Wound care and soft tissue repair have been a major human concern for millennia. Despite considerable advancements in standards of living and medical abilities, difficult-to-heal wounds remain a ...major burden for patients, clinicians and the healthcare system alike. Due to an aging population, the rise in chronic diseases such as vascular disease and diabetes, and the increased incidence of antibiotic resistance, the problem is set to worsen. The global wound care market is constantly evolving and expanding, and has yielded a plethora of potential solutions to treat poorly healing wounds. In ancient times, before such a market existed, metals and their ions were frequently used in wound care. In combination with plant extracts, they were used to accelerate the healing of burns, cuts and combat wounds. With the rise of organic chemistry and small molecule drugs and ointments, researchers lost their interest in inorganic materials. Only recently, the advent of nano-engineering has given us a toolbox to develop inorganic materials on a length-scale that is relevant to wound healing processes. The robustness of synthesis, as well as the stability and versatility of inorganic nanotherapeutics gives them potential advantages over small molecule drugs. Both bottom-up and top-down approaches have yielded functional inorganic nanomaterials, some of which unite the wound healing properties of two or more materials. Furthermore, these nanomaterials do not only serve as the active agent, but also as the delivery vehicle, and sometimes as a scaffold. This review article provides an overview of inorganic hybrid nanotherapeutics with promising properties for the wound care field. These therapeutics include combinations of different metals, metal oxides and metal ions. Their production, mechanism of action and applicability will be discussed in comparison to conventional wound healing products.
RNA editing refers to non-transient RNA modifications that occur after transcription and prior to translation by the ribosomes. RNA editing is more widespread in cancer cells than in non-transformed ...cells and is associated with tumorigenesis of various cancer tissues. However, RNA editing can also generate neo-antigens that expose tumour cells to host immunosurveillance. Global RNA editing in melanoma and its relevance to clinical outcome currently remain poorly characterized. The present study compared RNA editing as well as gene expression in tumour cell lines from melanoma patients of short or long metastasis-free survival, patients relapsing or not after immuno- and targeted therapy and tumours harbouring BRAF or NRAS mutations. Overall, our results showed that NTRK gene expression can be a marker of resistance to BRAF and MEK inhibition and gives some insights of candidate genes as potential biomarkers. In addition, this study revealed an increase in Adenosine-to-Inosine editing in Alu regions and in non-repetitive regions, including the hyperediting of the MOK and DZIP3 genes in relapsed tumour samples during targeted therapy and of the ZBTB11 gene in NRAS mutated melanoma cells. Therefore, RNA editing could be a promising tool for identifying predictive markers, tumour neoantigens and targetable pathways that could help in preventing relapses during immuno- or targeted therapies.
CONFLICT OF INTEREST Alex Navarini declares being a consultant and advisor and/or receiving speaking fees and/or grants and/or served as an investigator in clinical trials for AbbVie, Almirall, ...Amgen, Biomed, BMS, Boehringer Ingelheim, Celgene, Eli Lilly, Galderma, GSK, LEO Pharma, Janssen-Cilag, MSD, Novartis, Pfizer, Pierre Fabre Pharma, Regeneron, Sandoz, Sanofi, and UCB. The remaining authors declare no conflict of interest. DATA AVAILABILITY STATEMENT Data are available with the permission of the patient from the corresponding author Michael Kunz upon reasonable request.
Efficient vaccination can be achieved by injections of in vitro transcribed mRNA (ivt mRNA) coding for antigens. This vaccine format is particularly versatile and allows the production of ...individualised vaccines conferring, T-cell immunity against specific cancer mutations. The CDR3 hypervariable regions of immune receptors (T-cell receptor, TCR or B-cell receptor, BCR) in the context of T- or B-cell leukaemia or lymphoma are targetable and specific sequences, similar to cancer mutations. We evaluated the functionality of an mRNA-based vaccine designed to trigger immunity against TCR CDR3 regions in an EL4 T-lymphoma cell line-derived murine in vivo model. Vaccination against the hypervariable TCR regions proved to be a feasible approach and allowed for protection against T-lymphoma, even though immune escape in terms of TCR downregulation paralleled the therapeutic effect. However, analysis of human cutaneous T-cell lymphoma samples indicated that, as is the case in B-lymphomas, the clonotypic receptor may be a driver mutation and is not downregulated upon treatment. Thus, vaccination against TCR CDR3 regions using customised ivt mRNA is a promising immunotherapy method to be explored for the treatment of patients with T-cell lymphomas.
