Glioma invasion

Journal ArticleA characteristic pathological feature of malignant glioma cells is their ability to extensively invade surrounding brain parenchyma-particularly along white matter tracts- thus rendering focal therapies incapable of controlling tumor growth and resulting in inevitable recurrence. In this regard, identification of factors responsible for such invasion has become a central theme in glioma research, and elucidation of intracellular signal transduction systems and regulatory mechanisms important for controlling the process of invasion are of great clinical interest. In the article by Kubiatowski, et al., in this issue (Kubiatowski T, Jang T, Lachyankar MB, et al: Association of increased phosphatidylinositol 3-kinase signaling with increased invasiveness and gelatinase activity in malignant gliomas. J Neurosurg 95:480-488, September, 2001), the authors have demonstrated that increased phosphatidylinositol 3-kinase (PI3-K) activity correlates with Akt phosphorylation and also increased matrix metalloproteinase (MMP)-2 and -9 production. Matrix metalloproteinases are fundamentally involved with proteolytic degradation of the extracellular matrix (gelatin), a preliminary step in the invasion process.6 The increased MMP-2/-9 production associated with PI3-K activity correlates with invasion through matrigel, as demonstrated in this study. Pharmacological inhibition of PI3-K activity byWortmannin and LY294002 decreases invasion of glioma cells, suggesting that targeting of this pathway is of potential therapeutic importance

Linking Proteomic and Transcriptional Data through the Interactome and Epigenome Reveals a Map of Oncogene-induced Signaling

Cellular signal transduction generally involves cascades of post-translational protein modifications that rapidly catalyze changes in protein-DNA interactions and gene expression. High-throughput measurements are improving our ability to study each of these stages individually, but do not capture the connections between them. Here we present an approach for building a network of physical links among these data that can be used to prioritize targets for pharmacological intervention. Our method recovers the critical missing links between proteomic and transcriptional data by relating changes in chromatin accessibility to changes in expression and then uses these links to connect proteomic and transcriptome data. We applied our approach to integrate epigenomic, phosphoproteomic and transcriptome changes induced by the variant III mutation of the epidermal growth factor receptor (EGFRvIII) in a cell line model of glioblastoma multiforme (GBM). To test the relevance of the network, we used small molecules to target highly connected nodes implicated by the network model that were not detected by the experimental data in isolation and we found that a large fraction of these agents alter cell viability. Among these are two compounds, ICG-001, targeting CREB binding protein (CREBBP), and PKF118–310, targeting β-catenin (CTNNB1), which have not been tested previously for effectiveness against GBM. At the level of transcriptional regulation, we used chromatin immunoprecipitation sequencing (ChIP-Seq) to experimentally determine the genome-wide binding locations of p300, a transcriptional co-regulator highly connected in the network. Analysis of p300 target genes suggested its role in tumorigenesis. We propose that this general method, in which experimental measurements are used as constraints for building regulatory networks from the interactome while taking into account noise and missing data, should be applicable to a wide range of high-throughput datasets.National Science Foundation (U.S.) (DB1-0821391)National Institutes of Health (U.S.) (Grant U54-CA112967)National Institutes of Health (U.S.) (Grant R01-GM089903)National Institutes of Health (U.S.) (P30-ES002109

