PUBLICATION NEWS

22.11.2018

Our fellow Alessio Terenzi has published as co-author in Scientific Reports: “Biological activity of Pt^IV prodrugs triggered by riboflavin-mediated bioorthogonal photocatalysis”.

The new study is a joint effort between the group of Prof. Luca Salassa (Donostia International Physics Center) and the groups of Profs. Walter Berger and Bernhard K. Keppler (Research Platform “Translational Cancer Therapy Research”, University of Vienna and Medical University of Vienna). The study highlights the possibility of combining photocatalysis and Pt(IV) prodrugs in the treatment of cancer. Congratulations!!

Abstract: 

We have recently demonstrated that riboflavin (Rf) functions as unconventional bioorthogonal photocatalyst for the activation of Pt^IV prodrugs. In this study, we show how the combination of light and Rf with two Pt^IV prodrugs is a feasible strategy for light-mediated pancreatic cancer cell death induction. In Capan-1 cells, which have high tolerance against photodynamic therapy, Rf-mediated activation of the cisplatin and carboplatin prodrugs cis,cis,trans-[Pt(NH₃)₂(Cl)₂(O₂CCH₂CH₂CO₂H)₂] (1) and cis,cis,trans-[Pt(NH₃)₂(CBDCA)(O₂CCH₂CH₂CO₂H)₂] (2, where CBDCA = cyclobutane dicarboxylate) resulted in pronounced reduction of the cell viability, including under hypoxia conditions. Such photoactivation mode occurs to a considerable extent intracellularly, as demonstrated for 1 by uptake and cell viability experiments. ¹⁹⁵Pt NMR, DNA binding studies using circular dichroism, mass spectrometry and immunofluorescence microscopy were performed using the Rf-1 catalyst-substrate pair and indicated that cell death is associated with the efficient light-induced formation of cisplatin. Accordingly, Western blot analysis revealed signs of DNA damage and activation of cell death pathways through Rf-mediated photochemical activation. Phosphorylation of H₂AX as indicator for DNA damage, was detected for Rf-1 in a strictly light-dependent fashion while in case of free cisplatin also in the dark. Photochemical induction of nuclear pH₂AX foci by Rf-1 was confirmed in fluorescence microscopy again proving efficient light-induced cisplatin release from the prodrug system.

INDICAR-Workshop 2018

21.09.2017

The INDICAR-Workshop 2018 took place in Bratislava (Slovakia), from 13th to 14th Sep. 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. As the INDICAR Programme ends November 2018, the fellows presented and discussed their work with a particular focus on how to wrap up outcomes and what the results may mean for future research.

NEW PUBLICATION

03.08.2018

Our fellow Luca Tubiana just published as corresponding author in the European Physical Journal E Soft Matter: “Implementing efficient concerted rotations using Mathematica and C code⋆”. Congratulations Luca!

Abstract:

In this article we demonstrate a general and efficient metaprogramming implementation of concerted rotations using Mathematica. Concerted rotations allow the movement of a fixed portion of a polymer backbone with fixed bending angles, like a protein, while maintaining the correct geometry of the backbone and the initial and final points of the portion fixed. Our implementation uses Mathematica to generate a C code which is then wrapped in a library by a Python script. The user can modify the Mathematica notebook to generate a set of concerted rotations suited for a particular backbone geometry, without having to write the C code himself. The resulting code is highly optimized, performing on the order of thousands of operations per second.

NEW PUBLICATION

25.07.2018

Our fellow Alessio Terenzi has published as co-author in the European Journal of Medicinal Chemistry: “Fluorescent organometallic rhodium(I) and ruthenium(II) metallodrugs with 4-ethylthio-1,8-naphthalimide ligands: Antiproliferative effects, cellular uptake and DNA-interaction”. Congratulations!

Abstract:

Fluorescent 4-ethylthio-1,8-naphthalimides containing rhodium(I) N-heterocyclic carbene (NHC) and ruthenium (II) NHC fragments were synthesised and evaluated for their antiproliferative effects, cellular uptake and DNA-binding activity. Both types of organometallics triggered ligand dependent efficient cytotoxic effects against tumor cells with the rhodium(I) NHC derivatives causing stronger effects than the ruthenium (II) NHC analogues. Antiproliferative effects could also be observed against several pathogenic Gram-positive bacterial strains, whereas the growth of Gram-negative bacteria was not substantially affected. Cellular uptake was confirmed by atomic absorption spectroscopy as well as by fluorescence microscopy indicating a general ligand dependent accumulation in the cells. An in-depth study on the interaction with DNA confirmed insertion of the naphthalimide moiety between the planar bases of B-DNA via an intercalation mechanism, as well as its stacking on top of the quartets of G-quadruplex structures. Furthermore, additional coordinative binding of the organometallic complexes to the model DNA base 9-ethylguanine could be detected. The studied compounds thus represent promising bioorganometallics featuring strong pharmacological effects in combination with excellent cellular imaging properties.

