In the context of research aimed at identifying the causes of the progressive decline in cellular and tissue functions characteristic of aging, in recent decades, increasing attention has been devoted to the sirtuin family. Sirtuins are named after the Sir2 protein of Saccharomyces cerevisiae, a product of the SIR gene family, known as “silent information regulator 2”. Sirtuins are NAD+-dependent protein deacetylases and deacylases characterized by a conserved catalytic domain of approximately 275 amino acids. The removal of acetyl groups from acetyl-lysine residues on proteins is critical in regulating a wide range of biological functions, including gene silencing, genome stability, longevity, metabolism, and cellular physiology. In humans, the sirtuin family comprises seven isoforms (SIRT1–SIRT7), each with specific substrate preferences and primarily, but not exclusively, localized in the nucleus (SIRT1, SIRT6, and SIRT7), cytoplasm (SIRT2), and mitochondria (SIRT3, SIRT4, and SIRT5). Sirtuins may regulate numerous cellular processes associated with survival and longevity, including transcription and DNA repair, inflammation, glucose and lipid metabolism, oxidative stress, mitochondrial function, apoptosis, autophagy, and stress resistance. Sirtuins’ dependence on NAD+ allows them to function as cellular energy sensors, linking metabolic demands to selective lysine deacylation in various subcellular organelles. The aim of this review is to provide an update on this family of molecules, describing their molecular structures, physiological functions, roles in aging processes, and potential to be modulated to serve as a strategy for promoting healthy aging.

The Basal Cell Carcinoma (BCC) is a sort of unique tumour due to its combined peculiar histological features and clinical behaviour, such as the constant binary involvement of the epithelium and the stroma, the virtual absence of metastases and the predilection of specific anatomical sites for both onset and spread. A potential correlation between the onset of BCC and a dysembryogenetic process has long been hypothesised. A selective investigation of PubMed-indexed publications supporting this theory retrieved 64 selected articles published between 1901 and 2024. From our analysis of the literature review, five main research domains on the dysembryogenetic pathogenesis of BCC were identified: (1) The correlation between the topographic distribution of BCC and the macroscopic embryology, (2) the correlation between BCC and the microscopic embryology, (3) the genetic BCC, (4) the correlation between BCC and the hair follicle and (5) the correlation between BCC and the molecular embryology with a specific focus on the Hedgehog signalling pathway. A large amount of data from microscopic and molecular research consistently supports the hypothesis of a dysembryogenetic pathogenesis of BCC. Such evidence is promoting advances in the clinical management of this disease, with innovative targeted molecular therapies on an immune modulating basis being developed.

Background. The favorable regenerative effects of some mineral waters on wound healing have long been empirically demonstrated. Objectives. The aim of this experimental study is to investigate the effects of an Italian salso-bromo-iodic mineral water (Rivanazzano, Italy) on an in vitro human native fibroblast culture model to identify any potential regenerative actions. Materials and methods. Human native fibroblasts were cultured under different experimental conditions: - Dulbecco's modified Eagle's medium (DMEM) reconstituted with distilled water (control); - DMEM reconstituted with filtered mineral water collected from the spring; - DMEM reconstituted with filtered mineral water collected at the balneotherapy facility; - DMEM reconstituted with filtered, heated mineral water collected at the balneotherapy facility; - DMEM partially replaced with filtered mineral water collected from the spring at different concentrations - DMEM partially replaced with filtered, heated mineral water collected at the balneotherapy facility at dif- DMEM partially replaced with filtered mineral water collected at the balneotherapy facility at different Cell proliferation and viability were evaluated using spectrophotometric analysis following staining with the XTT Microculture Tetrazolium Assay. Statistical analyses were performed for each experimental condiResults. The best outcomes were observed in fibroblasts cultured with DMEM partially replaced with filtered mineral water collected from the spring, within the range of 20-50%. Conclusions. Our research results showed that Rivanazzano salso-bromo-iodic mineral water has a stimulating effect on in vitro human native fibroblast cultures. This activity was most pronounced with water collected form the basis for clinical applications in wound healing and balneotherapy.

