205 research outputs found
Dural arachnoid granulations and "giant” arachnoid granulations
Although arachnoid granulations (AGs) were already described by Antonio Pacchioni more than 300years ago, two issues draw particular attention: first, the radiological features and differential diagnosis of the so-called giant AGs (GAGs) and second, their possible association with various disease processes. In order to evaluate the frequency, size and normal distribution of GAGs, an anatomical study of the dural sinuses was carried out. It involved all the autopsies performed during the period August 2002-February 2005 and included 651 cases: 306 females and 345 males, aged 13-99years (mean 69years). Grossly visible GAGs were identified in 24 cases: 7 females and 17 males, aged 45-92years (mean 69years). This is the largest population-based anatomical study on GAGs. It shows that GAGs, in general a rare finding (3.68%), are rather common in the adult population, especially in the elderly (aged >65years) and that they can reach remarkable size (up to 2.5cm and more in diameter). Giant AGs should be considered in the radiological differential diagnosis of intradural lesions, particularly those occurring in the transverse sinus of the elderl
The Insulin-Like Growth Factor 2 mRNA Binding Protein IMP2/IGF2BP2 is Overexpressed and Correlates with Poor Survival in Pancreatic Cancer
The insulin-like growth factor 2 (IGF2) mRNA binding protein IMP2 (IGF2BP2) is an
oncogenic protein known to be overexpressed in different tumor types. Pancreatic cancer is a very
lethal cancer that requires early diagnosis and new treatment options. The aim of our study was to
investigate the role of IMP2 in the initiation and progression of pancreatic ductal adenocarcinoma
(PDAC). IMP2 was significantly overexpressed in a human precursor (PanIN) lesions suggesting IMP2
as a marker for early stages of PDAC. In a PDAC cohort of matched normal and tumor samples IMP2
showed overexpression in tumor tissues compared with normal pancreatic tissue. Strict correlation
analysis (threshold R
2 > 0.75) revealed 22 genes highly positively and 9 genes highly negatively
correlating with IMP2. Besides genes involved in the inhibition of apoptosis (Bcl-XL), especially factors
involved in ubiquitination were strongly correlated with IMP2 expression: SMURF1 and FBXO45.
Moreover, protein kinase C (PKC) signaling pathway was distinctly affected: DXS1179E encoding
PKC iota, PKC substrate PLEK2, and inositol triphosphate receptor IP3R3 were positively correlated
with IMP2 expression. Besides tumor initiation, IMP2 also seemed to have an impact on tumor
progression. TGF-β treatment of Panc-1 pancreatic cancer cells to induce epithelial-mesenchymal
transition (EMT) was accompanied by increased IMP2 expression. EMT is important for cancer cells
to gain migratory and invasive potential, which is essential for metastasis. Concordantly, circulating
tumor cells showed higher IMP2 levels as compared with normal tissue from tumor origin and
with normal hematological cells. Accordingly, IMP2 protein levels correlated with poor survival.
In conclusion, as IMP2 seems to promote tumor progression of PDAC, it might be an interesting
diagnostic and prognostic marker as well as a novel target for the treatment of PDAC
Overexpression of eIF3a in Squamous Cell Carcinoma of the Oral Cavity and Its Putative Relation to Chemotherapy Response
The eukaryotic translation initiation factor eIF3a is one of the core subunits of the translation initiation complex eIF3, responsible for ribosomal subunit joining and mRNA recruitment to the ribosome. It is known to play an important role in general translation initiation as well as in the specific translational regulation of various gene products, among which many influence tumour development, progression, and the therapeutically important pathways of DNA damage repair. Therefore, beyond its role in protein synthesis, eIF3a is emerging as regulator in tumour pathogenesis and therapy response and, therefore, a potential tumor marker. By means of a tissue microarray (TMA) for histopathological and statistical assessment, we here show eIF3a expression in 103 cases of squamous cell carcinoma of the oral cavity (OSCC), representing tissues from 103 independent patients. A subset of the study cohort was treated with platinum based therapy. Our results show that the 170 kDa protein is upregulated in OSCC and correlates with good overall survival. Overexpressing tumors respond better to platinum-based chemotherapy, suggesting eIF3a as a putative predictive as well as prognostic tumor marker in OSCC
