Distant Skin Research Articles

TGFb-JMJD3 pathway regulates fibroblast to myofibroblast transition in wound repair

Abstract In normal wound healing, resident fibroblasts transition to myofibroblasts, which function to contract and close wounds. In pathologic conditions where wounds fail to heal (such as diabetes), fibroblasts do not increase myofibroblast gene expression; this mechanism is poorly understood. Using human wound scSeq and murine transgenic models, we examined the epigenetic mechanisms that may regulate this transition in the setting of injury. First, we identify that the cytokine TGFb increases myofibroblast genes in vitro. We performed an epigenetic superarray on TGFb-stimulated dermal fibroblasts, where JMJD3, an H3K27 demethylase, was significantly upregulated and was also confirmed by qPCR. ScSeq of human wounds identified JMJD3 as strongly upregulated in myofibroblasts. ChIP identified decreased H3K27me3, the activating mark of JMJD3 at myofibroblast genes further confirming its role in regulating myofibroblast genes. SiRNA knockdown of JMJD3 led to reduced myofibroblast gene expression. These findings were confirmed in a novel, tamoxifen induced, fibroblast specific knockout of JMJD3 unique to our lab. An unbaised superarray focused on remodelling and cell adhesion pathways identified that these mice have deficient levels of many structural and remodelling genes. Murine wounds were found to upregulate JMJD3 compared to distant skin, which was less pronounced in diabetic wounds. This work identifies JMJD3 as a TGFb-mediated regulator of fibroblast to myofibroblast transition.

Feeling the Heat. Mapping the Epigenetic Modifications of Histone during Burn Wound Healing.

Burn injuries are observed throughout a wide range of ages, with over 1.1 million Americans suffering burns yearly, and half of these require hospitalization. Epigenetic modifications are fast-acting mechanisms that allow the human body to respond and adapt to environmental changes, including burn injuries. There is a lack of understanding of the epigenetic role during burn-induced tissue repair. Here, we characterize the histone modifications that follow burn injury, aiming at future pharmacological intervention using drugs capable of targeting epigenetic events. A clinically relevant porcine burn model was used to recapitulate the skin healing process after the burn. Isolated skin tissues at different time points were used to detect the acetylation levels of histones H3K27, H4K5, H4K8, and H4K12 as significant players of gene transcription using MetaXpress High-Content Imaging Analysis. We observed that the acetylation of histones is dynamically adjusted throughout healing, and its modifications are uniquely expressed according to the anatomical location and time of healing. We also observed that histone H4K5 is the most widely expressed during healing, followed by histone H3K27. We observed that histones expressed in intact skin tissue adjacent to the burn site could sense the burn injury by changing its histone acetylation pattern compared to control skin from uninjured and distant skin. Using a clinically relevant animal model, we have generated a comprehensive landscape of epigenetic modifications during burn healing. Our data will help us identify novel epi-drugs capable of manipulating histone modifications during healing to accelerate the healing process.

Long-term Cancer Survival Trends by Updated Summary Stage.

Stage is the most important prognostic factor for understanding cancer survival trends. Summary stage (SS) classifies cancer based on the extent of spread: In situ, Localized, Regional, or Distant. Continual updating of staging systems poses challenges to stage comparisons over time. We use a consistent summary stage classification and present survival trends for 25 cancer sites using the joinpoint survival (JPSurv) model. We developed a modified summary stage variable, Long-Term Site-Specific Summary Stage, based on as consistent a definition as possible and applied it to a maximum number of diagnosis years, 1975-2019. We estimated trends by stage by applying JPSurv to relative survival data for 25 cancer sites in SEER-8, 1975-2018, followed through December 31, 2019. To help interpret survival trends, we report incidence and mortality trends using the joinpoint model. Five-year relative survival improved for nearly all sites and stages. Large improvements were observed for localized pancreatic cancer [4.25 percentage points annually, 2007-2012 (95% confidence interval, 3.40-5.10)], distant skin melanoma [2.15 percentage points annually, 2008-2018 (1.73-2.57)], and localized esophagus cancer [1.18 percentage points annually, 1975-2018 (1.11-1.26)]. This is the first analysis of survival trends by summary stage for multiple cancer sites. The largest survival increases were seen for cancers with a traditionally poor prognosis and no organized screening, which likely reflects clinical management advances. Our study will be particularly useful for understanding the population-level impact of new treatments and identifying emerging trends in health disparities research.

