Clinicopathological Relationships in an Aged Case of DOORS Syndrome With a p.Arg506X Mutation in the ATP6V1B2 Gene

DOORS [deafness, onychodystrophy, osteodystrophy, intellectual disability (mental retardation), and seizures] syndrome can be caused by mutations in the TBC1D24 and ATP6V1B2 genes, both of which are involved in endolysosomal function. Because of its extreme rarity, to date, no detailed neuropathological assessment has been performed to establish clinicopathological relationships and, thereby, understand better the neurobiology of this disease in aged cases. Accordingly, the aim of the current study was to highlight the clinicopathological characteristics of a novel case with a presumable de novo mutation in the ATP6V1B2 gene from a neuropathological point of view. This Caucasian male patient, who died at the age of 72 years, presented all the typical cardinal signs of DOORS syndrome. In addition, behavioral alterations, pyramidal signs, and Parkinsonism were observed. The p.R506X pathogenic mutation identified in the ATP6V1B2 gene was responsible for the clinical phenotype. The detailed neuropathological assessment revealed a limbic-predominant tauopathy in the forms of argyrophilic grain disease, primary age-related tauopathy, and age-related tau-astrogliopathy. In summary, we present the first detailed clinicopathological report of a patient with DOORS syndrome harboring a pathogenic mutation in the ATP6V1B2 gene. The demonstrated tauopathy may be considered as a consequence of lysosomal and/or mitochondrial dysfunction, similar to that found in Niemann-Pick type C disease, which is another lysosomal disorder characterized by premature neurodegenerative disorder

Case Report: Brainstem angiocentric glioma presenting in a toddler child–diagnostic and therapeutic challenges

Introduction: Angiocentric gliomas (AG) in brainstem location are exceedingly rare and might cause differential diagnostic problems and uncertainty regarding the best therapeutic approach. Hereby, we describe the clinicopathological findings in a brainstem AG presenting in a toddler child and review the literature

Analysis of risk factors - especially different types of plexitis - for postoperative relapse in Crohn's disease

AIM: To evaluate the presence of submucosal and myenteric plexitis and its role in predicting postoperative recurrence. METHODS: Data from all patients who underwent Crohn's disease (CD)-related resection at the University of Szeged, Hungary between 2004 and 2014 were analyzed retrospectively. Demographic data, smoking habits, previous resection, treatment before and after surgery, resection margins, neural fiber hyperplasia, submucosal and myenteric plexitis were evaluated as possible predictors of postoperative recurrence. Histological samples were analyzed blinded to the postoperative outcome and the clinical history of the patient. Plexitis was evaluated based on the appearance of the most severely inflamed ganglion or nerve bundle. Patients underwent regular follow-up with colonoscopy after surgery. Postoperative recurrence was defined on the basis of endoscopic and clinical findings, and/or the need for additional surgical resection. RESULTS: One hundred and four patients were enrolled in the study. Ileocecal, colonic, and small bowel resection were performed in 73.1%, 22.1% and 4.8% of the cases, respectively. Mean disease duration at the time of surgery was 6.25 years. Twenty-six patients underwent previous CD-related surgery. Forty-three point two percent of the patients were on 5-aminosalicylate, 20% on corticosteroid, 68.3% on immunomodulant, and 4% on anti-tumor necrosis factor-alpha postoperative treatment. Postoperative recurrence occurred in 61.5% of the patients; of them 39.1% had surgical recurrence. 92.2% of the recurrences developed within the first five years after the index surgery. Mean disease duration for endoscopic relapse was 2.19 years. The severity of submucosal plexitis was a predictor of the need for second surgery (OR = 1.267, 95%CI: 1.000-1.606, P = 0.050). Female gender (OR = 2.21, 95%CI: 0.98-5.00, P = 0.056), stricturing disease behavior (OR = 3.584, 95%CI: 1.344-9.559, P = 0.011), and isolated ileal localization (OR = 2.671, 95%CI: 1.033-6.910, P = 0.043) were also predictors of postoperative recurrence. No association was revealed between postoperative recurrence and smoking status, postoperative prophylactic treatment and the presence of myenteric plexitis and relapse. CONCLUSION: The presence of severe submucosal plexitis with lymphocytes in the proximal resection margin is more likely to result in postoperative relapse in CD

