IAP inhibitor-mediated sensitization of neuroblastoma towards TRAIL-induced apoptosis via a RIP1/FADD/caspase-8 cell death complex / by Behnaz Ahangarian Abhari
- Inhibitor of Apoptosis (IAP) proteins are expressed at high levels in many cancers and contribute to apoptosis resistance. Therefore, they represent promising anticancer drug targets. Here, we report that small molecule IAP inhibitors at subtoxic concentrations cooperate with monoclonal antibodies against TRAIL receptor 1 (Mapatumumab) or TRAIL receptor 2 (Lexatumumab) to induce apoptosis in neuroblastoma cells in a highly synergistic manner (combination index <0.1). Importantly, we identify RIP1 as a critical regulator of this synergism. RIP1 is required for the formation of a RIP1/FADD/caspase-8 complex that drives caspase-8 activation, cleavage of Bid into tBid, mitochondrial outer membrane permeabilization, full activation of caspase-3 and caspase-dependent apoptosis. Indeed, knockdown of RIP1 abolishes formation of the RIP1/FADD/caspase-8 complex, subsequent caspase activation and apoptosis upon treatment with IAP inhibitor and TRAIL receptor antibodies. Similarly, inhibition of RIP1 kinase activity by Necrostatin-1 inhibits IAP inhibitor- and TRAIL receptor-triggered apoptosis. By comparison, over-expression of the dominant-negative superrepressor IκBα-SR or addition of the TNFα-blocking antibody Enbrel does not inhibit IAP inhibitor- and Lexatumumab-induced apoptosis, pointing to a NF-κB- and TNFα-independent mechanism. Of note, IAP inhibitor also significantly reduces TRAIL receptor-mediated loss of cell viability of primary cultured neuroblastoma cells, underscoring the clinical relevance. By demonstrating that RIP1 plays a key role in the IAP inhibitor-mediated sensitization for Mapatumumab- or Lexatumumab-induced apoptosis, our findings provide strong rationale to develop the combination of IAP inhibitors and TRAIL receptor agonists as a new therapeutic strategy for the treatment of human cancer.
Once again on person marking in tibeto-burman : a reply to DeLancey 2010
Randy J. LaPolla
- In terms of the direction of development, I referred to Johanna Nichols' work on head-marking vs. dependant marking. Nichols did not make reference to any languages in Tibeto-Burman, but all of the Tibeto-Burman languages that do not have verb agreement systems are solidly dependent-marking (i.e., they have marking on the nouns for case or pragmatic function); those languages with verb agreement systems, a type of head marking, also have many dependent-marking features (of the same types as the non-pronominalized languages). The question, then, is which is older, the dependent-marking type or the headmarking (actually mixed) type?
Clausal noun-modifying constructions in sino-tibetan languages
Randy J. LaPolla
- Chinese is often taken as a prime example of an isolating language. Most relation marking takes the form of particles rather than affixes or inflections. Possibly relevant to the facts that are presented below, Chinese has been argued to not have grammaticalized the sort of pivot constructions normally associated with grammatical relations. That is, it has been argued to not have any particular alignment, as there are no grammatical relations, and the clause pattern is simply topic-comment (Chao 1968, Lü 1979, LaPolla 1993, 1995, 2009; LaPolla & Poa 2005, 2006). We will first talk more generally about structures found in Sino-Tibetan languages, and then focus on Modern Mandarin Chinese.
Motivation in all spheres of life : program & abstracts / International Conference on Motivation 2012, August 28 - 30, Frankfurt am Main, Germany
- This is the Proceedings of the "International Conference on Motivation 2012" carried out by the Special Interest Group "Motivation and Emotion" of the European Association for Research on Learning and Instruction (EARLI) in cooperation with the German Institute for International Educational Research (DIPF) and the Goethe University Frankfurt. (DIPF/author).
