Publications by authors named "Olinda Rebelo"

39 Publications

MiR-200c-based metabolic modulation in glioblastoma cells as a strategy to overcome tumor chemoresistance.

Hum Mol Genet 2021 Jul 10. Epub 2021 Jul 10.

Department of Life Sciences, University of Coimbra, Calçada Martim de Freitas, 3000-456 Coimbra, Portugal.

Glioblastoma (GB) is the most aggressive and common form of primary brain tumor characterized by fast proliferation, high invasion, and resistance to current standard treatment. The average survival rate post-diagnosis is 14.6 months, despite the aggressive standard post-surgery radiotherapy concomitant with chemotherapy with temozolomide (TMZ). Currently, efforts are being endowed to develop new and more efficient therapeutic approaches capable to overcome chemoresistance, inhibit tumor progression and improve overall patient survival rate. Abnormal microRNA (miRNA) expression has been correlated with chemoresistance, proliferation and resistance to apoptosis, which result from their master regulatory role of gene expression. Altered cell metabolism, favoring glycolysis, was identified as an emerging cancer hallmark and has been described in GB, thus offering a new target for innovative GB therapies. In this work, we hypothesized that a gene therapy-based strategy consisting of the overexpression of a miRNA downregulated in GB and predicted to target crucial metabolic enzymes might promote a shift of GB cell metabolism, decreasing the glycolytic dependence of tumor cells and contributing to their sensitization to chemotherapy with TMZ. The increase of miR-200c levels in DBTRG cells resulted in downregulation of mRNA of enzymes involved in bioenergetics pathways and impaired cell metabolism and mobility. Additionally, miR-200c overexpression prior to DBTRG cell exposure to TMZ resulted in cell cycle arrest. Overall, our results show that miR-200c overexpression could offer a way to overcome chemoresistance developed by GB cells in response to current standard chemotherapy, providing an improvement to current GB standard treatment, with benefit for patient outcome.
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http://dx.doi.org/10.1093/hmg/ddab193DOI Listing
July 2021

Vasculitic peripheral neuropathy in deficiency of adenosine deaminase 2.

Neuromuscul Disord 2021 May 14. Epub 2021 May 14.

Neurology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.

Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive inflammatory vasculopathy characterized by systemic vasculitis, early-onset stroke and livedo racemosa. We report a family cohort of 3 patients with ADA2 compound heterozygous mutation p.[Thr360Ala] and [Gly383Ser]. Two of them had progressive involvement of the peripheral nervous system in the fourth decade, both after stroke. In one patient, clinical and neurophysiological studies showed progression of mononeuritis multiplex to chronic axonal sensorimotor polyneuropathy, nerve biopsy had features of small vessel vasculitic neuropathy, and muscle biopsy disclosed neurogenic atrophy with reinnervation. The second patient presented with progressive sensory symptoms of the lower limbs and chronic axonal sensorimotor polyneuropathy in nerve conduction studies. These two patients had absent plasma ADA2 activity. The third patient had no neurological affection despite low, but not absent, plasma ADA2 activity. Patients were started on a tumor necrosis factor (TNF) inhibitor, which has presumed benefits for the vasculitic phenotype of DADA2.
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http://dx.doi.org/10.1016/j.nmd.2021.05.001DOI Listing
May 2021

Primary intramedullary spinal-cord lymphoma (PISCL): a rare entity with a challenging diagnosis.

BMJ Case Rep 2021 May 19;14(5). Epub 2021 May 19.

Neurology, Centro Hospitalar e Universitário de Coimbra EPE, Coimbra, Coimbra, Portugal.

Primary intramedullary spinal-cord lymphoma (PISCL) is a rare cause of myelopathy and constitutes only 1% of central nervous system lymphomas. Delay to diagnosis is common due to its rarity, its similarity to other causes of myelopathy and the difficulties in obtaining pathological diagnosis. We report a case of PISCL and discuss the challenges faced on diagnosis, namely the impact of corticosteroids on histological findings, the usefulness of MRI, positron-emission tomography/CT (PET/CT) and repeated lumbar punctures.
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http://dx.doi.org/10.1136/bcr-2021-242548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137158PMC
May 2021

Neurological impact of eosinophilic granulomatosis with polyangiitis.

Acta Neurol Belg 2021 Apr 27. Epub 2021 Apr 27.

Neurology Department, Coimbra University Hospital Centre, Praceta Mota Pinto, 3000-075, Coimbra, Portugal.

Nervous system (NS) affection may occur in Eosinophilic Granulomatosis with Polyangiitis (EGPA), but its clinical manifestations and pathophysiology are rarely described. Our aims are to characterize central and peripheral NS (CNS/PNS) involvement and compare biological markers in EGPA patients with and without neurological manifestations. Retrospective observational study, including EGPA patients with and without neurological manifestations. Demographics, clinical data, and immunological markers were analyzed. Descriptive and inferential statistics were performed. Sixteen patients were included; 11 (68.8%) of whom were male, with a mean age of 63.38 years; 8 with (Group 1) and 8 without (Group 2) neurological findings. Neurological impairment preceded EGPA diagnosis in 5 patients, and occurred during follow-up in 3 patients after a median of 4.0 years. CNS manifestations observed were stroke (n = 2), bilateral central retinal artery occlusion (n = 1), and compressive dorsal myelopathy due to extradural granulation tissue (n = 1). PNS manifestations were axonal polyneuropathy (n = 3), sensorineural hearing loss (n = 3), and multiplex mononeuropathy (n = 1). Two patients had both PNS and CNS involvement. There were no statistical differences regarding biological markers [eosinophil count, myeloperoxidase (MPO) antibodies titers] between the 2 groups. One patient from Group 1 was unresponsive to treatment and permanent neurological sequelae were observed in 7 cases. EGPA-related NS involvement can be heterogeneous and is responsible for long-term sequelae. In our sample, the main neurological scenarios were peripheral neuropathy, VIII cranial nerve neuropathy, ischemic lesions and compressive myelopathy. Patients with and without neurological manifestations did not differ in eosinophilic count and MPO titer.
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http://dx.doi.org/10.1007/s13760-021-01683-5DOI Listing
April 2021

Genomic and Epigenetic Advances in Focal Cortical Dysplasia Types I and II: A Scoping Review.

