Breast Cancer Stem-Like Cells Are Inhibited by a Non-Toxic Aryl Hydrocarbon Receptor Agonist

Cancer stem cells (CSCs) have increased resistance to cancer chemotherapy. They can be enriched as drug-surviving CSCs (D-CSCs) by growth with chemotherapeutic drugs, and/or by sorting of cells expressing CSC markers such as aldehyde dehydrogenase-1 (ALDH). CSCs form colonies in agar, mammospheres in low-adherence cultures, and tumors following xenotransplantation in Scid mice. We hypothesized that tranilast, a non-toxic orally active drug with anti-cancer activities, would inhibit breast CSCs.We examined breast cancer cell lines or D-CSCs generated by growth of these cells with mitoxantrone. Tranilast inhibited colony formation, mammosphere formation and stem cell marker expression. Mitoxantrone-selected cells were enriched for CSCs expressing stem cell markers ALDH, c-kit, Oct-4, and ABCG2, and efficient at forming mammospheres. Tranilast markedly inhibited mammosphere formation by D-CSCs and dissociated formed mammospheres, at pharmacologically relevant concentrations. It was effective against D-CSCs of both HER-2+ and triple-negative cell lines. Tranilast was also effective in vivo, since it prevented lung metastasis in mice injected i.v. with triple-negative (MDA-MB-231) mitoxantrone-selected cells. The molecular targets of tranilast in cancer have been unknown, but here we demonstrate it is an aryl hydrocarbon receptor (AHR) agonist and this plays a key role. AHR is a transcription factor activated by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), polycyclic aromatic hydrocarbons and other ligands. Tranilast induced translocation of the AHR to the nucleus and stimulated CYP1A1 expression (a marker of AHR activation). It inhibited binding of the AHR to CDK4, which has been linked to cell-cycle arrest. D-CSCs expressed higher levels of the AHR than other cells. Knockdown of the AHR with siRNA, or blockade with an AHR antagonist, entirely abrogated the anti-proliferative and anti-mammosphere activity of tranilast. Thus, the anti-cancer effects of tranilast are AHR dependent.We show that tranilast is an AHR agonist with inhibitory effects on breast CSCs. It is effective against CSCs of triple-negative breast cancer cells selected for anti-cancer drug resistance. These results suggest it might find applications in the treatment of breast cancer

South African Ebola diagnostic response in Sierra Leone : a modular high biosafety field laboratory

BACKGROUND : In August 2014, the National Institute for Communicable Diseases (NICD) in South Africa established a modular high-biosafety field Ebola diagnostic laboratory (SA FEDL) near Freetown, Sierra Leone in response to the rapidly increasing number of Ebola virus disease (EVD) cases. METHODS AND FINDINGS : The SA FEDL operated in the Western Area of Sierra Leone, which remained a ªhotspotº of the EVD epidemic for months. The FEDL was the only diagnostic capacity available to respond to the overwhelming demand for rapid EVD laboratory diagnosis for several weeks in the initial stages of the EVD crisis in the capital of Sierra Leone. Furthermore, the NICD set out to establish local capacity amongst Sierra Leonean nationals in all aspects of the FEDL functions from the outset. This led to the successful hand-over of the FEDL to the Sierra Leone Ministry of Health and Sanitation in March 2015. Between 25 August 2014 and 22 June 2016, the laboratory tested 11,250 specimens mostly from the Western Urban and Western Rural regions of Sierra Leone, of which 2,379 (21.14%) tested positive for Ebola virus RNA. CONCLUSIONS : he bio-safety standards and the portability of the SA FEDL, offered a cost-effective and practical alternative for the rapid deployment of a field-operated high biocontainment facility. The SA FEDL teams demonstrated that it is highly beneficial to train the national staff in the course of formidable disease outbreak and accomplished their full integration into all operational and diagnostic aspects of the laboratory. This initiative contributed to the international efforts in bringing the EVD outbreak under control in Sierra Leone, as well as capacitating local African scientists and technologists to respond to diagnostic needs that might be required in future outbreaks of highly contagious pathogens.S1 Video. ªHotº processing of Ebola clinical specimens, PPE and decontamination procedures in South African modular, field-operated biocontainment facility in Sierra Leone.Janusz T Paweska was supported by funding from National Research Foundation and the Global Disease Detection Programmehttp://www.plosntds.orgam2017Microbiology and Plant Patholog

A response surface methodology based approach to machining processes: modelling and quality of the models

Various techniques for developing prediction models for various machining performance measures such as surface roughness/surface integrity, cutting force, tool life/tool wear etc in machining processes are available. These methods include, but are not limited to, analytical, numerical, empirical, and artificial intelligence (AI) based methods. While empirical modelling often employs the use of response surface methodology (RSM), however, proper understanding must be established regarding RSM-based models with respect to their development, validation and acceptability. Therefore, the general framework for developing RSM-based prediction models and testing their quality are discussed in this paper. This is followed by a practical surfacebroughness (Rt) model developed for precision grinding of silicon, a machining process that is very difficult to model. The result shows that the procedural modelling frameworks work well for the Rt developed model

