HDAC6 is a unique histone deacetylase that targets cytoplasmic non-histone proteins and has a specific ubiquitin-binding activity. Both of these activities are required for HDAC6-mediated formation ...of aggresomes, which contain misfolded proteins that will ultimately be degraded via autophagy. HDAC6 deacetylase activity is increased following phosphorylation on serine 22 (phospho-HDAC6). In human, HDAC6 localizes in neuronal Lewy bodies in Parkinson’s disease (PD) and in oligodendrocytic Papp-Lantos bodies in Multiple System Atrophy (MSA). However, the expression of phospho-HDAC6 in post-mortem human brains is currently unexplored. Here, we evaluate and compare the distribution of HDAC6 and its phosphorylated form in human brains obtained from patients affected by three forms of parkinsonism: two synucleinopathies (PD and MSA) and a tauopathy (Progressive Supranuclear Palsy, PSP). We find that both HDAC6 and its phosphorylated form localize with pathological protein aggregates, including -Synuclein-positive Lewy bodies in PD and Papp-Lantos bodies in MSA, and phospho-Tau-positive neurofibrillary tangles in PSP. We further find a direct interaction of HDAC6 with -Synuclein with proximity ligation assay (PLA) in Lewy bodies and in neuropil of PD patients. Taken together, our findings suggest that both HDAC6 and phospho-HDAC6 regulate the homeostasis of intra-neuronal proteins in parkinsonism.
Abstract
Giant cell glioblastoma (gcGBM) is a rare (<1%) variant glioblastoma (GBM), in younger patients. Unlike the IDH-wild type GBM, they have a better prognosis. Mutations in the POLE and in MMR ...genes accelerate tumorigenesis, generating in some tumours an ultra-mutated phenotype. The lack of proofreading activity generates production of neoantigens, recalling tumour infiltrating lymphocytes, and immune-checkpoint ligands exposition. Aim of our study was to investigate MMR proteins expression, POLE mutations, related checkpoint molecules and the tumor immune-microenvironment in a group of gcGBMs compared to IDH-wild type GBMs. We performed a molecular and immunohistochemical analysis on 60 primary gcGBMs. All tumours where characterized for EGFR, PTEN, p53, IDH1, MGMT status by immunohistochemistry and/or molecular analysis. We investigated MMR protein (MSH6, MSH2, PML2 and MLH1), PD-L1, CTLA-4 and CD28 expression by immunohistochemistry in gcGBMs and in a group of standard GBMs. POLE mutations have been studied by direct sequencing of exons encoding its exonuclease activity. Then we assess the immunological status investigating the presence of lymphocytic infiltrates, microglia and macrophages, by CD3, CD4, CD8, CD68, CD163, MHC class II and IBA1. All the results obtained have been related to clinical data. The median survival time was 21 months, with 4 patients long survivors (>5 years), higher than in the standard group. The main findings where partial loss of expression of MMR proteins (overall MSH2 and MSH6) on 30% of cases, mostly related to presence of inflammatory infiltrates, also showing CD28 immunostaining. Microglia IBA1+ was significantly present in patients with longer survival. Correlation with PD-L1 and CTLA4 was found only in 2 cases. POLE sequencing displays mutation F367S on 20% of cases. Our results show that gcGBMs are an histological variant with increased tendency to ultra-mutated phenotype with a better prognosis and suggesting these patients as candidates for immunotherapy.
Null mutations in progranulin gene (GRN) reduce the progranulin production resulting in haploinsufficiency and are tightly associated with tau‐negative frontotemporal lobar degeneration with TAR ...DNA‐binding protein 43‐positive inclusions (FTLD‐TDP). Missense mutations of GRN were also identified, but their effects are not completely clear, in particular unanswered is the question of what neuropathology they elicit, also considering that their occurrence has been reported in patients with typical clinical features of Alzheimer disease. They describe two fraternal twins carrying the missense GRN Cys139Arg mutation affected by late‐onset dementia and we report the neuropathological study of one of them. Both patients were examined by neuroimaging, neuropsychological assessment and genetic analysis of GRN and other genes associated with dementia. The brain of one was obtained at autopsy and examined neuropathologically. One sister presented clinical and MRI features leading to the diagnosis of Alzheimer disease. The other underwent autopsy and the brain showed neuropathological hallmarks of Alzheimer disease with abundant Aβ‐amyloid deposition and Braak stage V of neurofibrillary pathology, in the absence of the hallmark lesions of FTLD‐TDP. Their findings may contribute to better clarify the role of progranulin in neurodegenerative diseases indicating that some GRN mutations, in particular missense ones, may act as strong risk factor for Alzheimer disease rather than induce FTLD‐TDP.
