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The deregulation of Polo-like kinase 1 is inversely linked to the prognosis of patients with diverse human tumors. Targeting Polo-like kinase 1 has been widely considered as one of the most promising strategies for molecular anticancer therapy. While the preclinical results are encouraging, the clinical outcomes are rather less inspiring by showing limited anticancer activity. It is thus of importance to identify molecules and mechanisms responsible for the sensitivity of Polo-like kinase 1 inhibition. We have recently shown that p21Cip1/CDKN1A is involved in the regulation of mitosis and its loss prolongs the mitotic duration accompanied by defects in chromosome segregation and cytokinesis in various tumor cells. In the present study, we demonstrate that p21 affects the efficacy of Polo-like kinase 1 inhibitors, especially Poloxin, a specific inhibitor of the unique Polo-box domain. Intriguingly, upon treatment with Polo-like kinase 1 inhibitors, p21 is increased in the cytoplasm, associated with anti-apoptosis, DNA repair and cell survival. By contrast, deficiency of p21 renders tumor cells more susceptible to Polo-like kinase 1 inhibition by showing a pronounced mitotic arrest, DNA damage and apoptosis. Furthermore, long-term treatment with Plk1 inhibitors induced fiercely the senescent state of tumor cells with functional p21. We suggest that the p21 status may be a useful biomarker for predicting the efficacy of Plk1 inhibition.
The transcription factor Tal1 is a critical activator or repressor of gene expression in hematopoiesis and leukaemia. The mechanism by which Tal1 differentially influences transcription of distinct genes is not fully understood. Here we show that Tal1 interacts with the peptidylarginine deiminase IV (PADI4). We demonstrate that PADI4 can act as an epigenetic coactivator through influencing H3R2me2a. At the Tal1/PADI4 target gene IL6ST the repressive H3R2me2a mark triggered by PRMT6 is counteracted by PADI4, which augments the active H3K4me3 mark and thus increases IL6ST expression. In contrast, at the CTCF promoter PADI4 acts as a repressor. We propose that the influence of PADI4 on IL6ST transcription plays a role in the control of IL6ST expression during lineage differentiation of hematopoietic stem/progenitor cells. These results open the possibility to pharmacologically influence Tal1 in leukaemia.
Predominant polarity in bipolar disorder and validation of the polarity index in a German sample
(2014)
Background: A large number of patients with bipolar disorder (BD) can be characterized by predominant polarity (PP), which has important implications for relapse prevention. Recently, Popovic et al. (EUR NEUROPSYCHOPHARM 22(5): 339¿346, 2012) proposed the Polarity Index (PI) as a helpful tool in the maintenance treatment of BD. As a numeric expression, it reflects the efficacy of drugs used in treatment of BD. In the present retrospective study, we aimed to validate this Index in a large and well characterized German bipolar sample.
Methods: We investigated 336 bipolar patients (BP) according to their PP and calculated the PI for each patient in order to prove if maintenance treatment differs according to their PP. Furthermore, we analysed whether PP is associated with demographic and clinical characteristics of BP.
Results: In our sample, 63.9% of patients fulfilled criteria of PP: 169 patients were classified as depressive predominant polarity (DPP), 46 patients as manic predominant polarity (MPP). The two groups differed significantly in their drug regime: Patients with DPP were more often medicated with lamotrigine and antidepressants, patients with MPP were more often treated with lithium, valproate, carbamazepine and first generation antipsychotics. However, patients with DPP and MPP did not differ significantly with respect to the PI, although they received evidence-based and guideline-driven treatment.
Conclusion: The reason for this negative finding might well be that for several drugs, which were used frequently, no PI value is available. Nevertheless we suggest PP as an important concept in the planning of BD maintenance treatment.
Background: In this study, we examined patients who had non-progressive disease for at least 2 years after diagnosis of inoperable locoregional recurrent or metastatic breast cancer under continuous trastuzumab treatment. Our primary goal was to assess the long-term outcome of patients with durable response to trastuzumab.
Methods: 268 patients with HER2-positive inoperable locally recurrent or metastatic breast cancer and non-progressive disease for at least 2 years under trastuzumab treatment were documented retrospectively or prospectively in the HER-OS registry, an online documentation tool, between December 2006 and September 2010 by 71 German oncology centers. The study end point was time to tumor progression.
Results: Overall, 47.1% of patients (95% confidence interval (CI): 39.9–54.1%) remained in remission for more than 5 years, while the median time to progression was 4.5 years (95% CI: 4.0–6.6 years). Lower age (<50 years) and good performance status (ECOG 0) at time of trastuzumab treatment initiation as well as complete remission after initial trastuzumab treatment were associated with longer time to progression. Interruption of trastuzumab therapy correlated with shorter time to progression.
Conclusions: HER2-positive patients, who initially respond to palliative treatment with trastuzumab, can achieve a long-term tumor remission of several years.
Zur Flora von Deutschland gehören sieben Arten der Wintergrüngewächse, die alle auch in Sachsen-Anhalt heimisch sind: Dolden-Winterlieb (Chimaphila umbellata [L.] BARTON), Einblütiges Wintergrün (Moneses uniflora [L.] A. GRAY), Birngrün (Orthilia secunda [L.] HOUSE), Grünblütiges Wintergrün (Pyrola chlorantha SW.), Mittleres Wintergrün (Pyrola media SW.), Kleines Wintergrün (Pyrola minor L.) und Rundblättriges Wintergrün (Pyrola rotundifolia L.). Im Mittelpunkt dieses Beitrages steht nur die aktuelle Verbreitung im Bundesland mit Bezug auf MTB-Q4, und zwar bezogen auf zwei Perioden von jeweils 10 Jahren: Nachweise im MTB-Q4 von 2005 bis 2014, sowie Nachweise im MTB-Q4 von 1995 bis 2004.
Die Mauerkronen der Nicolai-Kirche in Zerbst wurden im Jahr 2001 mit unterschiedlichen Methoden begrünt. Das Ziel dieser Maßnahmen war die Pufferung extremer Temperaturunterschiede, die häufig zu starken Schäden am Mauerwerk führen. In Vorbereitung von anstehenden Sanierungsmaßnahmen wurde der Artenbestand auf repräsentativen Abschnitten der Mauern erfasst. Auf diese Weise konnte ermittelt werden, welche Arten mit den extremen Standortbedingungen, wie Hitze, Trockenheit und große Temperaturunterschiede gut zurechtkommen und daher bei der Sanierung an Fehlstellen erfolgversprechend angesiedelt werden können.
Das Vorkommen von Bunias orientalis (Orientalische Zackenschote) konzentriert sich auf den Südwesten Sachsen-Anhalts. Bisher ist die Art vorrangig aus dem Straßenbegleitgrün bekannt, doch zunehmend kann das Einwandern in Halbtrockenrasen und Frischwiesen beobachtet werden. Ein Beispiel dafür ist die 2011 eingerichtete und ca. 24 ha große Ganzjahresstandweide bei Hainrode. 2013 konnten hier 58 Fundpunkte mit 644 Sprossen dokumentiert werden. Die Art wird von den weidenden Salers angenommen und verbissen. Das Abfressen führt zu geringeren Wuchshöhen und vermutlich ist die Reproduktion über Samen auch bei Neuaustrieb deutlich herabgesetzt. Es wird die Möglichkeit, mittels Beweidung der Südharzer Frischwiesen die weitere Ausbreitung von Bunias orientalis zu verhindern bzw. die Art über eine Beweidung zurückzudrängen, diskutiert.