Parecoxib decreases cellular growth and Bcl-2 protein levels in primary cultures of keloid fibroblasts.

Keloids seem to overexpress cyclo-oxygenase-2 (COX-2), suggesting a role in its deregulated pathway in inducing an altered epithelial-mesenchymal interaction, which may be responsible for the overgrowth of dermal components resulting in scars or keloid lesions. This study aimed to evaluate the effect of Parecoxib, a COX-2 inhibitor, on cell growth in fibroblast primary cultures obtained from human keloid tissues. Tissue explants were obtained from patients who underwent intralesional excision of untreated keloids; central fractions were isolated from keloid tissues and used for establishing distinct primary cultures. Appropriate aliquots of Parecoxib, a COX-2 inhibitor were diluted to obtain the concentration used in the experimental protocols in vitro (1, 10 or 100 µM). Treatment with Parecoxib (at all concentrations) caused a significant decrease in cellular growth from 24 hours onwards, and with a maximum at 72 hours (P < .02). Moreover, at 72 hours Parecoxib significantly reduced cellular vitality. Parecoxib treatment also induced an increase in fragmented nuclei with a maximum effect at 100 µM and a significant decrease in Bcl-2 and an increase in activated caspase-3 protein levels at 72 hours compared with control untreated cultures. Our findings suggest a potential use of the COX-2 inhibitor, Parecoxib, as the therapy for keloids.

What is the role of locoregional anesthesia in breast surgery? A systematic literature review focused on pain intensity, opioid consumption, adverse events, and patient satisfaction.

BACKGROUND: Breast surgery in the United States is common. Pain affects up to 50% of women undergoing breast surgery and can interfere with postoperative outcomes. General anesthesia is the conventional, most frequently used anaesthetic technique. Various locoregional anesthetic techniques are also used for breast surgeries. A systematic review of the use of locoregional anesthesia for postoperative pain in breast surgery is needed to clarify its role in pain management. OBJECTIVES: To systematically review literature to establish the efficacy and the safety of locoregional anesthesia used in the treatment of pain after breast surgery. METHODS: Embase, MEDLINE, Google Scholar and Cochrane Central Trials Register were systematically searched in Mars 2020 for studies examining locoregional anesthesia for management of pain in adults after breast surgery. The methodological quality of the studies and their results were appraised using the Consensus-based Standards for the Selection of Health Measurement Instruments (COSMIN) checklist and specific measurement properties criteria, respectively. RESULTS: Nineteen studies evaluating locoregional anesthesia were included: 1058 patients underwent lumpectomy/mastectomy, 142 breast augmentation and 79 breast reduction. Locoregional anesthesia provides effective anesthesia and analgesia in the perioperative setting, however no statistically significant difference emerged if compared to other techniques. For mastectomy only, the use of locoregional techniques reduces pain in the first hour after the end of the surgery if compared to other procedures (p = 0.02). Other potentially beneficial effects of locoregional anesthesia include decreased need for opioids, decreased postoperative nausea and vomiting, fewer complications and increased patient satisfaction. All this improves postoperative recovery and shortens hospitalization stay. In none of these cases, locoregional anesthesia was statistically superior to other techniques. CONCLUSION: The results of our review showed no differences between locoregional anesthesia and other techniques in the management of breast surgery. Locoregional techniques are superior in reducing pain in the first hour after mastectomy.

The Influence of Breast Cancer on the Distribution of Cherry Angiomas on the Anterior Thoracic Wall: A Case Series Study.