Downregulation of circulating miR 802-5p and miR 194-5p and upregulation of brain MEF2C along breast cancer brain metastasization

Breast cancer brain metastases (BCBM) have been under-investigated despite their high incidence and poor outcome. Micro RNAs (miRNAs), and particularly circulating miRNAs, regulate multiple cellular functions and their deregulation has been reported in different types of cancer and metastasis. However, their signature in plasma along brain metastasis development and their relevant targets remain undetermined. Here, we used a mouse model of BCBM and Next-Generation Sequencing (NGS) to establish the alterations in circulating miRNAs during brain metastasis formation and development. We further performed bioinformatics analysis to identify their targets with relevance in the metastatic process. We additionally analyzed human resected brain metastasis samples of breast cancer patients for target expression validation. Breast cancer cells were injected in the carotid artery of mice to preferentially induce metastasis in the brain, and samples were collected at different time points (5 h, 3, 7 and 10 days) to follow metastasis development. Metastases were detected from 7 days onwards, mainly in the brain. NGS revealed a deregulation of circulating miRNA profile during BCBM progression, raising from 18% at 3 days to 30% at 10 days following malignant cells' injection. Work was focused on those altered prior to metastasis detection, among which were miR-802-5p and miR-194-5p, whose downregulation was validated by qPCR. Using TargetScan and DIANA Tools the transcription factor myocyte enhancer factor 2C (MEF2C) was identified as a target for both miRNAs, and its expression was increasingly observed in malignant cells along brain metastasis development. Its upregulation was also observed in peritumoral astrocytes pointing to a role of MEF2C in the crosstalk between tumor cells and astrocytes. MEF2C expression was also observed in human BCBM, validating the observation in mouse. Collectively, downregulation of circulating miR-802-5p and miR-194-5p appears as a precocious event in BCBM and MEF2C emerges as a new player in brain metastasis development

A longitudinally extensive H3 K27M-mutant diffuse midline glioma in an elderly patient clinically mimicking central nervous system inflammation: a case report

Diffuse midline gliomas, H3 K27M-mutant, World Health Organization (WHO) grade IV represent a distinct glioma entity with a predominantly paediatric presentation and remarkably poor prognosis. This report presents a case of a 73-year-old woman with a diffuse midline glioma, H3 K27M-mutant, WHO grade IV with a remarkable longitudinal extension, extending from the cervical myelon to the basal ganglia. On imaging, the lesion was predominantly suggestive of inflammatory oedema, and it was clinically associated with progressive hemi- and later tetraparesis with severe autonomic and bulbar symptoms. Laboratory examinations suggested a generalized inflammatory process; however, neither infectious nor autoimmune aetiology could be confirmed. Biopsy was deemed unfeasible given the critical localization. Presuming a seronegative autoimmune encephalomyelitis, high-dose corticosteroid therapy and plasma exchanges were conducted, resulting in a modest but transient relief. The patient passed away two months after hospitalization. Neuropathological examination of the lesion revealed a high-grade diffuse glioma with H3 K27M mutation (grade IV). Although originally considered as a paediatric entity, our case confirms reports from recent years that diffuse midline gliomas, H3 K27M-mutant, WHO grade IV can occur in adults, even among the elderly, and can mimic inflammatory alterations, posing diagnostic difficulty. Our case is one of the oldest patients reported with this pathology, the oldest with an extensive diffusely infiltrating growth pattern, and with the most extensive lesion reported in adulthood