Expression of Pancreatitis-Associated Protein after Traumatic Brain Injury: A Mechanism Potentially Contributing to Neuroprotection in Human Brain
Neuronal cell death after severe traumatic brain injury (TBI) is caused by a complex interplay of pathological mechanisms including excitotoxicity, oxidative stress, mitochondrial dysfunction, extensive neuroinflammation, and ischemia-reperfusion injury. Pancreatitis-associated protein I (PAP I/reg2) was reported to be a survival factor for peripheral neurons, particularly sensory and motor neurons. In rat brains, by experimental TBI as well as by kainic acid induced brain seizure, PAP I and PAP III were found to be up-regulated in central neurons. In this study, we performed immunohistochemical staining in postmortem human brain from patients who died after severe TBI to demonstrate PAP expression on protein level in cerebellar Purkinje cells, pyramidal and granular neurons in cerebral cortex, and cortical neurons in the fore- and mid-brain. In primary cultures of rat brain cortical, hippocampal, and cerebellar neurons, we found neuroprotective effects for PAP I on H2O2-induced oxidative stress. Moreover, serum K+-deprivation induces apoptotic cell death in 55% of cerebellar granule neurons (CGN), whereas upon treatment with PAP I only 32% of CGN are apoptotic. Using Western blot analyses, we compared protein phosphorylation in neuronal signaling pathways activated by PAP I versus Interleukin-6 (IL-6). We found a rapid activation of Akt-kinase phosphorylation by PAP I with a peak at 15min, whereas IL-6 induces Akt-phosphorylation lasting longer than 30min. Phosphorylation of MAP-42/44 kinases is stimulated in a comparable fashion. Both, IL-6 and PAP I increase phosphorylation of NFκB for activation of gene transcription, whereas only IL-6 recruits STAT3 phosphorylation, indicating that STAT3 is not a target of PAP I transcription activation in brain neurons. Application of the Akt-inhibitor Wortmanin reveals only a partial inhibition of PAP I-dependent protection of CGN from H2O2-induced oxidative stress. Based on our findings, we suggest that PAP I is a long lasting neurotrophic signal for central neurons. The neuroprotective effects parallel those that have been described for effects of PAP I in ciliary neurotrophic factor (CNTF)-mediated survival of sensory and motor neurons. PAP I may act in autocrine and/or paracrine fashion and thus may contribute to endogenous protective mechanisms relevant under harmful conditions like oxidative stress, brain injury, or neurodegeneratio
Expression of O6-methylguanine-DNA methyltransferase in childhood medulloblastoma
Medulloblastomas (MB) are the most common malignant brain tumors in childhood. Alkylator-based drugs are effective agents in the treatment of patients with MB. In several tumors, including malignant glioma, elevated O6-methylguanine-DNA methyltransferase (MGMT) expression levels or lack of MGMT promoter methylation have been found to be associated with resistance to alkylating chemotherapeutic agents such as temozolomide (TMZ). In this study, we examined the MGMT status of MB and central nervous system primitive neuroectodermal tumor (PNET) cells and two large sets of primary MB. In sevenMB/PNET cell lines investigated, MGMT promoter methylation was detected only in D425 human MB cells as assayed by the qualitative methylation-specific PCR and the more quantitative pyrosequencing assay. In D425 human MB cells, MGMT mRNA and protein expression was clearly lower when compared with the MGMT expression in the other MB/PNET cell lines. In MB/PNET cells, sensitivity towards TMZ and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) correlated with MGMT methylation and MGMT mRNA expression. Pyrosequencing in 67 primary MB samples revealed a mean percentage of MGMT methylation of 3.7-92% (mean: 13.25%, median: 10.67%). Percentage of MGMT methylation and MGMT mRNA expression as determined by quantitative RT-PCR correlated inversely (n=46; Pearson correlation r 2=0.14, P=0.01). We then analyzed MGMT mRNA expression in a second set of 47 formalin-fixed paraffin-embedded primary MB samples from clinically well-documented patients treated within the prospective randomized multicenter trial HIT'91. No association was found between MGMT mRNA expression and progression-free or overall survival. Therefore, it is not currently recommended to use MGMT mRNA expression analysis to determine who should receive alkylating agents and who should no
Kupffer cells are protective in alcoholic steatosis
