Repurposing Antibacterial AM404 as a Potential Anticancer Drug for Targeting Colorectal Cancer Stem-Like Cells

Tumour-promoting inflammation is involved in colorectal cancer (CRC) development and therapeutic resistance. However, the antibiotics and antibacterial drugs and signalling that regulate the potency of anticancer treatment upon forced differentiation of cancer stem-like cell (CSC) are not fully defined yet. We screened an NIH-clinical collection of the small-molecule compound library of antibacterial/anti-inflammatory agents that identified potential candidate drugs targeting CRC-SC for differentiation. Selected compounds were validated in both in vitro organoids and ex vivo colon explant models for their differentiation induction, impediment on neoplastic cell growth, and to elucidate the mechanism of their anticancer activity. We initially focused on AM404, an anandamide uptake inhibitor. AM404 is a metabolite of acetaminophen with antibacterial activity, which showed high potential in preventing CRC-SC features, such as stemness/de-differentiation, migration and drug-resistance. Furthermore, AM404 suppressed the expression of FBXL5 E3-ligase, where AM404 sensitivity was mimicked by FBXL5-knockout. This study uncovers a new molecular mechanism for AM404-altering FBXL5 oncogene which mediates chemo-resistance and CRC invasion, thereby proposes to repurpose antibacterial AM404 as an anticancer agent

FLYWCH1, a novel suppressor of nuclear b-catenin, regulates migration and morphology in colorectal cancer

© 2018 American Association for Cancer Research. Wnt/b-catenin signaling plays a critical role during development of both normal and malignant colorectal cancer tissues. Phosphorylation of b-catenin protein alters its trafficking and function. Such conventional allosteric regulation usually involves a highly specialized set of molecular interactions, which may specifically turn on a particular cell phenotype. This study identifies a novel transcription modulator with an FLYWCH/Zn-finger DNA-binding domain, called "FLYWCH1." Using a modified yeast-2-hybrid based Ras-Recruitment system, it is demonstrated that FLYWCH1 directly binds to unphosphorylated (nuclear) b-catenin efficiently suppressing the transcriptional activity of Wnt/ b-catenin signaling that cannot be rescued by TCF4. FLYWCH1 rearranges the transcriptional activity of b-catenin/TCF4 to selectively block the expression of specific downstream genes associated with colorectal cancer cell migration and morphology, including ZEB1, EPHA4, and E-cadherin. Accordingly, overexpression of FLYWCH1 reduces cell motility and increases cell attachment. The expression of FLYWCH1 negatively correlates with the expression level of ZEB1 and EPHA4 in normal versus primary and metastatic colorectal cancer tissues in patients. Thus, FLYWCH1 antagonizes b-catenin/TCF4 signaling during cell polarity/migration in colorectal cancer. Implications: This study uncovers a new molecular mechanism by which FLYWCH1 with a possible tumor suppressive role represses b-catenin-induced ZEB1 and increases cadherin-mediated cell attachment preventing colorectal cancer metastasis

Percutaneous transluminal mitral commissurotomy in pregnant women with severe mitral stenosis

Background: Mitral stenosis tends to worsen during pregnancy because of the increase in the cardiac output and the heart rate. In nonresponders to medical therapy, percutaneous transluminal mitral commissurotomy (PTMC) may be performed when there is a suitable valvular anatomy. In this study, we aimed to investigate the clinical and fetal outcomes of pregnant women with mitral stenosis who underwent PTMC. Methods: Thirty-one patients undergoing PTMC during pregnancy were enrolled in this study. The mitral valve area (MVA), the transmitral valve mean gradient (MVMG), and the severity of mitral regurgitation were assessed pre- and postprocedurally by transthoracic and transesophageal echocardiography. The radiation time was measured during the procedure. The patients were followed up during pregnancy, and the neonates were monitored for weight, height, the head circumference, the birth Apgar score, and the adverse effects of radiation for at least 12 months. Results: PTMC was successfully performed on 29 (93.5) patients. No maternal death or pulmonary edema was reported. The mean MVA significantly increased (from 0.73±0.17 cm2to 1.28±0.24 cm2; P<0.001), and the mean MVMG significantly decreased (from 19.62±5.91 mmHg to 8.90±4.73 mmHg; P<0.001) after the procedure. A significant decrease in the systolic pulmonary artery pressure was also detected. Mitral regurgitation did not increase in severity in 16 (51.6) patients. There was no significant relationship between the Apgar score, weight, height, and the head circumference at birth and at the radiation time. Conclusion: In our series, PTMC during pregnancy was a safe and effective procedure. Lowering the radiation time with low frame-count techniques confers a significant decrease in radiation-related complications. © 2019, Tehran Heart Center. All Rights Reserved

