The clinical standard treatment for patients with malignant pleural mesothelioma (MPM) includes a cisplatin-based chemotherapy, leading to reduction of tumor size in only a minority of patients. ...Predicting response to chemotherapy in patients with MPM by using a genetic marker would, therefore, enable patient stratification.
In this retrospective biomarker study, eligible patients had resectable MPM, measurable disease, and available primary MPM tissue. All patients underwent first-line treatment with cisplatin and pemetrexed, followed by surgery. Thorough molecular analysis was performed (whole-exome and targeted deep sequencing, and copy-number analyses), and also mechanistic
data (viability assays, Western blots, and immunoprecipitation) using mesothelioma cell lines with and without siRNA-mediated BRCA1-associated protein 1 (BAP1) knockdown were provided.
In a training cohort of patients with MPM (
= 28), mutations or deletions of
each predicted resistance to chemotherapy in patients with primary MPM. The negative predictive value of
loss in patients with MPM was confirmed by amplicon sequencing and copy-number array technology in an independent test cohort (
= 39). Preliminary mechanistic studies using siRNA-based knockdown of BAP1 in MPM cell culture models along with immunoprecipitation assays confirmed chemoresistance
, possibly through inhibition of apoptosis and transcriptional regulation of the BAP1/HCF1/E2F1 axis.
Alterations in
in MPM were a negative predictor for response to chemotherapy and could possibly be used as a companion biomarker for treatment decision.
CDKN2A deletion is a common alteration in pleural mesothelioma (PM) and frequently associated with co-deletion of MTAP. Since the standard detection method for CDKN2A deletion and FISH analysis is ...relatively expensive, we here investigated the suitability of inexpensive p16 and MTAP IHC by comparing concordance between IHC and OncoScan CNV arrays on samples from 52 PM patients. Concordance was determined using Cohen’s kappa statistics. Loss of CDKN2A was associated with co-deletion of MTAP in 71% of cases. CDKN2A-MTAP copy-number normal cases were also IHC positive in 93% of cases for p16 and 100% for MTAP, while homozygous deletion of CDKN2A-MTAP was always associated with negative IHC for both proteins. In cases with heterozygous CDKN2A-MTAP loss, IHC expression of p16 and MTAP was negative in 100% and 71%, respectively. MTAP and p16 IHC showed high sensitivity (MTAP 86.5%, p16 100%) and specificity (MTAP 100%, p16 93.3%) for the detection of any gene loss. Loss of MTAP expression occurred exclusively in conjunction with loss of p16 labeling. Both p16 and MTAP IHC showed high concordance with Oncoscan CNV arrays (kappa = 0.952, p < 0.0001, and kappa = 0.787, p < 0.0001 respectively). We recommend combined MTAP and p16 immunohistochemistry to confirm the diagnosis of PM.
Von den Werken des deutsch-amerikanischen Philosophen Eric Voegelin sind in Deutschland vor allem zwei bekannt: seine kleine, 1938 veröffentlichte Studie Die politischen Religionen, die in den ...letzten Jahren viel Aufmerksamkeit auf sich zog, sowie seine New Science of Politics, in der er neben einer philosophischen Neubegründung der politischen Wissenschaft eine Kritik der westlichen Moderne vorlegte. Weit weniger bekannt ist seine umfangreiche History of Political Ideas, an der er zwischen 1939 und 1952 rastlos gearbeitet hatte. Die Gründe dafür sind vielfältig. Der wohl wichtigste ist, dass der Text, auf dessen Veröffentlichung Voegelin verzichtete, erst posthum, Ende der 1990er Jahre im Rahmen seiner Collected Works in acht Bänden erschien. Der Text ist in doppelter Hinsicht von Interesse: zum einen, weil Voegelin in ihm die Kernthese der Politischen Religionen auf breiter Grundlage weiterentwickelt und er zugleich den Hintergrund der New Science of Politics bildet. Zum anderen, weil er eine in sich geschlossene Philosophie und Kritik der westlichen Zivilisation darstellt. Der vorliegende Essay versteht sich als ein einführender Wegweiser in dieses konzeptionell höchst komplexe und methodisch vielschichtige Werk. Among the works of the German-American philosopher Eric Voegelin it is primarily two that are known in Germany: his study The Political Religions, published in 1938, which in recent years received considérable public attention, and The New Science of Politics, in which Voegelin – besides establishing a new philosophical rationale for political science – expressed his critique on Western Modernity. Far less known is his comprehensive History of Political Ideas, on which he had worked restlessly from 1939 to 1952. There are manifold reasons for this. Probably the most important one: the text whose publication Voegelin declined during his life time, was only released posthumously, in the late 1990ies, within the framework of The Collected Works of Eric Voegelin, published in eight volumes. The History is interesting in a two-fold way: First, in it Voegelin further developed, on a broad basis, the central thesis of the Political Religions, while at the same time it provides the background of The New Science of Politics. Second, it incorporâtes a self-contained philosophy as well as a critique on Western civilization. – The essay at hand may serve as an introductory guide to both a conceptually and methodically most complex work.