BACKGROUND/AIMS: Cherry angiomas (CAs) are one of the most common vascular manifestations of the skin. By and large, these benign lesions often only represent an aesthetic problem. In the literature, few authors have focused on the pathogenesis of these lesions, and some risk factors have been identified, such as the presence of cutaneous and non-skin neoplasias. In this study, the correlation between the distribution of CAs and breast cancer was investigated. METHODS: We carried out a study whereby 50 women with unilateral breast cancer and the presence of CAs on the anterior thoracic wall were evaluated, with a particular focus on the difference in the number of CAs between the two haemithoraces. The data was elaborated using the Wilcoxon signed-rank test in order to evaluate whether there was a statistical significance in the distribution of CAs. RESULTS: In 31 patients we found that the number of CAs was greater on the cancerous breast than on the contralateral one (p value <0.0001). This was confirmed both in the group of patients suffering from ductal breast cancer and in the group with early invasive breast tumours. CONCLUSION: It is not clear whether CAs develop prior to or following breast cancer, indicating the possibility that this cutaneous manifestation could take on a predictive, prognostic development or represent only an epiphenomenon. Further in-depth studies into the pathogenesis of CAs and the relationship with breast cancer could lead to noteworthy diagnostic-therapeutic advances.

Low Versus High Vacuum Suction Drainage of the Submuscular Pocket in Primary Breast Reconstruction: A Retrospective Study.

BACKGROUND: Placement of suction drainage in submuscular pockets is routinely performed in breast reconstruction. Days of drain permanence (DDP) are associated with hospital stay and related health care costs. The aims of this study are to retrospectively compare data related to DDP and total drainage volume between high and low vacuum suction drainage groups and to identify correlations with patient or surgery-related factors. METHODS: We retrospectively analyzed data of 100 patients undergoing immediate or delayed breast reconstruction with expanders and implants. We considered 2 groups depending on suction pressure applied by 2 different surgical teams: group A (number, 50 patients) with high vacuum suction and group B (number, 50 patients) with low vacuum suction. RESULTS: Days of drain permanence was not significantly different between group A and group B (P = 0.451). The same was found for total drainage volume (P = 0.183). The distribution of DDP was statistically different only between patients with or without intraoperative bleeding in group A (P = 0.005) and smoking or nonsmoking patients in group A (P = 0.045). Statistical significance was kept in multivariate regression. CONCLUSIONS: There is no significant difference in DDP and total drainage volume using low or high vacuum suction drainage in breast reconstruction. The only factors affecting drainage permanence were intraoperative filling of expander, smoking, and intraoperative bleeding. Therefore, we can reduce the DDP, avoiding overfilling of expander and using of high vacuum suction in nonsmoking patients and in patients with significant intraoperative bleeding.

Evaluation of peripheral microcirculation improvement of foot after tarsal tunnel release in diabetic patients by transcutaneous oximetry.

BACKGROUND: According to recent studies, peripheral nerve decompression in diabetic patients seems to not only improve nerve function, but also to increase microcirculation; thus decreasing the incidence of diabetic foot wounds and amputations. However, while the postoperative improvement of nerve function is demonstrated, the changes in peripheral microcirculation have not been demonstrated yet. The aim of this study is to assess the degree of microcirculation improvement of foot after the tarsal tunnel release in the diabetic patients by using transcutaneous oximetry. PATIENTS AND METHODS: Twenty diabetic male patients aged between 43 and 72 years old (mean age 61.2 years old) suffering from diabetic peripheral neuropathy with superimposed nerve compression underwent transcutaneous oximetry (PtcO2) before and after tarsal tunnel release by placing an electrode on the skin at the level of the dorsum of the foot. Eight lower extremities presented diabetic foot wound preoperatively. Thirty-six lower extremities underwent surgical release of the tibialis posterior nerve only, whereas four lower extremities underwent the combined release of common peroneal nerve, anterior tibialis nerve, and posterior tibialis nerve. RESULTS: Preoperative values of transcutaneous oximetry were below the critical threshold, that is, lower than 40 mmHg (29.1 ± 5.4 mmHg). PtcO2 values at one month after surgery (45.8 ± 6.4 mmHg) were significantly higher than the preoperative ones (P = 0.01). CONCLUSIONS: The results of postoperative increase in PtcO2 values demonstrate that the release of the tarsal tunnel determines a relevant increase in microcirculation in the feet of diabetic patients.

A scanning electron microscope study and statistical analysis of adipocyte morphology in lipofilling: comparing the effects of harvesting and purification procedures with 2 different techniques.

