NEW PUBLICATION

08.11.2017

Our fellow Anne Conibear published as corresponding author in the Journal of Peptide Science: “A comparative study of synthetic and semisynthetic approaches for ligating the epidermal growth factor to a bivalent scaffold”. Congratulations Anne!

A prominent target of monoclonal antibodies as targeted therapies for cancer is the epidermal growth factor receptor, which is overexpressed on the surface of various cancer cell types. Its natural binder, the epidermal growth factor (EGF), is a 53 amino acid polypeptide. Anticancer synthetic targeted immune system engagers (ISErs) comprising two ‘binder’ peptides, which are attached to a scaffold conveying immune stimulating ‘effector’ properties, via monodisperse polyethylene glycol chains. So far, preparation of ISErs has been limited to the use of small peptides (8–20 amino acids) as binding functionalities, and they have been entirely synthesized by solid phase peptide synthesis. Here, we describe a synthetic and a semisynthetic approach for the preparation of an ISEr bearing two murine EGF molecules as binding entities (ISEr-EGF2). EGF was either synthesized in segments by solid phase peptide synthesis or expressed recombinantly and ligated to the scaffold by native chemical ligation. We report the successful generation of synthetic and semisynthetic ISEr-EGF2 as well as several challenges encountered during the synthesis and ligations. We demonstrate the application of native chemical ligation for the design of larger ISEr constructs, facilitating new objectives for the coupling of small binder peptides and larger proteins to multivalent ISEr scaffolds.

TALKS AT VIENNA INTERNATIONAL SCHOOL

30.10.2017

Last Wednesday the INDICAR-Fellow Laura Cimatti visited Vienna International School. She presented interactive and engaging talks to grade 10 and 11 students. Laura talked about her research and everyday life of scientist, and answered students’ questions. Thanks Vienna International School for having us, it was a great experience and we hope to see you again soon!

INDICAR, HEADER OF CORDIS

09.10.2017

Our fellows’ picture is the Twitter header of @CORDIS_EU, the Community Research and Development Information Service of the European Commission. Thanks!!!

NEW PUBLICATION

05.10.2017

The INDICAR-Fellow Antje Koller published in the Journal of Pain and Symptom Management: Developing a short form of the German Barriers Questionnaire-II: A validation study in four steps. Congratulations Antje!

CONTEXT:

Patient-related barriers to cancer pain management are most commonly assessed with the Barriers Questionnaire-II (BQII; 27 items).

OBJECTIVES:

The aim of this study was to develop a valid short form of the BQII-German (BQII-G) to increase usability in clinical routines and reduce patient burden.

METHODS:

The validation study comprised a stepwise approach. In the first step, the linguistic validated version of the BQII-G was psychometrically tested for internal consistency and factor structure (N=207). The second step included an independent peer review in terms of expert ratings (4 nurses and 2 patients) of each of the BQII-G items regarding (rather) include or (rather) not include, according to the content validity index. The third step comprised a consensus process to integrate the expert ratings into a short form of the BQII-G (BQII-G12). The fourth step included a preliminary psychometric exploration of the short-version BQII-G12.

RESULTS:

Cronbach's α was .92 for the BQII-G. Steps 1 to 3 resulted in the BQII-G12 (12 items). The correlation showed that the BQII-G12 explains 84.3% (r=.92) of the variance of the BQII-G. Crohnbach's alpha of the BQII-G12 was .833.

CONCLUSIONS:

The BQII-G12 showed excellent psychometric properties in the preliminary testing, providing a new option for practice and Research.

INDICAR-Fellows attended a writing skills workshop

03.10.2017

INDICAR-Fellows attended yesterday the workshop „How to get your paper published”. The trainer, Helen Pickersgill (Life Science Editors), provided them with insights on how to write more competitive papers and get published in the top-Level Journal. During the morning session, INDICAR-Fellows learnt how to highlight the strengths and minimize the weaknesses of a paper, and how to engage the reader. The afternoon session was focused on the publication process and what the journals and editors are looking for.

INDICAR-Workshop 2017

20.09.2017

The INDICAR-Workshop 2017 took place in Kalamata (Greece), from Monday 11th to Thursday 14th Sep 2017. The INDICAR Workshop is the opportunity for post-doctoral researchers enrolled in the INDICAR Program to discuss common themes and exchange cross-disciplinary results with a particular focus on the techniques used to reach their goals. The event featured talks from invited guest speakers, post-doctoral researchers and PhD students. Besides, the event included in this edition talks from experts on science communication, technology transfer and industry. The workshop promoted broad discussion and interaction among participants. As a result, participants came up with new ideas and potential collaborations and start-ups in the field of cancer research.

