Role of ferroptosis in radiation-induced soft tissue injury.

Ionizing radiation has been pivotal in cancer therapy since its discovery. Despite its therapeutic benefits, IR causes significant acute and chronic complications due to DNA damage and the generation of reactive oxygen species, which harm nucleic acids, lipids, and proteins. While cancer cells are more vulnerable to ionizing radiation due to their inefficiency in repairing damage, healthy cells in the irradiated area also suffer. Various types of cell death occur, including apoptosis, necrosis, pyroptosis, autophagy-dependent cell death, immunogenic cell death, and ferroptosis. Ferroptosis, driven by iron-dependent lipid peroxide accumulation, has been recognized as crucial in radiation therapy's therapeutic effects and complications, with extensive research across various tissues. This review aims to summarize the pathways involved in radiation-related ferroptosis, findings in different organs, and drugs targeting ferroptosis to mitigate its harmful effects.

Deferoxamine topical cream superior to patch in rescuing radiation-induced fibrosis of unwounded and wounded skin.

Topical patch delivery of deferoxamine (DFO) has been studied as a treatment for this fibrotic transformation in irradiated tissue. Efficacy of a novel cream formulation of DFO was studied as a RIF therapeutic in unwounded and excisionally wounded irradiated skin. C57BL/6J mice underwent 30 Gy of radiation to the dorsum followed by 4 weeks of recovery. In a first experiment, mice were separated into six conditions: DFO 50 mg cream (D50), DFO 100 mg cream (D100), soluble DFO injections (DI), DFO 1 mg patch (DP), control cream (Vehicle), and irradiated untreated skin (IR). In a second experiment, excisional wounds were created on the irradiated dorsum of mice and then divided into four treatment groups: DFO 100 mg Cream (W-D100), DFO 1 mg patch (W-DP), control cream (W-Vehicle), and irradiated untreated wounds (W-IR). Laser Doppler perfusion scans, biomechanical testing, and histological analysis were performed. In irradiated skin, D100 improved perfusion compared to D50 or DP. Both D100 and DP enhanced dermal characteristics, including thickness, collagen density and 8-isoprostane staining compared to untreated irradiated skin. D100 outperformed DP in CD31 staining, indicating higher vascular density. Extracellular matrix features of D100 and DP resembled normal skin more closely than DI or control. In radiated excisional wounds, D100 facilitated faster wound healing and increased perfusion compared to DP. The 100 mg DFO cream formulation rescued RIF of unwounded irradiated skin and improved excisional wound healing in murine skin relative to patch delivery of DFO.

Pharmacological and cell-based treatments to increase local skin flap viability in animal models.

Local skin flaps are frequently employed for wound closure to address surgical, traumatic, congenital, or oncologic defects. (1) Despite their clinical utility, skin flaps may fail due to inadequate perfusion, ischemia/reperfusion injury (IRI), excessive cell death, and associated inflammatory response. (2) All of these factors contribute to skin flap necrosis in 10-15% of cases and represent a significant surgical challenge. (3, 4) Once flap necrosis occurs, it may require additional surgeries to remove the entire flap or repair the damage and secondary treatments for infection and disfiguration, which can be costly and painful. (5) In addition to employing appropriate surgical techniques and identifying healthy, well-vascularized tissue to mitigate the occurrence of these complications, there is growing interest in exploring cell-based and pharmacologic augmentation options. (6) These agents typically focus on preventing thrombosis and increasing vasodilation and angiogenesis while reducing inflammation and oxidative stress. Agents that modulate cell death pathways such as apoptosis and autophagy have also been investigated. (7) Implementation of drugs and cell lines with potentially beneficial properties have been proposed through various delivery techniques including systemic treatment, direct wound bed or flap injection, and topical application. This review summarizes pharmacologic- and cell-based interventions to augment skin flap viability in animal models, and discusses both translatability challenges facing these therapies and future directions in the field of skin flap augmentation.

Quality Assessment of Online Resources for Gender-affirming Surgery.