BACKGROUND: The aim of this study was to evaluate the effects on adipocyte morphology of 2 techniques of fat harvesting and of fat purification in lipofilling, considering that the number of viable healthy adipocytes is important in fat survival in recipient areas of lipofilling. METHODS: Fat harvesting was performed in 10 female patients from flanks, on one side with a 2-mm Coleman cannula and on the other side with a 3-mm Mercedes cannula. Thirty milliliter of fat tissue from each side was collected and divided into three 10 mL syringes: A, B, and C. The fat inside syringe A was left untreated, the fat in syringe B underwent simple sedimentation, and the fat inside syringe C underwent centrifugation at 3000 rpm for 3 minutes. Each fat graft specimen was processed for examination under low-vacuum scanning electron microscope. Diameter (µ) and number of adipocytes per square millimeter and number of altered adipocytes per square millimeter were evaluated. Untreated specimens harvested with the 2 different techniques were first compared, then sedimented versus centrifuged specimens harvested with the same technique were compared. Statistical analysis was performed using Wilcoxon signed rank test. RESULTS: The number of adipocytes per square millimeter was statistically higher in specimens harvested with the 3-mm Mercedes cannula (P = 0.0310). The number of altered cells was statistically higher in centrifuged specimens than in sedimented ones using both methods of fat harvesting (P = 0.0080) with a 2-mm Coleman cannula and (P = 0.0050) with a 3-mm Mercedes cannula. Alterations in adipocyte morphology consisted in wrinkling of the membrane, opening of pore with leakage of oily material, reduction of cellular diameter, and total collapse of the cellular membrane. CONCLUSIONS: Fat harvesting by a 3-mm cannula results in a higher number of adipocytes and centrifugation of the harvested fat results in a higher number of morphologic altered cells than sedimentation.

Functional and Aesthetic Comparison between Grafts and Local Flaps in Non-Melanoma Skin Cancer Surgery of the Face: A Cohort Study.

Background: Non-melanoma skin cancers represent more than 90 % of malignant skin tumors, with an incidence of 19.46 cases/100,000 people per year in Italy; however, their real incidence is underestimated. Although there are several therapeutic strategies, the only one that can guarantee a 95 % healing rate and the possibility of performing histological examination is surgical excision with subsequent reconstruction of the injured area with direct closure and with skin graft, local, regional, or free flaps in cases involving greater damage. Material and Methods: Fifty-four patients underwent post-oncological head/face reconstructive surgery with skin graft or local flap between November 2021 and February 2023. The aesthetic outcomes (and the subsequent impact on the patients' lives) were assessed using the Vancouver Scar Scale, Manchester Scar Scale, and Visual Analog Scale with scars ranked by three independent surgeon observers. Results: Patients who received reconstruction with local flaps demonstrated improved aesthetic and functional satisfaction, as well as improved aesthetic evaluation by independent surgeons. Conclusions: The use of local flaps permits a more pleasing reconstruction (functionally and aesthetically) of post-oncological tissue defects of the face.

All for one: Collaboration between dermatologist, radiation oncologist and radiologist in the clinical management of "difficult to treat" non melanoma skin cancer.

This series introduces the clinical management of difficult-to-treat non-melanoma skin cancers (NMSCs) through a multidisciplinary approach, emphasizing the integration of dermoscopy and Ultra high-frequency ultrasound (UHFUS) for accurate diagnosis and treatment planning, particularly in cases referred for radiotherapy (RT). Dermoscopy aids in diagnosing both pigmented and non-pigmented skin lesions, guiding treatment margins and reducing the benign-to-malignant biopsy ratio. UHFUS provides valuable insights into tumor size, depth, and vascularity, complementing clinical evaluations and assisting in RT planning. Three challenging cases are presented, highlighting the pivotal role of dermoscopy and UHFUS in decision-making and treatment optimization. Collaboration between dermatologists, radiation oncologists, and radiologists enhances diagnostic accuracy, tailoring treatment plans to individual patient needs and preferences, ultimately improving patient outcomes and experience. The integration of these imaging techniques holds promise for optimizing non-surgical treatments like RT and monitoring treatment progress, offering a personalized approach to NMSC management.

The Role of Sentinel Node Biopsy in the Era of Adjuvant Therapy for Melanoma.

