The impact of COVID-19 pandemic in patients with a diagnosis of Oral Lichen Planus: Pain perception and psychological profile analysis.

OBJECTIVES: To assess the impact of COVID-19 in patients affected by OLP, in terms of level of pain, stress, depression and anxiety and their impact on the clinical manifestation of the disease. MATERIAL AND METHODS: A longitudinal design was employed. Psychometric evaluations of anxiety, stress, and depression were conducted using the DASS21 scale, while pain levels were measured using the VAS scale. Clinical diagnosis and phenotype evaluation were performed. RESULTS: The study included 24 patients with an average age of 62.9 years, with 70.8% presenting erosive OLP. Results revealed a significant worsening of anxiety, stress, and depression scores during the pandemic. Pain level (1.5 ± 1.2 pre-pandemic VS 3.8 ± 1.1 during the pandemic, p < 0.0001) was also negatively affected. CONCLUSIONS: These findings highlight the potential interplay between psychological stress and oral health conditions, emphasizing the need for a comprehensive understanding of OLP's complex etiology and its response to external stressors. CLINICAL RELEVANCE: Multidisciplinary care strategies to address both physical and psychological aspects of OLP patients is recommended following the present findings. Further research is warranted to confirm these observations in larger multicenter studies and to guide tailored guidance approaches for OLP patients during challenging times.

Oroantral Communications: Clinical Efficacy of a Double-layered Technique With/Without the Palatal Connective Tissue Flap: A Superiority, Single-center, University-based Randomized Clinical Trial.

The aim of this study was to compare the clinical results of combining a pedicle connective palatal flap coupled with the trapezoid buccal flap against the buccal flap alone in the closure of the oroantral fistula. Individuals with oroantral communication were consecutively included and eventually randomly allocated into 2 groups. In the group test, oroantral fistula was treated with the association of a buccal flap with a pedicle palatal connective tissue flap; in group control, a classic buccal sliding flap was performed. Patients' outcomes were recorded at 48 hours, 1 week, 2 weeks, and 1 month after surgery for assessment of primary (success rate) and secondary endpoints, such as experienced pain, discomfort, and complications. The success rate was 96.6% for the test group and 86.6% for the control group. No significant difference between the 2 groups could be observed regarding discomfort and pain. More pronounced pain was detected in the test group during the early healing period. This surgical procedure was demonstrated to be successful, with a high success rate and low patient discomfort.

Epigenetic Regulation Mediated by Sphingolipids in Cancer.

Epigenetic changes are heritable modifications that do not directly affect the DNA sequence. In cancer cells, the maintenance of a stable epigenetic profile can be crucial to support survival and proliferation, and said profile can differ significantly from that of healthy cells. The epigenetic profile of a cancer cell can be modulated by several factors, including metabolites. Recently, sphingolipids have emerged as novel modulators of epigenetic changes. Ceramide and sphingosine 1-phosphate have become well known in cancer due to activating anti-tumour and pro-tumour signalling pathways, respectively, and they have recently been shown to also induce several epigenetic modifications connected to cancer growth. Additionally, acellular factors in the tumour microenvironment, such as hypoxia and acidosis, are now recognised as crucial in promoting aggressiveness through several mechanisms, including epigenetic modifications. Here, we review the existing literature on sphingolipids, cancer, and epigenetic changes, with a focus on the interaction between these elements and components of the chemical tumour microenvironment.

Accuracy and Security Analysis of a Cranio-Maxillofacial Plastic Surgery Robot Equipped With Piezosurgery in Genioplasty.

ABSTRACT: This study aims to verify that the craniofacial plastic surgery robot with piezosurgery is more accurate and safer than traditional operations in genioplasty. This study chose data from the Digital Plastic Surgery of Plastic Surgery Hospital in the Chinese Academy of Medical Sciences and Peking Union Medical College. The CT data of the patient's skull were reconstructed in the software, and the authors designed the measurement index. The surgical plan was designed as an ideal scheme (control group). Patients underwent traditional surgery according to the preoperative surgery plan (clinical group). Guided by surgical navigation, the osteotomy was operated on patients' same size plaster model using the surgery robot equipped with a piezosurgery (robot group). At last, the accuracy was calculated by CT data. There was no significant difference between the robotic group and control groups in the postoperative measurement index (P < 0.05). There was no significant difference between the robotic group and the control group ( P > 0.05) in the line of osteotomy, but there was a significant difference between the clinical group and the control group in the line of the osteotomy.

