The Hippo pathway in colorectal cancer

Colorectal cancer (CRC) is one the most frequently diagnosed neoplastic diseases worldwide. Currently, aside from traditional chemotherapy, advanced CRCs are treated with modern drugs targeting cellular components such as epithelial growth factor receptor (EGFR). Since up to 70% of metastasized CRCs are drug resistant, the description of recent progress in cellular homeostasis regulation may shed new light on the development of new molecular targets in cancer treatment. The Hippo pathway has recently become subject of intense investigations since it plays a crucial role in cell proliferation, differentiation, apoptosis and tumourigenesis. Components of the Hippo pathway are deregulated in various human malignancies, and expression levels of its major signal transducers were proposed as prognostic factors in colorectal cancer. In this review we focused on recent data regarding Hippo pathway, its up-stream signals and down-stream effectors. Hippo negatively regulates its major effectors, YAP1 and TAZ kinases, which act as transcriptional co-activators inducing expression of genes involved not only in tissue repair and proliferation but are also oncoproteins involved in tumour development and progression. The deregulation of Hippo pathway components was found in many malignancies. The interactions between Hippo and Wnt/β-catenin signalling, crucial in the maintenance of cell homeostasis, have been described in relation to the control of intestinal stem cell proliferation and CRC development. The recently discovered positive feedback loop between activated YAP1 and increased EGFR/KRAS signalling found in oesophageal, ovarian and hepatocellular cancer has been related to the CRC progression and resistance to EGFR inhibitors during CRC therapy

Tabu search for the RNA partial degradation problem

ABSTRACT: In recent years, a growing interest has been observed in research on RNA (ribonucleic acid), primarily due to the discovery of the role of RNA molecules in biological systems. They not only serve as templates in protein synthesis or as adapters in the translation process, but also influence and are involved in the regulation of gene expression. The RNA degradation process is now heavily studied as a potential source of such riboregulators. In this paper, we consider the so-called RNA partial degradation problem (RNA PDP). By solving this combinatorial problem, one can reconstruct a given RNA molecule, having as input the results of the biochemical analysis of its degradation, which possibly contain errors (false negatives or false positives). From the computational point of view the RNA PDP is strongly NP-hard. Hence, there is a need for developing algorithms that construct good suboptimal solutions. We propose a heuristic approach, in which two tabu search algorithms cooperate, in order to reconstruct an RNA molecule. Computational tests clearly demonstrate that the proposed approach fits well the biological problem and allows to achieve near-optimal results. The algorithm is freely available at http://www.cs.put.poznan.pl/arybarczyk/tabusearch.php

Crystal structure of 3,6-bis­­(pyridin-2-yl)-1,4-di­hydro-1,2,4,5-tetra­zine

The structure of the title compound, C12H10N6, at 100 K has monoclinic (P21/n) symmetry. Crystals were obtained as a yellow solid by reduction of 3,6-bis­(pyridin-2-yl)-1,2,4,5-tetra­zine. The structure displays inter­molecular hydrogen bonding of the N—H⋯N type, ordering mol­ecules into infinite ribbons extending along the [100] direction.Funding for this research was provided by: Narodowe Centrum Nauki (grant No. 2015/19/B/ST4/01773); EFRD in Operational Programme Development of Eastern Poland 2007–2013, the Oxford Diffraction SuperNova DualSource diffractometer (award No. POPW.01.03.00-20-004/11)

Oxidation of 2-mercaptopyridine N-oxide upon iodine agent: structural and FT-IR studies on charge-assisted hydrogen bonds CAHB(+) and I…I halogen interactions in 2,2′-dithiobis(pyridine N-oxide) ionic cocrystal