Loss of the CDKN2A gene and its protein p16 is a common event in pleural mesothelioma, which is frequently investigated to confirm the diagnosis. The loss of CDKN2A is often accompanied by ...simultaneous loss of the genes located in the vicinity, including the MTAP gene and protein. Detection of CDKN2A loss is usually achieved by relatively expensive fluorescent in situ hybridization (FISH) analysis. Here, we investigated if inexpensive immunohistochemistry (IHC) for p16 and MTAP could be used as an alternative detection method. Comparing CDKN2A and MTAP gene status, analyzed by the copy-number variation array, with p16/MTAP IHC revealed high sensitivity and specificity of the IHC for detecting gene loss. Our data show that p16/MTAP IHC can be used as an alternative to p16 FISH for detection of CDKN2A/MTAP loss. We recommend combined MTAP and p16 immunohistochemistry to confirm the diagnosis of PM. CDKN2A deletion is a common alteration in pleural mesothelioma (PM) and frequently associated with co-deletion of MTAP. Since the standard detection method for CDKN2A deletion and FISH analysis is relatively expensive, we here investigated the suitability of inexpensive p16 and MTAP IHC by comparing concordance between IHC and OncoScan CNV arrays on samples from 52 PM patients. Concordance was determined using Cohen’s kappa statistics. Loss of CDKN2A was associated with co-deletion of MTAP in 71% of cases. CDKN2A-MTAP copy-number normal cases were also IHC positive in 93% of cases for p16 and 100% for MTAP, while homozygous deletion of CDKN2A-MTAP was always associated with negative IHC for both proteins. In cases with heterozygous CDKN2A-MTAP loss, IHC expression of p16 and MTAP was negative in 100% and 71%, respectively. MTAP and p16 IHC showed high sensitivity (MTAP 86.5%, p16 100%) and specificity (MTAP 100%, p16 93.3%) for the detection of any gene loss. Loss of MTAP expression occurred exclusively in conjunction with loss of p16 labeling. Both p16 and MTAP IHC showed high concordance with Oncoscan CNV arrays (kappa = 0.952, p < 0.0001, and kappa = 0.787, p < 0.0001 respectively). We recommend combined MTAP and p16 immunohistochemistry to confirm the diagnosis of PM.
Among the works of the German-American philosopher Eric Voegelin it is primarily two that are known in Germany: his study The Political Religions, published in 1938, which in recent years received ...considerable public attention, and The New Science of Politics, in which Voegelin -- besides establishing a new philosophical rationale for political science -- expressed his critique on Western Modernity. Far less known is his comprehensive History of Political Ideas, on which he had worked restlessly from 1939 to 1952. There are manifold reasons for this. Probably the most important one: the text whose publication Voegelin declined during his life time, was only released posthumously, in the late 1990ies, within the framework of The Collected Works of Eric Voegelin, published in eight volumes. The History is interesting in a two-fold way: First, in it Voegelin further developed, on a broad basis, the central thesis of the Political Religions, while at the same time it provides the background of The New Science of Politics. Second, it incorporates a self-contained philosophy as well as a critique on Western civilization, -- The essay at hand may serve as an introductory guide to both a conceptually and methodically most complex work. Adapted from the source document.