Delayed Severe Gingivitis After Placement of Orthodontic Braces in an Atopic Teenager: A Case Report and Literature Review.

We report a case of a 15-year-old atopic patient presenting with delayed, severe ulcerative hypertrophic gingivitis after placement of orthodontic braces, which required removal of braces and restorative laser surgical procedures. Patch testing to multiple metals and chemicals showed weak positive reactions to steel bands and formaldehyde. The patient experienced urticarial, gingivitis, and other intraoral symptoms after patch testing and re-exposure to nickel-containing products. In contrast, nickel, cobalt, and cobalt-chromium (Co-Cr) bracket patch testing sites were negative. Nickel-caused contact dermatitis is Type IV delayed hypersensitivity reaction occurring at least 24 h after exposure. This reaction can result in intraoral blisters, ulcerations, eczematous and urticarial reactions of the face and more distant skin areas. This case illustrates the intraoral delayed response, symptom resolution after removing the braces, and brackets and local reactions upon subsequent nickel exposure, despite negative patch testing and lymphocyte stimulation test to nickel. This case further illustrates the difficulty associated with diagnosing nickel allergy.

Immunoexpression of CD1a and Histopathology in Lesional and Non Lesional Skin in Psoriasis: A Cross-sectional Study

Introduction: Psoriasis is a long-lasting autoimmune disease mediated by T-lymphocytes and dendritic cells. Langerhans cells are a unique population of dendritic cells found in the epidermis, where they can be identified by Cluster of Differentiation 1a (CD1a) positivity. They play an important role in the pathogenesis of psoriasis. Aim: To evaluate the utility of immunoexpression of CD1a in the early diagnosis of psoriasis and to study the histopathology of skin biopsies from clinically diagnosed cases of psoriasis. Materials and Methods: A cross-sectional study was conducted from September 2017 to August 2019 at Gandhi Hospital, Secunderabad, Telangana, India. Skin biopsies were taken from 50 patients with psoriasis from the Outpatient Department (OPD). Histopathological features in early psoriasis were studied, and CD1a immunoexpression in lesional, perilesional, and distant skin was analysed. The data were analysed using Student’s t-test with the Statistical Package for the Social Sciences (SPSS) software. Results: Half of the cases were found in two age groups: 51-60 years (15 patients, 30%) and 11-20 years (10 patients, 20%). The majority of the cases were males (36 patients, 72%). Most of the biopsies were taken from the lower limb (24 patients, 48%), followed by the back (13 patients, 26%). In this study, the average number of CD1a positive Langerhans cells was highest (54.92±5.26) in perilesional skin compared to lesional skin (30±3.96), which was statistically significant (p-value=0.04). Conclusion: Based on the observations in this study, a strong positive reaction of CD1a in perilesional skin can be used to diagnose psoriasis in the early clinical stages, before full-blown clinical psoriatic plaques have appeared. Early diagnosis may prompt physicians to initiate treatment early

Determination of the adequate vascular perfusion time of cross-leg free latissimus dorsi myocutaneous flaps in reconstruction of complex lower extremity defects.