Modeling healthcare authorization and claim submissions using the openEHR dual-model approach

<p>Abstract</p> <p>Background</p> <p>The TISS standard is a set of mandatory forms and electronic messages for healthcare authorization and claim submissions among healthcare plans and providers in Brazil. It is not based on formal models as the new generation of health informatics standards suggests. The objective of this paper is to model the TISS in terms of the openEHR archetype-based approach and integrate it into a patient-centered EHR architecture.</p> <p>Methods</p> <p>Three approaches were adopted to model TISS. In the first approach, a set of archetypes was designed using ENTRY subclasses. In the second one, a set of archetypes was designed using exclusively ADMIN_ENTRY and CLUSTERs as their root classes. In the third approach, the openEHR ADMIN_ENTRY is extended with classes designed for authorization and claim submissions, and an ISM_TRANSITION attribute is added to the COMPOSITION class. Another set of archetypes was designed based on this model. For all three approaches, templates were designed to represent the TISS forms.</p> <p>Results</p> <p>The archetypes based on the openEHR RM (Reference Model) can represent all TISS data structures. The extended model adds subclasses and an attribute to the COMPOSITION class to represent information on authorization and claim submissions. The archetypes based on all three approaches have similar structures, although rooted in different classes. The extended openEHR RM model is more semantically aligned with the concepts involved in a claim submission, but may disrupt interoperability with other systems and the current tools must be adapted to deal with it.</p> <p>Conclusions</p> <p>Modeling the TISS standard by means of the openEHR approach makes it aligned with ISO recommendations and provides a solid foundation on which the TISS can evolve. Although there are few administrative archetypes available, the openEHR RM is expressive enough to represent the TISS standard. This paper focuses on the TISS but its results may be extended to other billing processes. A complete communication architecture to simulate the exchange of TISS data between systems according to the openEHR approach still needs to be designed and implemented.</p

Direct non-cyclooxygenase-2 targets of celecoxib and their potential relevance for cancer therapy

Celecoxib (Celebrex®) was developed as a selective cyclooxygenase-2 (COX-2) inhibitor for the treatment of chronic pain. However, it now appears that this compound harbours additional pharmacologic activities that are entirely independent of its COX-2-inhibitory activity. This review presents the recently emerged direct non-COX-2 targets of celecoxib and their proposed role in mediating this drug's antitumour effects

Induction of oxidative stress as a mechanism of action of chemopreventive agents against cancer

Prevention is a promising option for the control of cancer. Cellular redox changes have emerged as a pivotal and proximal event in cancer. In this review, we provide a brief background on redox biochemistry, discuss the important distinction between redox signalling and oxidative stress, and outline the ‘multiple biological personalities' of reactive oxygen and nitrogen species: at low concentrations they protect the cell; at higher concentrations they can damage many biological molecules, such as DNA, proteins, and lipids; and, as we argue here, they may also prevent cancer by initiating the death of the transformed cell. Nitric oxide-donating aspirin is discussed as an instructive example: it generates a state of oxidative stress through which it affects several redox-sensitive signalling pathways, leading ultimately to the elimination of the neoplastic cell via apoptosis or necrosis. As additional examples, we discuss the chemopreventive n–3 polyunsaturated fatty acids and conventional nonsteroidal anti-inflammatory drugs, which induce cell death through redox changes. We conclude that modulation of redox biochemistry represents a fruitful approach to cancer prevention