Validation of a Cleanroom Compliant Sonication-Based Decellularization Technique: A New Concept in Nerve Allograft Production.

Defects of the peripheral nervous system are extremely frequent in trauma and surgeries and have high socioeconomic costs. If the direct suture of a lesion is not possible, i.e., nerve gap > 2 cm, it is necessary to use grafts. While the gold standard is the autograft, it has disadvantages related to its harvesting, with an inevitable functional deficit and further morbidity. An alternative to autografting is represented by the acellular nerve allograft (ANA), which avoids disadvantages of autograft harvesting and fresh allograft rejection. In this research, the authors intend to transfer to human nerves a novel technique, previously implemented in animal models, to decellularize nerves. The new method is based on soaking the nerve tissues in decellularizing solutions while associating ultrasounds and freeze-thaw cycles. It is performed without interrupting the sterility chain, so that the new graft may not require post-production γ-ray irradiation, which is suspected to affect the structural and functional quality of tissues. The new method is rapid, safe, and inexpensive if compared with available commercial ANAs. Histology and immunohistochemistry have been adopted to evaluate the new decellularized nerves. The study shows that the new method can be applied to human nerve samples, obtaining similar, and, sometimes better, results compared with the chosen control method, the Hudson technique.

Curcumin-Loaded Nanoparticles Impair the Pro-Tumor Activity of Acid-Stressed MSC in an In Vitro Model of Osteosarcoma.

In the tumor microenvironment, mesenchymal stromal cells (MSCs) are key modulators of cancer cell behavior in response to several stimuli. Intratumoral acidosis is a metabolic trait of fast-growing tumors that can induce a pro-tumorigenic phenotype in MSCs through the activation of the NF-κB-mediated inflammatory pathway, driving tumor clonogenicity, invasion, and chemoresistance. Recent studies have indicated that curcumin, a natural ingredient extracted from Curcuma longa, acts as an NF-κB inhibitor with anti-inflammatory properties. In this work, highly proliferating osteosarcoma cells were used to study the ability of curcumin to reduce the supportive effect of MSCs when stimulated by acidosis. Due to the poor solubility of curcumin in biological fluids, we used spherical polymeric nanoparticles as carriers (SPN-curc) to optimize its uptake by MSCs. We showed that SPN-curc inhibited the release of inflammatory cytokines (IL6 and IL8) by acidity-stimulated MSCs at a higher extent than by free curcumin. SPN-curc treatment was also successful in blocking tumor stemness, migration, and invasion that were driven by the secretome of acid-stressed MSCs. Overall, these data encourage the use of lipid-polymeric nanoparticles encapsulating NF-κB inhibitors such as curcumin to treat cancers whose progression is stimulated by an activated mesenchymal stroma.

Cause and effect of microenvironmental acidosis on bone metastases.

Skeletal involvement is a frequent and troublesome complication in advanced cancers. In the process of tumor cells homing to the skeleton to form bone metastases (BM), different mechanisms allow tumor cells to interact with cells of the bone microenvironment and seed in the bone tissue. Among these, tumor acidosis has been directly associated with tumor invasion and aggressiveness in several types of cancer although it has been less explored in the context of BM. In bone, the association of local acidosis and cancer invasiveness is even more important for tumor expansion since the extracellular matrix is formed by both organic and hard inorganic matrices and bone cells are used to sense protons and adapt or react to a low pH to maintain tissue homeostasis. In the BM microenvironment, increased concentration of protons may derive not only from glycolytic tumor cells but also from tumor-induced osteoclasts, the bone-resorbing cells, and may influence the progression or symptoms of BM in many different ways, by directly enhancing cancer cell motility and aggressiveness, or by modulating the functions of bone cells versus a pro-tumorigenic phenotype, or by inducing bone pain. In this review, we will describe and discuss the cause of acidosis in BM, its role in BM microenvironment, and which are the final effectors that may be targeted to treat metastatic patients.

Biomarkers of bone healing induced by a regenerative approach based on expanded bone marrow-derived mesenchymal stromal cells.