Lower limb defects may be present due to various causes including infections, vascular diseases, tumor resections, and crush or avulsion injuries. Management of lower leg defects is acomplex problem, especially when they are large with deep soft tissue loss. These wounds are difficult to be covered with local skin flaps, distant skin flaps or even conventional free flaps because of the compromised recipient vessels. In such cases, the vascular pedicle of the free flap could be anastomosed to the recipient vessels of the contralateral healthy leg temporarily and then divided after adequate neo-vascularization of the flap from the wound bed. The ideal time to divide such pedicles should be investigated and accurately assessed to have the maximum success rate possible for these challenging conditions and procedures. Sixteen patients who did not have asuitable adjacent recipient vessel for free flap reconstruction had been operated with cross leg free latissimus dorsi flap between February 2017 and June 2021. The mean soft tissue defect dimension was 12 ×11 cm (the smallest 6 × 7 cm; the largest 20 × 14cm). Gustilo type 3B tibial fractures were present in 12 patients, while no fractures were present in the other 4 patients. Preoperatively, arterial angiography was performed on all patients. After the fourth week post-operatively, non-crushing clamp was applied around the pedicle for 15minutes. The clamping time was increased by 15 minutes on each consequent day (average 14 days). On the last 2 days, the pedicle was clamped for 2 hours, and bleeding was assessed by aneedle prick test. Clamping time was assessed in each case to reach ascientific calculation of the adequate vascular perfusion time needed for full flap nourishment. All flaps survived completely except two cases of distal flaps necrosis. Cross-leg free latissimus dorsi can provide asolution for large soft-tissue defects in lower extremities especially with absence of any suitable recipient vessels or when the use of vein grafts would not be feasible. However, ideal time before dividing the cross vascular pedicle should be identified to have the maximum success rate possible.

In and out: Leishmania metastasis by hijacking lymphatic system and migrating immune cells.

The lymphatic system plays a crucial role in mounting immune response against intracellular pathogens, and recent studies have documented its role in facilitating tumor dissemination linked largely with cancer cells. However, in mucocutaneous leishmaniasis (MCL) caused by Leishmania Viannia subgenus showing infectious metastasis and resulting in severe distant secondary lesions, the route of escape of these parasites to secondary sites has not yet been investigated in detail. Our results demonstrated that when infection was associated with inflammation and additionally exacerbated by the presence of dsRNA viral endosymbiont (LRV1), lymphatic vessels could serve as efficient routes for infected cells to egress from the primary site and colonize distant organs. We challenged this hypothesis by using the intracellular Leishmania protozoan parasites Leishmania guyanensis (Lgy) associated with or without a dsRNA viral endosymbiont, exacerbating the infection and responsible for a strong inflammatory response, and favoring metastasis of the infection. We analyzed possible cargo cells and the routes of dissemination through flow cytometry, histological analysis, and in vivo imaging in our metastatic model to show that parasites disseminated not only intracellularly but also as free extracellular parasites using migrating immune cells, lymph nodes (LNs), and lymph vessels, and followed intricate connections of draining and non-draining lymph node to finally end up in the blood and in distant skin, causing new lesions.

Short-Interval, Low-Dose Peptide Receptor Radionuclide Therapy in Combination with PD-1 Checkpoint Immunotherapy Induces Remission in Immunocompromised Patients with Metastatic Merkel Cell Carcinoma.

Merkel cell carcinoma (MCC) is a neuroendocrine skin cancer of the elderly, with high metastatic potential and poor prognosis. In particular, the primary resistance to immune checkpoint inhibitors (ICI) in metastatic (m)MCC patients represents a challenge not yet met by any efficient treatment modality. Herein, we describe a novel therapeutic concept with short-interval, low-dose 177Lutetium (Lu)-high affinity (HA)-DOTATATE [177Lu]Lu-HA-DOTATATE peptide receptor radionuclide therapy (SILD-PRRT) in combination with PD-1 ICI to induce remission in patients with ICI-resistant mMCC. We report on the initial refractory response of two immunocompromised mMCC patients to the PD-L1 inhibitor avelumab. After confirming the expression of somatostatin receptors (SSTR) on tumor cells by [68Ga]Ga-HA-DOTATATE-PET/CT (PET/CT), we employed low-dose PRRT (up to six treatments, mean activity 3.5 GBq per cycle) at 3–6 weeks intervals in combination with the PD-1 inhibitor pembrolizumab to restore responsiveness to ICI. This combination enabled the synergistic application of PD-1 checkpoint immunotherapy with low-dose PRRT at more frequent intervals, and was very well tolerated by both patients. PET/CTs demonstrated remarkable responses at all metastatic sites (lymph nodes, distant skin, and bones), which were maintained for 3.6 and 4.8 months, respectively. Both patients eventually succumbed with progressive disease after 7.7 and 8 months, respectively, from the start of treatment with SILD-PRRT and pembrolizumab. We demonstrate that SILD-PRRT in combination with pembrolizumab is safe and well-tolerated, even in elderly, immunocompromised mMCC patients. The restoration of clinical responses in ICI-refractory patients as proposed here could potentially be used not only for patients with mMCC, but many other cancer types currently treated with PD-1/PD-L1 inhibitors.

