Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation

Activating B-RAF(V600E) (also known as BRAF) kinase mutations occur in ～7% of human malignancies and ～60% of melanomas. Early clinical experience with a novel class I RAF-selective inhibitor, PLX4032, demonstrated an unprecedented 80% anti-tumour response rate among patients with B-RAF(V600E)-positive melanomas, but acquired drug resistance frequently develops after initial responses. Hypotheses for mechanisms of acquired resistance to B-RAF inhibition include secondary mutations in B-RAF(V600E), MAPK reactivation, and activation of alternative survival pathways. Here we show that acquired resistance to PLX4032 develops by mutually exclusive PDGFRβ (also known as PDGFRB) upregulation or N-RAS (also known as NRAS) mutations but not through secondary mutations in B-RAF(V600E). We used PLX4032-resistant sub-lines artificially derived from B-RAF(V600E)-positive melanoma cell lines and validated key findings in PLX4032-resistant tumours and tumour-matched, short-term cultures from clinical trial patients. Induction of PDGFRβ RNA, protein and tyrosine phosphorylation emerged as a dominant feature of acquired PLX4032 resistance in a subset of melanoma sub-lines, patient-derived biopsies and short-term cultures. PDGFRβ-upregulated tumour cells have low activated RAS levels and, when treated with PLX4032, do not reactivate the MAPK pathway significantly. In another subset, high levels of activated N-RAS resulting from mutations lead to significant MAPK pathway reactivation upon PLX4032 treatment. Knockdown of PDGFRβ or N-RAS reduced growth of the respective PLX4032-resistant subsets. Overexpression of PDGFRβ or N-RAS(Q61K) conferred PLX4032 resistance to PLX4032-sensitive parental cell lines. Importantly, MAPK reactivation predicts MEK inhibitor sensitivity. Thus, melanomas escape B-RAF(V600E) targeting not through secondary B-RAF(V600E) mutations but via receptor tyrosine kinase (RTK)-mediated activation of alternative survival pathway(s) or activated RAS-mediated reactivation of the MAPK pathway, suggesting additional therapeutic strategies.     

Influence of growth conditions on the electrochemical synthesis of SnS thin films and their optical properties

Tin sulfide (SnS) thin films were prepared by electrodeposition onto fluorine-doped tin oxide (FTO) glass substrates using an aqueous solution containing SnCl₂ and Na₂S₂O₃ at various deposition potentials (E) and bath concentrations. The pH value and temperature of the solution were kept constant. The deposited films were characterized using X-ray diffraction (XRD), field-emission scanning electron microscopy (FESEM), photoluminescence (PL), and ultraviolet–visible (UV–Vis) spectroscopy. The FESEM images demonstrated that changes in the deposition potential (E) and solution concentration led to marked changes in the morphology of the deposited SnS films. Energy-dispersive X-ray analysis (EDXA) results showed that the Sn/S atomic ratio strongly depended on both the solution concentration and the deposition potential. To obtain an Sn/S atomic ratio approximately equal to 1, the optimal Sn2+/S₂O₃2- molar ratio and E parameter were 1/8 and -1.0 V, respectively. The XRD patterns showed that the synthesized SnS was obviously polycrystalline, with an orthorhombic structure. The effects of the variations of bath concentration and deposition potential on the band-gap energy (E_g) were studied using PL and UV–Vis experiments. The PL spectra of all the SnS films contained two peaks in the visible region and one peak in the infrared (IR) region. The UV–Vis spectra showed that the optical band-gap energy varies from 1.21 to 1.44 eV.     

A Soft Systems Methodology Approach to Occupational Cancer Control Problem: a Case Study of the Ministry of Petroleum of Iran

Petroleum industries of Iran offer some of the best job opportunities within Iranian labor market. However, due to the attributes of the chemicals used in these industries, their staffs are exposed to various risk factors of several chronic diseases. Such exposures might lead to cancer incidence after a decade or two. The Ministry of Petroleum (MoP) runs an organization, namely Petroleum Industry Health Organization (PIHO), which is responsible for the health insurance of the personnel working in Petroleum industries. PIHO and Health, Safety & Environment (HSE) units play fundamental roles in providing the employees with health services during their professional life and retirement period. Yet, these organizations still do not have a system to specify occupational cancer control mechanisms at the MoP. The negative influences of cancer on patients suffering from it as well as its heavy costs of treatment have forced MoP to put measures of coping with this chronic disease in the first priority. This paper aims to define the structure and design a framework for MoP’s occupational cancer control problem as the first step for improving the described situation. Given the presence of various stakeholders and actors, and the wide range of complexities of this problematic situation, we have adopted Soft System Methodology (SSM). We have reached an agreement with the problem owners on a rich picture, CATWOE analysis, root definition and a conceptual model for the way this situation could improve within real world circumstances. The results were obtained through various sessions with practitioner from different departments of MoP, while the conflict of interests was common.     

Complement factor 5 is a quantitative trait gene that modifies liver fibrogenesis in mice and humans

Fibrogenesis or scarring of the liver is a common consequence of all chronic liver diseases. Here we refine a quantitative trait locus that confers susceptibility to hepatic fibrosis by in silico mapping and show, using congenic mice and transgenesis with recombined artificial chromosomes, that the gene Hc (encoding complement factor C5) underlies this locus. Small molecule inhibitors of the C5a receptor had antifibrotic effects in vivo, and common haplotype-tagging polymorphisms of the human gene C5 were associated with advanced fibrosis in chronic hepatitis C virus infection. Thus, the mouse quantitative trait gene led to the identification of an unknown gene underlying human susceptibility to liver fibrosis, supporting the idea that C5 has a causal role in fibrogenesis across species.