ANNE CONIBEAR PRESENTED HER RESEARCH AT THE 7TH CHEMICAL PROTEIN SYNTHESIS MEETING

19.09.2017

The INDICAR-Fellow Anne Conibear attended the 7th Chemical Protein Synthesis Meeting  that took place on Sept 4-7 in Haifa, Israel.  There, she presented her poster 'Synthetic Targeted Innate Immune Stimulators to Explore Avidity Effects', Anne Conibear, Andre Pötgens and Christian Becker. Well done Anne! 

NICOLA SILVA PRESENTED HIS RESEARCH AT THE EMBO CONFERENCE ON MEIOSIS

29.08.2017

The INDICAR-Fellow Nicola Silva presented yesterday his poster: “Interplay between BRCA1 and catabolism of ADP-ribose ensures crossover homeostasis and maintenance of genome integrity” at the EMBO Conference on Meiosis in Hvar, Croatia. Well done!

NEW PUBLICATION

21.08.2017

The INDICAR-Fellow Anne Conibear published in the journal Bioconjugate Chemistry: “Multifunctional αvβ6 integrin-specific peptide-Pt(IV) conjugates for cancer cell targeting”. Congratulations Anne!

Increasing the specificity of cancer therapy, and thereby decreasing damage to normal cells, requires targeting to cancer-cell specific features. The αvβ6 integrin is a receptor involved in cell adhesion and is frequently up-regulated in cancer cells compared to normal cells. We have selected a peptide ligand reported to bind specifically to the β6 integrin and have synthesized a suite of multispecific molecules to explore the potential for targeting of cancer cells. A combination of solid-phase peptide synthesis and chemoselective ligations was used to synthesize multifunctional molecules composed of integrin-targeting peptides, cytotoxic platinum(IV) prodrugs, and fluorescent or affinity probes joined with flexible linkers. The modular synthesis approach facilitates the construction of peptide–drug conjugates with various valencies and properties in a convergent manner. The binding and specificity of the multifunctional peptide conjugates were investigated using a cell line transfected with the β6 integrin and fluorescence microscopy. This versatile and highly controlled approach to synthesizing labeled peptide–drug conjugates has the potential to target potent cytotoxic drugs specifically to cancer cells, reducing the doses required for effective treatment.

 

TWO INDICAR-FELLOWS GAVE TALKS AT THE METALLOMICS CONFERENCE IN VIENNA

17.08.2017

Yesterday, two of our fellows gave talks at the Metallomics conference in Vienna. Kostas presented his research: “Restoring cellular sensitivity to platinum‐based drugs by targeted inhibition of STAT3” and Alessio: “Ruthenium arene complexes for G‐quadruplex DNA recognition”. Great job!!

LUCA TUBIANA PRESENTED HIS RESEARCH AT THE WORKSHOP ON PHYSICAL VIROLOGY IN TRIESTE

19.07.2017

Yesterday, our fellow Luca Tubiana presented his talk “Influence of Mutations on the Compactness of Viral ssRNA Genomes. A Detailed Computational Study of MS2 and BMV RNA2” at the Workshop on Physical Virology, organized by International Centre For Theoretical Physics of Unesco IAEA in Trieste (Italy).

You can watch Luca’s talk here.

NEW PUBLICATION

18.07.2017

The INDICAR-Fellow Mohamed Elgendy has co-authored the paper “PP2A Controls Genome Integrity by Integrating Nutrient-Sensing and Metabolic Pathways with the DNA Damage Response” published in the journal Molecular Cell. Congratulations!