Evaluation of a subcutaneously implanted biodegradable matrix with and without cisplatin in horses

SummaryObjectiveThe aim of this study was to determine the biodegradability and platinum release profile of a calcium sulphate matrix (Matrix III) implanted subcutaneously in horses.Study designMatrix III with and without cisplatin was implanted subcutaneously in the cervical region of five horses with normal cervical skin.MethodsFive 3‐mm beads of Matrix III alone and ten 3‐mm beads containing 7% cisplatin were implanted subcutaneously in the cervical region. Tissues were harvested every 7 days for 35 days. Biodegradability and histologic tissue reaction were determined. Inductively coupled plasma mass spectrometry was used to determine platinum concentration 3, 6, 9, 12 and 15 mm from each implantation site. Plasma and distant skin biopsies were harvested every 7 days. Repeated measures ANOVA was performed to determine differences between the 5 weeks and the five distances from the implant.ResultsMatrix III alone caused local inflammation that resolved early, and the implant had absorbed completely by 28 days leaving only focal fibrosis. Matrix III containing 7% cisplatin incited persistent histologically evident inflammation that appeared to be clinically insignificant. The implants had not been completely absorbed by 35 days. Platinum tissue concentration decreased with time after implantation and as distance from the implant increased. Therapeutic concentrations remained in the tissue at Day 35.ConclusionsMatrix III with 7% cisplatin resulted in chemotherapeutic platinum concentrations sustained for 35 days.

Primary Cutaneous Blastomycosis with Secondary Pulmonary Involvement: A Case Report

Cutaneous blastomycosis is the second most common presentation of Blastomyces Dermatitidis infection. Commonly, skin involvement results from hematogenous spread of infection from a distant site but direct skin involvement can also occur from trauma and animal scratch or bite resulting in cutaneous inoculation blastomycosis. Clinical features of cutaneous blastomycosis are nonspecific and overlap with other fungal and bacterial infections and skin malignancies. A high degree of suspicion is required for diagnosis while evaluating a patient with recurrent skin lesions not responding to antibiotics. In these cases, fungal cultures and histology are of paramount importance for prompt diagnosis and treatment. We present a case of primary cutaneous blastomycosis with secondary lung involvement.

Proteolytic activity accelerates the TH17/TH22 recall response to an epicutaneous protein allergen-induced TH2 response

Epicutaneous exposure to protein allergens, such as papain, house dust mite (HDM), and ovalbumin (OVA), represents an important mode of sensitization for skin diseases including protein contact dermatitis, immunologic contact urticaria, and atopic dermatitis. These diseases are inducible by re-exposure to an allergen at both original skin sensitization and distant skin sites. In this study, we examined the serum IgE/IgG1 response, differentiation of T-helper (TH) cells, and epicutaneous TH recall response in mice pre-sensitized with protein allergens through the back skin and subsequently challenged on the ear skin. Repeated epicutaneous sensitization with allergenic proteins including papain, HDM, OVA, and protease inhibitor-treated papain, but not bovine serum albumin, induced serum allergen-specific antibody production, passive cutaneous anaphylaxis responses, and TH2 differentiation in the skin draining lymph node (DLN) cells. Sensitization with papain or HDM, which have protease activity, resulted in the differentiation of TH17 as well as TH2. In papain- or HDM-sensitized mice, a subsequent single challenge on the ear skin induced the expression of TH2 and TH17/TH22 cytokines. These results suggest that allergenic proteins induce the differentiation of TH2 in skin DLN cells and an antibody response. These findings may be useful for identifying proteins of high and low allergenic potential. Moreover, allergenic proteins containing protease activity may also differentiate TH17 and induce TH2 and TH17/TH22 recall responses at epicutaneous challenge sites. This suggests that allergen protease activity accelerates the onset of skin diseases caused by protein allergens.