Sentinel lymph node biopsy (SLNB) is a surgical procedure aimed to detect nodal metastases in patients with clinically occult disease. Since the advent of new systemic therapies, its role in melanoma has been extensively debated over the last years. In this article, three possible scenarios are discussed, considering the SLNB impact on the management of melanoma patients. First, pT1b and pT2a patients with negative SLNB (stages IA and IB) and those with positive SLNB (stage IIIA) would all not benefit from adjuvant treatment. Therefore, SLNB might be avoided in these categories of patients. Second, in IIB and IIC, melanoma patients are already candidates for adjuvant treatment; therefore, SLNB in patients with T3b, T4a, or T4b melanoma would not change treatment decisions. On the other end of the spectrum, patients with pT2b and pT3a melanomas (clinical stage IIA) represent the only two groups whose management would be significantly affected by the SLNB status, being adjuvant therapy only indicated for SLN-positive patients. Further studies are needed to investigate which melanoma patient deserves SLNB.

Free fibular flap with periosteal excess for mandibular reconstruction.

BACKGROUND: In microvascular transfer of fibular osteocutaneous flap for mandible reconstruction after cancer ablation, good bone union is necessary to allow timely radiation therapy after surgery. As the area of bone contact between fibula and the original mandible at the edge of the mandibular defect is small, a periosteal excess at both ends of the fibula covering the bone junction can be used to increase the chance of bone union. The purpose of this study is to investigate whether a periosteal excess surrounding both ends of the fibula flap can provide better blood supply and, therefore, ensure bone union and wound healing at 6 weeks after surgery and before radiation therapy initiation. PATIENTS AND METHODS: The transfer of fibular osteocutaneous flap with periosteal excess was only applied to reconstruct segmental mandibular defects. As a consequence, only cases in which osteotomy of fibula was not performed were included in this study. A total of 34 fibular flaps without osteotomies were performed between 2000 and 2008; 17 with and 17 without the periosteal excess. The bone union was evaluated in terms of osseous callus formation using X-rays and CT three-dimensional images at 6 weeks after surgery, and results were assessed by three independent radiologists. RESULTS: There was a significant difference between reconstructions with and without the periosteal excess in terms of bone union (P = 0.022). With reference to postoperative complications, the group reconstructed without periosteal excess presented a higher number of complications, mainly consisting of partial and total flap necrosis, respectively six (35.29%) and two (11.76%) cases. In the group reconstructed with periosteal excess, no loss of the skin island has occurred. A significant difference was observed in terms of partial flap necrosis (P = 0.024), while the other complications did not reveal a statistically significant difference (P > 0.05). CONCLUSIONS: The use of a periosteal excess at both ends of the fibula flap provides better blood supply and is, therefore, able to ensure good bone healing and skin paddle survival regardless of the radiotherapy.

Correction of Rippling in Implant-based Breast Reconstruction with Serratus Fascia Flap.

Implant-based breast reconstruction represents the most popular procedure for the treatment of women undergoing skin-sparing mastectomy. In selected patients, it allows for obtaining an excellent appearance of the reconstructed breast with great satisfaction to the patient. However, aesthetic and functional results can be affected by complications requiring reoperation. Among them, rippling is an undesired occurrence associated with implant-based reconstruction. It consists of a cutaneous manifestation, visible and/or palpable, of the implant wrinkles and edge which appear mostly when the patient leans forward. To treat this contour deformity, several techniques have been described such as acellular dermal matrices and autologous tissues. In this study, we intend to add the serratus anterior fascial flap within the autologous options in the treatment of implant rippling, reporting our experience.

Multiple Foci of Basal Cell Carcinoma Arising in Rhinophyma: A Case Report and Literature Review.

