Skin-resident T cells sense ultraviolet radiation-induced injury and contribute to DNA repair.

Skin-resident T cells have been shown to play important roles in tissue homeostasis and wound repair, but their role in UV radiation (UVR)-mediated skin injury and subsequent tissue regeneration is less clear. In this study, we demonstrate that acute UVR rapidly activates skin-resident T cells in humans and dendritic epidermal γδ T cells (DETCs) in mice through mechanisms involving the release of ATP from keratinocytes. Following UVR, extracellular ATP leads to an increase in CD69 expression, proliferation, and IL-17 production, and to changes in DETC morphology. Furthermore, we find that the purinergic receptor P2X7 and caspase-1 are necessary for UVR-induced IL-1 production in keratinocytes, which increases IL-17 secretion by DETCs. IL-17, in turn, induces epidermal TNF-related weak inducer of apoptosis and growth arrest and DNA damage-associated gene 45, two molecules linked to the DNA repair response. Finally, we demonstrate that DETCs and human skin-resident T cells limit DNA damage in keratinocytes. Taken together, our findings establish a novel role for skin-resident T cells in the UVR-associated DNA repair response and underscore the importance of skin-resident T cells to overall skin regeneration.

An Unmet Need: Surgical Gloves with Variable Finger Lengths.

Sterile gloves are essential for plastic surgery, but little research has been published on glove fit. Sterile gloves are produced by all manufacturers, with finger lengths fixed for all sizes. Many wearers have fingers that are shorter or longer than usual, causing functional limitations due to incorrect glove finger length and fingertip fit. Methods: A multiquestion confidential electronic survey of glove finger length fit was sent to 6810 plastic surgery glove wearers from three organizations: American Society of Plastic Surgeons, International Society of Plastic and Aesthetic Nurses, and Association of Plastic Surgery Physician Assistants. Data were collected for this descriptive study in 2020-2021, and statistical analyses were performed using SPSS (version 27). Sample gloves from six brands were directly measured for finger length. Results: The survey yielded 500 responses, with some respondents not answering all questions. The response rate from American Society of Plastic Surgeons members was 8.2%, and was 7.3% from all groups combined. The most common reason for glove finger length dissatisfaction was fingers being too long (41.61%). Although there was variation in measured glove finger lengths, the variation was not uniform. Of all responders, 28.6% were very likely, and 16.16%, moderately likely, to want to use gloves with longer or shorter fingers if available, constituting a total of 44. 76%. Of these, 36.55% would pay increased cost (10%-25%) for such gloves. Conclusions: A high percentage of glove users would want gloves with variable finger lengths. Current surgical gloves do not support hand anatomy variations.

Hspa8 and ICAM-1 as damage-induced mediators of γδ T cell activation.

Tissue-resident γδ T cells form the first line of defense at barrier surfaces where they survey host tissue for signs of stress or damage. Following recognition of injury, γδ T cells play a crucial role in the wound-healing response through the production of growth factors and cytokines that promote proliferation in surrounding epithelial cells. To initiate this response, γδ T cells require interactions with a variety of epithelial-expressed costimulatory molecules in addition to primary signaling through their TCR. In the epidermis these signals include the coxsackie and adenovirus receptor (CAR), histocompatibility antigen 60c (H60c), and plexin B2, which interact with γδ T cell-expressed junctional adhesion molecule-like protein (JAML), NKG2D, and CD100, respectively. Here we identify heat shock protein family A member 8 (Hspa8) and ICAM-1 as two additional keratinocyte-expressed costimulatory molecules for epidermal resident γδ T cells (termed DETC). These molecules were rapidly up-regulated in the epidermis following wounding in both mouse and human tissue. Both Hspa8 and ICAM-1 had a costimulatory effect on DETC, inducing proliferation, CD25 up-regulation, and IL-2 production. We also provide evidence that DETC can be activated through the potential ICAM-1 and Hspa8 receptors LFA-1 and CD316. Finally, knockdown of Hspa8 in keratinocytes reduced their ability to activate DETC in culture and ICAM-1-/- mice exhibited impaired rates of healing in skin-organ culture suggesting a role for these proteins in the DETC-mediated damage response. Together with previous work on CAR, H60c, and plexin B2, these results add to a picture of a complex keratinocyte wound signature that is required for efficient DETC activation.