BACKGROUND: Safety and feasibility of a regenerative strategy based on the use of culture-expanded mesenchymal stromal cells (MSCs) have been investigated in phase 2 trials for the treatment of nonunion and osteonecrosis of the femoral head (ONFH). As part of the clinical study, we aimed to evaluate if bone turnover markers (BTMs) could be useful for predicting the regenerative ability of the cell therapy product. MATERIALS AND METHODS: The bone defects of 39 patients (nonunion: n = 26; ONFH: n = 13) were treated with bone marrow-derived MSCs, expanded using a clinical-grade protocol and combined with biphasic calcium phosphate before implantation. Bone formation markers, bone-resorption markers and osteoclast regulatory proteins were measured before treatment (baseline) and after 12 and 24 weeks from surgery. At the same time-points, clinical and radiological controls were performed to evaluate the bone-healing progression. RESULTS: We found that C-Propeptide of Type I Procollagen (CICP) and C-terminal telopeptide of type-I collagen (CTX) varied significantly, not only over time, but also according to clinical results. In patients with a good outcome, CICP increased and CTX decreased, and this trend was observed in both nonunion and ONFH. Moreover, collagen biomarkers were able to discriminate healed patients from non-responsive patients with a good diagnostic accuracy. DISCUSSION: CICP and CTX could be valuable biomarkers for monitoring and predicting the regenerative ability of cell products used to stimulate the repair of refractory bone diseases. To be translated in a clinical setting, these results are under validation in a currently ongoing phase 3 clinical trial.

Auto-Allo Graft Parallel Juxtaposition for Improved Neuroregeneration in Peripheral Nerve Reconstruction Based on Acellular Nerve Allografts.

INTRODUCTION: Nerve repair poses a significant surgical challenge, and much research on this topic for improvement in reconstruction of segmental defects is ongoing. The aims of the study were to reconfirm the accuracy and safety of a previously described nerve decellularization method on a larger experimental population of rabbits, as well as on human nerves, and to establish in vivo the efficacy of a new-concept mixed graft, comprising autologous and acellular nerve allograft components within the same graft. METHODS: Acellular nerve allografts were implanted into tibial nerve defects of 5 rabbits (group A), autografts were implanted, representing the criterion standard, in other 5 animals (group B), and the innovative technique was used in the remaining 5 (group C). Twelve weeks postoperatively, nerve conduction evaluations were performed; animals were euthanatized, and grafts were harvested and morphologically, histomorphometrically, and immunohistochemically analyzed. Eventually, a preliminary in vitro validation of the decellularization method was performed on human nerves from a cadaver. RESULTS: No clinical adverse effect was revealed during all the experimental times. No tissue reaction was observed, and in all groups, regenerated fascicles and bundles were shown by histology. However, both histology and histomorphometry demonstrated a better regenerative efficiency in group C. The morphological evaluation of the human nerve treated with the novel method showed complete decellularization. CONCLUSION: The microsurgical combined model demonstrated a better neuroregeneration than did pure autografts and acellular nerve allografts. The decellularization method seemed effective also on human nerves. Deeper investigations are necessary to further validate and transfer this new encouraging protocol to the clinical arena.

Therapeutic implications of tumor interstitial acidification.

Interstitial acidification is a hallmark of solid tumor tissues resulting from the combination of different factors, including cellular buffering systems, defective tissue perfusion and high rates of cellular metabolism. Besides contributing to tumor pathogenesis and promoting tumor progression, tumor acidosis constitutes an important intrinsic and extrinsic mechanism modulating therapy sensitivity and drug resistance. In fact, pharmacological properties of anticancer drugs can be affected not only by tissue structure and organization but also by the distribution of the interstitial tumor pH. The acidic tumor environment is believed to create a chemical barrier that limits the effects and activity of many anticancer drugs. In this review article we will discuss the general protumorigenic effects of acidosis, the role of tumor acidosis in the modulation of therapeutic efficacy and potential strategies to overcome pH-dependent therapy-resistance.

Biological effects of metal degradation in hip arthroplasties.