Front Neurosci 2020 22;14:580357. Epub 2021 Jan 22.

iCBR/CIMAGO, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.

Focal cortical dysplasias (FCDs) are a group of malformations of cortical development that constitute a common cause of drug-resistant epilepsy, often subjected to neurosurgery, with a suboptimal long-term outcome. The past few years have witnessed a dramatic leap in our understanding of the molecular basis of FCD. This study aimed to provide an updated review on the genomic and epigenetic advances underlying FCD etiology, to understand a genotype-phenotype correlation and identify priorities to lead future translational research. A scoping review of the literature was conducted, according to previously described methods. A comprehensive search strategy was applied in PubMed, Embase, and Web of Science from inception to 07 May 2020. References were screened based on title and abstract, and posteriorly full-text articles were assessed for inclusion according to eligibility criteria. Studies with novel gene variants or epigenetic regulatory mechanisms in patients that underwent epilepsy surgery, with histopathological diagnosis of FCD type I or II according to Palmini's or the ILAE classification system, were included. Data were extracted and summarized for an overview of evidence. Of 1,156 candidate papers, 39 met the study criteria and were included in this review. The advent of next-generation sequencing enabled the detection in resected FCD tissue of low-level brain somatic mutations that occurred during embryonic corticogenesis. The mammalian target of rapamycin (mTOR) signaling pathway, involved in neuronal growth and migration, is the key player in the pathogenesis of FCD II. Somatic gain-of-function variants in and its activators as well as germline, somatic, and second-hit mosaic loss-of-function variants in its related repressors have been reported. However, the genetic background of FCD type I remains elusive, with a pleomorphic repertoire of genes affected. DNA methylation and microRNAs were the two epigenetic mechanisms that proved to have a functional role in FCD and may represent molecular biomarkers. Further research into the possible pathogenic causes of both FCD subtypes is required, incorporating single-cell DNA/RNA sequencing as well as methylome and proteomic analysis. The collected data call for an integrated clinicopathologic and molecular genetic diagnosis in current practice not only to improve diagnostic accuracy but also to guide the development of future targeted treatments.
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http://dx.doi.org/10.3389/fnins.2020.580357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862327PMC
January 2021

World Health Organization Grade III Meningiomas: A Retrospective Study at an Academic Medical Center.

World Neurosurg 2021 May 28;149:e877-e893. Epub 2021 Jan 28.

Department of Neurosurgery, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Clinical Academic Center of Coimbra (CACC), Coimbra, Portugal.

Background: Meningiomas are the most common primary brain tumors and are generally considered benign. However, a rare subgroup of meningiomas, classified as World Health Organization (WHO) grade III meningiomas, can show extremely aggressive behavior and high rates of recurrence. Despite ongoing research, data on the clinical outcome of this subgroup of meningiomas are still limited.

Methods: Medical records of patients with WHO grade III meningiomas diagnosed between 2000 and 2018 at the Coimbra University Hospital Center were retrospectively reviewed and several variables of interest and their relation to patients' survival were analyzed.

Results: Of the 26 patients included in the final analysis, 23 had anaplastic meningiomas, 2 had papillary meningiomas, and 1 had a rhabdoid meningioma. Median overall survival and median progression-free survival were 2.45 and 1.22 years, respectively. Overall survival at 1, 2 and 5 years was 73%, 57%, and 35%, respectively. Adjuvant radiotherapy correlated with improved survival for subtotally resected meningiomas but not for gross totally resected meningiomas. There was a trend toward improved overall survival with gross total resection versus subtotal resection, but this difference failed to reach statistical significance.

Conclusions: This study provides insight into the clinical outcomes of WHO grade III meningiomas and suggests that adjuvant radiotherapy may not be beneficial for patients who underwent gross total resection. This rare subset of meningiomas still portends a devastating prognosis and the impact of extent of resection and adjuvant therapies in these patients needs further clarification.
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http://dx.doi.org/10.1016/j.wneu.2021.01.080DOI Listing
May 2021

Downregulation of long non-protein coding RNA MVIH impairs glioblastoma cell proliferation and invasion through an miR-302a-dependent mechanism.

Hum Mol Genet 2021 Mar;30(1):46-64

CNC - Center for Neuroscience and Cell Biology, CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, IIIUC - Institute for Interdisciplinary Research, Coimbra, Portugal.

Glioblastoma (GB) is the most frequent and malignant type of brain tumor, for which no effective therapy exists. The high proliferative and invasive nature of GB, as well as its acquired resistance to chemotherapy, makes this type of cancer extremely lethal shortly after diagnosis. Long non-protein coding RNAs (lncRNA) are a class of regulatory RNAs whose levels can be dysregulated in the context of diseases, unbalancing several physiological processes. The lncRNA associated with microvascular invasion in hepatocellular carcinoma (lncRNA-MVIH), overexpressed in several cancers, was described to co-precipitate with phosphoglycerate kinase 1 (PGK1), preventing secretion of this enzyme to the extracellular environment and promoting cell migration and invasion. We hypothesized that, by silencing the expression of lncRNA-MVIH, the secretion of PGK1 would increase, reducing GB cell migration and invasion capabilities. We observed that lncRNA-MVIH silencing in human GB cells significantly decreased glycolysis, cell growth, migration, and invasion and sensitized GB cells to cediranib. However, no increase in extracellular PGK1 was observed as a consequence of lncRNA-MVIH silencing, and therefore, we investigated the possibility of a mechanism of miRNA sponge of lncRNA-MVIH being in place. We found that the levels of miR-302a loaded onto RISC increased in GB cells after lncRNA-MVIH silencing, with the consequent downregulation of several miR-302a molecular targets. Our findings suggest a new mechanism of action of lncRNA-MVIH as a sponge of miR-302a. We suggest that lncRNA-MVIH knockdown may be a promising strategy to address GB invasiveness and chemoresistance, holding potential towards its future application in a clinical context.
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http://dx.doi.org/10.1093/hmg/ddab009DOI Listing
March 2021

Tumefactive demyelinating lesions spectrum disorders and the potential role of contemporary disease modifying treatments: a case report.