ENTPD1 (CD39) Expression Inhibits UVR-Induced DNA Damage Repair through Purinergic Signaling and Is Associated with Metastasis in Human Cutaneous Squamous Cell Carcinoma.

UVR and immunosuppression are major risk factors for cutaneous squamous cell carcinoma (cSCC). Regulatory T cells promote cSCC carcinogenesis, and in other solid tumors, infiltrating regulatory T cells and CD8+ T cells express ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1) (also known as CD39), an ectoenzyme that catalyzes the rate-limiting step in converting extracellular adenosine triphosphate (ATP) to extracellular adenosine (ADO). We previously showed that extracellular purine nucleotides influence DNA damage repair. In this study, we investigate whether DNA damage repair is modulated through purinergic signaling in cSCC. We found increased ENTPD1 expression on T cells within cSCCs when compared with the expression on T cells from blood or nonlesional skin, and accordingly, concentrations of derivative extracellular adenosine diphosphate (ADP), adenosine monophosphate (AMP), and ADO are increased in tumors compared with those in normal skin. Importantly, ENTPD1 expression is significantly higher in human cSCCs that metastasize than in those that are nonmetastatic. We also identify in a mouse model that ENTPD1 expression is induced by UVR in an IL-27-dependent manner. Finally, increased extracellular ADO is shown to downregulate the expression of NAP1L2, a nucleosome assembly protein we show to be important for DNA damage repair secondary to UVR. Together, these data suggest a role for ENTPD1 expression on skin-resident T cells to regulate DNA damage repair through purinergic signaling to promote skin carcinogenesis and metastasis.

Calculation of silicone breast implant volumes using breast magnetic resonance imaging.

BACKGROUND: Patients needing silicone gel-filled breast implant surgical revision often do not have information as to the size of their implants. Clinical estimates may be erroneous and an accurate, in vivo method of determining breast implant volume would be very useful in planning surgery. OBJECTIVE: Our objective was to determine whether magnetic resonance imaging (MRI) scans of the breast in combination with a computer-assisted detection (CAD) system could provide accurate estimation of implant volumes in patients with silicone gel-filled implants, using known implant volumes for comparison. METHODS: All MRI scans were performed for medical necessity before implant revision surgery or for follow-up. Scans and silicone implant volume calculations were performed in 20 patients (39 breasts). Fifteen patients (n = 27 breasts) had known implant volumes. The MRI images were analyzed blindly by a single radiologist using the image processing features of an MRI CAD system (DynaCAD; Invivo, Birmingham, MI) in a novel way. Computed implant volumes were compared to known implant volumes obtained from documented preoperative notes (n = 17) or following implant removal via implant markings (n = 10). RESULTS: Average deviation of the 27 known implant volumes from those calculated by MRI DynaCAD analysis was only 0.82% (SD, 3.95%). In four of 27 breasts (14.8%), MRI calculations matched the clinical volumes exactly. The widest volume deviation range for all implants was +11.4% to -4.44%. A variety of implant types were found, with 11 confirmed ruptures. CONCLUSIONS: The calculation of silicone gel-filled breast implant volume using breast MRI scans and a commercially-available CAD system appears to be sufficiently accurate that it may have significant clinical benefit in planning revision implant surgery. Calculations can be easily obtained in five minutes. To our knowledge, this is the first report describing this method to reliably measure silicone implant volumes preoperatively.

Soft Tissue and Skin Reinforcement with Acellular Dermal Matrix to Protect Implanted Cardioverters/Defibrillators and Pacemakers.