2-Mercaptopyridine N-oxide (I) undergoes spontaneous dimerization to the disulfide form due to reaction with iodine acting as an oxidizing reagent. As a result, a di-N-oxide disulfide derivative of pyridine is obtained. During the process of crystallization, one of N-oxide groups undergoes protonation and a cation form of disulfide moiety cocrystallizes with I3 − counterion forming a salt structure. Therefore, in the crystalline state, the 2,2′-dithiobis(pyridine N-oxide) molecule exists in a not observed previously form of monocation. Interestingly, the protonated N-oxide group does not form hydrogen-bonded salt bridges (of the CAHB(±) type with I3 − anions) but prefers to be involved in intermolecular interactions with the unprotonated N-oxide group of the adjacent molecule This results in formation of intermolecular CAHB(+) hydrogen bridges finally linking molecules into infinite chains. The crystal structure is also stabilized by other various noncovalent interactions, including iodine...iodine and sulfur...iodine contacts

Protein and siRNA delivery by transportan and transportan 10 into colorectal cancer cell lines

Introduction. Cell penetrating peptides (CPPs) have the ability to translocate through cell membranes with high efficiency and therefore can introduce biological agents with pharmaceutical properties into the cell. Transportan (TP) and its shorter analog transportan 10 (TP10) are among the best studied CPPs, however, their effects on viability of and cargo introduction into colorectal cancer (CRC) cells have yet not been investigated. The aim of our study was to evaluate the cytotoxic effects of TP and TP10 on representative CRC lines and the efficiency of protein (streptavidin) and siRNA cargo delivery by TP-biotinylated derivatives (TP-biot). Material and methods. HT29 (early stage CRC model) and HCT116 (metastatic CRC model) cell lines were incubated with TP, TP10, TP-biot1, TP-biot13 and TP10-biot1. The effects of studied CPPs on cell viability and cell cycle were assessed by MTT and annexin V assays. The uptake of streptavidin-FITC complex into cells was determined by flow cytometry and fluorescence microscopy, with the inhibition of cellular vesicle trafficking by brefeldin A. The efficiency of siRNA for SASH1 gene delivery was measured by quantitative PCR (qPCR). Results. Since up to 10 µM concentrations of each CPP showed no significant cytotoxic effect, the concentrations of 0.5–5 µM were used for further analyses. Within this concentration range none of the studied CPPs affected cell viability and cell cycle. The efficient and endocytosis-independent introduction of streptavidin-FITC complex into cells was observed for TP10-biot1 and TP-biot1 with the cytoplasmic location of the fluorescent cargo; decreased SASH1 mRNA level was noticed with the use of siRNA and analyzed CPPs. Conclusions. We conclude that TP, TP10 and their biotinylated derivatives can be used as efficient delivery vehicles of small and large cargoes into CRC cells

Cardiac Rehabilitation in Heart Failure. Part II. Does Higher Intensity Means Better Outcome?

Heart failure (HF) due to its universality has become a huge challenge for modern medicine. Second part of the twentieth century brought significant changes in the rehabilitation, diagnostic and pharmacological procedures. There are no definitive guidelines for Cardiac Rehabilitation (CR) in HF. Based on previous studies, the article tried to describe and illustrate the mechanism of effective CR and its intensity in HF patients, which could be helpful in CR protocol development. Cardiac Rehabilitation has confirmed efficacy in increased physical level of participation in inter alia, home/work/recreational activities, improved psychosocial well-being, functional independence, prevention of disability, long-term adherence to maintaining physically active lifestyle, improved cardiopulmonary fitness, strength, muscle endurance, and flexibility, reduced cardiovascular events risk and risk of mortality. Before and after CR conduction, baseline and final aerobic capacity should be examined with an ergospirometry test to evaluate CR protocol intensity and check its effectiveness, respectively. Frequency of training-bouts in CR protocol in HF patients were from 3 to 7 days per week, intensity ranged from 40% to 80% VO2max or 9 to 14 on rating of the perceived exertion (RPE) scale or 6 to 20 on the Borg scale. Duration of single bout-exercise ranged from 20 to 60 minutes