Identifying potential drug targets for keloid: A Mendelian randomization study.

Keloids are a skin fibrosis disease characterized by troublesome symptoms, a varying degree of recurrence and inevitable side effects from treatments. Thus, identifying their drug targets is necessary. A two-sample MR analysis was conducted using proteins from the intersection of the deCODE database and "The Druggable Genome and Support for Target Identification and Validation in Drug Development" as the exposure variable. The outcome variable was based on recently published GWAS of keloids. SMR and colocalization analysis was employed to distinguish pleiotropy from linkage. Candidate targets underwent drug target analysis. The primary findings were validated through scRNA-seq data, Western Blot and immunofluorescence staining on keloids. Seven proteins were identified as potential drug targets for keloids. Among these proteins, HHIP, NTM, KLKB1, and CRIPTO showed positive correlations with keloids, while PLXNC1, SCG3 and PDGF-D exhibited negative correlations. Combined with the scRNA-seq data, NTM, PLXNC1, and PDGF-D were found highly expressed in the fibroblasts. NTM showed a significant increase in keloids as compared to normal scars. In accordance with the analysis, higher levels of protein expression of NTM in keloids compared to normal skin was observed. The identified proteins may be appealing drug targets for keloids treatment with a special emphasis on NTM.

Acellular dermal matrix-assisted tissue expansion for giant congenital melanocytic nevi of the extremities and trunk in pediatric patients.

BACKGROUND: Tissue expansion for treating giant congenital melanocytic nevi (GCMN) is a commonly employed surgical method. However, the procedure's efficacy is often hindered by anatomical and histological characteristics as well as blood supply, particularly in the extremities and trunk. Enhancing expansion efficiency while reducing complications is thus a topic to be investigated, especially for pediatric patients undergoing rapid physical and psychological development with higher risks of non-compliance to medical instructions. OBJECT: To explore the effectiveness of expansion in extremities and trunk by immobilizing the acellular dermal matrix (ADM) in the gravitational force zone of inflating expanders. METHODS: All patients involved in this research underwent ADM-assisted tissue expansion in either the extremities or trunk. ADM was fully flattened, securely fixed to the lower pole of the expander, and subsequently attached to the inner surface of the expanding flap. RESULTS: From 2021 to 2023, a total of nine pediatric patients with GCMN underwent the ADM-assisted tissue expansion. All patients achieved the desired expanding volume without experiencing petechiae, ecchymosis, or skin ulceration in the ADM-covered area. The process was well tolerated by all patients, with no reports of itching, pain, allergic reaction, or fever. During the flap transfer, the ADM was observed to be firmly adhered to the expanding flap with discernible capillary network. CONCLUSION: ADM-assisted tissue expansion demonstrates promise in augmenting expansion efficiency and reducing the time needed for surgical intervention in the extremities and trunk, thereby presenting significant clinical value for pediatric patients afflicted with GCMN.

Phentolamine Significantly Enhances Macrolide Antibiotic Antibacterial Activity against MDR Gram-Negative Bacteria.

OBJECTIVES: Multidrug-resistant (MDR) Gram-negative bacterial infections have limited treatment options due to the impermeability of the outer membrane. New therapeutic strategies or agents are urgently needed, and combination therapies using existing antibiotics are a potentially effective means to treat these infections. In this study, we examined whether phentolamine can enhance the antibacterial activity of macrolide antibiotics against Gram-negative bacteria and investigated its mechanism of action. METHODS: Synergistic effects between phentolamine and macrolide antibiotics were evaluated by checkerboard and time-kill assays and in vivo using a Galleria mellonella infection model. We utilized a combination of biochemical tests (outer membrane permeability, ATP synthesis, ΔpH gradient measurements, and EtBr accumulation assays) with scanning electron microscopy to clarify the mechanism of phentolamine enhancement of macrolide antibacterial activity against Escherichia coli. RESULTS: In vitro tests of phentolamine combined with the macrolide antibiotics erythromycin, clarithromycin, and azithromycin indicated a synergistic action against E. coli test strains. The fractional concentration inhibitory indices (FICI) of 0.375 and 0.5 indicated a synergic effect that was consistent with kinetic time-kill assays. This synergy was also seen for Salmonella typhimurium, Klebsiella pneumoniae, and Actinobacter baumannii but not Pseudomonas aeruginosa. Similarly, a phentolamine/erythromycin combination displayed significant synergistic effects in vivo in the G. mellonella model. Phentolamine added singly to bacterial cells also resulted in direct outer membrane damage and was able to dissipate and uncouple membrane proton motive force from ATP synthesis that, resulted in enhanced cytoplasmic antibiotic accumulation via reduced efflux pump activity. CONCLUSIONS: Phentolamine potentiates macrolide antibiotic activity via reducing efflux pump activity and direct damage to the outer membrane leaflet of Gram-negative bacteria both in vitro and in vivo.

