p185(BCR/ABL) has a lower sensitivity than p210(BCR/ABL) to the allosteric inhibitor GNF-2 in Philadelphia chromosome-positive acute lymphatic leukemia
Afsar Ali Mian
Oliver Gerhard Ottmann
- BACKGROUND: The t(9;22) translocation leads to the formation of the chimeric breakpoint cluster region/c-abl oncogene 1 (BCR/ABL) fusion gene on der22, the Philadelphia chromosome. The p185(BCR/ABL) or the p210(BCR/ABL) fusion proteins are encoded as a result of the translocation, depending on whether a "minor" or "major" breakpoint occurs, respectively. Both p185(BCR/ABL) and p210(BCR/ABL) exhibit constitutively activated ABL kinase activity. Through fusion to BCR the ABL kinase in p185(BCR/ABL) and p210(BCR/ABL) "escapes" the auto-inhibition mechanisms of c-ABL, such as allosteric inhibition. A novel class of compounds including GNF-2 restores allosteric inhibition of the kinase activity and the transformation potential of BCR/ABL. Here we investigated whether there are differences between p185(BCR/ABL) and p210(BCR/ABL) regarding their sensitivity towards allosteric inhibition by GNF-2 in models of Philadelphia chromosome-positive acute lymphatic leukemia.
DESIGN AND METHODS: We investigated the anti-proliferative activity of GNF-2 in different Philadelphia chromosome-positive acute lymphatic leukemia models, such as cell lines, patient-derived long-term cultures and factor-dependent lymphatic Ba/F3 cells expressing either p185(BCR/ABL) or p210(BCR/ABL) and their resistance mutants.
RESULTS: The inhibitory effects of GNF-2 differed constantly between p185(BCR/ABL) and p210(BCR/ABL) expressing cells. In all three Philadelphia chromosome-positive acute lymphatic leukemia models, p210(BCR/ABL)-transformed cells were more sensitive to GNF-2 than were p185BCR/ABL-positive cells. Similar results were obtained for p185(BCR/ABL) and the p210(BCR/ABL) harboring resistance mutations.
CONCLUSIONS: Our data provide the first evidence of a differential response of p185(BCR/ABL)- and p210(BCR/ABL)- transformed cells to allosteric inhibition by GNF-2, which is of importance for the treatment of patients with Philadelphia chromosome-positive acute lymphatic leukemia.
Effect of using different U/S probe Standoff materials in image geometry for interventional procedures: the example of prostate
- PURPOSE: This study investigates the distortion of geometry of catheters and anatomy in acquired U/S images, caused by utilizing various stand-off materials for covering a transrectal bi-planar ultrasound probe in HDR and LDR prostate brachytherapy, biopsy and other interventional procedures. Furthermore, an evaluation of currently established water-bath based quality assurance (QA) procedures is presented.
MATERIAL AND METHODS: Image acquisitions of an ultrasound QA setup were carried out at 5 MHz and 7 MHz. The U/S probe was covered by EA 4015 Silicone Standoff kit, or UA0059 Endocavity balloon filled either with water or one of the following: 40 ml of Endosgel(®), Instillagel(®), Ultraschall gel or Space OAR™ gel. The differences between images were recorded. Consequently, the dosimetric impact of the observed image distortion was investigated, using a tissue equivalent ultrasound prostate phantom - Model number 053 (CIRS Inc., Norfolk, VA, USA).
RESULTS: By using the EA 4015 Silicone Standoff kit in normal water with sound speed of 1525 m/s, a 3 mm needle shift was observed. The expansion of objects appeared in radial direction. The shift deforms also the PTV (prostate in our case) and other organs at risk (OARs) in the same way leading to overestimation of volume and underestimation of the dose. On the other hand, Instillagel(®) and Space OAR™ "shrinks" objects in an ultrasound image for 0.65 mm and 0.40 mm, respectively.