Protein kinase C and cardiac dysfunction: a review

Heart failure (HF) is a physiological state in which cardiac output is insufficient to meet the needs of the body. It is a clinical syndrome characterized by impaired ability of the left ventricle to either fill or eject blood efficiently. HF is a disease of multiple aetiologies leading to progressive cardiac dysfunction and it is the leading cause of deaths in both developed and developing countries. HF is responsible for about 73,000 deaths in the UK each year. In the USA, HF affects 5.8 million people and 550,000 new cases are diagnosed annually. Cardiac remodelling (CD), which plays an important role in pathogenesis of HF, is viewed as stress response to an index event such as myocardial ischaemia or imposition of mechanical load leading to a series of structural and functional changes in the viable myocardium. Protein kinase C (PKC) isozymes are a family of serine/threonine kinases. PKC is a central enzyme in the regulation of growth, hypertrophy, and mediators of signal transduction pathways. In response to circulating hormones, activation of PKC triggers a multitude of intracellular events influencing multiple physiological processes in the heart, including heart rate, contraction, and relaxation. Recent research implicates PKC activation in the pathophysiology of a number of cardiovascular disease states. Few reports are available that examine PKC in normal and diseased human hearts. This review describes the structure, functions, and distribution of PKCs in the healthy and diseased heart with emphasis on the human heart and, also importantly, their regulation in heart failure

Use of endovascular embolization to treat a ruptured arteriovenous malformation in a pregnant woman: a case report

<p>Abstract</p> <p>Introduction</p> <p>Pregnancy has been linked to increased rates of arteriovenous malformation rupture. This link remains a matter of debate and very few studies have addressed the management of arteriovenous malformation in pregnancy. Unruptured arteriovenous malformations in pregnant woman generally warrant conservative management due to the low rupture risk. When pregnant women present with ruptured arteriovenous malformation, however, surgery is often indicated due to the increased risk of re-rupture and associated mortality. Endovascular embolization is widely accepted as an important component of contemporary, multimodal therapy for arteriovenous malformations. Although rarely curative, embolization can facilitate subsequent surgical resection or radiosurgery. No previous reports have been devoted to the endovascular management of an arteriovenous malformation in a pregnant woman.</p> <p>Case presentation</p> <p>A 23-year-old Caucasian woman presented with headache and visual disturbance after the rupture of a left parieto-occipital arteriovenous malformation in the 22nd week of her pregnancy. After involving high-risk obstetric consultants and taking precautions to shield the fetus from ionizing radiation, we proceeded with a single stage of endovascular embolization followed soon after by open surgical resection of the arteriovenous malformation. There were several goals for the angiography in this patient: to better understand the anatomy of the arteriovenous malformation, including the number and orientation of feeding arteries and draining veins; to look for associated pre-nidal or intra-nidal aneurysms; and to partially embolize the arteriovenous malformation via safely-accessible feeders to facilitate surgical resection and minimize blood loss and operative morbidity.</p> <p>Conclusion</p> <p>From our experience and review of the literature, we maintain that ruptured arteriovenous malformations in pregnancy may be managed in a similar manner to those in non-gravid women. Precautions should be taken to reduce the operative time and exposure of the fetus to ionizing radiation and contrast agents.</p

Tamoxifen stimulates arachidonic acid release from rat liver cells by an estrogen receptor-independent, non-genomic mechanism

BACKGROUND: Tamoxifen is widely prescribed for the treatment of breast cancer. Its success has been attributed to the modulation of the estrogen receptor. I have previously proposed that the release of arachidonic acid from cells may also mediate cancer prevention. METHODS: Rat liver cells were radiolabelled with arachidonic acid. The release of [(3)H] arachidonic acid after various times of incubation of the cells with tamoxifen was measured. RESULTS: Tamoxifen, at micromolar concentrations, stimulates arachidonic acid release. The stimulation is rapid and is not affected by pre-incubation of the cells with actinomycin or the estrogen antagonist ICI-182,780. CONCLUSIONS: The stimulation of AA release by tamoxifen is not mediated by estrogen receptor occupancy and is non-genomic

Role of protein kinase C and NF-κB in proteolysis-inducing factor-induced proteasome expression in C2C12 myotubes

