Previous work has shown that cisplatin (CDDP) becomes concentrated in lysosomes, and that acquired resistance to CDDP is associated with abnormalities of protein trafficking and secretion. The lysosomal compartment in CDDP-sensitive 2008 human ovarian carcinoma cells was compared with that in CDDP-resistant 2008/

Summary Scar formation is a major medical problem that can have devastating consequences for patients. The adverse physiological and psychological effects of scars are broad, and there are currently no reliable treatments to prevent scarring. In contrast to adult wounds, early gestation fetal skin wounds repair rapidly and in the absence of scar formation. Despite extensive investigation, the exact mechanisms of scarless fetal wound healing remain largely unknown. For some time, it has been known that significant differences exist among the extracellular matrix, inflammatory response, cellular mediators, and gene expression profiles of fetal and postnatal wounds. These differences may have important implications in scarless wound repair.

ATP7B is a P-type ATPase that mediates the efflux of copper. Recent studies have demonstrated that ATP7B regulates the cellular efflux of cisplatin (DDP) and controls sensitivity to the cytotoxic effects of this drug. To determine whether DDP is a substrate for ATP7B, DDP transport was assayed in vesicles isolated from Sf9 cells infected with a baculovirus that expressed either the wild-type ATP7B or a mutant ATP7B that was unable to transport copper as a result of conversion of the transmembrane metal binding CPC motif to CPA. Only the wild-type ATP7B-expressing vesicles exhibited copper-dependent ATPase activity, copper-induced acyl-phosphate formation, and ATP-dependent transport of copper. The amount of DDP that became bound was higher for vesicles expressing either type of ATP7B than for those not expressing either form of ATP7B, but only the vesicles expressing wild-type ATP7B mediated ATP-dependent accumulation of the drug. At pH 4.6, the vesicles expressing the wild-type ATP7B exhibited ATPdependent accumulation of DDP with an apparent K m of 1.2 Ϯ 0.5 (S.E.M.) M and V max of 0.03 Ϯ 0.002 (S.E.M.) nmol/mg of protein/min. DDP also induced the acyl-phosphorylation of ATP7B but at a much slower rate than copper. Copper and DDP each inhibited the ATP-dependent transport of the other. These results establish that DDP is a substrate for ATP7B but is transported at a much slower rate than copper.

IntroductionNanoparticles (NPs) are small entities that consist of a hydroxyapatite core, which can bind ions, proteins, and other organic molecules from the surrounding environment. These small conglomerations can influence environmental calcium levels and have the potential to modulate calcium homeostasis in vivo. Nanoparticles have been associated with various calcium-mediated disease processes, such as atherosclerosis and kidney stone formation. We hypothesized that nanoparticles could have an effect on other calcium-regulated processes, such as wound healing. In the present study, we synthesized pH-sensitive calcium-based nanoparticles and investigated their ability to enhance cutaneous wound repair.MethodsDifferent populations of nanoparticles were synthesized on collagen-coated plates under various growth conditions. Bilateral dorsal cutaneous wounds were made on 8-week-old female Balb/c mice. Nanoparticles were then either administered intravenously or applied topically to the wound bed. The rate of wound closure was quantified. Intravenously injected nanoparticles were tracked using a FLAG detection system. The effect of nanoparticles on fibroblast contraction and proliferation was assessed.ResultsA population of pH-sensitive calcium-based nanoparticles was identified. When intravenously administered, these nanoparticles acutely increased the rate of wound healing. Intravenously administered nanoparticles were localized to the wound site, as evidenced by FLAG staining. Nanoparticles increased fibroblast calcium uptake in vitro and caused contracture of a fibroblast populated collagen lattice in a dose-dependent manner. Nanoparticles also increased the rate of fibroblast proliferation.ConclusionIntravenously administered, calcium-based nanoparticles can acutely decrease open wound size via contracture. We hypothesize that their contraction effect is mediated by the release of ionized calcium into the wound bed, which occurs when the pH-sensitive nanoparticles disintegrate in the acidic wound microenvironment. This is the first study to demonstrate that calcium-based nanoparticles can have a therapeutic benefit, which has important implications for the treatment of wounds.