Full‐thickness defect reconstruction of the pinna using a distant direct skin flap technique in three dogs

AbstractThree dogs were referred for further investigation and pinna reconstruction. Two dogs presented with pinna defects secondary to dog fights and one dog with a pinna mass. Cytologic examination of the pinna mass was consistent with a cutaneous benign histiocytoma, thus surgical excision was performed leaving a full‐thickness pinna defect. In all three dogs, full‐thickness pinna defects were reconstructed using a two‐stage pedicle flap that originated from the skin of either the neck region or the dorsum of the head. Time interval between the two stages of the surgical procedure was 2 weeks. Postoperative complications included dehiscence, poor ear carriage and failure of complete coverage of the defect. At a median follow‐up of 7 months, cosmetic results were fair to good.

Delayed presentation of inflammatory breast carcinoma during the COVID-19 pandemic.

BackgroundBreast cancer may present with distinct cutaneous manifestations that may be paraneoplastic or secondary to direct skin infiltration, distant skin metastases, or dermal lymphatic tumor embolization (inflammatory breast carcinoma).Case reportA 51-year-old Asian woman visited the emergency care department during the outbreak of COVID-19 in Northern Italy. About 6 months before, she had noted the onset of right breast swelling accompanied by skin redness and itching. She never consulted a physician, and, over time, the local skin condition progressed to a large scaly plaque covering the entire breast surface including the nipple. At presentation, abduction of the right upper limb was impaired due to severe shoulder pain. CT scan showed the presence of bilateral breast masses with necrotic and colliquative features, and multiple skeletal, nodal, pulmonary, and brain images suggestive of metastases. An ultrasound-guided core biopsy of the contralateral breast showed grade 2 non-special type infiltrating carcinoma. The patient was referred to the breast oncology unit and is currently being treated with aromatase inhibitors and chemotherapy.ConclusionThe COVID-19 pandemic has disrupted the entire spectrum of oncological care including breast cancer. Hopefully, telemedicine will contribute to increase patients’ confidence and will provide earlier diagnosis and treatment while minimizing the risk of contagion.

High inflammation in hidradenitis suppurativa extends to perilesional skin and can be subdivided by lipocalin-2 expression

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease presenting with diverse manifestations ranging from nodules and abscesses to draining tunnels. Whether the underlying inflammation from lesions extends to relatively healthy-appearing adjacent perilesional and distant nonlesional skin has not been systematically evaluated. We sought to characterize lesional, perilesional, and nonlesional skin in patients with HS. Skin biopsy samples were collected under ultrasound guidance from patients with active, untreated moderate-to-severe HS. Site-matched control biopsy samples from healthy volunteers were used for comparison. RNA sequencing demonstrated that HS skin clustered separately from healthy control skin, with perilesional and lesion skin clustering together and away from nonlesional skin. Immunohistochemistry analysis identified psoriasiform hyperplasia with keratin 16 positivity in both perilesional and lesional skin, with comparable levels of CD3+, CD11c+, and neutrophil elastase-positive cellular infiltration. There was a marked upregulation of IL-17 signaling in perilesional and lesional skin. HS samples clustered on the basis of expression of lipocalin-2 (LCN2), with samples characterized by high LCN2 expression in the skin exhibiting a differing transcriptomic profile with significantly higher overall inflammation than that of skin characterized by low LCN2 levels. Perilesional HS skin has a transcriptomic and molecular profile comparable to that of lesional skin. HS can be grouped into 2 distinct subtypes based on molecular levels of LCN2 in the skin, with the LCN2-high subtype exhibiting an overall higher inflammatory burden and an upregulation of targetable cytokines. To our knowledge, this is the first study to characterize a unique HS subtype (and a potential endotype) that may guide future therapeutic targets.

