Targeting of RET oncogene by naphthalene diimide-mediated gene promoter G-quadruplex stabilization exerts anti-tumor activity in oncogene-addicted human medullary thyroid cancer

Medullary thyroid cancer (MTC) relies on the aberrant activation of RET proto-oncogene. Though targeted approaches (i.e., tyrosine kinase inhibitors) are available, the absence of complete responses and the onset of resistance mechanisms indicate the need for novel therapeutic interventions. Due to their role in regulation of gene expression, G-quadruplexes (G4) represent attractive targets amenable to be recognized or stabilized by small molecules. Here, we report that exposure of MTC cells to a tri-substituted naphthalene diimide (NDI) resulted in a significant antiproliferative activity paralleled by inhibition of RET expression. Biophysical analysis and gene reporter assays showed that impairment of RET expression was consequent to the NDI-mediated stabilization of the G4 forming within the gene promoter. We also showed for the first time that systemic administration of the NDI in mice xenotransplanted with MTC cells resulted in a remarkable inhibition of tumor growth in vivo. Overall, our findings indicate that NDI-dependent RET G4 stabilization represents a suitable approach to control RET transcription and delineate the rationale for the development of G4 stabilizing-based treatments for MTC as well as for other tumors in which RET may have functional and therapeutic implications

The Intersection of GERD, Aspiration, and Lung Transplantation

Lung transplantation is a radical but life-saving treatment option for patients with end-stage lung diseases, such as idiopathic pulmonary fibrosis (IPF) and scleroderma. In light of the proposed association and controversy linking gastroesophageal reflux disease (GERD) to IPF and lung transplant outcome, the American Gastroenterological Association convened during the DDW in Washington in May 2015 a multidisciplinary group of experts in the field of GERD and lung transplantation to make considerations about the care of these patients based on available data and subsequent expert panel discussion at this symposium. The following topics were discussed: (1) pathophysiology of GERD-induced pulmonary symptoms, (2) GERD evaluation before and after lung transplantation, (3) outcome of lung transplantation for IPF and scleroderma, and (4) role of laparoscopic fundoplication before or after lung transplantation

Multiparty Languages: The Choreographic and Multitier Cases (Pearl)

Choreographic languages aim to express multiparty communication protocols, by providing primitives that make interaction manifest. Multitier languages enable programming computation that spans across several tiers of a distributed system, by supporting primitives that allow computation to change the location of execution. Rooted into different theoretical underpinnings - respectively process calculi and lambda calculus - the two paradigms have been investigated independently by different research communities with little or no contact. As a result, the link between the two paradigms has remained hidden for long. In this paper, we show that choreographic languages and multitier languages are surprisingly similar. We substantiate our claim by isolating the core abstractions that differentiate the two approaches and by providing algorithms that translate one into the other in a straightforward way. We believe that this work paves the way for joint research and cross-fertilisation among the two communities

Editorial: Open Education im Kontext der Digitalisierung

Editoria

Association of Caldendrin splice isoforms with secretory vesicles in neurohypophyseal axons and the pituitary

AbstractCaldendrin is a neuronal calcium-binding protein, which is highly enriched in the postsynaptic density fraction and exhibits a prominent somato-dendritic distribution in brain. Two additional splice variants derive from the caldendrin gene, which have unrelated N-termini and were previously only detected in the retina. We now show that these isoforms are present in neurohypophyseal axons and on secretory granules of endocrine cells. In light of the described interaction of the Caldendrin C-terminus with Q-type Cav2.1 calcium channels these data suggest that this interaction takes place in neurohypophyseal axons and pituitary cells indicating functions of the short splice variants in triggering Ca2+ transients to a vesicular target interaction

The Oncogenic Signaling Pathways in BRAF-Mutant Melanoma Cells are Modulated by Naphthalene Diimide-Like G-Quadruplex Ligands

Melanoma is the most aggressive and deadly type of skin cancer. Despite the advent of targeted therapies directed against specific oncogene mutations, melanoma remains a tumor that is very difficult to treat, and ultimately remains incurable. In the past two decades, stabilization of the non-canonical nucleic acid G-quadruplex structures within oncogene promoters has stood out as a promising approach to interfere with oncogenic signaling pathways in cancer cells, paving the way toward the development of G-quadruplex ligands as antitumor drugs. Here, we present the synthesis and screening of a library of differently functionalized core-extended naphthalene diimides for their activity against the BRAFV600E-mutant melanoma cell line. The most promising compound was able to stabilize G-quadruplexes that formed in the promoter regions of two target genes relevant to melanoma, KIT and BCL-2. This activity led to the suppression of protein expression and thus to interference with oncogenic signaling pathways involved in BRAF-mutant melanoma cell survival, apoptosis, and resistance to drugs. This G-quadruplex ligand thus represents a suitable candidate for the development of melanoma treatment options based on a new mechanism of action and could reveal particular significance in the context of resistance to targeted therapies of BRAF-mutant melanoma cells