NEW PUBLICATION

16.07.2018

The INDICAR-Fellow Alessio Terenzi co-authored a publication in the European Journal of Inorganic Chemistry: “Synthesis and Biological Evaluation of Organometallic Complexes Bearing Bis‐1,8‐naphthalimide Ligands”. Congratulations Alessio!

Abstract:

Organometallic N‐heterocyclic carbene (NHC) complexes with intercalating bis‐naphthalimide ligands were prepared and evaluated biologically. Cytotoxic effects against tumor cells or bacteria were strongly ligand dependent with minor influence of the metal (Ag, Ru, Rh, Au) centers. Complex 8b with a rhodium(I) NHC moiety was studied in more detail for its DNA interacting properties in comparison to the metal free ligand. These studies showed a good DNA binding pattern with some preference for the telomeric quadruplex structure hTelo. Complex 8b was also shown to trigger additional coordinative binding to the DNA and therefore represents an useful tool compound with a mixed intercalative/coordinative DNA binding mode.

KONSTANTINOS KIAKOS PRESENTED HIS VIDEO “DRUGGING CANCER” AT TOP KINO

19.06.2018

On the 7th of June the INDICAR Fellow Konstantinos Kiakos presented his video “Drugging Cancer” at Top Kino, together with participants of the CommunicationHub.

Last October Konstantinos enrolled the CommunicationHub 2017/18 program "My research as video", organized by Knowledge Transfer Center East (WTZ Ost). Konstantinos and his team worked on his video under the guidance and support of experts from Okto TV.

“Drugging Cancer” aims at disseminating the INDICAR program and Konstantinos’ research and to raise awareness on the research performed to discover new cancer drugs.

THE EUTOPIA PROJECT LEAD BY LUCA TUBIANA HAS BEEN AWARDED A COST GRANT

29.05.2018

The EUTOPIA (EUropean TOPology Interdisciplinary Action) project lead by  INDICAR Fellow Luca Tubiana has been awarded a COST grant. COST is an EU-funded program that provides funding and support to researchers to establish interdisciplinary networks in Europe and beyond.  EUTOPIA aims at forming an EU community of researchers from different fields working on the topological aspects of soft and bio-materials. The network of EUTOPIA members span 11 European countries. Thanks to the COST grant, EUTOPIA members will be able to perform scientific exchanges and organize meetings, conferences, training schools or other scientific networking activities.

TALKS AT VIENNA EUROPEAN SCHOOL

11.04.2018

On Wednesday 21st of March, the INDICAR Fellows Laura Cimatti and Mohamed Elgendy visited the Vienna European School. They presented grade 5 and 6 students interactive and engaging talks about the everyday life of a scientist and their research. This initiative aims to create awareness among secondary students of the research performed by INDICAR Fellows and to develop their interest in research careers. Thanks Vienna European School for having us, it was a great experience!

NEW PUBLICATION

28.03.2018

Our fellow Takahiko Akematsu published as corresponding author in the journal Genes: “Resistance to 6-Methylpurine is Conferred by Defective Adenine Phosphoribosyltransferase in Tetrahymena”. Congratulations Takahiko!

6-methylpurine (6mp) is a toxic analog of adenine that inhibits RNA and protein synthesis and interferes with adenine salvage mediated by adenine phosphoribosyltransferase (APRTase). Mutants of the ciliated protist Tetrahymena thermophila that are resistant to 6mp were isolated in 1974, but the mechanism of resistance has remained unknown. To investigate 6mp resistance in T. thermophila, we created 6mp-resistant strains and identified a mutation in the APRTase genomic locus (APRT1) that is responsible for 6mp resistance. While overexpression of the mutated APRT1 allele in 6mp-sensitive cells did not confer resistance to 6mp, reduced wild-type APRT1 expression resulted in a significant decrease in sensitivity to 6mp. Knocking out or reducing the expression of APRT1 by RNA interference (RNAi) did not affect robust cell growth, which indicates that adenine salvage is redundant or that de novo synthesis pathways provide sufficient adenosine monophosphate for viability. We also explored whether 6mp resistance could be used as a novel inducible selection marker by generating 6mp- and paromomycin-resistant double mutants. While 6mp- and paromomycin-resistant double mutants did express fluorescent proteins in an RNAi-based system, the system requires optimization before 6mp resistance can be used as an effective inducible selection marker.