Mult Scler Relat Disord 2021 Jan 1;47:102669. Epub 2020 Dec 1.

Neurology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal.

Marburg disease is a fulminant variant of multiple sclerosis (MS), in which the diagnosis may be particularly difficult and with high rates of mortality. We describe the case of a women with a clinical picture, radiographic features, and neuropathological findings consistent with the classical descriptions of Marburg disease. Initially, our patient did not improved with the acute phase treatments but later showed a good response to natalizumab (NTZ) treatment. This report highlights not only the utility of brain biopsy in the accurate diagnosis of this challenging condition but also the potential role of NTZ as an effective therapeutic option.
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http://dx.doi.org/10.1016/j.msard.2020.102669DOI Listing
January 2021

Inclusion body myositis and muscular granulomas - a rare finding.

Rheumatology (Oxford) 2021 02;60(2):989-990

Rheumatology Department, Local Health Unit of Guarda, Guarda, Portugal.

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http://dx.doi.org/10.1093/rheumatology/keaa344DOI Listing
February 2021

Laing early-onset distal myopathy with subsarcolemmal hyaline bodies caused by a novel variant in the gene.

Acta Myol 2020 Mar 1;39(1):24-28. Epub 2020 Mar 1.

Neuromuscular Disease Unit, Neurology Department, Coimbra University and Hospital Centre, Coimbra, Portugal.

Myopathies caused by gene mutations are clinically and pathologically heterogeneous and, until recently, difficult to diagnose. The availability of NGS panels for hereditary neuromuscular diseases changed our insight regarding their frequency and allowed a better perception of the different phenotypes and morphological abnormalities associated. We present a male Portuguese patient with the classical phenotype of Laing early-onset distal myopathy (MPD1) beginning at 6 years of age, very slowly progressive, and with a mild to moderate impact on daily life by the age of 56. Muscle biopsy showed a myopathic pattern with hyaline bodies and cores. The NGS panel for structural myopathies identified a novel missense heterozygous variant, c.T4652C (p.Leu1551Pro), in the exon 34 of the gene.
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http://dx.doi.org/10.36185/2532-1900-004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315894PMC
March 2020

Management and Outcome of Solitary Spinal Amyloidoma-A Systematic Literature Review.

World Neurosurg 2020 08 24;140:325-331. Epub 2020 May 24.

Department of Neurosurgery, Coimbra University Hospital Centre, Coimbra, Portugal; Faculty of Medicine of the University of Coimbra, Coimbra, Portugal.

Background: Solitary spinal amyloidoma (SSA) is a rare and poorly characterized disease. There are few cases described, and the knowledge of this neoplasm is limited. A more accurate description of demographics, clinical findings, and outcomes may be useful for a better understanding of this pathology, as well as therapeutic intervention, adding value to the research of localized amyloidosis.

Methods: A systematic search was carried out from when registries began until February 2020. We also include a case diagnosed and treated in our department. Descriptive statistics were used to evaluate data, demographics, clinical findings, diagnostic modalities, therapeutics, and finally neurologic outcomes. The Kaplan-Meier method was used to assess overall survival and progression-free survival.

Results: The final cohort comprises 35 patients. The mean age at diagnosis was 61.97 years, and 68.60% of the patients were male. SSA developed more frequently in the thoracic spine (48.60%), followed by the cervical spine (17.10%). Intradural lesions were rare, and the average neoplastic score for spinal instability was 9.5 points. The most common symptoms were impaired motor function (74.29%) and axial back pain (65.70%). After surgery, neurologic recovery was reported in 82.90% of cases. Mean progression-free survival and mean overall survival were 47.26 and 156.66 months.

Conclusions: SSA is a rare subgroup of localized amyloidosis, usually being diagnosed in male patients between the sixth and eighth decades. The gold standard treatment seems to be surgical resection. SSA patients have excellent long-term survival and a low rate of local recurrence.
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http://dx.doi.org/10.1016/j.wneu.2020.05.159DOI Listing
August 2020

Primary spinal epidural lymphoma: a rare entity with an ambiguous management.

BMJ Case Rep 2020 Jan 26;13(1). Epub 2020 Jan 26.

Department of Neurosurgery, Coimbra University Hospital Centre, Coimbra, Portugal.

Lymphomas are malignant lymphoid tumours arising from lymphocytic cells. They usually develop in the lymphoid tissues and can spread to other organs; however, primary extra-nodal locations such as the spinal epidural space are less common. The authors report the case of a primary diffuse large B-cell lymphoma of the thoracic spine in a 65-year-old man, who presented to the emergency department with signs of upper motor neuron lesion. The patient underwent surgery in order to decompress the spinal cord. The treatment was concluded with six cycles of chemotherapy with methotrexate, rituximab, cyclophosphamide, vincristine and prednisone followed by radiotherapy. At the 24-month follow-up, no signs of epidural lesion or bone contrast enhancement were observed in thoracic spine MRI. Surgical decompression is recommended in patients with signs of spinal cord injury in order to prevent irreversible neurological damage and is related to high rates of disease-free survival.
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http://dx.doi.org/10.1136/bcr-2019-233442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035830PMC
January 2020

Isomorphic diffuse glioma is a morphologically and molecularly distinct tumour entity with recurrent gene fusions of MYBL1 or MYB and a benign disease course.

