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Defects in apoptosis contribute to treatment resistance and poor outcome of pancreatic cancer, calling for novel therapeutic strategies. Here, we provide the first evidence that nuclear factor (NF) κB is required for Smac mimetic– mediated sensitization of pancreatic carcinoma cells for gemcitabine-induced apoptosis. The Smac mimetic BV6 cooperates with gemcitabine to reduce cell viability and to induce apoptosis. In addition, BV6 significantly enhances the cytotoxicity of several anticancer drugs against pancreatic carcinoma cells, including doxorubicin, cisplatin, and 5-fluorouracil. Molecular studies reveal that BV6 stimulates NF-κB activation, which is further increased in the presence of gemcitabine. Importantly, inhibition of NF-κB by overexpression of the dominant-negative IκBα superrepressor significantly decreases BV6- and gemcitabine-induced apoptosis, demonstrating that NF-κB exerts a proapoptotic function in this model of apoptosis. In support of this notion, inhibition of tumor necrosis factor α (TNFα) by the TNFα blocking antibody Enbrel reduces BV6- and gemcitabine-induced activation of caspase 8 and 3, loss of mitochondrial membrane potential, and apoptosis. By demonstrating that BV6 and gemcitabine trigger a NF-κB–dependent, TNFα-mediated loop to activate apoptosis signaling pathways and caspase-dependent apoptotic cell death, our findings have important implications for the development of Smac mimetic–based combination protocols in the treatment of pancreatic cancer.
Searching for new strategies to bypass apoptosis resistance, we investigated the potential of the Smac mimetic BV6 in Jurkat leukemia cells deficient in key molecules of the death receptor pathway. Here, we demonstrate for the first time that Smac mimetic primes apoptosis-resistant, FADD- or caspase-8-deficient leukemia cells for TNFα-induced necroptosis in a synergistic manner. In contrast to TNFα, Smac mimetic significantly enhances CD95-induced apoptosis in wild-type but not in FADD-deficient cells. Interestingly, Smac mimetic- and TNFα-mediated cell death occurs without characteristic features of apoptosis (i.e., caspase activation, DNA fragmentation) in FADD-deficient cells. By comparison, Smac mimetic and TNFα trigger activation of caspase-8, -9, and -3 and DNA fragmentation in wild-type cells. Consistently, the caspase inhibitor zVAD.fmk fails to block Smac mimetic- and TNFα-triggered cell death in FADD- or caspase-8-deficient cells, while it confers protection in wild-type cells. By comparison, necrostatin-1, an RIP1 kinase inhibitor, abolishes Smac mimetic- and TNFα-induced cell death in FADD- or caspase-8-deficient. Thus, Smac mimetic enhances TNFα-induced cell death in leukemia cells via two distinct pathways in a context-dependent manner: it primes apoptosis-resistant cells lacking FADD or caspase-8 to TNFα-induced, RIP1-dependent and caspase-independent necroptosis, whereas it sensitizes apoptosis-proficient cells to TNFα-mediated, caspase-dependent apoptosis. These findings have important implications for the therapeutic exploitation of necroptosis as an alternative cell death program to overcome apoptosis resistance.
Background & Aims: Thrombopoietin receptor agonists are a new class of compounds licenced for the treatment of immune thrombocytopenic purpura. They are currently being studied for patients with thrombopenia in advanced liver disease or under therapy for hepatitis C. There are indications that the risk for development of portal vein thrombosis in patients with advanced liver cirrhosis might be increased under therapy with thrombopoietin receptor agonists. We report a case of a patient with Child class B liver cirrhosis with concurrent immune thrombocytopenic purpura that developed portal vein thrombosis under therapy with the thrombopoietin receptor agonist romiplostim.
Methods: A 50-year-old woman with hepatitis C virus associated immune thrombocytopenic purpura and Child class B liver cirrhosis presented in our emergency with rapidly evolving hydropic decompensation and general malaise. For immune thrombocytopenic purpura, the patient was started on the thrombopoietin receptor agonist romiplostim nine months ago.
Results: During hospitalization, the platelet count was measured above 330,000/μl and partial portal vein thrombosis was diagnosed by imaging studies. The thrombotic event was assumed to be associated with the romiplostim treatment for immune thrombocytopenic purpura via excessive elevation of platelet count. After anticoagulation with heparin and cessation of romiplostim treatment, complete recanalisation of the portal vein was achieved.
Conclusions: We conclude that romiplostim should be used with precaution in patients with hepatitis C-associated immune thrombocytopenic purpura and advanced liver cirrhosis as the risk for thrombotic complications may increase significantly.
