acidic protein (GFAP). AQP4 expression was more marked in the astrocyte foot processes of subpial, perivascular and periventricular surfaces in all specimens. The majority of the canine brain sections (9/12) presented with an AQP4 predilection for white matter tracts. Interestingly, the two youngest dogs (21 days and 3 months old) were characterized by diffuse AQP4 labelling in both grey and white matter tracts. This result may suggest that brain development and ageing may play a role in the AQP4 distribution throughout the canine brain. Conclusions This is the first study to describe immunohistochemical distribution of AQP4 in normal canine brains. The AQP4 expression and distribution in non-pathological canine brains was comparable to other species. Larger studies are needed to substantiate the influence of breed and ageing on AQP4 expression in the normal canine brain.

scholarly journals Evaluating the utility of tumour mutational signatures for identifying hereditary colorectal cancer and polyposis syndrome carriers

2019 ◽  
Author(s):  
Peter Georgeson ◽  
Bernard J. Pope ◽  
Christophe Rosty ◽  
Mark Clendenning ◽  
Khalid Mahmood ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Excision Repair ◽  
Base Substitution ◽  
List Type ◽  
Mutational Signatures ◽  
Dna Mismatch ◽  
Pathogenic Variants ◽  
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Base Excision

ABSTRACTObjectiveGermline pathogenic variants (PVs) in the DNA mismatch repair (MMR) genes and in the base excision repair gene MUTYH underlie hereditary colorectal cancer (CRC) and polyposis syndromes. We evaluated the robustness and discriminatory potential of tumour mutational signatures in CRCs for identifying germline PV carriers.DesignWhole exome sequencing of formalin-fixed paraffin embedded (FFPE) CRC tissue was performed on 33 MMR germline PV carriers, 12 biallelic MUTYH germline PV carriers, 25 sporadic MLH1 methylated MMR-deficient CRCs (MMRd controls) and 160 sporadic MMR-proficient CRCs (MMRp controls) and included 498 TCGA CRC tumours. COSMIC V3 single base substitution (SBS) and indel (ID) mutational signatures were assessed for their ability to differentiate CRCs that developed in carriers from non-carriers.ResultsThe combination of mutational signatures SBS18 and SBS36 contributing >30% of a CRC’s signature profile was able to discriminate biallelic MUTYH carriers from all other non-carrier control CRCs with 100% accuracy (area under the curve (AUC) 1.0). SBS18 and SBS36 were associated with specific MUTYH variants p.Gly396Asp (p=0.025) and p.Tyr179Cys (p=5×10−5), respectively. The combination of ID2 and ID7 could discriminate the 33 MMR PV carrier CRCs from the MMRp control CRCs (AUC 0.99), however, SBS and ID signatures, alone or in combination, could not provide complete discrimination (AUC 0.79) between CRCs from MMR PV carriers and sporadic MMRd controls.ConclusionAssessment of SBS and ID signatures can discriminate CRCs from biallelic MUTYH carriers and MMR PV carriers from non-carriers with high accuracy, demonstrating utility as a potential diagnostic and variant classification tool.SIGNIFICANCE OF THE STUDYWhat is already known about this subject?Identifying carriers of pathogenic variants (PVs) in moderate/high-risk colorectal cancer (CRC) and polyposis susceptibility genes has clinical relevance for diagnosis, targeted screening and prevention strategies, prognosis, and treatment options. However, challenges still remain in the identification of carriers and the classification of rare variants in these genes.Previous studies have identified tumour mutational signatures that result from defective DNA repair including DNA mismatch repair (MMR) deficiency and base excision repair defects, DNA repair mechanisms that underlie the common hereditary CRC and polyposis syndromes but their diagnostic utility in CRC is unknown.What are the new findings?Single base substitution (SBS)-related mutational signatures derived from whole exome sequencing of formalin-fixed paraffin embedded (FFPE)-derived CRC tissue DNA can effectively discriminate CRCs that developed in biallelic MUTYH PV carriers from CRC-affected non-carriers.CRCs that develop in MMR PV carriers (Lynch syndrome) can be effectively differentiated from sporadic MMR-proficient CRC by a combination of indel (ID) signatures, but the SBS and ID tumour mutational signatures are less effective at discriminating Lynch syndrome-related CRC from sporadic MMR-deficient CRC resulting from MLH1 gene promoter hypermethylation.The SBS and ID mutational signatures associated with biallelic MUTYH PV carriers and MMR PV carriers are robust to changes in experimental settings.We demonstrate the optimal experimental settings for calculating mutational signatures and define thresholds that optimise sensitivity and specificity for classifying CRC aetiology as hereditary or non-hereditary.How might it impact on clinical practice in the foreseeable future?Deriving SBS- and ID-related mutational signatures from CRCs can identify carriers of PVs in hereditary CRC and polyposis susceptibility genes.The application of mutational signatures has the potential to improve the diagnosis of hereditary CRC and aid in variant classification, leading to improved clinical management and CRC prevention.