Chemerin acts via CMKLR1 and GPR1 to stimulate migration and invasion of gastric cancer cells: putative role of decreased TIMP-1 and TIMP-2

The chemokine-like peptide, chemerin, stimulates chemotaxis in several cell types. In this study we examined the expression of putative chemerin receptors in gastric cancer and the action of chemerin on cancer cell migration and invasion. Immunohistochemical studies of gastric tumors identified expression of two putative receptors, chemokine-like receptor-1 (CMKLR1) and G-protein coupled receptor 1(GPR1), in cancer cells; there was also some expression in stromal myofibroblasts although generally at a lower intensity. The expression of both receptors was detected in a gastric cancer cell line, AGS; chemerin itself was expressed in cultured gastric cancer myofibroblasts but not AGS cells. Chemerin stimulated (a) morphological transformation of AGS cells characterized by extension of processes and cell scattering, (b) migration in scratch wound assays and (c) both migration and invasion in Boyden chamber chemotaxis assays. These responses were inhibited by two putative receptor antagonists CCX832 and α-NETA. Inhibition of receptor expression by siRNA selectively reduced CMKLR1 or GPR1 and inhibited the action of chemerin indicating that both receptors contributed to the functional response. Using a proteomic approach employing stable isotope dynamic labeling of secretomes (SIDLS) to selectively label secreted proteins, we identified down regulation of tissue inhibitors of metalloproteinease (TIMP)1 and TIMP2 in media in response to chemerin. When cells were treated with chemerin and TIMP1 or TIMP2 the migration response to chemerin was reduced. The data suggest a role for chemerin in promoting the invasion of gastric cancer cells via CMKLR1 and GPR1at least partly by reducing TIMP1 and TIMP2 expression. Chemerin receptor antagonists have potential in inhibiting gastric cancer progression

Distinct miRNA profiles in normal and gastric cancer myofibroblasts and significance in Wnt signaling

Stromal cells influence epithelial function in both health and disease. Myofibroblasts are abundant stromal cells that influence the cellular microenvironment by release of extracellular matrix (ECM) proteins, growth factors, proteases, cytokines, and chemokines. Cancer-associated myofibroblasts (CAMs) differ from adjacent tissue (ATMs) and normal tissue myofibroblasts (NTMs), but the basis of this is incompletely understood. We report now the differential expression of miRNAs in gastric cancer CAMs. MicroRNA arrays identified differences in the miRNA profile in gastric and esophageal NTMs and in CAMs from stomach compared with NTMs. miR-181d was upregulated in gastric CAMs. Analysis of differentially regulated miRNAs indicated an involvement in Wnt signaling. Examination of a microarray data set then identified Wnt5a as the only consistently upregulated Wnt ligand in gastric CAMs. Wnt5a stimulated miR-181d expression, and knockdown of miR-181d inhibited Wnt5a stimulation of CAM proliferation and migration. Analysis of miR-181d targets suggested a role in chemotaxis. Conditioned medium from CAMs stimulated gastric cancer cell (AGS) migration more than that from ATMs, and miR-181d knockdown reduced the effect of CAM-CM on AGS cell migration but had no effect on AGS cell responses to ATM conditioned media. The data suggest that dysregulation of miRNA expression in gastric CAMs, secondary to Wnt5a signaling, accounts at least in part for the effect of CAMs in promoting cancer cell migration. stromal cells have emerged in recent years as important determinants of epithelial cell function in the gastrointestinal mucosa in health and disease (7, 23, 25). There are multiple stromal cell types, including inflammatory and immune cells, fibroblasts, pericytes, and myofibroblasts. The latter are sparse in many tissues, but in the gut there is normally a sheath of myofibroblasts that surrounds intestinal crypts and gastric glands. They may arise from activation of fibroblasts, for example, by TGFβ, by transdifferentiation of mesenchymal stem cells (26), or by epithelial-mesenchymal transition (20). Physiologically, they play a role in wound healing. They may also influence tumor progression (26). Myofibroblasts are often operationally defined as expressing α-smooth muscle actin (SMA), vimentin, and fibroblast activation protein and are negative for cytokeratin and usually desmin (7). An emerging body of evidence from multiple experimental platforms supports the idea that there are marked differences between different myofibroblast populations in both health and disease. For example, microarray studies reveal differences between myofibroblasts from different regions of the normal gastrointestinal tract (12). Moreover, there are marked differences in cancer at the levels of transcripts, proteins, and functions. Previously, we showed that myofibroblasts from gastric or esophageal cancer differ from their counterparts in adjacent tissue with evidence that myofibroblasts from advanced gastric tumors promote more aggressive phenotypes in cancer cells (3, 13, 14, 17). We also showed that esophageal cancer-associated myofibroblasts (CAMs) exhibit increased secretion of the chemokine-like peptide chemerin, which plays a role in mesenchymal stem cell recruitment (17). MicroRNAs (miRNAs) are short RNAs of ∼22 nucleotides that act posttranscriptionally to determine mRNA stability and translation (1). They regulate an impressive diversity of biological processes and importantly may contribute to cancer initiation and progression. In stomach and esophagus, previous studies have identified differentially expressed miRNAs (8, 11, 19). However, it is not known whether miRNAs contribute to the differences in function of different myofibroblast populations. In view of differences in the secretomes and proteomes of gastric or esophageal cancer-derived myofibroblasts compared with their respective adjacent tissue myofibroblasts (ATMs), in the present study we sought to determine whether there might also be differences in their miRNA expression profiles compared both with each other and with normal tissue myofibroblasts (NTMs). We now report that gastric and esophageal NTM miRNA profiles are readily distinguishable, that gastric CAMs differ from their respective NTMs in their miRNA profiles, and that Wnt5a (which is upregulated in gastric CAMs) may act in part via miR-181d to influence mesenchymal-epithelial signaling