Squamous cell carcinoma (SCC) is the most common neoplasm in organ transplant recipients (OTR) on long-term immunosuppression and occurs 60- to 100-fold more frequently than in the general ...population. Here, we present the receptor for advanced glycation end products (RAGE) and S100A8/A9 as important factors driving normal and tumor keratinocyte proliferation. RAGE and S100A8/A9 were transcriptionally upregulated in SCC compared to normal epidermis, as well as in OTR compared to immunocompetent patients (IC) with SCC. The proliferation of normal and SCC keratinocytes was induced by exposure to exogenous S100A8/A9 which in turn was abolished by blocking of RAGE. The migratory activities of normal and SCC keratinocytes were also increased upon exposure to S100A8/A9. We demonstrated that exogenous S100A8/A9 induces phosphorylation of p38 and SAPK/JNK followed by activation of ERK1/2. We hypothesize that RAGE and S100A8/A9 contribute to the development of human SCC by modulating keratinocyte growth and migration. These processes do not seem to be impaired by profound drug-mediated immunosuppression in OTR.
Approximately 20% of leg ulcers remain unresponsive to the best conservative standard of care. So far, these patients could either receive conventional skin grafts or had to accept their intractable ...wound. Skin substitutes from cell culture may represent a promising alternative to heal a major part of these patients on a non-surgical, potentially more cost-effective basis.
To systematically evaluate the first 68 patients treated in Switzerland (Swiss EpiDex® field trial 2004-2008).
Retrospective study on EpiDex treatment of a complete consecutive series of 68 patients with chronic wounds (66 chronic leg ulcers, 2 sores) unresponsive to best conservative standard of care. The primary end point was complete wound closure within 9 months after transplantation, the secondary end points change of wound surface area, pain reduction and overall judgement by the patient. Adverse effects were infection, dermatitis and others. Calculation of treatment costs was made.
By the end of the study, 50/68 (74%) of patients had their wound completely healed venous 29/37 (78%); mixed 7/9 (78%); others 14/22 (64%); 10/68 (15%) had the wound surface area reduced by >50%, and 8/68 (12%) did not respond to the EpiDex treatment. Wound pain disappeared completely in 78% and partially in 13%. Fifteen patients (22%) received antibiotics for wound infection, and 2 (3%) developed dermatitis (not related to the local therapy). Average treatment costs for venous ulcers amounted to EUR 5,357, compared to EUR 5,722-8,622 reimbursed according to the German DRG system (2010) for an in-patient skin graft.
EpiDex may effectively heal up to three quarters of recalcitrant chronic leg ulcers. Thus, it represents an intermediate step to avoid costly in-patient split-skin mesh graft treatments. Patients remain mobilized, and a donor site is avoided. Large wound size or a necrotic wound bed limit the use of EpiDex. Otherwise, it offers the opportunity to avoid conventional skin grafts in a significant number of chronic leg ulcer patients.
Hidradenitis suppurativa (HS) is a painful, inflammatory, debilitating skin disease with a chronic intermittent course. The central pathogenetic event seems to be the occlusion of the hair follicle. ...HS has a 1-year prevalence of about 1%. It typically presents after puberty with painful, deep-seated, inflamed lesions in the apocrine gland-bearing areas of the body: most commonly the axillae, inguinal, and anogenital regions. HS has a high negative impact on patients' quality of life even in patients with only limited disease burden, and the diagnosis of HS is often made with a long diagnostic delay. In this practical short version we present diagnostic and therapeutic recommendations which are based on a systematic literature search as well as an informal expert consensus of Swiss dermatologists and dermatosurgeons.
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