Despite the prominent pro-apoptotic role of p53, this protein has also been shown to promote cell survival in response to metabolic stress. However, the specific mechanism by which p53 protects cells from metabolic stress-induced death is unknown. Earlier we reported that carnitine palmitoyltransferase 1C (CPT1C), a brain-specific member of a family of mitochondria-associated enzymes that have a central role in fatty acid metabolism promotes cell survival and tumor growth. Unlike other members of the CPT family, the subcellular localization of CPT1C and its cellular function remains elusive. Here, we report that CPT1C is a novel p53-target gene with a bona fide p53-responsive element within the first intron. CPT1C is upregulated in vitro and in vivo in a p53-dependent manner. Interestingly, expression of CPT1C is induced by metabolic stress factors such as hypoxia and glucose deprivation in a p53 and AMP activated kinase-dependent manner. Furthermore, in a murine tumor model, depletion of Cpt1c leads to delayed tumor development and a striking increase in survival. Taken together, our results indicate that p53 protects cells from metabolic stress via induction of CPT1C and that CPT1C may have a crucial role in carcinogenesis. CPT1C may therefore represent an exciting new therapeutic target for the treatment of hypoxic and otherwise treatment-resistant tumors. Hypoxia is an important chronic stress on tumor cell growth and has been shown to correlate with poor disease-free and reduced overall survival in a variety of carcinomas and sarcomas. 1 To enhance survival in an altered environment such as hypoxia cancer cells undergo a so-called metabolic transformation. [2][3][4] The best-known aspect of metabolic transformation is the Warburg effect, whereby cancer cells upregulate glycolysis to limit their energy consumption. However, there is increasing evidence that not only glucose metabolism, but also fatty acid oxidation (FAO) is involved in metabolic transformation. Although glucose seems to be the major energy source for tumor growth and survival, there is increasing evidence that alternative energy sources such as fatty acid metabolism are altered in cancer cells, even under hypoxic conditions. Indeed, fatty acid synthase has been found to be upregulated in many human cancers, 5 and inhibitors of the fatty acid synthase show antitumor activity. 6 As recently published, we identified carnitine palmitoyltransferase (CPT) 1C (CPT1C) as a potential novel p53-target gene. 7 By their restriction of fatty acid import into mitochondria, 4 the CPT 1 (CPT1) family of enzymes represent key regulatory factors of FAO. There are three tissue-specific isoforms of CPT1: CPT1A that is found in liver, CPT1B in muscle and CPT1C in brain and testes. Loss-of-function of CPT1C was generated in mouse embryonic stem cells (Cpt1c gt/gt ES cells). Importantly, Cpt1c gt/gt ES cells readily succumbed to cell death under hypoxic conditions, whereas control cells were resistant. ES cells deficient for CPT1C showed a spontaneous induction in...

Background Fat grafting has been gaining attention in tissue augmentation over the past decade, not only for lipofilling, but also for its observed regenerative properties and overall skin texture improvement. Objectives The aim of this study was to analyze the effect of nanofat grafting on scars, wrinkles, and skin discolorations in our clinic. Methods Nanofat was prepared by a standard emulsification and filtration protocol. The resulting liquid was injected intradermally or directly into the scar tissue. Skin quality was evaluated based on a scoring system, and patient satisfaction was documented. Three physicians compared and analyzed standardized pre-and posttreatment photographs in respect to general improvement of skin aesthetics. Results Fifty-two patients were treated with nanofat from November 2013 to April 2016. The mean (± standard deviation) posttreatment follow up was 155 ± 49 days and average volume of harvested fat amounted to 165 cc. The primary harvesting areas were the abdomen and flanks, and the injected volume of nanofat ranged from 1 to 25 mL (mean, 4.6 mL). A total of 40 scars (76% of all patient defects) were effectively treated as well as 6 patients with wrinkles, and 6 patients with discoloration. Posttreatment clinical evaluations showed a marked improvement of scar quality and a high patient satisfaction. The results in our clinic showed that nanofat grafting softened the scars, made discolorations less pronounced, and wrinkles appeared less prominent. Conclusions Nanofat grafting has been shown to have beneficial effects in the treatment of scars, wrinkles, and skin discolorations. Level of Evidence 4

Background: The treatment of extensive skin defects and bradytrophic wounds remains a challenge in clinical practice. Despite emerging tissue engineering approaches, skin grafts and dermal substitutes are still the routine procedure for the majority of skin defects. Here, we review the role of vascularization and lymphangiogenesis for skin grafting and dermal substitutes from the clinician’s perspective. Summary: Graft revascularization is a dynamic combination of inosculation, angiogenesis, and vasculogenesis. The majority of a graft’s microvasculature regresses and is replaced by ingrowing microvessels from the wound bed, finally resulting in a chimeric microvascular network. After inosculation within 48–72 h, the graft is re-oxygenated. In contrast to skin grafts, the vascularization of dermal substitutes is slow and dependent on the ingrowth of vessel-forming angiogenic cells. Preclinical angiogenic strategies with adipose tissue-derived isolates are appealing for the treatment of difficult wounds and may markedly accelerate skin reconstruction in the future. However, their translation from bench to bedside is still restricted by major regulatory restrictions. Finally, the lymphatic system contributes to edema reduction and the removal of local wound debris. Therapeutic lymphangiogenesis is an emerging field of research in skin reconstruction. Key Messages: For the successful engraftment of skin grafts and dermal substitutes, the rapid formation of a microvascular network is of pivotal importance. Hence, to understand the biological processes behind revascularization of skin substitutes and to implement this knowledge into clinical practice is a prerequisite when treating skin defects. Furthermore, a functional lymphatic drainage crucially contributes to the engraftment of skin substitutes.

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