Background: As visibility of the transgender patient population and utilization of online resources increases, it is imperative that web-based gender-affirming surgery (GAS) materials for patients are readable, accessible, and of high quality. Methods: A search trends analysis was performed to determine frequency of GAS-related searches over time. The top 100 most common results for GAS-related terms were analyzed using six readability formulas. Accessibility of patient-facing GAS sources was determined by categorizing types of search results. Frequency of article types was compared in low- and high-population dense areas. Quality was assigned to GAS web-based sources using the DISCERN score. Results: Search engine trend data demonstrates increasing occurrence of searches related to GAS. Readability scores of the top 100 online sources for GAS were discovered to exceed recommended levels for patient proficiency. Availability of patient-facing online information related to GAS was found to be 60%, followed by information provided by insurance companies (17%). Differences in availability of online resources in varying dense cities were found to be minimal. The average quality of sources determined by the DISCERN score was found to be 3, indicating "potential important shortcomings." Conclusions: Despite increasing demand for web-based GAS information, the readability of online resources related to GAS was found to be significantly greater than the grade level of proficiency recommended for patients. A high number of nonpatient-facing search results appear in response to GAS search terms. Quality sources are still difficult for patients to find, as search results have a high incidence of low-quality resources.

Adipose-Derived Stromal Cell-Based Therapies for Radiation-Induced Fibrosis.

Significance: Half of all cancer patients receive radiation therapy as a component of their treatment regimen, and the most common resulting complication is radiation-induced fibrosis (RIF) of the skin and soft tissue. This thickening of the dermis paired with decreased vascularity results in functional limitations and esthetic concerns and poses unique challenges when considering surgical exploration or reconstruction. Existing therapeutic options for RIF of the skin are limited both in scope and efficacy. Cell-based therapies have emerged as a promising means of utilizing regenerative cell populations to improve both functional and esthetic outcomes, and even as prophylaxis for RIF. Recent Advances: As one of the leading areas of cell-based therapy research, adipose-derived stromal cells (ADSCs) demonstrate significant therapeutic potential in the treatment of RIF. The introduction of the ADSC-augmented fat graft has shown clinical utility. Recent research dedicated to characterizing specific ADSC subpopulations points toward further granularity in understanding of the mechanisms driving the well-established clinical outcomes seen with fat grafting therapy. Critical Issues: Various animal models of RIF demonstrated improved clinical outcomes following treatment with cell-based therapies, but the cellular and molecular basis underlying these effects remains poorly understood. Future Directions: Recent literature has focused on improving the efficacy of cell-based therapies, most notably through (1) augmentation of fat grafts with platelet-rich plasma and (2) the modification of expressed RNA through epitranscriptomics. For the latter, new and promising gene targets continue to be identified which have the potential to reverse the effects of fibrosis by increasing angiogenesis, decreasing inflammation, and promoting adipogenesis.

Transdermal deferoxamine administration improves excisional wound healing in chronically irradiated murine skin.

BACKGROUND: Radiation-induced skin injury is a well-known risk factor for impaired wound healing. Over time, the deleterious effects of radiation on skin produce a fibrotic, hypovascular dermis poorly suited to wound healing. Despite increasing understanding of the underlying pathophysiology, therapeutic options remain elusive. Deferoxamine (DFO), an iron-chelating drug, has been shown in prior murine studies to ameliorate radiation-induced skin injury as well as improve wound healing outcomes in various pathologic conditions when administered transdermally. In this preclinical study, we evaluated the effects of deferoxamine on wound healing outcomes in chronically irradiated murine skin. METHODS: Wild-type mice received 30 Gy of irradiation to their dorsal skin and were left to develop chronic fibrosis. Stented excisional wounds were created on their dorsal skin. Wound healing outcomes were compared across 4 experimental conditions: DFO patch treatment, vehicle-only patch treatment, untreated irradiated wound, and untreated nonirradiated wounds. Gross closure rate, wound perfusion, scar elasticity, histology, and nitric oxide assays were compared across the conditions. RESULTS: Relative to vehicle and untreated irradiated wounds, DFO accelerated wound closure and reduced the frequency of healing failure in irradiated wounds. DFO augmented wound perfusion throughout healing and upregulated angiogenesis to levels observed in nonirradiated wounds. Histology revealed DFO increased wound thickness, collagen density, and improved collagen fiber organization to more closely resemble nonirradiated wounds, likely contributing to the observed improved scar elasticity. Lastly, DFO upregulated inducible nitric oxide synthase and increased nitric oxide production in early healing wounds. CONCLUSION: Deferoxamine treatment presents a potential therapeutic avenue through which to target impaired wound healing in patients following radiotherapy.