OCCS Classification and Treatment Algorithm for Comminuted Mandibular Fractures Based on 109 Patients and 11 Years Experiences: A Retrospective Study.

Comminuted mandibular fractures (CMFs) pose significant challenges to surgeons for their serious complications and poor outcomes. We aimed at proposing a classification with treatment algorithm of each category for CMFs. Patients with CMFs were retrospectively reviewed and classified into five categories: Type I: relatively good occlusion, no or slightly displaced fragments, no continuity destruction or bone defect; Type II: relatively good occlusion, damaged morphology, low comminution degree but intact continuity without bone defect; Type III: damaged morphology and higher comminution degree with intact continuity and relatively good occlusion; Type IV: high comminution, impaired continuity and poor occlusion without segmental bone defect; Type V: segmental bone defect. Conservative treatment, open reduction and internal fixation or microvascular osteocutaneous free flap transplantation was performed, accordingly. Demographics, perioperative data, complications and reasons for reoperations were recorded. The chi-square test was used for statistical analysis. In total, 109 patients were included in the study. After surgery, in the following group, 5 manifested infections, 1 manifested bone non-union, and 2 experienced reoperations, while in the unfollowing group, 10 manifested infections, 5 manifested bone non-union and 8 experienced reoperations. The OCCS classification and algorithm for CMFs achieve better outcomes and with lower complication rate.

Construction of adipose tissue using a silica expander capsule and cell sheet-assembled of decellularized adipose tissue.

Delayed neovascularization and unstable adipose formation are major confounding factors in adipose tissue engineering. A system using decellularized adipose tissue (DAT), adipose-derived stem cells (ADSCs), and human umbilical vein endothelial cells (HUVECs) has been preliminarily studied, but it requires optimization, as adipogenic and angiogenic capabilities for maintaining a stable construct shape are limited. The current study aimed to address these limitations. Our initial modification involved the addition of exogenous chemokine (C-C motif) ligand 2 (CCL2), which resulted in enhanced adipogenesis and angiogenesis. However, further improvement was required due to delayed blood recanalization. To further optimize the system, a vascularized fibrous capsule derived from an implanted silica expander was utilized as a second modification. We hypothesized this would function as both a microbioreactor to fix the seed cells and exogenous CCL2 locally and as a vascular bed to promote neovascularization. Compared with that of the CCL2 loaded ADSC-HUVECs cell sheet assembled DAT system, adding the silica expander capsule resulted in significantly increased construct stability, new vessel intensity, a greater number of Oil Red O-positive lipid droplets, more enhanced tissue remodeling, and upregulated peroxisome proliferator-activated receptor gamma (PPARγ) & leptin expression. Thus, these two modifications helped optimize the currently available ADSC-HUVEC cell sheet assembled DAT system, providing an adipose tissue construction strategy with enhanced adipogenesis and angiogenesis to reconstruct soft tissue defects. Moreover, close-to-normal leptin expression provided the engineered adipose tissue with a glucometabolic function, in addition to remodeling capabilities. STATEMENT OF SIGNIFICANCE: Delayed neovascularization and unstable adipose formation are the two major problems in tissue engineering adipose. Here, we introduced an adipose tissue engineering construction strategy using a silica expander capsule along with hADSCs-HUVECs cell sheet-assembled DAT in a CCL2-rich microenvironment. Our data suggested that CCL2 could improve angiogenesis and adipogenesis in vitro and in vivo. The addition of tissue expander capsule could further improve the stability of construction and fabricated adipose tissue with increased new vessel intensity, greater numbers of Oil Red O-positive lipid droplets, more enhanced tissue remodeling, and upregulated leptin expression. CCL2 and expander capsule can have clinical utility for soft tissue defects repair, and these two factors can be useful in other tissue engineering.