Proteolysis-inducing factor (PIF) is a sulphated glycoprotein produced by cachexia-inducing tumours, which initiates muscle protein degradation through an increased expression of the ubiquitin–proteasome proteolytic pathway. The role of kinase C (PKC) in PIF-induced proteasome expression has been studied in murine myotubes as a surrogate model of skeletal muscle. Proteasome expression induced by PIF was attenuated by 4alpha-phorbol 12-myristate 13-acetate (100 nM) and by the PKC inhibitors Ro31-8220 (10 muM), staurosporine (300 nM), calphostin C (300 nM) and Gö 6976 (200 muM). Proteolysis-inducing factor-induced activation of PKCalpha, with translocation from the cytosol to the membrane at the same concentration as that inducing proteasome expression, and this effect was attenuated by calphostin C. Myotubes transfected with a constitutively active PKCalpha (pCO2) showed increased expression of proteasome activity, and a longer time course, compared with their wild-type counterparts. In contrast, myotubes transfected with a dominant-negative PKCalpha (pKS1), which showed no activation of PKCalpha in response to PIF, exhibited no increase in proteasome activity at any time point. Proteolysis-inducing factor-induced proteasome expression has been suggested to involve the transcription factor nuclear factor-kappaB (NF-kappaB), which may be activated through PKC. Proteolysis-inducing factor induced a decrease in cytosolic I-kappaBalpha and an increase in nuclear binding of NF-kappaB in pCO2, but not in pKS1, and the effect in wild-type cells was attenuated by calphostin C, confirming that it was mediated through PKC. This suggests that PKC may be involved in the phosphorylation and degradation of I-kappaBalpha, induced by PIF, necessary for the release of NF-kappaB from its inactive cytosolic complex

Pituitary surgery for small prolactinomas as an alternative to treatment with dopamine agonists

Despite the fact that consensus guidelines recommend long-term dopamine agonist (DA) therapy as a first-line approach to the treatment of small prolactinoma, some patients continue to prefer a primary surgical approach. Concerns over potential adverse effects of long-term medical therapy and/or the desire to become pregnant and avoid long-term medication are often mentioned as reasons to pursue surgical removal. In this retrospective study, 34 consecutive patients (30 female, 4 male) preferably underwent primary pituitary surgery without prior DA treatment for small prolactinomas (microprolactinoma 1–10 mm, macroprolactinoma 11–20 mm) at the Department of Neurosurgery, University of Bern, Switzerland. At the time of diagnosis, 31 of 34 patients (91%) presented with symptoms. Patients with microprolactinomas had significantly lower preoperative prolactin (PRL) levels compared to patients with macroprolactinomas (median 143 μg/l vs. 340 μg/l). Ninety percent of symptomatic patients experienced significant improvement of their signs and symptoms upon surgery. The postoperative PRL levels (median 3.45 μg/l) returned to normal in 94% of patients with small prolactinomas. There was no mortality and no major morbidities. One patient suffered from hypogonadotropic hypogonadism after surgery despite postoperative normal PRL levels. Long-term remission was achieved in 22 of 24 patients (91%) with microprolactinomas, and in 8 of 10 patients (80%) with macroprolactinomas after a median follow-up period of 33.5 months. Patients with small prolactinomas can safely consider pituitary surgery in a specialized centre with good chance of long-term remission as an alternative to long-term DA therapy

Berberine enhances inhibition of glioma tumor cell migration and invasiveness mediated by arsenic trioxide