CONCLUSIONS: The use of EA 4015 Silicone Standoff kit for image acquisition, leads to erroneous contouring of PTV and OARs and reconstruction and placement of catheters, which results to incorrect dose calculation during prostate brachytherapy. Moreover, the reliability of QA procedures lies mostly in the right temperature of the water used for accurate simulation of real conditions of transrectal ultrasound imaging.
Novel therapeutic venues for glioblastoma: novel rising preclinical treatment opportunities
Markus David Siegelin
- High grade gliomas, including anaplastic glioma WHO grade III and glioblastoma WHO IV (GBM), carry a dismal prognosis. Taking all nowadays-available therapeutics options, including radiation, chemotherapy and surgery, for GBM into consideration the prognosis after initial diagnosis is about 12 month. Despite this bad prognosis, researchers gained a tremendous insight into the molecular and genetic signatures of low and high grade gliomas. Several different subtypes of GBM were demonstrated with respect to their genetic background. These genetic alterations include p53 mutation in secondary GBMs and EGFR amplification in primary GBMs, respectively. Very recently, great excitement was raised after the discovery of IDH1 mutation in low-grade gliomas and secondary GBMs. This discovery is of great significance since it allows further categorizing of GBMs and is helpful in distinguishing low-grade gliomas from non-neoplastic adjacent brain tissue. Despite all this progress there is an urgent need for fresh additional therapeutic strategies. In addition to the identification of novel therapeutic regimens it is of utmost importance to gain an understanding about the molecular mechanisms on how GBMs manage to evade from almost any anti-cancer treatment regimen. In experimental models of glioblastoma there are a number of novel therapeutic regimens that exhibited promising results. These novel therapeutics include, but are not limited to: Apoptosis-based therapeutics (Tumor necrosis factor alpha related apoptosis inducing ligand, TRAIL), tyrosinkinase-inhibitors, Heat-shock-protein 90 (HSP90) inhibitors, polyphenols, novel drug combinations and intracranial application based strategies. This chapter will primarily review and focus on molecular mechanisms of resistance in GBM and rising new therapeutic venues for high-grade gliomas. High-grade gliomas are a group of primary heterogenous tumors of which glioblastoma World Health Organisation, WHO IV (GBM), is the most common one. Once the diagnosis of GBM is made, the average survival time is approximately 12-15 month (Hegi, Diserens et al., 2005). Treatment usually consists of temozolomide (commonly used chemotherapeutic drug for the treatment of GBM, TMZ), radiation (either alone or in combination with chemotherapeutics) and surgery (Hegi, Diserens et al., 2005)...
Application of the liposuction techniques and principles in specific body areas and pathologies
Jorge A. D’Angelo
- The buttocks have been a symbol of attraction, sexuality and eroticism since ancient times and therefore, they have an important role in defining the posterior body contour. More and more people are talking about and understand the meaning and the role that buttocks play in modeling and physical beauty. The three dimensional gluteoplasty (3-DGP) is an innovative technique that allows us to change volume, shape and firmness, not only in the buttocks but also in the adjacent regions such as the thighs and trochanters, becoming an ideal tool to answer the frequent reasons of consultation of our patients about this particular area of the body: ...
Use of radiobiological modeling in treatment plan evaluation and optimization of prostate cancer radiotherapy
Bengt K. Lind
- There are many tools available that are used to evaluate a radiotherapy treatment plan, such as isodose distribution charts, dose volume histograms (DVH), maximum, minimum and mean doses of the dose distributions as well as DVH point dose constraints. All the already mentioned evaluation tools are dosimetric only without taking into account the radiobiological characteristics of tumors or OARs. It has been demonstrated that although competing treatment plans might have similar mean, maximum or minimum doses they may have significantly different clinical outcomes (Mavroidis et al. 2001). For performing a more complete treatment plan evaluation and comparison the complication-free tumor control probability (P+) and the biologically effective uniform dose (D ) have been proposed (Källman et al. 1992a, Mavroidis et al. 2000). The D concept denotes that any two dose distributions within a target or OAR are equivalent if they produce the same probability for tumor control or normal tissue complication, respectively (Mavroidis et al. 2001)...