Tauopathies are sporadic or familial neurodegenerative diseases characterized by the accumulation of phosphorylated tau in neurons and glial cells and include encephalitis related to measles virus ...such as subacute sclerosing panencephalitis. We describe a 45‐year‐old woman, with a history of lymphoma treated with immunosuppressant therapy who underwent an open biopsy of the right frontal cortex for a suspect of encephalitis, and died 4 days later. The neuropathological assessment on the bioptic sample revealed edema, severe gliosis and microglial activation, with lymphomonocytic perivascular cuffing and neurons containing both nuclear and cytoplasmic eosinofilic inclusions that ultrastructurally appeared as tubular and curvilinear non‐membrane‐bound 12–18 nm structures, leading to the diagnosis of measles inclusion‐bodies encephalitis. The biopsy specimen showed several cortical neurons with intense perikaryal immunoreactivity for anti‐tau antibodies recognizing phosphorylated epitopes while on autoptic specimens no phosphorylated tau immunoreactivity was detected. Our findings suggest that in specific conditions biopsy‐derived human tau may be phosphorylated at sites that may result not phosphorylated in autopsy‐derived specimens, most likely caused by post‐mortem dephosphorylation.
Abstract
Null
mutations in progranulin gene (
GRN
) reduce the progranulin production resulting in haploinsufficiency and are tightly associated with tau‐negative frontotemporal lobar degeneration ...with TAR DNA‐binding protein 43‐positive inclusions (FTLD‐TDP). Missense mutations of
GRN
were also identified, but their effects are not completely clear, in particular unanswered is the question of what neuropathology they elicit, also considering that their occurrence has been reported in patients with typical clinical features of Alzheimer disease. They describe two fraternal twins carrying the missense
GRN
Cys139Arg mutation affected by late‐onset dementia and we report the neuropathological study of one of them. Both patients were examined by neuroimaging, neuropsychological assessment and genetic analysis of
GRN
and other genes associated with dementia. The brain of one was obtained at autopsy and examined neuropathologically. One sister presented clinical and MRI features leading to the diagnosis of Alzheimer disease. The other underwent autopsy and the brain showed neuropathological hallmarks of Alzheimer disease with abundant Aβ‐amyloid deposition and Braak stage V of neurofibrillary pathology, in the absence of the hallmark lesions of FTLD‐TDP. Their findings may contribute to better clarify the role of progranulin in neurodegenerative diseases indicating that some
GRN
mutations, in particular missense ones, may act as strong risk factor for Alzheimer disease rather than induce FTLD‐TDP.
•Long-term care residents are particularly vulnerable to COVID-19.•The prompt application of restrictive procedures might prevent the spread and progression of SARS-CoV-2 infection in assisted living ...facilities in the short term.•SARS-CoV-2 vaccination of residents and staff members would contribute to control/limit the prevalence and the spread of the virus.
Here, we aimed to describe the clinical outcomes of the residents of a long-term care facility during its closure to visitors and suppliers in response to the first COVID-19 pandemic from February 23 to June 22, 2020, and the results of the facility-wide SARS-CoV-2 testing of residents and staff in June 2020 before its partially reopening. Seventy-four residents and 53 members of staff were included in the present study. The staff underwent nasopharyngeal swab tests for SARS-CoV-2, and both the staff and residents underwent serological tests to detect IgG antibodies against SARS-CoV-2. The results of all of the tests were negative. Conversely, 94% of residents and 38% members of the staff were tested positive to the nasopharyngeal swab tests during the second COVID-19 pandemic wave (data collected from November 1 to November 30, 2020).
Our experience suggests that, in the presence of a life-threatening pandemic such as SARS-CoV-2 infection, the prompt use of restrictive procedures can prevent the spread and progression of disease in assisted living facilities in the short term but may fail in the long term, especially when the prevalence of the COVID-19 greatly increased outside the facility enhancing the risk of import the disease from outside. SARS-CoV-2 vaccination of residents and staff members would contribute to control/limit the prevalence and the spread of the virus.
A prospective controlled study of the diagnostic accuracy of blind percutaneous liver biopsy in comparison to laparoscopy plus guided biopsy for the recognition or exclusion of cirrhosis has been ...performed. One hundred twenty-six patients with a clinical diagnosis of chronic, diffuse, well-compensated liver disease were randomized into two groups and submitted either to percutaneous blind liver biopsy (PB: 64 patients) or to laparoscopy with guided biopsy (LB: 62 patients), in order to assess the accuracy of either procedure in diagnosing cirrhosis. PB correctly recognized or ruled out cirrhosis in 52 patients (82%). Inconclusive results were mostly false negative, as demonstrated by the presence on endoscopy of esophageal varices or by subsequent LB. LB demonstrated presence or absence of cirrhosis in all patients. The difference between the rate of accurate results of the two procedures is statistically significant. It is concluded that in patients without esophageal varices, LB should be the investigation of choice for the assessment of liver structure since the presence of cirrhosis can be missed in up to 20% of cases by PB.
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