<p>Abstract</p> <p>Background</p> <p>Arsenic trioxide (As₂O₃) exhibits promising anticarcinogenic activity in acute promyelocytic leukemic patients and induces apoptosis in various tumor cells <it>in vitro</it>. Here, we investigated the effect of the natural alkaloid berberine on As₂O₃-mediated inhibition of cancer cell migration using rat and human glioma cell lines.</p> <p>Methods</p> <p>The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay was used to determine the viability of rat C6 and human U-87 glioma cells after treatment with As₂O₃or berberine, and after co-treatment with As₂O₃and berberine. The wound scratch and Boyden chamber assays were applied to determine the effect of As₂O₃and berberine on the migration capacity and invasiveness of glioma cancer cells. Zymography and Western blot analyses provided information on the effect of As₂O₃and berberine on the intracellular translocation and activation of protein kinase C (PKC), and some PKC-related downstream factors. Most assays were performed three times, independently, and data were analyzed using ANOVA.</p> <p>Results</p> <p>The cell viability studies demonstrated that berberine enhances As₂O₃-mediated inhibition of glioma cell growth after 24 h incubation. Untreated control cells formed a confluent layer, the formation of which was inhibited upon incubation with 5 μM As₂O₃. The latter effect was even more pronounced in the presence of 10 μM berberine. The As₂O₃-mediated reduction in motility and invasion of glioma cells was enhanced upon co-treatment with berberine. Furthermore, it has been reported that PKC isoforms influence the morphology of the actin cytoskeleton, as well as the activation of metalloproteases MT1-MMP and MMP-2, reported to be involved in cancer cell migration. Treatment of glioma cells with As₂O₃and berberine significantly decreased the activation of PKC α and ε and led to actin cytoskeleton rearrangements. The levels of two downstream transcription factors, myc and jun, and MT1-MMP and MMP-2 were also significantly reduced.</p> <p>Conclusion</p> <p>Upon co-treatment of glioma cells with As₂O₃and berberine, cancer cell metastasis can be significantly inhibited, most likely by blocking the PKC-mediated signaling pathway involved in cancer cell migration. This study is potentially interesting for the development of novel chemotherapeutic approaches in the treatment of malignant gliomas and cancer development in general.</p

Antiretroviral treatment use, co-morbidities and clinical outcomes among Aboriginal participants in the Australian HIV Observational Database (AHOD)

Background: There are few data regarding clinical care and outcomes of Indigenous Australians living with HIV and it is unknown if these differ from non-Indigenous HIV-positive Australians. Methods: AHOD commenced enrolment in 1999 and is a prospective cohort of HIV-positive participants attending HIV outpatient services throughout Australia, of which 20 (74 %) sites report Indigenous status. Data were collected up until March 2013 and compared between Indigenous and non-Indigenous participants. Person-year methods were used to compare death rates, rates of loss to follow-up and rates of laboratory testing during follow-up between Indigenous and non-Indigenous participants. Factors associated with time to first combination antiretroviral therapy (cART) regimen change were assessed using Kaplan Meier and Cox Proportional hazards methods. Results: Forty-two of 2197 (1.9 %) participants were Indigenous. Follow-up amongst Indigenous and non-Indigenous participants was 332 & 16270 person-years, respectively. HIV virological suppression was achieved in similar proportions of Indigenous and non-Indigenous participants 2 years after initiation of cART (81.0 % vs 76.5 %, p = 0.635). Indigenous status was not independently associated with shorter time to change from first- to second-line cART (aHR 0.95, 95 % CI 0.51-1.76, p = 0.957). Compared with non-Indigenous participants, Indigenous participants had significantly less frequent laboratory monitoring of CD4 count (rate:2.76 tests/year vs 2.97 tests/year, p = 0.025) and HIV viral load (rate:2.53 tests/year vs 2.93 tests/year, p < 0.001), while testing rates for lipids and blood glucose were almost half that of non-indigenous participants (rate:0.43/year vs 0.71 tests/year, p < 0.001). Loss to follow-up (23.8 % vs 29.8 %, p = 0.496) and death (2.4 % vs 7.1 %, p = 0.361) occurred in similar proportions of indigenous and non-Indigenous participants, respectively, although causes of death in both groups were mostly non-HIV-related. Conclusions: As far as we are aware, these are the first data comparing clinical outcomes between Indigenous and non-Indigenous HIV-positive Australians. The forty-two Indigenous participants represent over 10 % of all Indigenous Australians ever diagnosed with HIV. Although outcomes were not significantly different, Indigenous patients had lower rates of laboratory testing for HIV and lipid/glucose parameters. Given the elevated risk of cardiovascular disease in the general Indigenous community, the additional risk factor of HIV infection warrants further focus on modifiable risk factors to maximise life expectancy in this population