KONSTANTINOS KIAKOS’ RESEARCH ON VIDEO

26.03.2018

Last week, the INDICAR Fellow Konstantinos Kiakos and his team filmed a video about the INDICAR Programme, his research and its impact on society as well. Dr. Kiakos enrolled last October the CommunicationHub 2017/18 “My research as video“, organized by the Knowledge Transfer Center East (WTZ Ost). As part of this programme, he has received support and guidance from experts from Okto TV to create his video.

Dr. Kiakos recently filed a U.S. provisional patent on the therapeutic composition and methods of use based on a series of novel STAT3 small-molecule Inhibitors.

ANNE CONIBEAR PUBLICATION FEATURED ON THE COVER OF CHEMBIOCHEM

26.02.2018

Anne Conibear research article “Synthetic cancer-targeting innate immune stimulators give insights into avidity effects”, published in the journal ChemBioChem, has been featured on the cover. Congratulations Anne!

GOOD BYE FIRST-CALL FELLOWS, WE WILL MISS YOU!

23.02.18

Last Monday INDICAR bade farewell to its fellows from the first cohort. The event gathered supervisors, fellows, peers, and colleagues to thank their support to the INDICAR Programme and to celebrate INDICAR Fellows’ accomplishments.

We wish our fellows all the best in their careers!

CONGRATULATIONS TO ANTJE KOLLER ON BEING AWARDED THE "BACK-TO-RESEARCH" GRANT

29.01.2018

We are delighted to announce that our fellow Antje Koller have been awarded the "Back-to-Research" Grant, from the University of Vienna.

The funding scheme is addressed to female postdoctoral researchers who, during the last five years, have reduced or interrupted their research because of care obligations in their families. The grant provides researchers with the possibility to complete research applications and/or publications in order to ensure that they can re-enter or continue their academic careers.

NEW PUBLICATION

22.01.2018

The INDICAR-Fellow Anne Conibear published the paper “Recent Advances in Peptide-Based Approaches for Cancer Treatment”, in the journal Current Medicinal Chemistry. Congratulations Anne!

Peptide-based pharmaceuticals have recently experienced a renaissance due to their ability to fill the gap between the two main classes of available drugs, small molecules and biologics. Peptides combine the high potency and selectivity typical of large proteins with some of the characteristic advantages of small molecules such as synthetic accessibility, stability and the potential of oral bioavailability. One of the applications in which peptide-based approaches have grown rapidly is cancer therapy, with a focus on new and established targets. Many novel peptide-based methods for cancer treatment have been developed in the last few years, ranging from naturally-occurring and modified peptides to peptide-drug conjugates, peptide nanomaterials and peptide-based vaccines. This review focuses on recent advances, advantages and challenges of these selected peptide-based approaches for cancer treatment.

KONSTANTINOS KIAKOS FILES A U.S. PROVISIONAL PATENT

10.01.2018

The INDICAR fellow Konstantinos Kiakos has filed a U.S. provisional patent on the therapeutic composition and methods of use based on a series of novel STAT3 small-molecule inhibitors. This new class of compounds provides a method for selective and effective reduction of pSTAT3 in cancer cells, leading to apoptosis. The STAT3 inhibitors described in the invention can chemo- and radio- sensitize cancer cells and reverse platinum drug resistance.

AUSTRIAN CAFÉ

30.11.2017

Yesterday, the Austrian Café took place at the Irish pub Flanagans. INDICAR fellows and friends discussed the paper presented by Alessio: “Local epigenetic reprogramming induced by G-quadruplex ligands”. With this activity, INDICAR aims to foster informal and relaxed scientific discussions. As a result, INDICAR fellows have the opportunity to network and obtain feedback about their research from peers.

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!!!

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.

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!

Mec1^ATR 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 Mec1^ATR 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 19^th 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

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!

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.