Pressure injuries are one of the most common and costly complications occurring in US hospitals. With up to 3 million patients affected each year, hospital‐acquired pressure injuries (HAPIs) place a substantial burden on the US healthcare system. In the current study, US hospital discharge records from 9.6 million patients during the period from October 2009 through September 2014 were analysed to determine the incremental cost of hospital‐acquired pressure injuries by stage. Of the 46 108 patients experiencing HAPI, 16.3% had Stage 1, 41.0% had Stage 2, 7.0% had Stage 3, 2.8% had Stage 4, 7.3% had unstageable, 14.6% had unspecified, and 10.9% had missing staging information. In propensity score‐adjusted models, increasing HAPI severity was significantly associated with higher total costs and increased overall length of stay when compared with patients not experiencing a HAPI at the index hospitalisation. The average incremental cost for a HAPI was $21 767. Increasing HAPI severity was significantly associated with greater risk of in‐hospital mortality at the index hospitalisation compared with patients with no HAPI, as well as 1.5 to 2 times greater risk of 30‐, 60‐, and 90‐day readmissions. Additionally, increasing HAPI severity was significantly associated with increasing risk of other hospital‐acquired conditions, such as pneumonia, urinary tract infections, and venous thromboembolism during the index hospitalisation. By preventing pressure injuries, hospitals have the potential to reduce unreimbursed treatment expenditures, reduce length of stay, minimise readmissions, prevent associated complications, and improve overall outcomes for their patients.

Wound healing process is a complex and highly orchestrated process that ultimately results in the formation of scar tissue. Hypertrophic scar contracture is considered to be a pathologic and exaggerated wound healing response that is known to be triggered by repetitive mechanical forces. We now show that Transient Receptor Potential (TRP) C3 regulates the expression of fibronectin, a key regulatory molecule involved in the wound healing process, in response to mechanical strain via the NFkB pathway. TRPC3 is highly expressed in human hypertrophic scar tissue and mechanical stimuli are known to upregulate TRPC3 expression in human skin fibroblasts in vitro. TRPC3 overexpressing fibroblasts subjected to repetitive stretching forces showed robust expression levels of fibronectin. Furthermore, mechanical stretching of TRPC3 overexpressing fibroblasts induced the activation of nuclear factor-kappa B (NFκB), a regulator fibronectin expression, which was able to be attenuated by pharmacologic blockade of either TRPC3 or NFκB. Finally, transplantation of TRPC3 overexpressing fibroblasts into mice promoted wound contraction and increased fibronectin levels in vivo. These observations demonstrate that mechanical stretching drives fibronectin expression via the TRPC3-NFkB axis, leading to intractable wound contracture. This model explains how mechanical strain on cutaneous wounds might contribute to pathologic scarring.

More than 2.5 million people in the United States develop pressure injuries annually, which are one of the most common complications occurring in hospitals. Despite being common, hospital-acquired pressure injuries (HAPIs) are largely considered preventable by regular patient turning. Although current methodologies to prompt on-time repositioning have limited efficacy, a wearable patient sensor has been shown to optimize turning practices and improve clinical outcomes. The purpose of this study was to assess the cost-effectiveness of patient-wearable sensor in the prevention of HAPIs in acutely ill patients when compared to standard practice alone. A decision analytic model was developed to simulate the expected costs and outcomes from the payer’s perspective using data from published literature, including a recently published randomized controlled trial. Both univariate and probabilistic sensitivity analysis were conducted. The patient-wearable sensor was found to be cost saving (dominant). It resulted in better clinical outcomes (77% reduction in HAPIs) compared to standard care and an expected cost savings of $6,621 per patient over a one-year period. Applying the model to a cohort of 1,000 patients, an estimated 203 HAPIs would be avoided with annualized cost reduction of $6,222,884 through all patient treatment settings. The probabilistic analysis returned similar results. In conclusion, the patient-wearable sensor was found to be cost-effective in the prevention of HAPIs and cost-saving to payers and hospitals. These results suggest that patient-wearable sensors should be considered as a cost-effective alternative to standard care in the prevention of HAPIs.

In mammals, the early-gestation fetus has the regenerative ability to heal skin wounds without scar formation. This observation was first reported more than 3 decades ago, and has been confirmed in a number of in vivo animal models. Although an intensive research effort has focused on unraveling the mechanisms underlying scarless fetal wound repair, no suitable model of in vitro fetal skin healing has been developed. In this article, we report a novel model for the study of fetal wound healing. Fetal skin from gestational day 16.5 Balb/c mice (total gestation, 20 days) was grafted onto the chorioallantoic membrane of 12-day-old chicken embryos and cultured for up to 7 days. At 48 hours postengraftment, circular wounds (diameter = 1 mm) were made in the fetal skin using a rotating titanium sapphire laser (N = 45). The tissue was examined daily by visual inspection to look for signs of infection and ischemia. The grafts and the surrounding host tissue were examined histologically. In all fetal skin grafts, the wounds completely reepithelialized by postinjury day 7, with regeneration of the dermis. Fetal mouse skin xenografts transplanted onto the chorioallantoic membrane of fertilized chicken eggs provides a useful model for the study of fetal wound healing. This model can be used as an adjunct to traditional in vivo mammalian models of fetal repair.