Acta Neuropathol 2020 01 28;139(1):193-209. Epub 2019 Sep 28.

Department of Neuropathology, Institute of Pathology and Neuropathology, University Hospital of Tübingen, Tübingen, Germany.

The "isomorphic subtype of diffuse astrocytoma" was identified histologically in 2004 as a supratentorial, highly differentiated glioma with low cellularity, low proliferation and focal diffuse brain infiltration. Patients typically had seizures since childhood and all were operated on as adults. To define the position of these lesions among brain tumours, we histologically, molecularly and clinically analysed 26 histologically prototypical isomorphic diffuse gliomas. Immunohistochemically, they were GFAP-positive, MAP2-, OLIG2- and CD34-negative, nuclear ATRX-expression was retained and proliferation was low. All 24 cases sequenced were IDH-wildtype. In cluster analyses of DNA methylation data, isomorphic diffuse gliomas formed a group clearly distinct from other glial/glio-neuronal brain tumours and normal hemispheric tissue, most closely related to paediatric MYB/MYBL1-altered diffuse astrocytomas and angiocentric gliomas. Half of the isomorphic diffuse gliomas had copy number alterations of MYBL1 or MYB (13/25, 52%). Gene fusions of MYBL1 or MYB with various gene partners were identified in 11/22 (50%) and were associated with an increased RNA-expression of the respective MYB-family gene. Integrating copy number alterations and available RNA sequencing data, 20/26 (77%) of isomorphic diffuse gliomas demonstrated MYBL1 (54%) or MYB (23%) alterations. Clinically, 89% of patients were seizure-free after surgery and all had a good outcome. In summary, we here define a distinct benign tumour class belonging to the family of MYB/MYBL1-altered gliomas. Isomorphic diffuse glioma occurs both in children and adults, has a concise morphology, frequent MYBL1 and MYB alterations and a specific DNA methylation profile. As an exclusively histological diagnosis may be very challenging and as paediatric MYB/MYBL1-altered diffuse astrocytomas may have the same gene fusions, we consider DNA methylation profiling very helpful for their identification.
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http://dx.doi.org/10.1007/s00401-019-02078-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477753PMC
January 2020

Subacute inflammatory myopathy associated with papillary cancer of the thyroid gland.

Acta Myol 2019 Jun 1;38(2):37-40. Epub 2019 Jun 1.

Neuromuscular Disease Unit, Neurology Department, Coimbra University and Hospital Centre, Coimbra, Portugal.

Inflammatory myopathies comprise a group of rare autoimmune muscle diseases characterized by a variable degree of muscle weakness, elevated creatine kinase levels and necrotic fibres associated with invading inflammatory cells at histologic examination. Although there are several reports about their relationship with malignancy, association with papillary cancer of the thyroid gland is extremely rare. We present a case of a female patientdiagnosed withinflammatory myopathy and apapillary cancer of the thyroid gland, with a remarkable clinical improvement after thyroid cancer surgery and radioactive iodine treatment, supporting a correlation between the two conditions.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6598410PMC
June 2019

MiR-144 overexpression as a promising therapeutic strategy to overcome glioblastoma cell invasiveness and resistance to chemotherapy.

Hum Mol Genet 2019 08;28(16):2738-2751

Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal.

Glioblastoma (GB) is the most aggressive and common form of primary brain tumor, characterized by fast proliferation, high invasion, and resistance to current standard treatment. The average survival rate post-diagnosis is only of 14.6 months, despite the aggressive standard post-surgery treatment approaches of radiotherapy concomitant with chemotherapy with temozolomide. Altered cell metabolism has been identified as an emerging cancer hallmark, including in GB, thus offering a new target for cancer therapies. On the other hand, abnormal expression levels of miRNAs, key regulators of multiple molecular pathways, have been correlated with pathological manifestations of cancer, such as chemoresistance, proliferation, and resistance to apoptosis. In this work, we hypothesized that gene therapy based on modulation of a miRNA with aberrant expression in GB and predicted to target crucial metabolic enzymes might impair tumor cell metabolism. We found that the increase of miR-144 levels, shown to be downregulated in U87 and DBTRG human GB cell lines, as well as in GB tumor samples, promoted the downregulation of mRNA of enzymes involved in bioenergetic pathways, with consequent alterations in cell metabolism, impairment of migratory capacity, and sensitization of DBTRG cells to a chemotherapeutic drug, the dichloroacetate (DCA). Taken together, our findings provide evidence that the miR-144 plus DCA combined therapy holds promise to overcome GB-acquired chemoresistance, therefore deserving to be explored toward its potential application as a complementary therapeutic approach to the current treatment options for this type of brain tumor.
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http://dx.doi.org/10.1093/hmg/ddz099DOI Listing
August 2019

Novel mosaic mutation in the dystrophin gene causing distal asymmetric muscle weakness of the upper limbs and dilated cardiomyopathy.

Acta Myol 2018 Jun 1;37(2):117-120. Epub 2018 Jun 1.

Neuromuscular Disease Unit, Coimbra University and Hospital Centre, Coimbra, Portugal.