Background: Rhinophyma is a benign condition caused by the excessive growth of sebaceous glands in the nasal tissue, presenting with symptoms such as nasal hypertrophy, erythema, and papules. Cases of basal cell carcinoma in rhinophyma have been reported in literature, but its etiological role remains unclear. It is uncertain whether rhinophyma is predisposed to neoplasm development or if their coexistence is coincidental. Material and Method: We conducted a literature survey to identify such cases reported over the years. Results: We identified 22 studies reporting a total of 47 cases in the literature, all involving male patients. The most common pattern of occurrence was the rapid growth of a nodular formation within the context of rhinophyma. Discussions and Conclusion: The elucidation of the association between basal cell carcinoma and rhinophyma remains challenging. The presence of multiple foci supports the theory that rhinophyma may play a role in their development, but larger studies are needed to establish a causal relationship.

Clinical epigenetics and restoring of metabolic health in severely obese patients undergoing batriatric and metabolic surgery.

Epigenetic-sensitive mechanisms, mainly DNA methylation, mirror the relationship between environmental and genetic risk factors able to affect the sensitiveness to development of obesity and its comorbidities. Bariatric and metabolic surgery may reduce obesity-related cardiovascular risk through tissue-specific DNA methylation changes. Among the most robust results, differential promoter methylation of ACACA, CETP, CTGF, S100A8, and S100A9 genes correlated significantly with the levels of mRNA before and after gastric bypass surgery (RYGB) in obese women. Additionally, promoter hypermethylation of NFKB1 gene was significantly associated with reduced blood pressure in obese patients after RYGB suggesting useful non-invasive biomarkers. Of note, sperm-related DNA methylation signatures of genes regulating the central control of appetite, such as MC4R, BDNF, NPY, and CR1, and other genes including FTO, CHST8, and SH2B1 were different in obese patients as compared to non-obese subjects and patients who lost weight after RYGB surgery. Importantly, transgenerational studies provided relevant evidence of the potential effect of bariatric and metabolic surgery on DNA methylation. For example, peripheral blood biospecimens isolated from siblings born from obese mothers before bariatric surgery showed different methylation signatures in the insulin receptor and leptin signaling axis as compared to siblings born from post-obese mothers who underwent surgery. This evidence suggests that bariatric and metabolic surgery of mothers may affect the epigenetic profiles of the offspring with potential implication for primary prevention of severe obesity. We update on tissue-specific epigenetic signatures as potential mechanisms underlying the restoration of metabolic health after surgery suggesting useful predictive biomarkers.

Mondor's disease as a complication in breast surgery in a male patient. The first ever reported case in literature.

Mondor's disease (MD) is an uncommon clinical condition characterized by thrombophlebitis of the superficial veins of the anterolateral thoracoabdominal wall. In this paper we present the first ever reported case of Mondor's disease in male patient after surgical correction of gynecomastia with liposuction assisted skin sparing adenectomy.

Optimizing Fat Grafting Using a Hydraulic System Technique for Fat Processing: A Time and Cost Analysis.

Background Many authors have researched ways to optimize fat grafting by looking for a technique that offers safe and long-term fat survival rate. To date, there is no standardized protocol. We designed a "hydraulic system technique" optimizing the relationship among the quantity of injected fat, operative time, and material cost to establish fat volume cutoffs for a single procedure. Methods Thirty-six patients underwent fat grafting surgery and were organized into three groups according to material used: standard, "1-track," and "2-tracks" systems. The amount of harvested and grafted fat as well as material used for each procedure was collected. Operating times were recorded and statistical analysis was performed to establish the relationship with the amount of treated fat. Results In 15 cases the standard system was used (mean treated fat 72 [30-100] mL, mean cost 4.23 ± 0.27 euros), in 11 cases the "1-track" system (mean treated fat 183.3 [120-280] mL, mean cost 7.63 ± 0.6 euros), and in 10 cases the "2-tracks" one (mean treated fat 311[220-550] mL, mean cost 12.47 ± 1 euros). The mean time difference between the standard system and the "1-track" system is statistically significant starting from three fat syringes (90 mL) in 17.66 versus 6.87 minutes. The difference between the "1-track" system and "2-tracks" system becomes statistically significant from 240 mL of fat in 15 minutes ("1-track") versus 9.3 minutes for the "2-tracks" system. Conclusion Data analysis would indicate the use of the standard system, "1-track," and "2-tracks" to treat an amount of fat < 90 mL of fat, 90 ÷ 240 mL of fat, and ≥ 240 mL of fat, respectively.