Metals and metal alloys are the most used materials in orthopedic implants. The focus is on total hip arthroplasty (THA) that, though well tolerated, may be associated with local and remote adverse effects in the medium-long term. This review aims to summarize data on the biological consequences of the metal implant degradation that have been attributed predominantly to metal-on-metal (MoM) THA. Local responses to metals consist of a broad clinical spectrum ranging from small asymptomatic tissue lesions to severe destruction of bone and soft tissues, which are designated as metallosis, adverse reactions to metal debris (ARMD), aseptic lymphocytic vasculitis associated lesion (ALVAL), and pseudotumors. In addition, the dissemination of metal particles and ions throughout the body has been associated with systemic adverse effects, including organ toxicity, cancerogenesis, teratogenicity, and immunotoxicity. As proved by the multitude of studies in this field, metal degradation may increase safety issues associated with THA, especially with MoM hip systems. Data collection regarding local, systemic and long-term effects plays an essential role to better define any safety risks and to generate scientifically based recommendations.

The Effects of Systemic and Local Acidosis on Insulin Resistance and Signaling.

Most pathological conditions that cause local or systemic acidosis by overcoming the buffering activities of body fluids overlap with those diseases that are characterized by glucose metabolic disorders, including diabetes mellitus, inflammation, and cancer. This simple observation suggests the existence of a strong relationship between acidosis and insulin metabolism or insulin receptor signaling. In this review, we summarized the current knowledge on the activity of insulin on the induction of acidosis and, vice versa, on the effects of changes of extracellular and intracellular pH on insulin resistance. Insulin influences acidosis by promoting glycolysis. Although with an unclear mechanism, the lowering of pH, in turn, inhibits insulin sensitivity or activity. In addition to ketoacidosis that is frequently associated with diabetes, other important and more complex factors are involved in this delicate feedback mechanism. Among these, in this review we discussed the acid-mediated inhibiting effects on insulin binding affinity to its receptor, on glycolysis, on the recycling of glucose transporters, and on insulin secretion via transforming growth factor ß (TGF-ß) activity by pancreatic ß-cells. Finally, we revised current data available on the mutual interaction between insulin signaling and the activity of ion/proton transporters and pH sensors, and on how acidosis may enhance insulin resistance through the Nuclear Factor kappa B (NF-κB) inflammatory pathway.

Validation of Suitable Housekeeping Genes for the Normalization of mRNA Expression for Studying Tumor Acidosis.

Similar to other types of cancer, acidification of tumor microenvironment is an important feature of osteosarcoma, and a major source of cellular stress that triggers cancer aggressiveness, drug resistance, and progression. Among the different effects of low extracellular pH on tumor cells, we have recently found that short-term exposure to acidosis strongly affects gene expression. This alteration might also occur for the most commonly used housekeeping genes (HKG), thereby causing erroneous interpretation of RT-qPCR data. On this basis, by using osteosarcoma cells cultured at different pH values, we aimed to identify the ideal HKG to be considered in studies on tumor-associated acidosis. We verified the stability of 15 commonly used HKG through five algorithms (NormFinder, geNorm, BestKeeper, ΔCT, coefficient of variation) and found that no universal HKG is suitable, since at least four HKG are necessary for proper normalization. Furthermore, according to the acceptable range of values, YWHAZ, GAPDH, GUSB, and 18S rRNA were the most stable reference genes at different pH. Our results will be helpful for future investigations focusing on the effect of altered microenvironment on cancer behavior, particularly on the effectiveness of anticancer therapies in acid conditions.

Cancer-associated mesenchymal stroma fosters the stemness of osteosarcoma cells in response to intratumoral acidosis via NF-κB activation.

The role of mesenchymal stem cells (MSC) in osteosarcoma (OS), the most common primary tumor of bone, has not been extensively elucidated. We have recently shown that OS is characterized by interstitial acidosis, a microenvironmental condition that is similar to a wound setting, in which mesenchymal reactive cells are activated to release mitogenic and chemotactic factors. We therefore intended to test the hypothesis that, in OS, acid-activated MSC influence tumor cell behavior. Conditioned media or co-culture with normal MSC previously incubated with short-term acidosis (pH 6.8 for 10 hr, H+ -MSC) enhanced OS clonogenicity and invasion. This effect was mediated by NF-κB pathway activation. In fact, deep-sequencing analysis, confirmed by Real-Time PCR and ELISA, demonstrated that H+ -MSC differentially induced a tissue remodeling phenotype with increased expression of RelA, RelB and NF-κB1, and downstream, of CSF2/GM-CSF, CSF3/G-CSF and BMP2 colony-promoting factors, and of chemokines (CCL5, CXCL5 and CXCL1), and cytokines (IL6 and IL8), with an increased expression of CXCR4. An increased expression of IL6 and IL8 were found only in normal stromal cells, but not in OS cells, and this was confirmed in tumor-associated stromal cells isolated from OS tissue. Finally, H+ -MSC conditioned medium differentially promoted OS stemness (sarcosphere number, stem-associated gene expression), and chemoresistance also via IL6 secretion. Our data support the hypothesis that the acidic OS microenvironment is a key factor for MSC activation, in turn promoting the secretion of paracrine factors that influence tumor behavior, a mechanism that holds the potential for future therapeutic interventions aimed to target OS.