Hydrogen sulphide-induced hypometabolism in human-sized porcine kidneys

Background Since the start of organ transplantation, hypothermia-forced hypometabolism has been the cornerstone in organ preservation. Cold preservation showed to protect against ischemia, although post-transplant injury still occurs and further improvement in preservation techniques is needed. We hypothesize that hydrogen sulphide can be used as such a new preservation method, by inducing a reversible hypometabolic state in human sized kidneys during normothermic machine perfusion. Methods Porcine kidneys were connected to an ex-vivo isolated, oxygen supplemented, normothermic blood perfusion set-up. Experimental kidneys (n = 5) received a 85mg NaHS infusion of 100 ppm and were compared to controls (n = 5). As a reflection of the cellular metabolism, oxygen consumption, mitochondrial activity and tissue ATP levels were measured. Kidney function was assessed by creatinine clearance and fractional excretion of sodium. To rule out potential structural and functional deterioration, kidneys were studied for biochemical markers and histology. Results Hydrogen sulphide strongly decreased oxygen consumption by 61%, which was associated with a marked decrease in mitochondrial activity/function, without directly affecting ATP levels. Renal biological markers, renal function and histology did not change after hydrogen sulphide treatment. Conclusion In conclusion, we showed that hydrogen sulphide can induce a controllable hypometabolic state in a human sized organ, without damaging the organ itself and could thereby be a promising therapeutic alternative for cold preservation under normothermic conditions in renal transplantation

Structural Conformers of (1,3-Dithiol-2-ylidene)ethanethioamides: The Balance Between Thioamide Rotation and Preservation of Classical Sulfur-Sulfur Hypervalent Bonds

The reaction of N-(2-phthalimidoethyl)-N-alkylisopropylamines and S2Cl2 gave 4-N-(2-phthalimidoethyl)-N-alkylamino-5-chloro-1,2-dithiol-3-thiones that quantitatively cycloadded to dimethyl or diethyl acetylenedicarboxylate to give stable thioacid chlorides, which in turn reacted with one equivalent of aniline or a thiole to give thioanilides or a dithioester. Several compounds of this series showed atropisomers that were studied by a combination of dynamic NMR, simulation of the signals, conformational analysis by DFT methods, and single crystal X-ray diffraction, showing a good correlation between the theoretical calculations, the experimental values of energies, and the preferred conformations in the solid state. The steric hindering of the crowded substitution at the central amine group was found to be the reason for the presence of permanent atropisomers in this series of compounds and the cause of a unique disposition of the thioxo group at close-to-right angles with respect to the plane defined by the 1,3-dithiole ring in the dithiafulvene derivatives, thus breaking the sulfur–sulfur hypervalent bond that is always found in this kind of compounds.Ministerio de Economıá y Competitividad, Spain (Project CTQ2012- 31611), Junta de Castilla y León, Consejería de Educación y Cultura y Fondo Social Europeo (Project BU246A12-1), and the European Commission, Seventh Framework Programme (Project SNIFFER FP7-SEC-2012-312411

Erratum: COMPARE CPM-RMI trial: Intramyocardial transplantation of autologous bone marrow-derived CD133+ cells and MNCs during CABG in patients with recent MI: A phase II/III, multicenter, placebo-controlled, randomized, double-blind clinical trial. (Cell Journal (2018) 20:3 (449) DOI: 10.22074/cellj.2018.5197)

This article published in Cell J (Yakhteh), Vol 20, No 2, Jul-Sep 2018, on pages 267-277, four affiliations (1, 4, 5, and 10) were changed based on authors request. © 2018 Royan Institute (ACECR). All rights reserved