Matrix metalloproteinase (MMP)-7 in Barrett’s esophagus and esophageal adenocarcinoma : expression, metabolism and functional significance

Supported by grants from North West Cancer Research (Grant number: CR945), The Wellcome Trust (Grant number: 074287/Z/03/Z) and a research studentship (HG) from the Libyan Government.Matrix metalloproteinase (MMP)‐7, unlike many MMPs, is typically expressed in epithelial cells. It has been linked to epithelial responses to infection, injury, and tissue remodeling including the progression of a number of cancers. We have now examined how MMP‐7 expression changes in the progression to esophageal adenocarcinoma (EAC), and have studied mechanisms regulating its expression and its functional significance. Immunohistochemistry revealed that MMP‐7 was weakly expressed in normal squamous epithelium adjacent to EAC but was abundant in epithelial cells in both preneoplastic lesions of Barrett's esophagus and EAC particularly at the invasive front. In the stroma, putative myofibroblasts expressing MMP‐7 were abundant at the invasive front but were scarce or absent in adjacent tissue. Western blot and ELISA revealed high constitutive secretion of proMMP‐7 in an EAC cell line (OE33) that was inhibited by the phosphatidylinositol (PI) 3‐kinase inhibitor LY294002 but not by inhibitors of protein kinase C, or MAP kinase activation. There was detectable proMMP‐7 in cultured esophageal myofibroblasts but it was undetectable in media. Possible metabolism of MMP‐7 by myofibroblasts studied by proteomic analysis indicated degradation via extensive endopeptidase, followed by amino‐ and carboxpeptidase, cleavages. Myofibroblasts exhibited increased migration and invasion in response to conditioned media from OE33 cells that was reduced by MMP‐7 knockdown and immunoneutralization. Thus, MMP‑7 expression increases at the invasive front in EAC which may be partly attributable to activation of PI 3‐kinase. Secreted MMP‐7 may modify the tumor microenvironment by stimulating stromal cell migration and invasion.Publisher PDFPeer reviewe