scholarly journals Accumulation of meningeal lymphocytes, but not myeloid cells, correlates with subpial cortical demyelination and white matter lesion activity in progressive MS patients

2021 ◽  
Author(s):  
Shanzeh M Ahmed ◽  
Nina Fransen ◽  
Hanane Touil ◽  
Iliana Michailidou ◽  
Inge Huitinga ◽  
...  
Keyword(s):  
White Matter ◽  
Immune Cell ◽  
Myeloid Cells ◽  
Subcortical White Matter ◽  
Cortical Injury ◽  
Meningeal Inflammation ◽  
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Cell Accumulation ◽  
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Potential Link

Subpial cortical demyelination is an important component of multiple sclerosis (MS) pathology contributing to disease progression, yet mechanism(s) underlying its development remain unclear. Compartmentalized inflammation involving the meninges may drive this type of injury. Given recent findings identifying substantial white matter (WM) lesion activity in patients with progressive MS, elucidating whether and how WM lesional activity relates to meningeal inflammation and subpial cortical injury is of interest. Using post-mortem formalin-fixed paraffin-embedded tissue blocks (range, 5-72 blocks; median, 30 blocks) for each of 27 progressive MS patients, we assessed the relationship between meningeal inflammation, the extent of subpial cortical demyelination, and the state of subcortical WM lesional activity. Meningeal accumulations of T cells and B cells, but not myeloid cells, were spatially adjacent to subpial cortical lesions and greater immune-cell accumulation was associated with higher subpial lesion numbers. Patients with a higher extent of meningeal inflammation harboured a greater proportion of active and mixed (active-inactive) WM lesions, and an overall lower proportion of inactive and remyelinated WM lesions. Our findings support the involvement of meningeal lymphocytes in subpial cortical injury, and also point to a potential link between inflammatory subpial cortical demyelination and pathological mechanisms occurring in the subcortical white matter.

Sequencing Analysis and Phylogenetic Tree of HPV Isolated from Breast Cancer Patients at Thi-Qar Province/Iraq

2020 ◽  
pp. 37-40
Keyword(s):  
Nucleotide Sequence ◽  
Phylogenetic Tree ◽  
Evolutionary Relationship ◽  
Nucleotide Sequencing ◽  
Sequencing Analysis ◽  
Breast Cancer Patients ◽  
The North ◽  
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History Of

Genetic variety examination has demonstrated fundamental to the understanding of the epidemiological and developmental history of Papillomavirus (HPV), for the development of accurate diagnostic tests and for efficient vaccine design. The HPV nucleotide diversity has been investigated widely among high-risk HPV types. To make the nucleotide sequence of HPV and do the virus database in Thi-Qar province, and compare sequences of our isolates with previously described isolates from around the world and then draw its phylogenetic tree, this study done. A total of 6 breast formalin-fixed paraffin-embedded (FFPE) of the female patients were included in the study, divided as 4 FFPE malignant tumor and 2 FFPE of benign tumor. The PCR technique was implemented to detect the presence of HPV in breast tissue, and the real-time PCR used to determinant HPV genotypes, then determined a complete nucleotide sequence of HPV of L1 capsid gene, and draw its phylogenetic tree. The nucleotide sequencing finding detects a number of substitution mutation (SNPs) in (L1) gene, which have not been designated before, were identified once in this study population, and revealed that the HPV16 strains have the evolutionary relationship with the South African race, while, the HPV33 and HPV6 showing the evolutionary association with the North American and East Asian race, respectively.

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