Experimental investigation of the effect of cutting tool coating on delamination during of milling Metal Matrix Composite (MMC)

Metal Matrix Composite (MMC) has become one of the materials that is known to have high hardness and abrasive nature, due to the presence of silicon carbide (SiC) inside the composite. The characteristic nature of the MMC results in unpredictable cutting tool performance when it comes to a machining process. In order to explore a better means of improving the cutting of this material, coated tools were used to mill a MMC laminate composite. Therefore, experiments were carried out to cut a MMC laminate plate of 50 mm x 50 mm x 2 mm using 4 mm-diameter carbide end mills coated titanium aluminum nitride (TiAlN), as it is believed that TiAlN is one of the coatings, that has unique properties such as lower friction, higher adhesion, higher resistance to wear and crack. Box Behnken design was used to plan the running of experiments. Three independent cutting parameters, spindle speed, feed rate and depth of cut with values ranging from 4500-7500 rpm, 100-250 mm/min and 0.25-0.75 mm respectively, were studied. Experimental results show that delamination of the machined MMC was influenced mostly by feed rate and the depth of cut

Micromilling of tungsten carbide using focused ion beam

This paper describes the effect of focused ion beam (FIB) micromilling parameters on tungsten carbide for the fabrication of any microcomponents. The FIB parameters such as aperture size, ion dose, dwell time, etc. were investigated in this study. A series of experiments were conducted on tungsten carbide with varying operating parameters to establish the correlation how the parameters affect the micromilling process and quality of the final component. All the experiments were carried out with dry micromilling using serpentine scanning mode. Empirical models were formulated to predict the sputtered depth which increased with higher ion dose significantly but the relationship was nonlinear. Some of the experimental results are discussed with qualitative judgement as it was difficult to explain quantitatively

Prediction and experimental validation of temperature rise in ductile mode end milling of soda-lime glass

The suitable thermal, chemical, and corrosion resistance properties of glass make it possible to be used in a wide variety of product manufacturing, like lenses, mirrors, mold, semiconductor, biomedical, optical, and micro-electronics. However, machining of glass like any brittle material has big challenges owing to its inherent brittleness. Ductile mode machining is known to promote the material removal from a brittle material in ductile manner rather than by brittle fracture. In high-speed machining, the thermal softening effects can enhance flexibility in ductile machining of brittle materials. In this paper, an analytical model is developed to predict the amount of temperature generated in the immediate next removable layer (INRL) of the soda-lime glass work piece per unit depth of cut ∆T¯ INRL based on fundamental micro-machining principle and material physical properties. The model incorporates the effects of cutting speed, feed rate, strain rate, and thermal softening effect. The simulation and experimental results showed that at high cutting speed, glass softening can be achieved by adiabatic heating in order to facilitate ductile machining. The amount of adiabatic heating can be controlled by predicting the amount of the ∆T¯ INRL

Development of a low cost lapping process

Conventional process of producing silicon based products uses large work-piece and it is difficult to attain high flatness of the finished surface. Thus it is not unusual to find it difficult to fine finish small area of planar surfaces and attain high degree of flatness on the finished surfaces. The manufacturing of silicon wafers in particular involves numerous grinding, lapping, and polishing processes of large diameter wafers employing expensive equipment in order to produce the required optical quality and damage-free surfaces. In the finishing of thin silicon chips for making IC chips especially, it is difficult to lap and/polish the substrate and obtain low surface integrity, surface finish and at the same time generate flat planar surfaces. Therefore the understanding of lapping process is very essential for economic manufacture and process improvement of thin silicon chips. A low cost lapping process has been developed, the process tried out on thin silicon chips that generated damage-free with a mirror-like surfaces of low roughness values and reasonably high degree of flatness

Effect of carburization process on adhesion strength of Ti carbide layer on titanium alloy substrate

Titanium alloys are commonly used in biomedical application in hard tissues replacement especially for knee and hip implants. Surface modifications are required prior to diamond coating process for improving tribological and wear properties of the titanium alloy. In this study, experiments were carried out to investigate the effects of different carburizing times on the adhesion strength of carbide layer formed on the Ti-6Al-7Nb. Prior to carburization process, all samples were treated to remove residual stress and oxide scales by annealing and pickling processes respectively. Hard wood charcoal powder was used as a medium. The carburizing process was carried out for 6, 12 and 24 hours at 950 °C under normal atmospheric condition. Surface morphology, carbide layer thickness and adhesion strength were evaluated using SEM, XRD, 3D Surface Profilometer and Blast Wear Tester (BWT). It is found that a mixture of oxide and carbide layers formed on the substrate and the thickness of these layers increases with carburizing time. It is also revealed that the 24 hr carburizing time provides the strongest adhesion strength among the three and TiC as the dominant layer