Resident and circulating memory T cells persist for years in melanoma patients with durable responses to immunotherapy.

While T-cell responses to cancer immunotherapy have been avidly studied, long-lived memory has been poorly characterized. In a cohort of metastatic melanoma survivors with exceptional responses to immunotherapy, we probed memory CD8+ T-cell responses across tissues, and across several years. Single-cell RNA sequencing revealed three subsets of resident memory T (TRM) cells shared between tumors and distant vitiligo-affected skin. Paired T-cell receptor sequencing further identified clonotypes in tumors that co-existed as TRM in skin and as effector memory T (TEM) cells in blood. Clonotypes that dispersed throughout tumor, skin, and blood preferentially expressed a IFNG / TNF-high signature, which had a strong prognostic value for melanoma patients. Remarkably, clonotypes from tumors were found in patient skin and blood up to nine years later, with skin maintaining the most focused tumor-associated clonal repertoire. These studies reveal that cancer survivors can maintain durable memory as functional, broadly-distributed TRM and TEM compartments.

Moist wound dressing and its application in distant skin flap in cats.

Background and Aim:Wound healing is a dynamic and complex process that requires an appropriate environment to promote healing process. The healing of distant flaps in cats is determined by vascularization, nutrient sufficiency for the cells, and stability of skin flaps. This study aims to evaluate the healing of distant flaps treated with moist wound dressing through subjective and objective observation in five cats with wounds in the forelimb and hindlimb area to determine the time to cut the skin flaps from the donor site.Materials and Methods:In this study, five Indonesian local cats with wounds of various sizes in the limb were brought to the Veterinary Teaching Hospital. The sterile wound treatment included the administration of anesthesia, wound debridement, and distant flap closure in the thoracic and abdominal area. The distant flap and time to cut the skin flaps from the donor site were evaluated through subjective and objective examinations.Results:The subjective observation on the color of the distant skin flaps showed redness and response to pain on day 3 after surgery, whereas the objective observation, which was based on drug absorption capability and drug effect showed good results. On day 7 after surgery, the skin flaps from the donor site were cut and showed good progress.Conclusion:Overall, moist dressing helps in stabilizing the distant flap, allowing the distant flaps from the donor site to be cut on day 7 after surgery.

THYROID METASTASIS OF A SQUAMOUS CELL CARCINOMA OF THE TONGUE - A RARE CASE REPORT

Introduction: We present a patient with carcinoma of the tongue with а lymph node and thyroid metastasеs. The squamous cell cancer of the tongue’s 5-year survival rate has not been improved in the last three decades. Most common sites of metastases are the locoregional lymph nodes, followed by distant pulmonary, liver, bone and skin metastasеs. Only ten cases of metastases to the thyroid gland are reported in the literature. Case report: A 79-year old man presented to the University Hospital in Varna, Bulgaria. Two months before admission, he noticed swelling of the tongue and progressive weight loss. The inspection of the oral cavity revealed a lesion on the left margin of the tongue. A biopsy was performed with a histological result of differentiated squamous cell carcinoma of the tongue. A computed tomography scan of the head and neck region discovered a lesion in the right thyroid lobe. 18-fluoro-2-deoxy-glucose-positron emission tomography imaging showed a metabolically active tumor of the tongue with hypermetabolic metastatic cervical lymph nodes and a zone with abnormally elevated fixation of 18F-FDG in the central part of the soft palate. The described thyroid nodule did not have an increased tracer uptake. It was cytologically assessed after fine-needle aspiration biopsy (FNAB) as a metastasis from squamous cell carcinoma of the tongue. Conclusions: Distant metastases from tongue cancer to the thyroid gland are extremely rare and mostly occur in the advanced stages of malignancy.

