Hot perforation melts a hole in the material, causing a reinforced ring around the hole. Hot needle perforation also assists when high density pin patterns are utilized, as the heat aids the perforation of the material. Die and punch
Die and punch sets can be used for thicker materials or materials that require large holes; this process is the most common for metalworking. The workpiece is sheared by pressing (either by machine or hand tool) the punch through the workpiece and into the die. The middle section of the workpiece is scrap; commonly known as the chad in paper and similar materials. The punch and die are shaped to produce the desired shaped hole. The clearance (the distance between the outside circumference of the punch and the inner circumference of the die) must be properly maintained to ensure a clean cut. Burrs are produced on the side of the workpiece that is against the die.Common applications are fruit and vegetable bags, hole punching and ticket punching. Laser perforation
Laser cutting can place many precise holes in a web. Laser perforations look similar in many respects to hot needle perforations. However, laser systems are expensive. The big advantage of laser perforation is the consistency of the hole size, compared to mechanical perforation. This is very important in modified atmosphere packaging for fresh produce. The laser perforation is often carried out on roll slitting machines (slitter rewinder) as the printed material is slit down to the finished roll size.
This is irreversible and leads to cell apoptosis.Cyclophosphamide has relatively little typical chemotherapy toxicity as ALDHs are present in relatively large concentrations in bone marrow stem cells, liver and intestinal epithelium. ALDHs protect these actively proliferating tissues against toxic effects of phosphoramide mustard and acrolein by converting aldophosphamide to carboxycyclophosphamide that does not give rise to the toxic metabolites phosphoramide mustard and acrolein. This is because carboxycyclophosphamide cannot undergo β-elimination (the carboxylate acts as an electron-donating group, nullifying the potential for transformation), preventing nitrogen mustard activation and subsequent alkylation.Cyclophosphamide induces beneficial immunomodulatory effects in adaptive immunotherapy. Suggested mechanisms include:
Elimination of T regulatory cells (CD4+CD25+ T cells) in naive and tumor-bearing hosts
Induction of T cell growth factors, such as type I IFNs, and/or
Enhanced grafting of adoptively transferred, tumor-reactive effector T cells by the creation of an immunologic space niche.Thus, cyclophosphamide preconditioning of recipient hosts (for donor T cells) has been used to enhance immunity in naïve hosts, and to enhance adoptive T cell immunotherapy regimens, as well as active vaccination strategies, inducing objective antitumor immunity. History
As reported by O. M. Colvin in his study of the development of cyclophosphamide and its clinical applications,

Phosphoramide mustard, one of the principal toxic metabolites of cyclophosphamide, was synthesized and reported by Friedman and Seligman in 1954 …It was postulated that the presence of the phosphate bond to the nitrogen atom could inactivate the nitrogen mustard moiety, but the phosphate bond would be cleaved in gastric cancers and other tumors which had a high phosphamidase content.