Cardiac pacemakers and implantable cardioverters/defibrillators are often placed in older patients with thin skin and scanty subcutaneous tissue. These devices and cardiac leads are at risk for progressive skin erosion and exposure leading to infection. To prevent this severe complication, we developed a reinforcing insertion of acellular dermal matrix. Twenty-two of 24 patients had successful implantation with long-term avoidance of skin erosion.

Alterations in fibroblast alpha1beta1 integrin collagen receptor expression in keloids and hypertrophic scars.

Keloids and hypertrophic scars are significant symptomatic clinical problems characterized by excess collagen. Although extensive research has focused on fibroblasts and collagen turnover in these aberrant scars, little work has been done on the expression of integrins (cell membrane structures that link cells to extracellular matrix) within these lesions. Integrin-mediated regulation of collagen synthesis has previously been observed in explanted fibroblasts from normal and fibrotic dermis, and integrin alpha1 knockout mice maintain increased collagen synthesis consistent with a role for alpha1beta1 in providing negative feedback on collagen synthesis. These findings suggested the need to evaluate integrin roles in keloids and hypertrophic scars. In this study we examined integrin expression in keloids (n = 11), hypertrophic scars (n = 5), radiation ulcers (n = 2), and normal skin specimens (n = 8). We used a novel approach to analysis by isolating dermal fibroblasts directly from tissue (without explant culture) and determining surface integrin expression by flow cytometry. We found that keloids and hypertrophic scars have marked alterations in fibroblast integrin expression and contain several distinct populations of fibroblasts. One of these populations expresses high levels of alpha1 integrin, and the proportion of these cells is higher in keloids (63% +/- 3.6% SEM) and hypertrophic scars (45% +/- 2.7% SEM) than in normal skin tissues (28% +/- 4.7% SEM). The different populations of fibroblasts defined by integrin expression merge, however, when the cells are serially cultured, suggesting that there may be aspects of the dermal microenvironment that maintain the integrin phenotypic heterogeneity in dermal fibroblasts.

Salvage of pacemakers and automatic implantable cardioverter-defibrillators using dermis grafts.

BACKGROUND: Thin patients with thoracic pacemakers and automatic implantable cardioverter-defibrillators often have minimal tissue over the devices, with erosion through the surface a major concern. This erosion can lead to device infection and need for removal, or primary device infection can, in turn, lead to erosion. Even worse is exposure and infection of the leads to the heart, with fatalities having occurred. Pressure symptoms, as with shoulder seatbelt straps, can occur, and the visible deformity may be objectionable. METHODS: To correct these problems without device removal, we used a novel surgical approach. Thirteen patients had 15 grafts, of either the acellular dermal graft AlloDerm (LifeCell Corp, Branchburg, NJ [n = 13 for threatened exposure or pressure symptoms, including two repeats]) or autogenous dermis (n = 2 for existing open wounds with chronic drainage) placed over the devices. RESULTS: After all graft procedures, there was no skin breakdown; exposure and extrusion were completely prevented. Follow-up was 3 to 68 months (mean 36.8). The 2 open wound patients treated with dermis autografts had no recurrence of wound breakdown. Most patients with pressure symptoms had reduction in tenderness and pain. Patients liked the visible softening of the device contour, but not the subtly increased forward projection. The only immediate complication was one rapidly expanding hematoma leading to graft removal. One late complication was a mild infection, treated successfully. CONCLUSIONS: Acellular human dermal allografts, or live dermis autografts, provided significant protection over cardiac pacing devices in 13 patients with 15 grafts, with no subsequent surface exposures or extrusions.

A role for human skin-resident T cells in wound healing.