Massive accumulation of lipids is a characteristic of alcoholic liver disease. Excess of hepatic fat activates Kupffer cells (KCs), which affect disease progression. Yet, KCs contribute to the resolution and advancement of liver injury. Aim of the present study was to evaluate the effect of KC depletion on markers of liver injury and the hepatic lipidome in liver steatosis (Lieber-DeCarli diet, LDC, female mice, mixed C57BL/6J and DBA/2J background). LDC increased the number of dead hepatocytes without changing the mRNA levels of inflammatory cytokines in the liver. Animals fed LDC accumulated elevated levels of almost all lipid classes. KC ablation normalized phosphatidylcholine and phosphatidylinositol levels in LDC livers, but had no effect in the controls. A modest decline of trigylceride and diglyceride levels upon KC loss was observed in both groups. Serum aminotransferases and hepatic ceramide were elevated in all animals upon KC depletion, and in particular, cytotoxic very long-chain ceramides increased in the LDC livers. Meta-biclustering revealed that eight lipid species occurred in more than 40% of the biclusters, and four of them were very long-chain ceramides. KC loss was further associated with excess free cholesterol levels in LDC livers. Expression of inflammatory cytokines did, however, not increase in parallel. In summary, the current study described a function of KCs in hepatic ceramide and cholesterol metabolism in an animal model of LDC liver steatosis. High abundance of cytotoxic ceramides and free cholesterol predispose the liver to disease progression suggesting a protective role of KCs in alcoholic liver diseases
Targeting Glioma Stem Cells by Functional Inhibition of a Prosurvival OncomiR-138 in Malignant Gliomas
SummaryMalignant gliomas are the most aggressive forms of brain tumors, associated with high rates of morbidity and mortality. Recurrence and tumorigenesis are attributed to a subpopulation of tumor-initiating glioma stem cells (GSCs) that are intrinsically resistant to therapy. Initiation and progression of gliomas have been linked to alterations in microRNA expression. Here, we report the identification of microRNA-138 (miR-138) as a molecular signature of GSCs and demonstrate a vital role for miR-138 in promoting growth and survival of bona fide tumor-initiating cells with self-renewal potential. Sequence-specific functional inhibition of miR-138 prevents tumorsphere formation in vitro and impedes tumorigenesis in vivo. We delineate the components of the miR-138 regulatory network by loss-of-function analysis to identify specific regulators of apoptosis. Finally, the higher expression of miR-138 in GSCs compared to non-neoplastic tissue and association with tumor recurrence and survival highlights the clinical significance of miR-138 as a prognostic biomarker and a therapeutic target for treatment of malignant gliomas
Original paper expressiOn pattern Of isl-1, ttf-1 and pax5 in OlfactOry neurOblastOma
Olfactory neuroblastoma (ONB) is a rare neoplasm of the sinonasal area with neuroendocrine differentiation. ISL-1, TTF-1 and PAX5 are transcription factors that are frequently upregulated in tumors showing neuroendocrine differentiation. The aim of our study was to evaluate these markers in a group of ONBs. We included 11 ONBs from 4 large university hospitals. Immunohistochemical expression of TTF-1, PAX5 and ISL-1 was evaluated. TTF-1, ISL-1 and PAX5 were expressed in 3/11 cases (27.27%, h-score: 3-45), 7/11 cases (63.64%, h-score: 23-200), and in 3/11 cases (27.77%, h-score 3-85), respectively. The patient with the strongest PAX5 reactivity exhibited an aggressive clinical course with rapid dissemination to the spine and death shortly after the diagnosis. No significant correlation in the expression of PAX5 and TTF-1 (ρ = 0.43; p = 0.18) was observed. ISL-1 is widely expressed in tumors with neuroendocrine differentiation and therefore of limited value in their differential diagnosis. TTF-1 positivity does not exclude the diagnosis of primary ONB, although usually only a small percentage of cells are positive. PAX5 expression is infrequent (27.27%) in ONB; however, if present it can be associated with a very aggressive clinical course
Increased expression of retinoic acid-induced gene 1 in the dorsolateral prefrontal cortex in schizophrenia, bipolar disorder, and major depression
Loss of c-Jun N-terminal Kinase 1 and 2 Function in Liver Epithelial Cells Triggers Biliary Hyperproliferation Resembling Cholangiocarcinoma
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