Mec1ATR mediates the DNA damage response (DDR), integrating chromosomal signals and mechanical stimuli. We show that the PP2A phosphatases, ceramide-activated enzymes, couple cell metabolism with the DDR. Using genomic screens, metabolic analysis, and genetic and pharmacological studies, we found that PP2A attenuates the DDR and that three metabolic circuits influence the DDR by modulating PP2A activity. Irc21, a putative cytochrome b5 reductase that promotes the condensation reaction generating dihydroceramides (DHCs), and Ppm1, a PP2A methyltransferase, counteract the DDR by activating PP2A; conversely, the nutrient-sensing TORC1-Tap42 axis sustains DDR activation by inhibiting PP2A. Loss-of-function mutations in IRC21, PPM1, and PP2A and hyperactive tap42 alleles rescue mec1 mutants. Ceramides synergize with rapamycin, a TORC1 inhibitor, in counteracting the DDR. Hence, PP2A integrates nutrient-sensing and metabolic pathways to attenuate the Mec1ATR response. Our observations imply that metabolic changes affect genome integrity and may help with exploiting therapeutic options and repositioning known drugs.

TALKS AT SACRE COEUR HIGH SCHOOL

21.06.2017

On Monday 19th of June two INDICAR-Fellows, Cornelia Rumpf-Kienzl and Luca Tubiana, visited Sacre Coeur High School. They presented the 6A and 5E students their research in cancer and talked about everyday life of scientist as well. These talks developed the students’ interest in research careers. Thanks Sacre Coeur for having us, it was a great experience!

NEW PUBLICATION

19.06.2017

The INDICAR fellow Takahiko Akematsu just published the paper "Post-meiotic DNA double-strand breaks occur in Tetrahymena, and require Topoisomerase II and Spo11" in eLife. Congratulations!

https://elifesciences.org/articles/26176

Based on observations of markers for DNA lesions, such as phosphorylated histone H2AX (γH2AX) and open DNA ends, it has been suggested that post-meiotic DNA double-strand breaks (PM-DSBs) enable chromatin remodeling during animal spermiogenesis. However, the existence of PM-DSBs is unconfirmed, and the mechanism responsible for their formation is unclear. Here, we report the first direct observation of programmed PM-DSBs via the electrophoretic separation of DSB-generated DNA fragments in the ciliate Tetrahymena thermophila. These PM-DSBs are accompanied by switching from a heterochromatic to euchromatic chromatin structure in the haploid pronucleus. Both a topoisomerase II paralog with exclusive pronuclear expression and Spo11 are prerequisites for PM-DSB induction. Reduced PM-DSB induction blocks euchromatin formation, characterized by histone H3K56 acetylation, leading to a failure in gametic nuclei production. We propose that PM-DSBs are responsible for histone replacement during the reprogramming of generative to undifferentiated progeny nuclei.

 

 

NEW PUBLICATION

12.06.2017

The INDICAR-Fellow Nicola Silva contributed to Dr. Verena Jantsch work published in Genetics:
Nuclear Envelope Retention of LINC Complexes Is Promoted by SUN-1 Oligomerization in the Caenorhabditis elegans Germ Line”.

Abstract: SUN (Sad1 and UNC-84) and KASH (Klarsicht, ANC-1, and Syne homology) proteins are constituents of the inner and outer nuclear membranes. They interact in the perinuclear space via C-terminal SUN-KASH domains to form the linker of nucleoskeleton and cytoskeleton (LINC) complex thereby bridging the nuclear envelope. LINC complexes mediate numerous biological processes by connecting chromatin with the cytoplasmic force-generating machinery. Here we show that the coiled-coil domains of SUN-1 are required for oligomerization and retention of the protein in the nuclear envelope, especially at later stages of female gametogenesis. Consistently, deletion of the coiled-coil domain makes SUN-1 sensitive to unilateral force exposure across the nuclear membrane. Premature loss of SUN-1 from the nuclear envelope leads to embryonic death due to loss of centrosome–nuclear envelope attachment. However, in contrast to previous notions we can show that the coiled-coil domain is dispensable for functional LINC complex formation, exemplified by successful chromosome sorting and synapsis in meiotic prophase I in its absence.

NEW PUBLICATION

06.06.2017

Our fellow Antje Koller published the paper “Testing the Implementation of a Pain Self-Management Support Intervention for Oncology Patients in Clinical Practice: A randomized Controlled Pilot Study”, in the journal Cancer Nursing. Congratulations Antje!

Abstract:

Background: In oncology, pain control is a persistent problem. Significant barriers to cancer pain management are patient related. Pain self-management support interventions have shown to reduce pain intensity and patient-related barriers. Comparative effectiveness research is a suitable approach to test whether effects are sustained in clinical practice.