Jet fragmentation properties in proton-proton and Pb-Pb collisions with ALICE at the LHC
Hermes León Vargas
- According to the standard model of particle physics, the most fundamental building blocks of the known matter are quarks and leptons, while the interactions between these fundamental objects is mediated through bosons. On one hand the leptons can exist in nature as individual particles, while on the other hand quarks appear always as bound states called hadrons. The knowledge that hadrons are built from more fundamental particles dates back to the second half of the 20th century when the work by Gell-Mann and Zweig led to the development of the quark model. The experimental proof that the hadrons are bound objects composed of more elementary particles was done through the study of deep inelastic scattering of electrons off protons. These experiments were done in a similar fashion to the studies of the atomic model led by Rutherford at the beginning of the 20th century. Further experimental analysis led to the conclusion that a large fraction of the proton momentum is not carried alone by the quarks, but by the bosons that mediate the strong interaction called gluons. The cleanest experimental signature for the existence of the gluons came from electron-positron annihilation experiments, where a quark-antiquark pair is created and one of the quarks radiates a hard gluon. Due to confinement neither the quarks nor the gluon can be observed directly, but are measured experimentally as three collimated showers of particles named jets. Since the ground breaking experiments performed at DESY, jets have provided a tool to study the properties of quarks and gluons...
Translation : A Concept and Model for the Study of Culture
- It is no longer possible to ignore how crucial processes of cultural translation and their analysis have become, whether for cultural contact or interreligious relations and conflicts, for integration strategies in multicultural societies or for the exploration of productive interfaces between the humanities and the natural sciences. The globalisation of world society, in particular, demands increased attention to mediation processes and problems of transfer, in terms of both the circulation of global representations and 'travelling concepts' and of the interactions that make up cultural encounters. Here, translation becomes, on the one hand, a condition for global relations of exchange ('global translatability') and, on the other, a medium especially liable to reveal cultural differences, power imbalances and the scope for action. An explicit focus on translation processes— something increasingly prevalent across the humanities—may thus enable us to scrutinise more closely current and historical situations of cultural encounter as complex processes of cultural translation. Translation is opened up to a transnational cultural practice that in no way remains restricted to binary relationships between national languages, national literatures or national cultures.
Culture as Text : Reading and Interpreting Cultures
- '[C]ulture as text' initially proved to be a pivotal bridging metaphor between cultural anthropology and literary studies. Following an admittedly ambivalent career path, the concept of 'culture as text' has nevertheless continued to rise and has become an over-determined general principle, an emphatic key metaphor, even an overall "programmatic motto for the study of culture" […]. At first, this concept was still closely connected to ethnographic research and to the semiotic framework of interpretive cultural anthropology. However, since the end of the 1990s it has been utilised to encompass a much broader interdisciplinary horizon for the study of culture. 'Culture as text' advanced from being a conceptual metaphor for the condensation of cultural meanings to a rather free-floating formula frequently referred to in analyses within disciplines involved in the study of culture. Surprisingly, 'culture as text' has remained a consistent key phrase throughout the discourses concerned with the study of culture—even after the culture debate had long since turned away from the holistic understanding of culture implied by the formula.
The prognostic impact of epidermal growth factor receptor in patients with metastatic gastric cancer
- Background: The epidermal growth factor receptor (EGFR) is a potential target of anticancer therapy in gastric cancer. However, its prognostic role in metastatic gastric or gastroesophageal junction (GE) cancer has not been established yet.
Methods: EGFR status was analyzed by immunohistochemistry (IHC) in paraffin-embedded samples from 357 patients who received chemotherapy in 4 first-line trials. Automated RNA extraction from paraffin and RT-quantitative PCR were additionally used to evaluate EGFR mRNA expression in 130 patients.
Results: EGFR protein expression (any grade) and overexpression (3+) were observed in 43% and 11% of patients, respectively. EGFR positivity correlated with intestinal type histology (p = 0.05), but not with other clinicopathologic characteristics. Median follow-up was 18.2 months. Median overall survival (OS) was similar in patients with EGFR positive vs. those with EGFR negative tumors, regardless whether positivity was defined as ≥1+ (10.6 vs. 10.9 months, p = 0.463) or as 3+ (8.6 vs. 10.8 months, p = 0.377). The multivariate analysis indicated that EGFR status is not an independent prognostic factor (hazard ratio 0.85, 0.56 to 1.12, p = 0.247). There were also no significant differences in overall survival when patients were categorized according to median (p = 0.116) or quartile (p = 0.767) distribution of EGFR mRNA gene expression. Similar distributions of progression-free survival according to EGFR status were observed.