Impact of human adipose tissue-derived stem cells on dermatofibrosarcoma protuberans cells in an indirect co-culture: an in vitro study.

BACKGROUND: Autologous adipose tissue transfer may be performed for aesthetic needs following the resection of dermatofibrosarcoma protuberans (DFSP), the most common cutaneous soft tissue sarcoma, excluding Kaposi sarcoma. The regenerative effectiveness of cell-assisted lipotransfer is dependent on the presence of adipose tissue-derived stem cells (ADSCs). This is the first study to evaluate the potential oncological risks as ADSCs could unintentionally be sited within the proximity of the tumor microenvironment of DFSP cells. METHODS: Primary DFSP cells were indirectly co-cultured with ADSCs in a conditioned medium or in a Transwell system. The impact was analyzed by assessing proliferation, migration, invasion, angiogenesis, and tumor-associated genes and proteins. Results of these assays were compared between co-culture and mono-culture conditions. RESULTS: Our experimental results showed that ADSCs were able to promote proliferation, migration, invasion, and angiogenesis of DFSP cells; this was accompanied by a significant increase in the expression levels of beta-type platelet-derived growth factor receptor, collagen type I alpha 1 chain, vascular endothelial growth factor, hepatocyte growth factor, and basic fibroblast growth factor. CONCLUSIONS: The current report clearly demonstrates that ADSCs can enhance different malignant properties of DFSP cells in vitro, which should not be neglected when considering the clinical use of human ADSCs and its related derivatives in skin regenerative therapies.

Unsatisfactory Upper Blepharoplasty Revision Technique: Reconstruction of the Upper Orbital Septum and its Fusion Point.

BACKGROUND: The orbital septum prevents both superficial eyelid infection and the spread of bleeding into the orbit. The fusion point between the upper eyelid orbital septum and the levator aponeurosis or the tarsal plate plays an important role in determining the width of the natural double eyelid. We observed a number of unsatisfactory upper eyelid blepharoplasty outcomes resulting from improper handling of the orbital septum-such as excessive destruction of orbital septum tissue and failure to form a firm attachment point between the orbital septum and the levator aponeurosis or palpebrae plate-during primary surgery. OBJECTIVES: The three most common types of unsatisfactory upper blepharoplasty outcomes include abnormally high double eyelid creases, multiple creases, and disappearance of creases. In the repair operation, we try to determine the remaining orbital septum tissue for reconstruction and form a firm attachment between the orbital septum and the levator aponeurosis or tarsal plate. Follow-up after surgery was performed to observe whether our technique can ensure effective and favorable long-term natural-looking upper eyelid blepharoplasty outcome. METHODS: From January 2018 to January 2020, secondary blepharoplasty involving the above-mentioned unsatisfactory double eyelid results was performed in 83 patients, including 63 patients (141 eyes) with abnormally high skin creases, 6 patients (8 eyes) with multiple creases, and 14 patients (24 eyes) with double eyelid disappearance. The outcomes were assessed 6 months to 2 years after the surgery by reviewing the photographs to evaluate the esthetic outcomes including stability of double eyelid, double fold curve, symmetry, patient satisfaction, and the incidence of complications. RESULTS: After an average follow-up of 12 months, most patients achieved a better double eyelid appearance. The esthetic outcome was graded as good in 80 patients, poor due to recurrence of double eyelid disappearance in 2, and poor because of asymmetry of the double eyelid curve in length or width in 1 patient. All patients had acceptable scars. No cases of infection or ptosis were observed. CONCLUSION: Reconstructing the orbital septum and ensuring a firm fixation with the levator aponeurosis or tarsal plate is an effective method to repair unsatisfactory upper eyelid blepharoplasty. Moreover, it is very important to protect the orbital septum and proper treatment during the initial surgery. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Endoscopic endonasal resection of sinonasal teratocarcinosarcoma with intracranial breakthrough: illustrative case.

BACKGROUND: Teratocarcinosarcoma traversing the anterior skull base is rarely reported in literature. The heterogenous and invasive features of the tumor pose challenges for surgical planning. With technological advancements, the endoscopic endonasal approach (EEA) has been emerging as a workhorse of anterior skull base lesions. To date, no case has been reported of EEA totally removing teratocarcinosarcomas with intracranial extensions. OBSERVATIONS: The authors provided an illustrative case of a 50-year-old otherwise healthy man who presented with left-sided epistaxis for a year. Imaging studies revealed a 31 × 60-mm communicating lesion of the anterior skull base. Gross total resection via EEA was achieved, and multilayered skull base reconstruction was performed. LESSONS: The endoscopic approach may be safe and effective for resection of extensive teratocarcinosarcoma of the anterior skull base. To minimize the risk of postoperative cerebrospinal fluid leaks, multilayered skull base reconstruction and placement of lumbar drainage are vitally important.