The canal of Nuck is the female equivalent to the male processus vaginalis. Due to its rarity and the lack of awareness among physicians, a cyst in the canal of Nuck is a seldom-encountered entity in clinical practice and is commonly misdiagnosed. We report on a case of 42-year-old woman who presented with a painful swelling at her right groin and skin hypertrophy of the abdomen. The patient underwent successful open herniorrhaphy with excision of the cyst and mesh repair of the inguinal canal. The results were excellent both in the aesthetic and functional terms. In 1 month, there was a complete recovery with a return to social life. The 3-month healing score was 3 of 13 on the Vancouver Scar Scale. The technique is effective and reproducible. The patient's aesthetic and functional outcomes were excellent. In the following 6 months of follow-up, there were no recurrences or late complications.

Background/Aim: A native non-pathogenic bacterial microflora was identified in Comano (TN, Italy) spring water. The aim of this study was to investigate the regenerative effects of some of the bacterial lysates extracted from this water in a human ex-vivo skin experimental wound model. Materials and Methods: Bacterial lysates were extracted from four new isolates: lysate 1 (L1) -closest relative Rudaea cellulosilytica, phylum Proteobacteria; lysate 2 (L2) -closest relative Mesorhizobium erdmanii, phylum Proteobacteria; lysate 3 (L3) -closest relative Herbiconiux ginseng, phylum Actinobacteria; lysate 4 (L4) -closest relative Fictibacillus phosphorivorans, phylum Firmicutes. Their regenerative effects were investigated in a human ex-vivo skin experimental wound healing model at 3 (T1), 5 (T2), and 10 days (T3). Results: The samples cultured with the L2 lysate displayed both an earlier and complete restoration of all the skin layers and their features were the closest to the normal skin. The regenerated epidermis demonstrated a complete maturation as the normal epidermis. The papillary dermis appeared mature, and the reticular dermis displayed both collagen and elastic fibres regularly parallel to the skin surface. An anti-inflammatory effect was displayed by the L1 lysate, but this action did not constitute a regenerative effect, suggesting that pathways for inflammation and regeneration might be different. Conclusion: The therapeutic power of spring waters is not exclusively related to their mineral composition, but it may also be attributable to their native non-pathogenic bacterial microflora.

The growing demand for postbariatric body-contouring surgery after massive weight loss goes hand-in-hand with an increase in wound complications. Consequently, surgical reoperation or conservative management is necessary and represents a difficult challenge to healthcare professionals. Moreover, it is well known that postbariatric patients present aberrant wound healing due to multifactorial causes, such as preoperative illness, nutritional deficiencies, and vascular disease. To treat such complex wounds, several methods have been recommended, such as the use of negative pressure wound therapy, tissue-engineered skin substitutes, and collagen-based wound dressings. The case presented here is of a patient with deep wound dehiscence of the inner left thigh, 1 week after a medial thigh lift procedure, successfully managed with Vergenix Flowable Gel, a human recombinant type I collagen produced in plants. After 2 weeks of treatment, wound dehiscence was replaced with granulation tissue, and after 4 weeks, the patient was completely healed, with an acceptable aesthetic outcome of the surgical scar.

Several studies demonstrated the favorable effects of platelet rich plasma (PRP) on the skin and promoted its wide use in clinical practice. The growth factors stored in platelet alfa-granules allow for the tissue regeneration and the main fields of application of PRP in current clinical practice are the cartilage and musculoskeletal defects, osteoarthritis and other bone disorders, chronic and difficult to heal wounds, and aesthetic procedures. The relevant number of different PRP preparation protocols may explain the inconsistency of the different clinical outcomes reported in the literature. Despite the technological advances in PRP preparation, the objective assessment of the clinical efficacy of PRP from the literature reports still is difficult due to the low homogeneity of the samples in terms of both inclusion criteria and size. Therefore, it might be useful to establish standardized and reproducible experimental models to confirm and objectively measure the effectiveness of the available clinical results. Many experimental investigations have been carried out to objectively assess the effectiveness of PRP and platelet gel on several tissues. As far as the skin is concerned, the studies carried out to date are limited to fibroblasts in in-vitro culture models or to collagen, vascular supply, epithelium, and hair follicle in in-vivo models. The skin, however, is a very complex organ, where different cell lines coexist and feature complex mutual interaction. A model that combines the advantages of both in-vitro and in-vivo cultures is the ex-vivo model. The demonstration of the platelet derived growth factors effects through the ex-vivo human full-thickness skin culture model is a keystone to support the evidence of the PRP effectiveness, as it represents an objective, fast, reproducible, and ethical investigational method.