Murine embryonic stem (mES) cells remain undifferentiated in the presence of leukemia inhibitory factor (LIF), and activation of signal transducer and activator of transcription 3 (STAT3) via LIF ...receptor (LIFR) signaling appears sufficient for maintenance of mES cell pluripotency. Anecdotal and contradictory accounts exist for the action of LIF in the culture of human embryonic stem cells, and the nature of LIF signaling and whether the LIF-STAT3 pathway is conserved in human embryonic stem cells (hESCs) has not been systematically explored. In this study, we show that the LIFRbeta and the signaling subunit gp130 are expressed in hESCs and that human LIF can induce STAT3 phosphorylation and nuclear translocation in hESCs. Nevertheless, despite the functional activation of the LIF-STAT3 signaling pathway, human LIF is unable to maintain the pluripotent state of hESCs. Feeder-free culture conditions that maintain hESCs in an undifferentiated state do not show activation of STAT3, suggesting that distinct signaling mechanisms govern the self-renewal of hESCs.
The main obstacle to cure HIV-1 is the latent reservoir. Antiretroviral therapy effectively controls viral replication, however, it does not eradicate the latent reservoir. Latent CD4
+
T cells are ...extremely rare in HIV-1 infected patients, making primary CD4
+
T cell models of HIV-1 latency key to understanding latency and thus finding a cure. In recent years several primary CD4
+
T cell models of HIV-1 latency were developed to study the underlying mechanism of establishing, maintaining and reversing HIV-1 latency. In the search of biomarkers, primary CD4
+
T cell models of HIV-1 latency were used for bulk and single-cell transcriptomics. A wealth of information was generated from transcriptome analyses of different primary CD4
+
T cell models of HIV-1 latency using latently- and reactivated HIV-1 infected primary CD4
+
T cells. Here, we performed a pooled data-analysis comparing the transcriptome profiles of latently- and reactivated HIV-1 infected cells of 5
in vitro
primary CD4
+
T cell models of HIV-1 latency and 2
ex vivo
studies of reactivated HIV-1 infected primary CD4
+
T cells from HIV-1 infected individuals. Identifying genes that are differentially expressed between latently- and reactivated HIV-1 infected primary CD4
+
T cells could be a more successful strategy to better understand and characterize HIV-1 latency and reactivation. We observed that natural ligands and coreceptors were predominantly downregulated in latently HIV-1 infected primary CD4
+
T cells, whereas genes associated with apoptosis, cell cycle and HLA class II were upregulated in reactivated HIV-1 infected primary CD4
+
T cells. In addition, we observed 5 differentially expressed genes that co-occurred in latently- and reactivated HIV-1 infected primary CD4
+
T cells, one of which, MSRB2, was found to be differentially expressed between latently- and reactivated HIV-1 infected cells. Investigation of primary CD4
+
T cell models of HIV-1 latency that mimic the
in vivo
state remains essential for the study of HIV-1 latency and thus providing the opportunity to compare the transcriptome profile of latently- and reactivated HIV-1 infected cells to gain insights into differentially expressed genes, which might contribute to HIV-1 latency.
Der Rückblick auf das europäisch-chinesische Verhältnis während der vergangenen 50 Jahre zeigt, dass die Beziehungen durch Prozesse zunehmender Annäherung gekennzeichnet sind. Während auf Seiten der ...Europäer der Ausbau der Wirtschaftsbeziehungen im Vordergrund stand - und noch steht -, umfasst das Zielspektrum der chinesischen Seite auch global-strategische Fragen. Nachdem dabei bis Mitte der achtziger Jahre Bildung und Erhaltung einer anti-sowjetischen Einheitsfront im Mittelpunkt stand, zeichnet sich in den neunziger Jahren das Bemühen Pekings ab, das Gewicht Europas bei der Schaffung eines multipolaren internationalen Systems zu nutzen. Weitere Zielsetzungen sind die Nutzung des europäischen Wirtschaftspotentials für die chinesische Reformpolitik, die Beendigung der offenen europäischen Kritik an der Menschenrechtssituation in China sowie die weitere Isolierung Taiwans. During the past 50 years the relations between the Peoples Republic of China and the Western European states were characterized by a continuing process of rapprochement. While Europe put its main emphasis on economic issues, China's objectives included global-strategic issues as well. After up to the mid-eighties the policy of an anti-Soviet united front had been of prime importance, in the nineties Beijing has tried to utilize its efforts in creating a multipolar international system. Further objectives are the utilization of the European economic potential for the Chinese reform policy, the end of open European criticism concerning the human rights situation in China, as well as isolating Taiwan.
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