A53T-alpha-synuclein-overexpression in the mouse nigrostriatal pathway leads to early increase of 14-3-3 epsilon and late increase of GFAP
Helmut E. Meyer
- Parkinson’s disease (PD) is a neurodegenerative disorder frequent at old age characterized by atrophy of the nigrostriatal projection. Overexpression and A53T-mutation of the presynaptic, vesicle-associated chaperone alpha-synuclein are known to cause early-onset autosomal dominant PD. We previously generated mice with transgenic overexpression of human A53T-alpha-synuclein (A53T-SNCA) in dopaminergic substantia nigra neurons as a model of early PD. To elucidate the early and late effects of A53T-alpha-synuclein on the proteome of dopaminergic nerve terminals in the striatum, we now investigated expression profiles of young and old mice using two-dimensional fluorescence difference in gel electrophoresis (2D-DIGE) and mass spectrometry. In total, 15 proteins were upregulated and 2 downregulated. Mice before the onset of motor anomalies showed an upregulation of the spot containing 14-3-3 proteins, in particular the epsilon isoform, as well as altered levels of chaperones, vesicle trafficking and bioenergetics proteins. In old mice, the persistent upregulation of 14-3-3 proteins was aggravated by an increase of glial fibrillary acidic protein (GFAP) suggesting astrogliosis due to initial neurodegeneration. Independent immunoblots corroborated GFAP upregulation and 14-3-3 upregulation for the epsilon isoform, and also detected significant eta and gamma changes. Only for 14-3-3 epsilon a corresponding mRNA increase was observed in midbrain, suggesting it is transcribed in dopaminergic perikarya and accumulates as protein in presynapses, together with A53T-SNCA. 14-3-3 proteins associate with alpha-synuclein in vitro and in pathognomonic Lewy bodies of PD brains. They act as chaperones in signaling, dopamine synthesis and stress response. Thus, their early dysregulation probably reflects a response to alpha-synuclein toxicity.
Electronic supplementary material: The online version of this article (doi:10.1007/s00702-011-0717-3) contains supplementary material, which is available to authorized users.
Why pitch sensitivity matters: event-related potential evidence of metric and syntactic violation detection among spanish late learners of german
Maria Paula Roncaglia-Denissen
Sonja A. Kotz
- Event-related potential (ERP) data in monolingual German speakers have shown that sentential metric expectancy violations elicit a biphasic ERP pattern consisting of an anterior negativity and a posterior positivity (P600). This pattern is comparable to that elicited by syntactic violations. However, proficient French late learners of German do not detect violations of metric expectancy in German. They also show qualitatively and quantitatively different ERP responses to metric and syntactic violations. We followed up the questions whether (1) latter evidence results from a potential pitch cue insensitivity in speech segmentation in French speakers, or (2) if the result is founded in rhythmic language differences. Therefore, we tested Spanish late learners of German, as Spanish, contrary to French, uses pitch as a segmentation cue even though the basic segmentation unit is the same in French and Spanish (i.e., the syllable). We report ERP responses showing that Spanish L2 learners are sensitive to syntactic as well as metric violations in German sentences independent of attention to task in a P600 response. Overall, the behavioral performance resembles that of German native speakers. The current data suggest that Spanish L2 learners are able to extract metric units (trochee) in their L2 (German) even though their basic segmentation unit in Spanish is the syllable. In addition Spanish in contrast to French L2 learners of German are sensitive to syntactic violations indicating a tight link between syntactic and metric competence. This finding emphasizes the relevant role of metric cues not only in L2 prosodic but also in syntactic processing.
