Abstract Chordomas are rare bone tumors with few therapeutic options. Here we show, using whole-exome and genome sequencing within a precision oncology program, that advanced chordomas ( n = 11) may be characterized by genomic patterns indicative of defective homologous recombination (HR) DNA repair and alterations affecting HR-related genes, including, for example, deletions and pathogenic germline variants of BRCA2 , NBN , and CHEK2 . A mutational signature associated with HR deficiency was significantly enriched in 72.7% of samples and co-occurred with genomic instability. The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib, which is preferentially toxic to HR-incompetent cells, led to prolonged clinical benefit in a patient with refractory chordoma, and whole-genome analysis at progression revealed a PARP1 p.T910A mutation predicted to disrupt the autoinhibitory PARP1 helical domain. These findings uncover a therapeutic opportunity in chordoma that warrants further exploration, and provide insight into the mechanisms underlying PARP inhibitor resistance.
We report the release of PredictProtein for the Debian operating system and derivatives, such as Ubuntu, Bio-Linux, and Cloud BioLinux. The PredictProtein suite is available as a standard set of open source Debian packages. The release covers the most popular prediction methods from the Rost Lab, including methods for the prediction of secondary structure and solvent accessibility (profphd), nuclear localization signals (predictnls), and intrinsically disordered regions (norsnet). We also present two case studies that successfully utilize PredictProtein packages for high performance computing in the cloud: the first analyzes protein disorder for whole organisms, and the second analyzes the effect of all possible single sequence variants in protein coding regions of the human genome.
// Steffen Dietz 1, * , Holger Sültmann 1, * , YueJun Du 2, 3 , Eva Reisinger 4 , Anja Lisa Riediger 5 , Anna-Lena Volckmar 6 , Albrecht Stenzinger 6 , Matthias Schlesner 7 , Dirk Jäger 5 , Markus Hohenfellner 2 , Stefan Duensing 8 , Carsten Grüllich 5, * and Sascha Pahernik 2, 9, * 1 Cancer Genome Research Group, German Cancer Consortium (DKTK), Heidelberg, Germany, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany 2 Department of Urology, Heidelberg University Hospital, Heidelberg, Germany 3 Department of Urology, Nanfang Hospital of Southern Medical University, Guangzhou, China 4 Data Management Group, Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), and Heidelberg Center for Personalized Oncology (DKFZ-HIPO), Heidelberg, Germany 5 Department of Medical Oncology, National Center for Tumor Diseases (NCT), Heidelberg University Hospital, Heidelberg, Germany 6 Institute of Pathology, University Hospital Heidelberg, and German Cancer Consortium (DKTK), Heidelberg, Germany 7 Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany 8 Section of Molecular Urooncology, Department of Urology, Heidelberg University Hospital, Heidelberg, Germany 9 Department of Urology, Nuremberg General Hospital, Paracelsus Medical University, Nuremberg, Germany * These authors contributed equally to this work Correspondence to: Holger Sültmann, email: h.sueltmann@dkfz.de Keywords: clonal evolution, metastatic clear cell renal cell carcinoma, next generation sequencing, therapy resistance, tyrosine kinase inhibitors Received: March 16, 2017 Accepted: May 12, 2017 Published: May 23, 2017 ABSTRACT The availability of tyrosine kinase inhibitors (TKI) during the past ten years has led to improved response and overall survival of patients suffering from metastatic clear cell renal cell carcinoma (ccRCC). However, most of these tumors will eventually progress due to resistance evolving under therapy. The objective of this pilot study was to determine whether molecular alterations in ccRCC tissues sampled over the course of the disease might be suggestive of potential therapies. We performed whole exome sequencing of nine samples from four patients in the MORE (Molecular Renal Cancer Evolution) trial. We analyzed the mutational patterns in the tissues at baseline and compared them to those detectable in biopsy samples after progression under TKI therapy. We found limited genetic concordance between primary and secondary tumor sites with private mutations in FLT4, MTOR, ITGA5, SETD2, PBRM1 , and BRCA1 on progression. One patient who showed an increased mutational load in the metastasis responded to nivolumab treatment. Our data provide evidence for clonal evolution and diverse pathways leading to acquired TKI resistance of ccRCC. Acquired resistance to TKI in metastatic ccRCC is due to intra-tumor heterogeneity and clonal evolution of resistant subclones. Mutations occurring under progression might be informative for alternative targeted therapies.
Aims: The brain derived neurotrophic factor (BDNF) is known for almost 30 years. Several investigations described an important role of this neurotrophine not only in fetal brain growth but also in differentiation and repair of neurons in the adult brain. BDNF plasma levels are proven to be lower in depressed patients than in healthy subjects which is supposed to cause a lack of neurogenesis. In a couple of studies, treatment with antidepressants, ECT and TMS led to a significant BDNF plasma level increase. Other studies found no correlation. Method: Here we report the findings of a placebo-controlled, randomized tDCS trial in 20 patients with therapy-resistant major depression. All patients underwent an active 1 resp. 2 mA and sham tDCS over two weeks in a double-blind cross over design. BDNF was measured at baseline, after two, four and six weeks. Results: There was no correlation between severity of depressive symptoms and BDNF plasma level. Overall, clinical improvement by tDCS was modest and did not result in BDNF plasma level increase. Contrarily, tDCS led to a BDNF plasma level decrease by trend. 1 mA and 2 mA tDCS was not superior to sham tDCS in clinical results and BDNF changes. Discussion: Our study population consisted in therapy-resistant patients with probably severily decreased neuronal activity. This might have a restraining effect on BDNF-evoked neuroplasticity. In conclusion, results of BDNF trials are widespread and this question should be addr
Der Tagungsband Arbeit und Vernetzung im Informationszeitalter widmet sich der Frage, ob und wie die Geschlechterverhaltnisse in der Informationsgesellschaft in Bewegung geraten. In theoretischen wie empirischen Reflexionen zeichnen die 13 Beitrage exemplarisch die Komplexitat, Widerspruchlichkeit und Uneindeutigkeit der Auswirkungen des gesellschaftlichen Wandels auf deren Mitglieder nach und verdeutlichen die anhaltende Wirkungsmacht der Kategorie Geschlecht auch in einer vernetzten Welt.
Transcranial direct current stimulation (tDCS) of the prefrontal cortex (PFC) has been reported to exert significant antidepressant effects in patients with major depression. Several recent studies found an improvement of depressive symptoms in drug-free patients. Here we report the case of a 66-year-old female patient suffering from recurrent major depressive episodes who underwent anodal tDCS of the left dorsolateral PFC over 4 weeks as an add-on treatment to a stable antidepressant medication. Only a modest improvement of depressive symptoms was observed after tDCS, i.e. reduction of the baseline scores in the Hamilton Depression Rating Scale from 23 to 19 and in the Beck Depression Inventory from 27 to 20. However, there was an increase from 52 to 90% in the Regensburg Verbal Fluency Test. In addition, EEG was used to assess the acute effects of tDCS. Low resolution brain electromagnetic tomography (LORETA) showed a left unilateral focal effect (25–40% reduced power) in the delta, theta and alpha frequency bands. The same effect appeared in the surface analysis of the EEG. The absolute, as well as the relative power decreased significantly in the delta, theta and alpha bands after a comparison of the spectral analysis. Though tDCS over 4 weeks did not exert clinically meaningful antidepressant effects in this case of therapy-resistant depression, the findings for cognitive measures and EEG suggest that beneficial effects may occur in depressed subjects and future studies need to further explore this approach also in therapy-resistant major depression.