A group of heterogeneous muscle diseases are caused by dystrophin gene () mutations. We hereby present a male patient with a diagnosis of symptomatic dilated cardiomyopathy at 44 years-old who developed, soon after, weakness of distal right upper limb. At the age of 58, neurological examination revealed severe atrophy of right thenar muscles, flexion contractures on the right elbow, wrist and fingers, bilateral calf hypertrophy, myotatic areflexia in the upper limbs and hyporeflexia in the lower limbs. Manual muscle examination showed distal weakness of right upper limb muscles, severe on abductor pollicis brevis and extensor pollicis longus, and milder on interossei, finger extensors and brachioradialis muscles. Further testing revealed CK of 1500 U/L, a myopathic pattern on electromyography, and myopathic changes on right deltoid muscle biopsy, with immunohistochemistry showing focal sub-expression of dystrophin. Cardiac workup revealed a severe reduction in left ventricular ejection fraction, with a left ventricle of increased dimensions and global hypo-contractibility. A next-generation sequencing based panel for muscular diseases was performed and a nonsense mutation (c.C7525T) was identified in exon 51 of gene, present in 70% of the gene readings (consistent with mosaicism).
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6060426PMC
June 2018

Macrophagic myofasciitis: a challenging diagnosis.

BMJ Case Rep 2018 Jul 3;2018. Epub 2018 Jul 3.

Internal Medicine, Centro Hospitalar e Universitario de Coimbra EPE, Coimbra, Portugal.

A 25-year-old man admitted for generalised muscle pain with an insidious onset 3 years ago. He had exercise intolerance and decrease in muscle strength, requiring gait support. He was previously healthy, with no chronic medication or recent history of drugs or toxics. National vaccination plan actualised with hepatitis B and tetanus vaccines administered 10 and 2 years, respectively, before symptom onset. No analytical, imaging or electromyography changes were found. Muscle biopsy revealed an inflammatory infiltrate predominantly macrophagic with aluminium deposits suggestive of macrophagic myofasciitis (MMF). It is probably associated with vaccines previously administered. MMF lesion can be regarded as pathological only if detected at least 18 months after last aluminic immunisation, as our case illustrates.
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http://dx.doi.org/10.1136/bcr-2018-224602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6040558PMC
July 2018

Prognostic stratification of adult primary glioblastoma multiforme patients based on their tumor gene amplification profiles.

Oncotarget 2018 Jun 15;9(46):28083-28102. Epub 2018 Jun 15.

Centre for Cancer Research (CIC IBMCC-CSIC/USAL), Department of Medicine, CIBERONC, University of Salamanca, Salamanca, Spain.

Several classification systems have been proposed to address genomic heterogeneity of glioblastoma multiforme, but they either showed limited prognostic value and/or are difficult to implement in routine diagnostics. Here we propose a prognostic stratification model for these primary tumors based on tumor gene amplification profiles, that might be easily implemented in routine diagnostics, and potentially improve the patients management. Gene amplification profiles were prospectively evaluated in 80 primary glioblastoma multiforme tumors using single-nucleotide polymorphism arrays and the results obtained validated in publicly available data from 267/347 cases. Gene amplification was detected in 45% of patients, and chromosome 7p11.2 including the gene, was the most frequently amplified chromosomal region - either alone (18%) or in combination with amplification of DNA sequences in other chromosomal regions (10% of cases). Other frequently amplified DNA sequences included regions in chromosomes 12q(10%), 4q12(7%) and 1q32.1(4%). Based on their gene amplification profiles, glioblastomas were subdivided into: i) tumors with no gene amplification (55%); ii) tumors with chromosome 7p/ gene amplification (with or without amplification of other chromosomal regions) (38%); and iii) glioblastoma multiforme with a single (11%) or multiple (6%) amplified DNA sequences in chromosomal regions other than chromosome 7p. From the prognostic point of view, these amplification profiles showed a significant impact on overall survival of glioblastoma multiforme patients (p>0.001). Based on these gene amplification profiles, a risk-stratification scoring system was built for prognostic stratification of glioblastoma which might be easily implemented in routine diagnostics, and potentially contribute to improved patient management.
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http://dx.doi.org/10.18632/oncotarget.25562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6021328PMC
June 2018

Nucleolin is expressed in patient-derived samples and glioblastoma cells, enabling improved intracellular drug delivery and cytotoxicity.

Exp Cell Res 2018 09 11;370(1):68-77. Epub 2018 Jun 11.

CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; FFUC - Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal. Electronic address:

One of the major challenges in Glioblastoma (GBM) therapy relates with the existence of glioma stem-like cells (GSCs), known to be chemo- and radio-resistant. GSCs and non-stem GBM cells have the ability to interchange, emphasizing the importance of identifying common molecular targets among those cell sub-populations. Nucleolin overexpression has been recently associated with breast cancer sub-populations with different stem-like phenotype. The goal of this work was to evaluate the potential of cell surface nucleolin as a target in GBM cells. Different levels of nucleolin expression resulted in a 3.4-fold higher association of liposomes targeting nucleolin (functionalized with the nucleolin-binding F3 peptide) in U87, relative to GBM11 glioblastoma cells. Moreover, nucleolin was suggested as a potential marker in OCT4-, NANOG-positive GSC, and in the corresponding non-stem GBM cells, as well as in SOX2-positive GSC. Doxorubicin delivered by liposomes targeting nucleolin enabled a level of cytotoxicity that was 2.5- or 4.6-fold higher compared to the non-targeted counterparts. Importantly, an overexpression of nucleolin was also observed in cells of patient-derived samples, as compared with normal brain. Overall, these results suggested nucleolin as a therapeutic target in GBM.
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http://dx.doi.org/10.1016/j.yexcr.2018.06.005DOI Listing
September 2018

The long non-coding RNA is transcriptionally activated by HOXA9 and is an independent prognostic marker in patients with malignant glioma.

Oncotarget 2018 Mar 28;9(21):15740-15756. Epub 2018 Feb 28.

Life and Health Sciences Research Institute, School of Medicine, University of Minho, Braga, Portugal.