MDA-MB-231 breast cancer cells fuel osteoclast metabolism and activity: A new rationale for the pathogenesis of osteolytic bone metastases.

Recent progress in dissecting the molecular paracrine circuits of cancer and stromal cells in bone metastases (BM) are offering new options to improve current merely palliative approach. The study of tumor-stroma metabolic interplay may further ameliorate this scenario. In this context, we demonstrated that highly glycolytic MDA-MB-231 cancer cells, that form osteolytic BM in vivo, release a large amount of lactate at a significantly higher level than MCF7 cells. Thus, we speculated that lactate released from carcinoma cells is uptaken and metabolically used by osteoclasts, the key players of osteolysis associated with BM. First, we demonstrated that the release of lactate at the bone site is mediated by monocarboxylate transporter 4 (MCT4), as revealed by immunostaining and MCT4 localization at the plasma membrane of tumor cells in mouse model of BM and in human tissue sections of BM. Then, we showed that in vitro lactate is uptaken by osteoclasts to be used as a fuel for the oxidative metabolism of osteoclasts, ultimately enhancing Type I collagen resorption. The passive transport of lactate into osteoclasts was mediated by MCT1: MCT1 expression is significantly upregulated during osteoclast differentiation and Type I collagen resorption is significantly impaired when osteoclasts are treated with 7-(N-benzyl-N-methylamino)-2-oxo-2H-chromene-3-carboxylic acid, an MCT-1 inhibitor. Together, these data demonstrate that lactate released by glycolytic breast carcinoma cells in the bone microenvironment promotes the formation of osteolytic lesions, and provide the rationale for further studies on the use of MCT1 targeting as a novel therapeutic approach in advanced cancer patients with BM.

Lateral approach for sinus floor elevation: large versus small bone window - a split-mouth randomized clinical trial.

OBJECTIVES: To test whether a reduction of bone window dimension, in a split-mouth randomized study design, focused on lateral sinus floor elevations, can achieve better results than a wider window in terms of augmented bone height and a reduction of patient discomfort and surgical complications. MATERIALS AND METHODS: Of the sixteen subjects enrolled in the study, each underwent a bilateral sinus lift procedure based on two different access flaps to maxillary sinus. Test side: small access window (6 × 6 mm) + bone filling using a special device. Control side: large access window (10 × 8 mm) + manual bone filling. Alveolar bone height and width were measured at pre-op and 6-month post-op CT scans; repeatable measurements were obtained using radiographic stents. Surgical intervention duration was also recorded. Patients' evaluation of surgical discomfort was assessed using a VAS diagram at 7-day, 14-day and 30-day follow-up. RESULTS: A significant bone augmentation in height and width of alveolar crest was obtained in both test (8.71 ± 1.11 mm, 4.70 ± 0.58 mm) and control (8.5 ± 2.02 mm, 4.68 ± 0.70 mm) sides, although no significant differences were found between the two groups. Neither any significant differences emerge in data concerning the duration of the intervention (Test 42.62 ± 6.67 min, Control 41.68 ± 8.34 min). Patients' opinion relating to surgical discomfort showed a preference for test procedure at 7-day, 14-day and 30-day follow-up. CONCLUSIONS: A reduction of window dimensions did not affect the safety of the surgical procedure. The two testing techniques showed no statistically significant differences in surgical intervention duration. Patients' opinion at 7-day and 14-day post-op showed a preference for test procedure.

Alpha-lipoic Acid After Median Nerve Decompression at the Carpal Tunnel: A Randomized Controlled Trial.