The Impact of Direct Oral Anticoagulant Prophylaxis for Thromboembolism in Thrombophilic Patients Undergoing Abdominoplastic Surgery.

Congenital or acquired thrombophilia is observed in 10-15% of the general population; therefore, careful screening is carried out in patients at higher risk of venous thrombo-embolism (VTE). High risk of VTE is a contraindication in patients undergoing abdominoplasty. We evaluated rivaroxaban, an oral Xa inhibitor, with enoxaparin, a subcutaneously low molecular weight heparin (LMWH), in 48 female patients with documented thrombophilia, undergoing thrombo-prophylaxis after abdominoplasty. Patients were stratified into two groups according to thrombo-prophylaxis procedure: enoxaparin Group (n = 28) and rivaroxaban Group (n = 20). Hematologic outcomes were evaluated including VTE and hematoma. No episodes of VTE occurred in both groups; two patients during their course of enoxaparin presented severe hematoma for drainage and hemostasis revision. This study suggests that abdominoplasty, in patients with thrombophilia, in combination with thrombo-prophylaxis can be performed safely. Rivaroxaban was as effective as LMWH for preventing VTE, with only a moderate risk of clinically relevant bleeding. More research is needed to determine the optimal timing and duration of prophylaxis in patients undergoing plastic surgery.

Immune reactivity during COVID-19: Implications for treatment.

Clinical symptoms of COVID-19 include fever, cough, and fatigue which may progress to acute respiratory distress syndrome (ARDS). The main hematological laboratory findings associated with the severe form of disease are represented by lymphopenia and eosinopenia which mostly occur in the elderly population characterized by cardiovascular comorbidities and immunosenescence. Besides, increased levels of D-dimer, procalcitonin, and C reactive protein (CRP) seem to be powerful prognostic biomarkers helping to predict the onset of coagulopathy. The host immune response to SARS-CoV-2 can lead to an aberrant inflammatory response or "cytokine storm" which contributes to the severity of illness. At immunological level, patients affected by a severe form of COVID-19 show poor clinical trajectories characterized by differential "immunotypes" for which T cell response seems to play a critical role in understanding pathogenic mechanisms of disease. Also, patients with mild to severe COVID-19 displayed macrophage activation syndrome (MAS), very low human leukocyte antigen D related (HLA-DR) expression with a parallel reduction of CD04+ lymphocytes, CD19 lymphocytes, and natural killer (NK) cells. Corticosteroids resulted the best therapy for the immune dysregulation whereas repurposing of tocilizumab (IL-6 receptor antagonist) appears to have mixed results in patients with COVID-19. Besides, anticoagulative therapy was associated with reduced in-hospital mortality and need of intubation among COVID-19 patients. Furthermore, the beneficial use of intravenous immunoglobulin (IVIG) and passive immunotherapy with convalescent plasma needs to be validated in large controlled clinical trials. In this review, we summarize the main hematological parameters with a prognostic value in COVID-19 and the basis of immunological reactivity during COVID-19, with a focus on ongoing clinical trials evaluating immune targets as possible therapeutic strategies.

Network Medicine Approach in Prevention and Personalized Treatment of Dyslipidemias.

Dyslipidemias can affect molecular networks underlying the metabolic homeostasis and vascular function leading to atherogenesis at early stages of development. Since disease-related proteins often interact with each other in functional modules, many advanced network-oriented algorithms were applied to patient-derived big data to identify the complex gene-environment interactions underlying the early pathophysiology of dyslipidemias and atherosclerosis. Both the proprotein convertase subtilisin/kexin type 7 (PCSK7) and collagen type 1 alpha 1 chain (COL1A1) genes arose from the application of TFfit and WGCNA algorithms, respectively, as potential useful therapeutic targets in prevention of dyslipidemias. Moreover, the Seed Connector algorithm (SCA) algorithm suggested a putative role of the neuropilin-1 (NRP1) protein as drug target, whereas a regression network analysis reported that niacin may provide benefits in mixed dyslipidemias. Dyslipidemias are highly heterogeneous at the clinical level; thus, it would be helpful to overcome traditional evidence-based paradigm toward a personalized risk assessment and therapy. Network Medicine uses omics data, artificial intelligence (AI), imaging tools, and clinical information to design personalized therapy of dyslipidemias and atherosclerosis. Recently, a novel non-invasive AI-derived biomarker, named Fat Attenuation Index (FAI™) has been established to early detect clinical signs of atherosclerosis. Moreover, an integrated AI-radiomics approach can detect fibrosis and microvascular remodeling improving the customized risk assessment. Here, we offer a network-based roadmap ranging from novel molecular pathways to digital therapeutics which can improve personalized therapy of dyslipidemias.

