Combination of the Deacetylase Inhibitor Panobinostat and the Multi-Kinase Inhibitor Sorafenib for the Treatment of Metastatic Hepatocellular Carcinoma - Review of the Underlying Molecular Mechanisms and First Case Report

Advanced hepatocellular carcinoma still represents an unmet medical need that has only a limited overall survival despite the introduction of the multi-kinase inhibitor sorafenib. Recently, inhibitors of histone and other protein deacetylases have been established as novel therapeutic approaches to cancer diseases. We here review the molecular rationale for combining these two novel targeted therapies and report a patient with metastasized hepatocellular carcinoma who showed a partial remission of primary and metastatic lesions for five months after a combination therapy with sorafenib and the orally available pan-deacetylase inhibitor panobinostat

Duets recorded in the wild reveal that interindividually coordinated motor control enables cooperative behavior

Many organisms coordinate rhythmic motor actions with those of a partner to generate cooperative social behavior such as duet singing. The neural mechanisms that enable rhythmic interindividual coordination of motor actions are unknown. Here we investigate the neural basis of vocal duetting behavior by using an approach that enables simultaneous recordings of individual vocalizations and multiunit vocal premotor activity in songbird pairs ranging freely in their natural habitat. We find that in the duet-initiating bird, the onset of the partner's contribution to the duet triggers a change in rhythm in the periodic neural discharges that are exclusively locked to the initiating bird's own vocalizations. The resulting interindividually synchronized neural activity pattern elicits vocalizations that perfectly alternate between partners in the ongoing song. We suggest that rhythmic cooperative behavior requires exact interindividual coordination of premotor neural activity, which might be achieved by integration of sensory information originating from the interacting partner

Inhibition of DNA methyltransferase activity and expression by treatment with the pan-deacetylase inhibitor panobinostat in hepatocellular carcinoma cell lines

Background Hepatocellular carcinoma (HCC) still represents an unmet medical need. Epigenetic inactivation of tumor suppressor genes like RASSF1A or APC by overexpression of DNA methyltransferases (DNMTs) has been shown to be common in HCC and to be linked to the overall prognosis of patients. Inhibitors of protein and histone deacetylases (DACi) have been demonstrated to possess strong anti-tumor effects in HCC models. Methods We therefore investigated whether DACi also has any influence on the expression and activity of DNMTs and methylated target genes in HepG2 and Hep3B cell culture systems and in a xenograft model by immunohistochemistry, westernblotting, RT-qPCR and methylation-specific PCR. Results Our findings demonstrate a rapid inhibition of DNMT activity 6 h after treatment with 0.1 μM of the pan-DACi panobinostat. A downregulation of DNMT mRNAs and protein were also observed at later points in time. This loss of DNMT activity and expression was paralleled by a diminished methylation of the target genes RASSF1A and APC and a concomitant re-expression of APC mRNA and protein. Analysis of HepG2 xenograft specimens confirmed these results in vivo. Conclusion We suggest a dual mode of action of DACi on DNA methylation status: a rapid inhibition of enzyme activity due to interference with posttranslational acetylation and a delayed effect on transcriptional control of DNMT genes by HDAC or miRNA mechanisms

Standard Operating Procedures (SOPs) for Palliative Care in German Comprehensive Cancer Centers - an evaluation of the implementation status

Background The working group for palliative medicine within the Comprehensive Cancer Center (CCC) network funded by the German Cancer Aid in Germany has developed and published 14 Standard Operating Procedures (SOPs) for palliative care in CCCs. This study analyzed to what extent these SOPs have been implemented in the clinical routine in the CCC network one year after their publication. Methods An online-based survey on the implementation status, limitations in daily practice and further themes was conducted between April and July 2018. In total, 125 health professionals in specialized palliative care from all 16 CCC locations were invited to participate. The data were analyzed descriptively using SPSS. Results The response rate was 52.8%. More than half of the respondents (57.6%) knew about the free availability of SOPs on the CCC network website. The extent to which each SOP was being used actively in practice by the survey respondents ranged from a low of 22.7% (for the “Fatigue” SOP) to a highest of 48.5% (for the “Palliative Sedation” and “Respiratory Distress” SOPs). The respondents became aware of the SOP through recommendations from colleagues, team meetings or from the head of the department. The SOPs “Respiratory distress of an adult palliative patient” and “Palliative sedation” were perceived as the most practically oriented and understandable. Barriers to use SOPs were mainly limited time resources and lack of knowledge of existence and availability. Conclusions In practice, better knowledge about the SOPs and at the same time increased use can be achieved through systematic training or discussion of SOPs in regular team meetings. There is a need to take measures to optimize the implementation in clinical practice

VDS36-Interaktionsanalyse zur Beziehungsdiagnostik in kognitiv-behavioralen Therapien