Objectives. Patients affected by chronic conditions frequently present surgical need. This scenario requires a reflection on the traditional health approach. Innovative clinical pathways should be identified in order to cope with the specific needs presented by individual patients. Methods. Retrospective evaluation of the clinical-surgical multidisciplinary management of an extremely complex patient treated in a second level rehabilitation Institute. Results. An accurate analysis of the patient's clinical needs allowed to define an adequate health project, which is the basis w achieve the planned rehabilitation goals. In the presented clinical case, multidisciplinary management was the cornerstone to reach a final good clinical outcome. Conclusions. The management of an acute surgical affection in elderly patients and subjects affected by chronic conditions require more resources. When approaching such complex cases, technical skills and economic issues - but also ethical and social background - should be taken into consideration, especially in a rehabilitation research institute.

BACKGROUND:The combination of surgery and postoperative radiotherapy allows for the most effective results with keloids. In this trial, surgery and intraoperative radiation therapy (IORT) technology were used-the hypothesis being that the earlier the application of postoperative radiotherapy, the better the wound healing evolution.METHODS:The study included 16 patients with 21 keloids. The keloids were radically excised and repaired with direct suture or local skin flaps. Collimated electron radiotherapy was applied within 45 minutes of surgery. The outcomes were assessed according to the modified Patient and Observer Scar Assessment Scale; the modified Vancouver Scar Scale; and the modified Common Terminology Criteria for Adverse Events v. 4.0 for skin and subcutaneous tissue disorders.RESULTS:Recurrences were observed in one out of 16 patients, and in two out of 21 keloids (9.5%). The modified Patient and Observer Scar Assessment Scale demonstrated a statistically significant improvement in pain, itching, color, stiffness, thickness, and irregularity after the treatment. The modified Patient and Observer Scar Assessment Scale displayed a statistically significant improvement in the scar vascularity, pigmentation, thickness, and pliability after the treatment. The modified Vancouver Scar Scale demonstrated a statistically significant improvement in 90.48% of the scars after the treatment. The modified Common Terminology Criteria for Adverse Events v. 4.0 for skin and subcutaneous tissue disorders demonstrated an improvement in erythema multiforme and skin pain across the whole sample, with a temporary hyperpigmentation in 19% of the scars after the treatment.CONCLUSION:The combination of surgery and collimated electron radiotherapy with IORT technology demonstrated favorable results in 90.5% of the cases.

The peculiar combined, or binary involvement of epithelium and stroma makes basal cell carcinoma (BCC) a unique tumour. Nerve fibres have been shown to play an active role in different cancers. A prospective observational study was carried out on punch biopsies harvested within BCC surgical excision specimens. A total of 10 samples of histologically diagnosed BCC, derived from 10 different patients (five females, five males), was included in the study. Within the BCCs, seven different histological sub-types were identified: morphea-like, basosquamous, micronodular, mixed nodular-micronodular, adenoid, nodular and superficial multifocal. Nerve fibres were stained for indirect immunofluorescence targeting protein gene product 9.5. Three different morphological patterns of nerve fibre distribution within the BCCs were identified. Pattern 1 displayed a normal skin nerve pattern, in which the fibres were dislodged by the growing tumour masses. Pattern 2 featured a ball of curved, tangled nerve fibres close to the tumour masses, slightly resembling piloneural collar nerve fibres, wrapped around hair follicles in the normal anatomical setting. Pattern 3 showed nerve fibres crowding in the sub-epidermal layer with focal epidermal hyperinnervation. Such a pattern is reminiscent of the typical anatomical neuro-epithelial interaction in mechanosensory organs. Our study may disclose a hidden third player, of nerves. Thus, tissue involvement of BCCs may be better represented by the triad of epithelium, stroma and nerves, each component retaining some features associated with its developmental setting.

Adult adipose tissue-derived mesenchymal stem cells (ASCs) constitute a vital population of multipotent cells capable of differentiating into numerous end-organ phenotypes. However, scientific and translational endeavors to harness the regenerative potential of ASCs are currently limited by an incomplete understanding of the mechanisms that determine cell-lineage commitment and stemness. In the current study, we used reduced representation bisulfite sequencing (RRBS) analysis to identify epigenetic gene targets and cellular processes that are responsive to 5 '-azacitidine (5 '-AZA). We describe specific changes to DNA methylation of ASCs, uncovering pathways likely associated with the enhancement of their proliferative capacity. We identified 4,797 differentially methylated regions (FDR < 0.05) associated with 3,625 genes, of which 1,584 DMRs annotated to the promoter region. Gene set enrichment of differentially methylated promoters identified "phagocytosis," "type 2 diabetes," and "metabolic pathways" as disproportionately hypomethylated, whereas "adipocyte differentiation" was the most-enriched pathway among hyper-methylated gene promoters. Weighted coexpression network analysis of DMRs identified clusters associated with cellular proliferation and other developmental programs. Furthermore, the ELK4 binding site was disproportionately hyper-methylated within the promoters of genes associated with AKT signaling. Overall, this study offers numerous preliminary insights into the epigenetic landscape that influences the regenerative capacity of human ASCs.