Unmasking a temperature-dependent effect of the P. anserina i-AAA protease on aging and development
Heinz D. Osiewacz
- Different molecular pathways involved in maintaining mitochondrial function are of fundamental importance to control cellular homeostasis. Mitochondrial i-AAA protease is part of such a surveillance system, and PaIAP is the putative ortholog in the fungal aging model Podospora anserina. Here, we investigate the role of PaIAP in aging and development. Deletion of the gene encoding PaIAP resulted in a specific phenotype. When incubated at 27°C, spore germination and fruiting body formation are not different from that of the corresponding wild-type strain. Unexpectedly, the lifespan of the deletion strain is strongly increased. In contrast, cultivation at an elevated temperature of 37°C leads to impairments in spore germination and fruiting body formation and to a reduced lifespan. The higher PaIAP abundance in wild-type strains of the fungus grown at elevated temperature and the phenotype of the deletion strain unmasks a temperature-related role of the protein. The protease appears to be part of a molecular system that has evolved to allow survival under changing temperatures, as they characteristically occur in nature.
Portal vein thrombosis and arterioportal shunts: effects on tumor response after chemoembolization of hepatocellular carcinoma
Thomas J. Vogl
Nagy Naguib Naeem Naguib
- AIM: To evaluate the effect of portal vein thrombosis and arterioportal shunts on local tumor response in advanced cases of unresectable hepatocellular carcinoma treated by transarterial chemoembolization.
METHODS: A retrospective study included 39 patients (mean age: 66.4 years, range: 45-79 years, SD: 7) with unresectable hepatocellular carcinoma (HCC) who were treated with repetitive transarterial chemoembolization (TACE) in the period between March 2006 and October 2009. The effect of portal vein thrombosis (PVT) (in 19 out of 39 patients), the presence of arterioportal shunt (APS) (in 7 out of 39), the underlying liver pathology, Child-Pugh score, initial tumor volume, number of tumors and tumor margin definition on imaging were correlated with the local tumor response after TACE. The initial and end therapy local tumor responses were evaluated according to the response evaluation criteria in solid tumors (RECIST) and magnetic resonance imaging volumetric measurements.
RESULTS: The treatment protocols were well tolerated by all patients with no major complications. Local tumor response for all patients according to RECIST criteria were partial response in one patient (2.6%), stable disease in 34 patients (87.1%), and progressive disease in 4 patients (10.2%). The MR volumetric measurements showed that the PVT, APS, underlying liver pathology and tumor margin definition were statistically significant prognostic factors for the local tumor response (P = 0.018, P = 0.008, P = 0.034 and P = 0.001, respectively). The overall 6-, 12- and 18-mo survival rates from the initial TACE were 79.5%, 37.5% and 21%, respectively.
CONCLUSION: TACE may be exploited safely for palliative tumor control in patients with advanced unresectable HCC; however, tumor response is significantly affected by the presence or absence of PVT and APS.
Anti-angiogenesis in hepatocellular carcinoma treatment: current evidence and future perspectives
- Hepatocellular carcinoma (HCC) is among the most common cancer diseases worldwide. Arterial hypervascularisation is an essential step for HCC tumorigenesis and can be targeted by transarterial chemoembolization (TACE). This interventional method is the standard treatment for patients with intermediate stage HCC, but is also applied as “bridging” therapy for patients awaiting liver transplantation in many centers worldwide. Usually the devascularization effect induced by TACE is transient, consequently resulting in repeated cycles of TACE every 4-8 wk. Despite documented survival benefits, TACE can also induce the up-regulation of proangiogenic and growth factors, which might contribute to accelerated progression in patients with incomplete response. In 2007, sorafenib, a multi-tyrosine kinase and angiogenesis inhibitor, was approved as the first systemic treatment for advanced stage HCC. Other active targeted compounds, either inhibitors of angiogenesis and/or growth factors, are currently being investigated in numerous clinical trials. To overcome revascularisation or tumor progression under TACE treatment it seems therefore attractive to combine TACE with systemic targeted agents, which might theoretically block the effects of proangiogenic and growth factors. Over the last 12 mo, several retrospecretrospective or prospective cohort studies combining TACE and sorafenib have been published. Nevertheless, robust results of the efficacy and tolerability of such combination strategies as proven by randomized, controlled trials are awaited in the next two years.