The lncRNA has been implicated in several human cancers. Here, we evaluated the molecular alterations and upstream regulatory mechanisms of in glioma, the most common primary brain tumors, and its clinical relevance. gene expression, methylation, copy-number and prognostic value were investigated in human gliomas integrating data from online datasets and our cohorts. High levels of were associated with higher grades of glioma, particularly IDH wild-type cases. Mechanistically, was overexpressed in a gene dosage-independent manner, while DNA methylation levels of particular CpGs in locus were associated with expression levels in GBM clinical specimens and cell lines. Concordantly, the demethylating agent 5-Aza-2'-deoxycytidine affected transcriptional levels in a cell line-dependent manner. Importantly, was frequently co-expressed with in high-grade gliomas from TCGA, Oncomine, and our Portuguese and French datasets. Integrated analyses, chromatin immunoprecipitation, and qPCR data showed that HOXA9 binds directly to the promoter of . Clinically, GBM patients with high expression had a significantly reduced overall survival, independently of other prognostic variables. In summary, this work reveals as a novel direct regulator of , and establishes as an independent prognostic marker, providing new therapeutic opportunities to treat this highly aggressive cancer.
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http://dx.doi.org/10.18632/oncotarget.24597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5884661PMC
March 2018

Disclosing the functional changes of two genetic alterations in a patient with Chronic Progressive External Ophthalmoplegia: Report of the novel mtDNA m.7486G>A variant.

Neuromuscul Disord 2018 04 23;28(4):350-360. Epub 2017 Nov 23.

FMUC - Faculty of Medicine, University of Coimbra, Coimbra, Portugal; CNC - Center for Neuroscience and Cell Biology, Laboratory of Biochemical Genetics, University of Coimbra, Coimbra, Portugal. Electronic address:

Chronic Progressive External Ophthalmoplegia (CPEO) is characterized by ptosis and ophthalmoplegia and is usually caused by mitochondrial DNA (mtDNA) deletions or mt-tRNA mutations. The aim of the present work was to clarify the genetic defect in a patient presenting with CPEO and elucidate the underlying pathogenic mechanism. This 62-year-old female first developed ptosis of the right eye at the age of 12 and subsequently the left eye at 45 years, and was found to have external ophthalmoplegia at the age of 55 years. Histopathological abnormalities were detected in the patient's muscle, including ragged-red fibres, a mosaic pattern of COX-deficient muscle fibres and combined deficiency of respiratory chain complexes I and IV. Genetic investigation revealed the "common deletion" in the patient's muscle and fibroblasts. Moreover, a novel, heteroplasmic mt-tRNA variant (m.7486G>A) in the anticodon loop was detected in muscle homogenate (50%), fibroblasts (11%) and blood (4%). Single-fibre analysis showed segregation with COX-deficient fibres for both genetic alterations. Assembly defects of mtDNA-encoded complexes were demonstrated in fibroblasts. Functional analyses showed significant bioenergetic dysfunction, reduction in respiration rate and ATP production and mitochondrial depolarization. Multilamellar bodies were detected by electron microscopy, suggesting disturbance in autophagy. In conclusion, we report a CPEO patient with two possible genetic origins, both segregating with biochemical and histochemical defect. The "common mtDNA deletion" is the most likely cause, yet the potential pathogenic effect of a novel mt-tRNA variant cannot be fully excluded.
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http://dx.doi.org/10.1016/j.nmd.2017.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5952895PMC
April 2018

Intracranial myopericytoma: a tumour in a rare location.

BMJ Case Rep 2018 Jan 23;2018. Epub 2018 Jan 23.

Department of Neuropathology, Centro Hospitalar e Universitario de Coimbra EPE, Coimbra, Portugal.

A 49-year-old female with history of headache, nausea and vomiting with some weeks of evolution, without neurological symptoms. Radiology revealed an expansive lesion near the inferior vermix and cerebellar tonsils, with heterogeneous gadolinium uptake and mass effect on the fourth ventricle, representing a probable extraventricular origin for the lesion. Pathological examination showed a proliferation of oval/spindle cell proliferation with eosinophil cytoplasm and small and monotonous nuclei, without mitoses. The cells had a concentric growth, surrounding thin-walled blood vessels with foci of stromal myxoid degeneration and whorled pattern. The vessels had a haemangiopericytoma pattern and were lined by non-atypical endothelial cells. The tumorous cells expressed vimentin, alpha-smooth actin and heavy-chain caldesmon and were negative for epithelial membrane antigen, protein S100, HMB45, CD34, calponin and desmin, thus providing the final diagnosis of intracranial myopericytoma.
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http://dx.doi.org/10.1136/bcr-2017-223111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5786981PMC
January 2018

The Expression of Connexins and SOX2 Reflects the Plasticity of Glioma Stem-Like Cells.

Transl Oncol 2017 Aug 24;10(4):555-569. Epub 2017 Jun 24.

Instituto Estadual do Cérebro Paulo Niemeyer (IECPN)-Secretaria de Estado de Saúde, Rio de Janeiro, Brazil. Electronic address:

Glioblastoma (GBM) is the most malignant primary brain tumor, with an average survival rate of 15 months. GBM is highly refractory to therapy, and such unresponsiveness is due, primarily, but not exclusively, to the glioma stem-like cells (GSCs). This subpopulation express stem-like cell markers and is responsible for the heterogeneity of GBM, generating multiple differentiated cell phenotypes. However, how GBMs maintain the balance between stem and non-stem populations is still poorly understood. We investigated the GBM ability to interconvert between stem and non-stem states through the evaluation of the expression of specific stem cell markers as well as cell communication proteins. We evaluated the molecular and phenotypic characteristics of GSCs derived from differentiated GBM cell lines by comparing their stem-like cell properties and expression of connexins. We showed that non-GSCs as well as GSCs can undergo successive cycles of gain and loss of stem properties, demonstrating a bidirectional cellular plasticity model that is accompanied by changes on connexins expression. Our findings indicate that the interconversion between non-GSCs and GSCs can be modulated by extracellular factors culminating on differential expression of stem-like cell markers and cell-cell communication proteins. Ultimately, we observed that stem markers are mostly expressed on GBMs rather than on low-grade astrocytomas, suggesting that the presence of GSCs is a feature of high-grade gliomas. Together, our data demonstrate the utmost importance of the understanding of stem cell plasticity properties in a way to a step closer to new strategic approaches to potentially eliminate GSCs and, hopefully, prevent tumor recurrence.
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http://dx.doi.org/10.1016/j.tranon.2017.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5487246PMC
August 2017

Phenotyping GABA transaminase deficiency: a case description and literature review.