Background:. Traditionally, nonmelanoma skin cancers (NMSCs) are considered mainly UV-related malignancies. Nevertheless, a strong correlation between the embryologically relevant sites (ERS) of the head and neck and the preferential sites of onset of basal cell carcinomas (BCCs) has long been supposed and demonstrated. The aim of this research was the investigation of the potential correlation between the ERS of the head and neck and the sites of tumor onset in all of the NMSCs. Methods:. The distribution of 1165 NMSC was correlated with the ERS of the head and neck using the universally accepted anatomical diagrams featuring the congenital head and neck clefts and an original anatomical diagram showing the most credited sites of the embryonic fusion planes of the auricle. Results:. In our sample, both BCC and SSC display an increased likelihood of onset in the ERS of the head and neck. A proportion of 93.10% BCCs was distributed within ERS, while 6.90% derived from non-embryologically relevant sites (P < 0.001). A proportion of 69.70% SCCs was distributed within ERS, while 30.30% derived from non-embryologically relevant sites (P < 0.001). The probability of tumors within ERS was significantly higher for BCC versus SCC (P < 0.001), with BCCs having a 5-fold increase in the probability of occurring in ERS compared to SCCs (P < 0.001). Conclusions:. The ERS might host areas of cellular instability yielding to the development of an NMSC. The environmental UV exposure plays a relatively main role versus dysontogenic factors in the pathogenesis of SCC.

This study reports on the development of an original, ex-vivo wounded skin culture protocol using autologous Platelet Rich Plasma (PRP) and enriched Dulbecco's Modified Eagle's Medium (DMEM). Human skin samples obtained from specimens harvested during reduction mammoplasty procedures, were injured in their central portion-to create a standard wound-and cultured under three different conditions: - enriched DMEM with saline solution in the central wound (control)- enriched DMEM with the same medium in the central wound- enriched DMEM plus 2.5% autologous PRP, with the same PRP added medium in the central wound. Morphological analysis was carried out at 0 h (T0) and on days 1, 3, 5 and 10 (T1-T3-T5-T10) using Hematoxylin and Eosin; Masson's trichrome staining; Weigert staining and Ki-67 staining to identify the skin histological features in the different experimental conditions. The combination of DMEM and PRP allowed a favorable modulation of the epithelial cells and fibroblasts proliferation, and a relevant anti-inflammatory action. PRP also demonstrated an inhibitory effect on both the collagen and elastic fibers' de-structuration and a favorable modulation of the re-organization of these fibers. The step by step histological and immune-histo-chemical regenerative effects of PRP on human skin wound repair and regeneration process was observed over a period of 10 days.

INTRODUCTION: Metastases represent one of the most outstanding characteristics of malignant neoplasms and are relatively rare in the skin, in spite of the great extension of the cutaneous organs. Development of cutaneous metastases from colon cancer is a rare event, usually occurring in widely disseminated disease and commonly leading to a poor prognosis. As to location, cutaneous metastases often favor areas close to the primary malignancy, such as lung cancer and skin metastases on the trunk. However, remote sites as the scalp may be also involved. CASE PRESENTATION: We present the case of a 92-year-old female patient with a massive single nodular skin lesion on her left supraclavicular area, that came back positive for cutaneous metastasis of colon adenocarcinoma. DISCUSSION: Cutaneous metastasis of colorectal cancer a rare event (2.3%-6%) that usually occur two years after the detection or resection of the primary tumor. It seldom occurs before the identification of the primary tumor and involvement of secondary organs, such as the liver. There are few cases reported with only cutaneous metastases. CONCLUSION: In conclusion, dermatological evaluation of patients who are undergoing screening or who have already been diagnosed with cancer is extremely important. (C) 2019 The Authors. Published by Elsevier Ltd on behalf of US Publishing Group Ltd.

