ABSTRACT
Rhabdomyosarcoma (RMS) is a solid tumor whose metastatic progression can be accelerated through interleukin-4 receptor alpha (Il4ra) mediated interaction with normal muscle stem cells (satellite cells). To understand the function of Il4ra in this tumor initiation phase of RMS, we conditionally deleted Il4ra in genetically-engineered RMS mouse models. Nullizygosity of Il4ra altered the latency, site and/or stage distribution of RMS tumors compared to IL4RA intact models. Primary tumor cell cultures taken from the genetically-engineered models then used in orthotopic allografts further defined the interaction of satellite cells and RMS tumor cells in the context of tumor initiation: in alveolar rhabdomyosarcoma (ARMS), satellite cell co-injection was necessary for Il4ra null tumor cells engraftment, whereas in embryonal rhabdomyosarcoma (ERMS), satellite cell co-injection decreased latency of engraftment of Il4ra wildtype tumor cells but not Il4ra null tumor cells. When refocusing on Il4ra wildtype tumors by single cell sequencing and cytokine studies, we have uncovered a putative signaling interplay of Il4 from T-lymphocytes being received by Il4ra + rhabdomyosarcoma tumor cells, which in turn express Ccl2, the ligand for Ccr2 and Ccr5. Taken together, these results suggest that mutations imposed during tumor initiation have different effects than genetic or therapeutic intervention imposed once tumors are already formed. We also propose that CCL2 and its cognate receptors CCR2 and/or CCR5 are potential therapeutic targets in Il4ra mediated RMS progression.
ABSTRACT
Inherently safer design (ISD) concepts have been with us for over two decades since their elaboration by Kletz [Chem. Ind. 9 (1978) 124]. Interest has really taken off globally since the early nineties after several major mishaps occurred during the eighties (Bhopal, Mexico city, Piper-alfa, Philips Petroleum, to name a few). Academic and industrial research personnel have been actively involved into devising inherently safer ways of production. The regulatory bodies have also shown deep interest since ISD makes the production safer and hence their tasks easier. Research funding has also been forthcoming for new developments as well as for demonstration projects.A natural question that arises is as to how to measure ISD characteristics of a process? Several researchers have worked on this [Trans. IChemE, Process Safety Environ. Protect. B 71 (4) (1993) 252; Inherent safety in process plant design, Ph.D. Thesis, VTT Publication Number 384, Helsinki University of Technology, Espoo, Finland, 1999; Proceedings of the Mary Kay O'Connor Process Safety Center Symposium, 2001, p. 509]. Many of the proposed methods are very elegant, yet too involved for easy adoption by the industry which is scared of yet another safety analysis regime. In a recent survey [Trans. IChemE, Process Safety Environ. Prog. B 80 (2002) 115], companies desired a rather simple method to measure ISD. Simplification is also an important characteristic of ISD. It is therefore desirable to have a simple ISD measurement procedure. The ISD measurement procedure proposed in this paper can be used to differentiate between two or more processes for the same end product. The salient steps are: Consider each of the important parameters affecting the safety (e.g., temperature, pressure, toxicity, flammability, etc.) and the range of possible values these parameters can have for all the process routes under consideration for an end product. Plot these values for each step in each process route and compare. No addition of values for disparate hazards (temperature, pressure, inventory, toxicity, flammability, etc.) is being suggested to derive an overall ISD index value since that conceals the effects of different parameters. Further, addition of numbers with different units ( degrees C for temperature, atm/bar for pressure, t for inventory, etc.) is inappropriate in scientific sense. The proposed approach has a major advantage of expanding consideration in future to incorporate economic, regulatory, pollution control and worker health aspects, as well as factors such as the experience one has or 'the comfort level' one feels with each of the processes under consideration. Additionally, it would also guide the designers and decision makers into affecting specific changes in the processes to reduce the unsafe features. We demonstrate our simple approach by using the example of six routes to make methyl methacrylate as documented by Edwards and Lawrence [Trans. IChemE, Process Safety Environ. Protect. B 71 (4) (1993) 252; Quantifying inherent safety of chemical process routes, Ph.D. Thesis, Loughborough University, Loughborough, UK, 1996] and show that the decision could well have been different if addition of disparate hazards had not been done.