J Inherit Metab Dis 2016 09 4;39(5):743-747. Epub 2016 Jul 4.

Centro Hospitalar e Universitário de Coimbra, Praceta Prof. Mota Pinto, 3000-075, Coimbra, Portugal.

Gamma-aminobutyric acid transaminase (GABA-T) deficiency is an autosomal recessive disorder reported in only three unrelated families. It is caused by mutations in the ABAT gene, which encodes 4-aminobutyrate transaminase, an enzyme of GABA catabolism and mitochondrial nucleoside salvage. We report the case of a boy, deceased at 12 months of age, with early-onset epileptic encephalopathy, severe psychomotor retardation, hypotonia, lower-limb hyporeflexia, central hypoventilation, and rapid increase in weight and, to a lesser rate, length and head circumference. He presented signs of premature pubarche, thermal instability, and water-electrolyte imbalance. Serum total testosterone was elevated (43.3 ng/dl; normal range <16), as well as serum growth hormone (7.7 ng/ml; normal range <1). Brain magnetic resonance imaging (MRI) showed decreased myelination and generalized brain atrophy, later confirmed by post-mortem examination. ABAT gene sequencing was performed post-mortem, identifying a homozygous variant c.888G > T (p.Gln296His),not previously described. In vitro analysis concluded that this variant is pathogenic. The clinical features of this patient are similar to those reported so far in GABA-T deficiency. However, distinct mutations may have a different effect on enzymatic activity, which potentially could lead to a variable clinical outcome. Clinical investigation aiming for a diagnosis should not end with the patient's death, as it may allow a more precise genetic counselling for the family.
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http://dx.doi.org/10.1007/s10545-016-9951-zDOI Listing
September 2016

Characterization of an FTLD-PDB family with the coexistence of SQSTM1 mutation and hexanucleotide (G₄C₂) repeat expansion in C9orf72 gene.

Neurobiol Aging 2016 Apr 30;40:191.e1-191.e8. Epub 2015 Dec 30.

CNC-Center for Neuroscience and Cell Biology, Neurogenetics Department, University of Coimbra, Portugal; Neurology Department, Coimbra University Hospital, Coimbra, Portugal.

The C9orf72 expansion is considered a major genetic cause of familial frontotemporal dementia (FTD) in several patients' cohorts. Interestingly, C9orf72 expansion carriers, present also abundant neuronal p62-positive inclusions. Although p62/SQSTM1 mutations were initially associated with Paget disease of bone (PDB), they have been also identified in FTD. We describe an FTD-PDB family in which the proband presented with behavioral FTD phenotype and concomitant Paget disease. The molecular genetic analysis revealed the co-occurrence of 2 mutations; the pathogenic C9orf72 expansion and p.P392L heterozygous missense mutation in SQSTM1 gene. Amongst the 6 family members analyzed, the p.P392L SQSTM1 mutation segregated as expected with PDB, whereas the C9orf72 expansion segregated with frontal cognitive impairment or dementia in all but one carrier. The coexistence of these conditions could be underestimated since neither patients with FTD nor patients with PDB undergo bone scintigraphy or cognitive assessment, respectively. The number of cases with double mutations could also be over looked as the molecular strategy adopted in most laboratories ends with the identification of one pathogenic mutation in one of the known causative genes. Therefore, we advocate for further clinical and molecular evaluation in suspect cases.
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http://dx.doi.org/10.1016/j.neurobiolaging.2015.12.015DOI Listing
April 2016

Macrophagic myofasciitis and vaccination: consequence or coincidence?

Rheumatol Int 2015 Jan 13;35(1):189-92. Epub 2014 Jun 13.

Rheumatology Unit, Centro Hospitalar e Universitário de Coimbra, Praceta Prof. Mota Pinto, 3000-075, Coimbra, Portugal,

Macrophagic myofasciitis (MMF) characterized by specific muscle lesions assessing long-term persistence of aluminum hydroxide within macrophages at the site of previous immunization has been reported with increasing frequency in the past 10 years. We describe clinical and laboratory findings in patients with MMF. We did a retrospective analysis of 16 cases observed in our Neuropathology Laboratory, between January 2000 and July 2013. The mean age of the 16 patients was 48.8 ± 18.0 years; 80.0 % were female. Chronic fatigue syndrome was found in 8 of 16 patients. Half of the patients had elevated creatinine kinase levels, and 25.0 % had a myopathic electromyogram. Thirteen patients received intramuscular administration of aluminum-containing vaccine prior to the onset of symptoms. MMF may mirror a distinctive pattern of an inflammatory myopathy. The vaccines containing this adjuvant may trigger MMF in some patients.
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http://dx.doi.org/10.1007/s00296-014-3065-4DOI Listing
January 2015

Creutzfeldt-Jakob disease: typical imaging findings.

BMJ Case Rep 2014 Mar 28;2014. Epub 2014 Mar 28.

Department Medical Imaging, Coimbra University and Hospital Centre, Coimbra, Portugal.