Objective: In this pilot randomized controlled trial, the implementation of the ANtiPain intervention into clinical practice was tested to assess the effects on pain intensity, function-related outcomes, self-efficacy, and patient-related barriers to pain management to prepare a larger effectiveness trial.

Methods: Within 14 months, 39 adult oncology patients with pain scores of 3 or higher on a 10-point numeric rating scale were recruited in an academic comprehensive cancer center in Southern Germany. Patients in the control group (n=19) received standard care. Patients in the intervention group (n=20) received ANtiPain, a cancer pain self-management support intervention based on 3 key strategies: provision of information, skill building, and nurse coaching. An intervention session was performed in-hospital. After discharge, follow-up was provided via telephone calls. Data were collected at baseline and 1 and 6 weeks after discharge. Effect sizes were calculated for all outcomes.

Results: Large effects were found for activity hindrance (Cohen d=0.90), barriers (d=0.91), and self-efficacy (d=0.90). Small to moderate effects were found for average and worst pain (Cohen d=0.17-0.45).

Conclusions: Key findings of this study involved function-related outcomes and self-efficacy.

Implications for Practice: Because these outcomes are particularly meaningful for patients, the integration of ANtiPain to routine clinical practice may be substantial. A larger study will be based on these findings.

MC Fellowship

Our fellow Alessio Terenzi was granted a Marie Curie fellowship under the H2020-MSCA-IF-2016 call. After he has finished his INDICAR fellowship, he is going to join Prof. Luca Salassa (Inorganic Photochemistry Lab) at the Donostia International Physics Center / University of The Basque Country (San Sebastian, Spain). Congratulations!

NEW PUBLICATION

Alessio Terenzi published in the Journal Dalton Transactions: "Self-assembled Pt2L2 boxes strongly bind G-quadruplex DNA and influence gene expression in cancer cells" pubs.rsc.org/en/Content/ArticleLanding/2017/DT/C6DT03876J

Furthermore, Alessio Terenzi was awarded the front cover of the first issue of Dalton Transaction in 2017: pubs.rsc.org/en/content/articlepdf/2017/dt/c7dt90006f

NEW PUBLICATION

Mohamed Elgendy (http://indicar.univie.ac.at/fellows/elgendy-mohamed/) just published an article in the  Journal of Clinical Investigation (Impact Factor 13.2): "Dual modulation of MCL-1 and mTOR determines the response to sunitinib" https://www.jci.org/articles/view/84386

"In brief, the paper unravels mechanisms by which tumors adapt to and resist a drug called Sunitinib that's the first line therapy (best option) for renal cancer, making almost all the patients treated with this drug relapse within months. We also identified a clinical approach to make those tumors sensitive to this drug and potentially expand the lifespan of those patients."

This publication was also featured in one of the biggest newspapers in Italy: http://www.repubblica.it/salute/2016/11/28/news/tumori_resistenza_ai_farmaci_ieo-153021807/

INDICAR Workshop 2016

INDICAR - Workshop took place in Palermo, Italy, from Monday 12th Sept until Friday 16th Sept 2016.

The programme and timetable can be found on the webpage of the Workshop.

NEW PUBLICATION

NEW PUBLICATION

Our INDICAR fellow Alessio Terenzi just published the paper "Another step toward DNA selective targeting: NiII and CuII complexes of a Schiff base ligand able to bind gene promoter G-quadruplexes" in Dalton Transactions.

Abstract: DNA G-rich sequences are able to form four-stranded structures organized in stacked guanine tetrads. These structures, called G-quadruplexes, were found to have an important role in the regulation of oncogenes expression and became, for such a reason, appealing targets for anticancer drugs. Aiming at finding selective G-quadruplex binders, we have designed, synthesized and characterized a new water soluble Salen-like Schiff base ligand and its NiII and CuII metal complexes. UV-Vis, circular dichroism and FRET measurements indicated that the nickel complex can stabilize oncogene promoter G-quadruplexes with high selectivity, presenting no interactions with duplex DNA at all. The same compound exhibited dose-dependent cytotoxic activity in MCF-7 breast cancer cells when combined with lipofectamine as lipophilic carrier.

http://pubs.rsc.org/en/content/articlelanding/2016/dt/c6dt00648e

Interview

Two of our INDICAR fellows (Laura Cimatti and Anne Conibear) gave an interesting interview to the UNI:VIEW Magazin of the University of Vienna. Click here to read the interview (in German).