Conclusions: Unlike different cancer types where EGFR-positive disease is associated with an adverse prognostic value, EGFR positivity is not prognostic of patient outcome in metastatic gastric or GE cancer.
Genome-wide analysis of rare copy number variations reveals PARK2 as a candidate gene for attention-deficit/hyperactivity disorder
Trang T. Nguyen
Maria R. Dauvermann
Franziska A. Degenhardt
Markus M. Nöthen
Heinz Erich Wichmann
Carla Marie Thérèse Tiesler
Stephen V. Faraone
Tobias J. Renner
Benno G. Schimmelmann
- Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental disorder. Genetic loci have not yet been identified by genome-wide association studies. Rare copy number variations (CNVs), such as chromosomal deletions or duplications, have been implicated in ADHD and other neurodevelopmental disorders. To identify rare (frequency ≤1%) CNVs that increase the risk of ADHD, we performed a whole-genome CNV analysis based on 489 young ADHD patients and 1285 adult population-based controls and identified one significantly associated CNV region. In tests for a global burden of large (>500 kb) rare CNVs, we observed a nonsignificant (P=0.271) 1.126-fold enriched rate of subjects carrying at least one such CNV in the group of ADHD cases. Locus-specific tests of association were used to assess if there were more rare CNVs in cases compared with controls. Detected CNVs, which were significantly enriched in the ADHD group, were validated by quantitative (q)PCR. Findings were replicated in an independent sample of 386 young patients with ADHD and 781 young population-based healthy controls. We identified rare CNVs within the parkinson protein 2 gene (PARK2) with a significantly higher prevalence in ADHD patients than in controls (P=2.8 × 10(-4) after empirical correction for genome-wide testing). In total, the PARK2 locus (chr 6: 162 659 756-162 767 019) harboured three deletions and nine duplications in the ADHD patients and two deletions and two duplications in the controls. By qPCR analysis, we validated 11 of the 12 CNVs in ADHD patients (P=1.2 × 10(-3) after empirical correction for genome-wide testing). In the replication sample, CNVs at the PARK2 locus were found in four additional ADHD patients and one additional control (P=4.3 × 10(-2)). Our results suggest that copy number variants at the PARK2 locus contribute to the genetic susceptibility of ADHD. Mutations and CNVs in PARK2 are known to be associated with Parkinson disease.
Loss of the abundant nuclear non-coding RNA MALAT1 is compatible with life and development
- The metastasis-associated lung adenocarcinoma transcript 1, MALAT1, is a long non-coding RNA (lncRNA) that has been discovered as a marker for lung cancer metastasis. It is highly abundant, its expression is strongly regulated in many tumor entities including lung adenocarcinoma and hepatocellular carcinoma as well as physiological processes, and it is associated with many RNA binding proteins and highly conserved throughout evolution. The nuclear transcript MALAT-1 has been functionally associated with gene regulation and alternative splicing and its regulation has been shown to impact proliferation, apoptosis, migration and invasion.
Here, we have developed a human and a mouse knockout system to study the loss-of-function phenotypes of this important ncRNA. In human tumor cells, MALAT1 expression was abrogated using Zinc Finger Nucleases. Unexpectedly, the quantitative loss of MALAT1 did neither affect proliferation nor cell cycle progression nor nuclear architecture in human lung or liver cancer cells. Moreover, genetic loss of Malat1 in a knockout mouse model did not give rise to any obvious phenotype or histological abnormalities in Malat1-null compared with wild-type animals. Thus, loss of the abundant nuclear long ncRNA MALAT1 is compatible with cell viability and normal development.