Beziehungsdiagnostik ist heute auch in kognitiv-behavioralen Therapien einer der wichtigsten Aspekte der Verhaltensdiagnostik und Fallkonzeption. Eine systematische Analyse funktionaler und dysfunktionaler Interaktionsmuster erfasst sowohl die Wahrnehmungs- als auch die Reaktionskomponente. Die VDS36-Interaktionsanalyse greift auf das Instrumentarium von Lorna Smith-Benjamins 3-Ebenen- Circumplexmodell zurück. Dieses wird in vereinfachter Form dem Patienten und evtl. einer Bezugsperson (z. B. Partner oder Therapeut) zum Ausfüllen gegeben. Die Auswertung lässt sich rasch bewerkstelligen und ergibt anschauliche Grafiken. Eine Evaluierung des VDS36-Fragebogens mit 36 Paaren (nichtklinische Stichprobe) erfolgte mit den Partnerschaftsfragebögen von Hahlweg (1996) und zeigte gute Übereinstimmung zwischen Problembereichen, Streitverhalten sowie Hostilitätspol einerseits und zwischen Zärtlichkeit/Erotik, Gemeinschaft/Kommunikation und Affiliationspol des Circumplexmodells andererseits. Die Erfassung der Entwicklungsstufen nach Piaget und Kegan zeigten, dass eine hoch signifikante Korrelation zwischen Zwischenmenschlichkeit und Affiliation auf der einen Seite und zwischen Souveränität und Hostilität auf der anderen Seite besteht. Dagegen spielt die Dominanzdimension keine signifikante Rolle

Zebra Finch Mates Use Their Forebrain Song System in Unlearned Call Communication

<div><p>Unlearned calls are produced by all birds whereas learned songs are only found in three avian taxa, most notably in songbirds. The neural basis for song learning and production is formed by interconnected song nuclei: the song control system. In addition to song, zebra finches produce large numbers of soft, unlearned calls, among which “stack” calls are uttered frequently. To determine unequivocally the calls produced by each member of a group, we mounted miniature wireless microphones on each zebra finch. We find that group living paired males and females communicate using bilateral stack calling. To investigate the role of the song control system in call-based male female communication, we recorded the electrical activity in a premotor nucleus of the song control system in freely behaving male birds. The unique combination of acoustic monitoring together with wireless brain recording of individual zebra finches in groups shows that the neuronal activity of the song system correlates with the production of unlearned stack calls. The results suggest that the song system evolved from a brain circuit controlling simple unlearned calls to a system capable of producing acoustically rich, learned vocalizations.</p></div

Association between neuronal activation, stack calls and song in 26 units in 25 pairs.

<p>Out of 17 units where both stacks and song were present in sufficient quantity to permit statistical analysis, 16 had firing patterns that were associated both with stacks and song.</p><p>Association between neuronal activation, stack calls and song in 26 units in 25 pairs.</p

The detailed relationships between stack calls produced by pairs of zebra finches.

<p><b>A.</b> The temporal relationship is shown as a peristimulus-time-histogram (PSTH; upper graph), where the onset times of the male calls are aligned to the onset times of the female calls. The horizontal lines in the PSTH are the 1% confidence intervals. In the raster diagram (lower panel) the female calls are shown as red dots. Each male call is represented by a black dot. The probability of male stack calls occurring within half a second before or after the female stack is clearly and significantly increased. Data from one pair kept in a soundbox: 8472 male stacks and 11047 female stacks were recorded in a 35 h period (5 days with 7 h of recording each, starting at 8∶00 AM). Binwidth is 100 msec. <b>B.</b> Relative contributions of calls that were answered, were an answer, or were not connected to any stack call of the partner. Data from 5 established pairs.</p

Charting calling relationships in a group.

<p>Four pairs of zebra finches. Based on the PSTH, metrics were calculated to describe the strength of the correlation between stack calls. The calls were recorded with carry-on microphones. Indicated in the upper matrix (<b>A</b>) are the PSTH’s from which the metrics were calculated. The animals to whose calls the PSTH’s were aligned are indicated along the left vertical side of the matrix. The animals whose calls were counted in the histograms are indicated along the bottom of the matrix. The lower matrix (<b>B</b>) shows the strength of the relationship regardless of symmetry. The matrix shows different possible calling relationships. For instance, pair 4 and pair 2 do not call with any other animal in the aviary. In contrast, the male of pair 1 is answered not only by the female of pair 1, but also by the female of pair 3. The partners of pair 3 are the only pair that did not interact at all in our experiments with groups. The associations of the callers with themselves are grayed out because they represent autocorrelations, whereas all the others are cross-correlations. Two sonograms of stack calls are shown in panel B. Duration in msec is shown underneath the sonograms.</p

Activity of RA neurons associated with calling and singing.

<p>All data from one representative example where the same RA unit fired during song as well as before stack call production. The recording was 4 h. <b>A.</b> Properties of the recorded unit and the stack calling exchange of the recorded male with his partner. Left: Interspike interval (ISI) histogram of the unit that was isolated after sorting. The histogram describes a neuron that has a modal ISI of 30.4 msec, which is typical for RA neurons recorded in free moving finches. Center: PSTH of male and female stacks aligned on the 137 male calls. Right: 196642 superimposed waveforms of the unit. <b>B.</b> RA activity associated with different stack call categories. RA unit firings aligned to the onset of the stack call. The call is amplified x10 as compared with the song shown in C. Stack calls categorized as “answered” (green, N = 44), “answer” (red, N = 28), or “no connection” (dark grey, N = 65) are associated with elevated RA firing before the call is produced. The RA activity patterns are very similar and seem independent of the stack call category. The call has an average FM value of 24.3 which is well within the range for stacks. The stack does not resemble any song syllable <b>C.</b> Binned activity of an RA neuron, aligned to 33 songs produced by this animal. The pattern is aligned to the first of the three repeated syllables (arrow). Binwidth: 5 msec. During song production, the firing rate of the unit corresponds with specific syllables.</p