PURPOSE: The postoperative course of median nerve decompression in carpal tunnel syndrome may be associated with complications. The aim of this study was to explore the possible effects of alpha-lipoic acid (ALA) in the postoperative period after surgical decompression of the median nerve at the wrist. METHODS: We conducted a double-blind prospective, randomized, controlled trial. A total of 64 patients with proven carpal tunnel syndrome were enrolled and randomly assigned into 1 of 2 groups: group A (n = 32) patients had surgical decompression of the median nerve followed by ALA for 40 days, and group P (n = 32) patients had surgical decompression followed by placebo. The primary end point of the study was a comprehensive indicator of sensory and motor nerve conduction velocity (electrophysiology score) at 3 months after surgery, Other end points were static 2-point discrimination, Boston Carpal Tunnel score, presence or absence of pillar pain, and use of analgesics beyond the second postoperative day. RESULTS: Alpha-lipoic acid did not improve nerve conduction velocity or Boston Carpal Tunnel score significantly. However, a statistically significant reduction in the postoperative incidence of pillar pain was noted in the ALA group. In addition, static 2-point discrimination improved in both groups. CONCLUSIONS: Postoperative administration of ALA for 40 days after median nerve decompression may result in a lower incidence of pillar pain. This treatment is relatively well tolerated, which may support its value as standard postoperative supplementation after carpal tunnel decompression if further studies on larger samples confirm these preliminary findings. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic I.

Treatment for long bone metastases based on a systematic literature review.

PURPOSE: To provide treatment guidelines for patients with long bone metastatic disease based on a systematic review of the literature and to propose an algorithm to guide orthopedic surgeons in decision-making for these patients. MATERIALS AND METHODS: We performed a computerized literature search in MEDLINE, EMBASE and Scopus for studies on patients with long bone metastases. We used the key words "long bones", "metastasis" and "treatment" for published studies that evaluated any treatment for long bone metastases. The articles found were then studied to determine the accuracy of surgical treatments for long bone metastases in every anatomic location, regardless of cancer type, stage and grade of the oncologic disease. Guidelines inferred from this literature review were collected, and an algorithm was proposed. RESULTS: There was no clear evidence to support excision of a long bone metastatic lesion at the same surgical setting with internal fixation or prosthetic reconstruction. However, en bloc resection of an isolated bone metastasis may have a beneficial effect on survival. The life expectancy of the patients should be considered for any surgical treatment. Internal fixation preferably with reconstruction nails is indicated for meta-diaphyseal lesions; their rate of mechanical failure and complications ranges from 2 to 22 %. Prosthetic reconstruction is indicated for extensive lytic lesions or pathologic fractures in a meta-epiphyseal locations; their rate of mechanical failure and complications ranges from 3.7 to 35 %. Most of the internal fixation-related complications occur more than 1 year after treatment, in contrast to prosthetic reconstruction-related complications that may occur earlier. CONCLUSIONS: Intramedullary nail fixation or prosthetic reconstruction should be chosen on the basis of the location of the lesion, the extent of bone destruction and the stability of the construct to outlast the expected life of the patient. Implant-related complication is similar but may occur earlier with prosthetic reconstructions.

Mesenchymal progenitors expressing TRAIL induce apoptosis in sarcomas.

Sarcomas are frequent tumors in children and young adults that, despite a relative chemo-sensitivity, show high relapse rates with up to 80% of metastatic patients dying in 5 years from diagnosis. The real ontogeny of sarcomas is still debated and evidences suggest they may derive from precursors identified within mesenchymal stromal/stem cells (MSC) fractions. Recent studies on sarcoma microenvironment additionally indicated that MSC could take active part in generation of a supportive stroma. Based on this knowledge, we conceived to use modified MSC to deliver tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) targeting different sarcoma histotypes. Gene modified MSC expressing TRAIL were cocultured with different osteosarcoma, rhabdomyosarcoma, and Ewing's Sarcoma (ES) cell lines assessing viability and caspase-8 activation. An in vivo model focused on ES was then implemented considering the impact of MSC-TRAIL on tumor size, apoptosis, and angiogenesis. MSC expressing TRAIL induced significantly high apoptosis in all tested lines. Sarcoma death was specifically associated with caspase-8 activation starting from 8 hours of coculture with MSC-TRAIL. When injected into pre-established ES xenotransplants, MSC-TRAIL persisted within its stroma, causing significant tumor apoptosis versus control groups. Additional histological and in vitro studies reveal that MSC-TRAIL could also exert potent antiangiogenic functions. Our results suggest that MSC as TRAIL vehicles could open novel therapeutic opportunities for sarcoma by multiple mechanisms.