The aim of the study was the objective assessment of the effectiveness of a microfragmented dermal extract obtained with Rigenera™ technology in promoting the wound healing process in an in vivo homogeneous experimental human acute surgical wound model. The study included 20 patients with 24 acute postsurgical soft tissue loss and a planned sequential two-stage repair with a dermal substitute and an autologous split-thickness skin graft. Each acute postsurgical soft tissue loss was randomized to be treated either with an Integra® dermal substitute enriched with the autologous dermal micrografts obtained with Rigenera™ technology (group A—Rigenera™ protocol) or with an Integra® dermal substitute only (group B—control). The reepithelialization rate in the wounds was assessed in both groups at 4 weeks through digital photography with the software “ImageJ.” The dermal cell suspension enrichment with the Rigenera™ technology was considered effective if the reepithelialized area was higher than 25% of the total wound surface as this threshold was considered far beyond the expected spontaneous reepithelialization rate. In the Rigenera™ protocol group, the statistical analysis failed to demonstrate any significant difference vs. the controls. The old age of the patients likely influenced the outcome as the stem cell regenerative potential is reduced in the elderly. A further explanation for the unsatisfying results of our trial might be the inadequate amount of dermal stem cells used to enrich the dermal substitutes. In our study, we used a 1 : 200 donor/recipient site ratio to minimize donor site morbidity. The gross dimensional disparity between the donor and recipient sites and the low concentration of dermal mesenchymal stromal stem cells might explain the poor epithelial proliferative boost observed in our study. A potential option in the future might be preconditioning of the dermal stem cell harvest with senolytic active principles that would fully enhance their regenerative potential. This trial is registered with trial protocol number NCT03912675.

Objective: Previous studies have shown regenerative power of the skin with Comano (Trento, Italy) spring water and resident non-pathogenic microflora. This study investigated the action of bacterial lysates that were isolated from Comano spring water on in vitro culture of human skin fibroblasts. Methods: For this study, we selected the following four bacterial lysates: L1 (closest relative: Rudaea cellulosilytica), L2 (closest relative: Mesorhizobium erdmanii), L3 (closest relative: Herbiconiux ginsengi), and L4 (closest relative: Fictibacillus phosphorivorans). Human fibroblasts were cultured under Dulbecco’s modified Eagle’s medium (DMEM) with bacterial lysates added or DMEM (controls). Cell proliferation was evaluated by spectrophotometric absorbance analysis after the XTT-Microculture Tetrazolium Assay. Results: At 24 hours, cultures with L2, L3, and L4 showed a higher absorbance compared with controls. At 48 hours, cultures with L1, L2, and L3 showed slightly lower absorbance compared with controls, and culture with L4 showed a higher absorbance than in the other experimental conditions. At 72 hours, absorbance was lower in cultures with L1, L2, and L3 than in controls, and absorbance was higher in culture with L4 than in the other experimental conditions. Conclusions: Our study indicates a favorable action of Comano spring water microbiota on proliferation of human skin fibroblasts.

Objectives: This study aims at the identification of the distribution of basal cell carcinomas (BCCs) in the auricle in correlation with the currently most credited sites of the embryonic fusion planes of the auricle. Methods: An overall number of 69 patients with 72 BCCs of the auricle were enrolled in the study over a period of 14 years, from June 2003 to October 2017. All the cases underwent medical preoperative digital photography and the specific location of each BCC was coded on an original full-size anatomical diagram of the auricle derived from the reports by Streeter, Wood-Jones, Park, Porter, and Minoux showing the currently most credited sites of the embryonic fusion planes arbitrarily featured as two 5-mm-wide ribbon-like areas: (1) the hyoid-mandibular fusion plane (HM-FP) running from the upper margin of the tragus toward the concha and then deflecting toward the lower margin of the tragus and (2) the free ear fold-hyoid fusion plane (FEFH-FP) running from the cranial-most portion of the helix to the mid-portion of the ascending helix. The latter fusion planes were comprehensively termed embryological fusion planes (EFP) while all of the remaining surface of the auricle was comprehensively termed non-fusion area (NFA). The surfaces of all of the latter areas were calculated using the ImageJ software. Results: According to our data, the greatest number of BCCs was observed within the currently most credited sites of the embryonic fusion planes of the auricle. The latter sites displayed a 12-fold increased tumor incidence in comparison with the remaining surface of the ear. Conclusions: A correspondence between the sites of onset of BCCs and the sites of merging and/or fusion of embryonal processes was demonstrated in the auricle. Therefore, the latter sites might be considered as high-risk areas for the development of a BCC. Such an evidence provides further support to the hypothesis of an embryological pathogenesis of BCC.

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