Epicutaneous challenge with protease allergen requires its protease activity to recall TH2 and TH17/TH22 responses in mice pre-sensitized via distant skin

Epicutaneous exposure to allergenic proteins is an important sensitization route for skin diseases like protein contact dermatitis, immunologic contact urticaria, and atopic dermatitis. Environmental allergen sources such as house dust mites contain proteases, which are frequent allergens themselves. Here, the dependency of T-helper (TH) cell recall responses on allergen protease activity in the elicitation phase in mice pre-sensitized via distant skin was investigated. Repeated epicutaneous administration of a model protease allergen, i.e. papain, to the back skin of hairless mice induced skin inflammation, serum papain-specific IgE and TH2 and TH17 cytokine responses in the sensitization sites, and antigen-restimulated draining lymph node cells. In the papain-sensitized but not vehicle-treated mice, subsequent single challenge on the ear skin with papain, but not with protease inhibitor-treated papain, up-regulated the gene expression of TH2 and TH17/TH22 cytokines along with cytokines promoting these TH cytokine responses (TSLP, IL-33, IL-17C, and IL-23p19). Up-regulation of IL-17A gene expression and cells expressing RORγt occurred in the ear skin of the presensitized mice even before the challenge. In a reconstructed epidermal model with a three-dimensional culture of human keratinocytes, papain but not protease inhibitor-treated papain exhibited increasing transdermal permeability and stimulating the gene expression of TSLP, IL-17C, and IL-23p19. This study demonstrated that allergen protease activity contributed to the onset of cutaneous TH2 and TH17/TH22 recall responses on allergen re-encounter at sites distant from the original epicutaneous sensitization exposures. This finding suggested the contribution of protease-dependent barrier disruption and induction of keratinocyte-derived cytokines to the recall responses.

Topically applied liposome-in-hydrogels for systematically targeted tumor photothermal therapy

Transdermal drug delivery for local or systemic therapy provides a potential anticancer modality with a high patient compliance. However, the drug delivery efficiency across the skin is highly challenging due to the physiological barriers, which limit the desired therapeutic effects. In this study, we prepared liposome-in-hydrogels containing a tumor targeting photosensitizer IR780 (IR780/lipo/gels) for tumor photothermal therapy (PTT). The formulation effectively delivered IR780 to subcutaneous tumor and deep metastatic sites, while the hydrogels were applied on the skin overlying the tumor or on an area of distant normal skin. The photothermal antitumor activity of topically administered IR780/lipo/gels was evaluated following laser irradiation. We observed significant inhibition of the rate of the tumor growth without any toxicity associated with the topical administration of hydrogels. Collectively, the topical administration of IR780/lipo/gels represents a new noninvasive and safe strategy for targeted tumor PTT.

Innate Immune Memory to Repeated Borrelia burgdorferi Exposure Correlates with Murine In Vivo Inflammatory Phenotypes.

Borrelia burgdorferi, the causative agent of Lyme disease, is transmitted by the bite of an infected tick. Once inoculated into the host dermis, it disseminates to various organs including distant skin sites, the heart, the joint and the nervous system. Most humans will develop an early skin manifestation called erythema migrans at the tick bite site. This can be followed by symptoms such as carditis, neuritis, meningitis, or arthritis if not treated. A specific mouse strain, C3H/HeN develops arthritis with B. burgdorferi infection whereas another strain, C57BL/6, develops minimal to no arthritis. Neither strain of mice show any skin signs of rash or inflammation. Factors that determine the presence of skin inflammation and the joint arthritis susceptibility in the host are only partially characterized. We show in this study that murine fibroblast-like synoviocytes display trained immunity, a program in some cells that results in increased inflammatory responses if the cell has previously come in contact with a stimulus, and that trained immunity in fibroblast-like synoviocytes tested ex vivo correlates with Lyme arthritis susceptibility. Conversely, skin fibroblasts do not exhibit trained immunity, which correlates with the absence of skin symptoms in these mice. Moreover, we demonstrate that the trained phenotype in FLS is affected by the cell environment, which depends on the host genetic background. Future studies expanding this initial report of the role of trained immunity on symptoms of B. burgdorferi infection may provide insight into the pathogenesis of disease in murine models.