Epidermal T cells have been shown to play unique roles in tissue homeostasis and repair in mice through local secretion of distinct growth factors in the skin. Human epidermis contains both alphabeta(+) and gammadelta(+) T cells whose functional capabilities are not understood. We demonstrate that human epidermal T cells are able to produce insulin-like growth factor 1 (IGF-1) upon activation and promote wound healing in a skin organ culture model. Moreover, an analysis of the functional capabilities of T cells isolated from acute versus chronic wounds revealed a striking difference. Both alphabeta(+) and Vdelta1(+) T cells isolated from acute wounds actively produced IGF-1, demonstrating that they are activated during tissue damage to participate in wound repair. In contrast, IGF-1 production could not be detected in T cells isolated from chronic wounds. In fact, skin T cells isolated from chronic wounds were refractory to further stimulation, suggesting an unresponsive state. Collectively, these results define a novel role for human epidermis-resident T cells in wound healing and provide new insight into our understanding of chronic wound persistence.

Reduction of pacemaker pressure symptoms using nonantigenic preserved human dermis grafts.

Skin pressure symptoms can occur in thin patients with pacemakers, with erosion through the skin surface a possibility. To correct this problem without device removal, two patients had nonantigenic preserved human dermis grafts placed over their pacemakers. This acellular nonantigenic human dermal substitute provided significant thickness over the devices and improvement in pressure symptoms.

Cultured pressure ulcer fibroblasts show replicative senescence with elevated production of plasmin, plasminogen activator inhibitor-1, and transforming growth factor-beta1.

In a 16-patient study, cultured fibroblast populations from normal skin were able to replicate an average of 14.8 +/- 2.2 times before becoming senescent, while fibroblast populations from the ulcer bed reached the end of their replicative life span after 7.2 +/- 1.9 population doublings (p= 0.001). Fibroblast populations from 10 of 16 pressure ulcers became senescent after fewer than five population doublings, whereas when populations of fibroblasts from adjacent normal skin were studied, only 2 of 16 became senescent within this same time period. In addition, only an occasional fibroblast from normal skin stained positively for senescence-associated beta-galactosidase compared to approximately 50% of equally aged ulcer bed fibroblasts (p = 0.0060). Senescent ulcer bed fibroblasts secreted significantly more plasmin than early passage ulcer bed fibroblasts (p= 0.0237), nearly six times as much plasmin as early passage normal skin fibroblasts (p < 0.0001), three and a half times the level of normal skin fibroblasts of the same age (11.52 +/- 4.58 microg/mg protein; p= 0.0003), and more than one and a half times the level of senescent normal skin fibroblasts (p= 0.0525). Senescent pressure ulcer fibroblasts generated significantly more plasminogen activator inhibitor-1 (1179.27 +/- 25.37 ng/mg protein) than normal skin fibroblasts of the same age (132.16 +/- 16.20 ng/mg protein; p = 0.0357). Also, senescent ulcer bed fibroblasts produced higher levels of transforming growth factor-beta1, but these were not significantly different from senescent normal skin fibroblasts. Although senescent ulcer fibroblasts produce elevated levels of plasminogen activator inhibitor-1 and transforming growth factor-beta1, the ratio of these factors to plasmin levels suggests that this may have little influence on extracellular matrix synthesis or maintenance in the chronic wound. These data show that cultured fibroblasts from most patient pressure ulcers profile a wound environment that is associated with an increasing population of senescent fibroblasts; however, factors within the chronic wound environment that promote cellular senescence remain unclear. We have proposed that a prolonged inflammatory response may be a contributing factor to the chronic wound condition.

Squamous cell carcinoma of the skin.

LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Identify the subtypes of squamous cell carcinoma of the skin. 2. Identify factors that affect recurrence and/or metastasis. 3. Develop a surgical management plan for treating high-risk squamous cell carcinoma of the skin. In treating squamous cell carcinoma of the skin, a key concept in proper management is understanding why certain tumors are more prone to both recurrence and metastasis. When developing a surgical management plan, an understanding of "high risk" is essential. This article concentrates on identifying those tumor subtypes and factors that may serve as predictors of high-risk status as well as on providing management suggestions.