Seroconversion rates following influenza vaccination in patients with hematologic malignancies after hematopoietic stem cell transplantation (HSCT) are known to be lower compared to healthy adults. The aim of our diagnostic study was to determine the rate of seroconversion after 1 or 2 doses of a novel split virion, inactivated, AS03-adjuvanted pandemic H1N1 influenza vaccine (A/California/7/2009) in HSCT recipients (ClinicalTrials.gov Identifier: NCT01017172). Blood samples were taken before and 21 days after a first dose and 21 days after a second dose of the vaccine. Antibody (AB) titers were determined by hemagglutination inhibition assay. Seroconversion was defined by either an AB titer of ≤1:10 before and ≥1:40 after or ≥1:10 before and ≥4-fold increase in AB titer 21 days after vaccination. Seventeen patients (14 allogeneic, 3 autologous HSCT) received 1 dose and 11 of these patients 2 doses of the vaccine. The rate of seroconversion was 41.2% (95% confidence interval [CI] 18.4-67.1) after the first and 81.8% (95% CI 48.2-97.7) after the second dose. Patients who failed to seroconvert after 1 dose of the vaccine were more likely to receive any immunosuppressive agent (P = .003), but time elapsed after or type of HSCT, age, sex, or chronic graft-versus-host disease was not different when compared to patients with seroconversion. In patients with hematologic malignancies after HSCT the rate of seroconversion after a first dose of an adjuvanted H1N1 influenza A vaccine was poor, but increased after a second dose.
Osteoid osteoma is a benign bone tumor of undetermined etiology, composed of a central zone named nidus which is an atypical bone completely enclosed within a wellvascularized stroma and a peripheral sclerotic reaction zone. There are three types of radiographic features: cortical, medullary and subperiosteal. Forty-four patients with osteoid osteoma were studied retrospectively. In plain films, 35 patients presented as the cortical type, six cases were located in the medullary zone and three had subperiosteal osteoid osteoma. In all the cases, the nidus was visualized on computed tomography (CT) scan. The nidus was visible in four out of five patients who had also undergone magnetic resonance imaging (MRI). Double-density sign, seen on radionuclide bone scans was positive in all patients. MRI is more sensitive in the diagnosis of bone marrow and soft tissue abnormalities adjacent to the lesion, and in the nidus that is located closer to the medullary zone. On the other hand, CT is more specific when it comes to detecting the lesion’s nidus.
This case study evaluated the response of objective and subjective markers of overreaching to a highly demanding conditioning training mesocycle in elite tennis players to determine 1) whether players would become functionally or non-functionally overreached, and 2) to explore how coherently overreaching markers would respond. Performance, laboratory and cardiac autonomous activity markers were evaluated in three experienced male tennis professionals competing at top 30, top 100 and top 1000 level before and after their strength and conditioning training was increased by 120, 160 and 180%, respectively, for 30 days. Every week, subjective ratings of stress and recovery were evaluated by means of a questionnaire. After 74, 76 and 55 h of training, increases in V̇O2max (+8, +5 and +18%) and speed strength indices (+9, +23 and +5%) were observed in all players. Changes of maximal heart rate (-5, -6, +4 beats per minute), laboratory markers (e.g. insulin-like growth factor -26, -17, -9%; free testosterone to cortisol ratio -63, +2, -12%) and cardiac autonomous activity markers (heart rate variability -49, -64, -13%) were variable among the players. Improved performance provides evidence that overreaching was functional in all players. However, several overreaching markers were altered and these alterations were more pronounced in the two top 100 players. The response of overreaching indicators was not coherent.
Im Jahre 2004 sind am Universitätsklinikum Frankfurt zwei Patienten mit X-CGD gentherapeutisch behandelt worden. Nach einer initialen Phase mit Nachweis ausreichender Mengen Oxidase-positiver Zellen im Blut der Patienten und einer deutlichen klinischen Besserung vorbestehender Infektionsherde kam es zu einem Verlust der Transgenexpression durch epigenetische Veränderungen des viralen Promotors. Ferner entwickelte sich durch Insertionsmutagenese eine klonale Expansion in der Hämatopoese und schließlich ein myelodysplastisches Syndrom mit Monosomie 7 bei beiden Patienten. In der Zusammenschau mit anderen Gentherapiestudien zur X-CGD zeigt sich, dass bislang ein langanhaltendes Engraftment funktionierender genkorrigierter Zellen nur im Zusammenhang mit einer Insertionsmutagenese beobachtet wurde. Zukünftige gentherapeutische Strategien zur Behandlung der X-CGD müssen das Risiko einer Insertionsmutagenese minimieren und gleichzeitig die Effektivität des Engraftments genkorrigierter Zellen steigern. Dies soll durch den Einsatz von SIN-Vektoren sowie einer Intensivierung der Konditionierung der Patienten erreicht werden.
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.
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.
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.