Clinical epigenetics and acute/chronic rejection in solid organ transplantation: An update.

The lack of a precise stratification algorithm for predicting patients at high risk of graft rejection challenges the current solid organ transplantation (SOT) clinical setting. In fact, the established biomarkers for transplantation outcomes are unable to accurately predict the onset time and severity of graft rejection (acute or chronic) as well as the individual response to immunosuppressive drugs. Thus, identifying novel molecular pathways underlying early immunological responses which can damage transplant integrity is needed to reach precision medicine and personalized therapy of SOT. Direct epigenetic-sensitive mechanisms, mainly DNA methylation and histone modifications, may play a relevant role for immune activation and long-term effects (e.g., activation of fibrotic processes) which may be translated in new non-invasive biomarkers and drug targets. In particular, the measure of DNA methylation by using the blood-based "epigenetic clock" system may be an added value to the donor eligibility criteria providing an estimation of the heart biological age as well as a predictive biomarkers. Besides, monitoring of DNA methylation changes may aid to predict acute vs chronic graft damage in kidney transplantation (KT) patients. For example, hypermethylation of genes belonging to the Notch and Wnt pathways showed a higher predictive value for chronic injury occurring at 12 months post-KT with respect to established clinical parameters. Detecting higher circulating cell-free DNA (cfDNA) fragments carrying hepatocyte-specific unmethylated loci in the inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4), insulin like growth factor 2 receptor (IGF2R), and vitronectin (VTN) genes may be useful to predict acute graft injury after liver transplantation (LT) in serum samples. Furthermore, hypomethylation in the forkhead box P3 (FOXP3) gene may serve as a marker of infiltrating natural Treg percentage in the graft providing the ability to predict acute rejection events after heart transplantation (HTx). We aim to update on the possible clinical relevance of DNA methylation changes regulating immune-related pathways underlying acute or chronic graft rejection in KT, LT, and HTx which might be useful to prevent, monitor, and treat solid organ rejection at personalized level.

MiR-200c-3p maintains stemness and proliferative potential in adipose-derived stem cells by counteracting senescence mechanisms.

Adipose-derived mesenchymal stem cells (ASCs) are promising therapeutic tools in regenerative medicine because they possess self-renewal, differentiation and immunomodulatory capacities. After isolation, ASCs are passaged multiple times in vitro passages to obtain a sufficient amount of cells for clinical applications. During this time-consuming procedure, ASCs become senescent and less proliferative, compromising their clinical efficacy. Here, we sought to investigate how in vitro passages impact ASC proliferation/senescence and expression of immune regulatory proteins. MicroRNAs are pivotal regulators of ASC physiology. Particularly, miR-200c is known to maintain pluripotency and targets the immune checkpoint Programmed death-ligand 1 (PD-L1). We therefore investigated its involvement in these critical characteristics of ASCs during in vitro passages. We found that when transiently expressed, miR-200c-3p promotes proliferation, maintains stemness, and contrasts senescence in late passaged ASCs. Additionally, this miRNA modulates PD-L1 and Indoleamine 2,3-Dioxygenase (IDO1) expression, thus most likely interfering with the immunoregulatory capacity of ASCs. Based on our results, we suggest that expression of miR-200c-3p may prime ASC towards a self-renewing phenotype by improving their in vitro expansion. Contrarily, its inhibition is associated with senescence, reduced proliferation and induction of immune regulators. Our data underline the potential use of miR-200c-3p as a switch for ASCs reprogramming and their clinical application.