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http://dx.doi.org/10.1136/bcr-2014-203997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3975535PMC
March 2014

[Conventional and diffusion-weighted magnetic resonance imaging and proton spectroscopy in MELAS].

Acta Med Port 2012 2;25 Suppl 1:59-64. Epub 2012 Nov 2.

Serviço de Imagiologia dos Hospitais da Universidade de Coimbra, Coimbra, Portugal.

Introduction: MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) is a mitochondrial hereditary dysfunction in which the physiopathological mechanism of cerebral lesions is not totally understood as yet. Typically, these lesions are described as having normal to increased apparent diffusion coefficient (ADC), and this has been used to distinguish stroke-like lesions from ischemic lesions. Notwithstanding this, within the last few years, there have been reports of diffusion restriction in stroke-like episodes.

Objectives: Analysis of the diffusion characteristics on serial magnetic resonance imaging (MRI) over a 16 month period, on a patient with MELAS and stroke-like lesions, to investigate the controversial changes of the ADC, reported in the last years. Evaluation of the proton spectroscopy changes in stroke-like lesions and apparently spared brain.

Methods: We performed four serial magnetic resonance imaging (MRI), including two stroke-like episodes, in a 28-year-old man with MELAS (mitochondrial DNA mutation A3243G). Qualitative analysis of the magnetic resonance images, including the single voxel spectroscopy and ADC maps, with analysis of evolution patterns of the last ones.

Results: Both MRI that were performed during those episodes of stroke-like lesion revealed areas of diffusion restriction, coexisting areas of high ADC. During the chronic phase, there was a regression of those changes. Proton spectroscopy showed the presence of lactate and reduction of N-acetyl aspartate peak in stroke-like lesion and the presence of lactate in apparently spared brain.

Conclusions: All alterations that were recorded strengthen the view that cytotoxic oedema can occur in stroke-like lesions. Thus, their presence should not weaken the possibility of MELAS, especially if those lesions affect the temporal, parietal and/or occipital lobes, or if they predominantly involve the cortical gray matter, spanning vascular borders and if proton spectroscopy reveals lactate peak in the apparently spared brain.
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December 2013

[Bilateral hyperintensity of the pulvinar and dorsomedial nucleus of the thalamus in sporadic Creutzfeldt-Jakob disease].

Acta Med Port 2012 2;25 Suppl 1:41-4. Epub 2012 Nov 2.

Serviço de Imagiologia, Hospitais da Universidade de Coimbra, Coimbra, Portugal.

Introduction: Creutzfedt-Jakob Disease (CJD) is a rapidly progressive neurodegenerative disease caused by prions. Early diagnosis and the determination of its form are epidemiologically important, with strong impact on public health. Bilateral pulvinar hyperintensity, either alone (pulvinar sign) or in association with the dorsomedial nucleus of the thalamus (double hockey stick sign) on T2, FLAIR and diffusion weighted imaging (DWI), is a criterion for the probable diagnosis of the variant CJD (vCJD). Bilateral hyperintensity of the caudate, putamina and cortex is the usual pattern found in the sporadic CJD (sCJD).

Objective: Analysis of the imaging aspects on a sCJD patient showing T2 hyperintensity of the pulvinar and dorsomedial thalamic nucleus, in order to assess the magnetic resonance imaging (MRI) accuracy in the discrimination between vCJD and sCJD, when this lesion pattern is present.

Methods: We performed a MRI on a 62-year-old female with definitive diagnosis of sCJD made by anatomopathologic study of the brain tissue. Qualitative analysis of MRI, including DWI, T2 and FLAIR sequences, as well as lesional patterns found.

Results: Brain MRI showed hyperintensity of the caudate, putamina, pulvinar and dorsomedial nucleus of the thalamus, in DWI, T2 and FLAIR sequences; hypersignal of the caudate and putamina was greater than the signal intensity of the thalami. Hyperintensity of the hippocampus and frontal, temporal and parietal cortex were more obvious in FLAIR and DWI.

Comment: Hyperintensity of the pulvinar and dorsomedial nucleus of the thalamus on sCJD may complicate the differential diagnosis with vCJD. True pulvinar sign and double hockey stick sign, consistent with vCJD, must only be considered if the hyperintensity is greater than signal intensity of the caudate and putamina.
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December 2013

Amplified and homozygously deleted genes in glioblastoma: impact on gene expression levels.

PLoS One 2012 28;7(9):e46088. Epub 2012 Sep 28.

Centre for Neuroscience and Cell Biology, University of Coimbra, Portugal.

Background: Glioblastoma multiforme (GBM) displays multiple amplicons and homozygous deletions that involve relevant pathogenic genes and other genes whose role remains unknown.

Methodology: Single-nucleotide polymorphism (SNP)-arrays were used to determine the frequency of recurrent amplicons and homozygous deletions in GBM (n = 46), and to evaluate the impact of copy number alterations (CNA) on mRNA levels of the genes involved.

Principal Findings: Recurrent amplicons were detected for chromosomes 7 (50%), 12 (22%), 1 (11%), 4 (9%), 11 (4%), and 17 (4%), whereas homozygous deletions involved chromosomes 9p21 (52%) and 10q (22%). Most genes that displayed a high correlation between DNA CNA and mRNA levels were coded in the amplified chromosomes. For some amplicons the impact of DNA CNA on mRNA expression was restricted to a single gene (e.g., EGFR at 7p11.2), while for others it involved multiple genes (e.g., 11 and 5 genes at 12q14.1-q15 and 4q12, respectively). Despite homozygous del(9p21) and del(10q23.31) included multiple genes, association between these DNA CNA and RNA expression was restricted to the MTAP gene.

Conclusions: Overall, our results showed a high frequency of amplicons and homozygous deletions in GBM with variable impact on the expression of the genes involved, and they contributed to the identification of other potentially relevant genes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0046088PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3460955PMC
March 2013
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