Tarsal-Fixation With Aponeurotic Flap Linkage in Blepharoplasty: Bridge Technique.

BACKGROUND: Double eyelid blepharoplasty is the most popular cosmetic surgery among Asian populations. Although various surgical procedures have been reported, certain complications still arise, including asymmetry or the disappearance of the double eyelid crease, an unnatural double eyelid crease curve, and distinct scars. OBJECTIVES: The aim of this study was to describe a new blepharoplasty technique intended to reduce the various complications and create dynamic, natural-looking double eyelids. METHODS: From September 2018 to June 2019, the new technique was performed on 92 Chinese patients. The core of our technique was to construct a reliable motion transmitter, the orbital septum-levator aponeurosis flap, which was sutured to the tarsus. The outcomes were assessed 6 months after the surgery by reviewing medical records and photographs to assess the aesthetic outcomes, the relapse rate, and the incidence of complications. RESULTS: In the aesthetic outcome assessment, 86 patients were graded as good and 4 were graded as fair; of the latter, 2 had uneven scars and 2 showed showed a slight asymmetry of the double eyelid curve in length or width. Two patients were graded as poor because of the disappearance of the double eyelid crease. The relapse rate was 2.2%. Two patients had temporary hematoma. Six patients had lagophthalmos that subsided within 30 days. No cases of infection or ptosis were observed. CONCLUSIONS: The bridge technique is an effective method for creating dynamic, natural-looking double eyelids. However, the long-term outcome of this new surgical approach requires further study.

Dermatofibrosarcoma protuberans: our 10-year experience on 80 patients.

Background: Dermatofibrosarcoma protuberans (DFSP) is a rare soft tissue sarcoma. Its high recurrence rate is a clinical challenge.Objective: To analyze DFSP clinicopathologic factors and review our experience of treatments.Materials and methods: A total of 80 patients who were treated between 2007 and 2017 in Shanghai Ninth People's Hospital were evaluated. Outcomes were compared focusing on recurrence following different treatment methods. Classical DFSP and transformed DFSP were classified as the two subtypes.Results: The recurrence rate after local excision was significantly higher than that after wide margin excision. Patients undergoing wide margin excision (margins over 3 cm) were found to have lower recurrence rate compared with those margins less than 3 cm, while 10 underwent Mohs surgery were not found recurrence. Transformed DFSP had a greater tendency to recur.Conclusions: Clean margin of excision should be achieved to prevent recurrence of DFSP. Slow Mohs surgery is recommended to treat DFSP.

Construction of a dermis-fat composite in vivo: Optimizing heterogeneous acellular dermal matrix with in vitro pretreatment.

Dermis-fat composite tissues have been widely used in plastic and reconstructive surgery and were previously constructed using hydrogel-type scaffolds. The constructs can be used for in vitro cosmetic and pharmaceutical testing but are not mechanically strong enough for in vivo applications. In this study, we used heterogeneous (porcine) acellular dermal matrix (PADM) as dermal layer scaffold. PADM was pretreated with the laser micropore technique and then precultured with rat adipose-derived stem cells (rADSCs) in vitro. rADSCs proliferated well on pretreated/unpretreated PADM, showing increased expression of genes associated with inflammatory regulation, proangiogenesis, and stemness, indicating that pretreated/unpretreated PADM both provide a beneficial microenvironment for rADSCs to exert their paracrine function. After in vitro processing, the rADSCs-polyporous PADM and PADM without pretreatments were implanted into the back of rats respectively, followed by adipose tissue transplantation. After implantation, the inflammation induced by pretreated PADM was significantly attenuated and localized compared to the unpretreated group. Moreover, the vascularization was faster, and more adipose tissue was formed in the pretreated group. Sound dermis-fat composite tissue was constructed with sufficient strength, which can potentially be used for actual repair application.

Physiological correction of mild to moderate congenital blepharoptosis: A retrospective cohort study involving 97 Eastern Asian patients.

BACKGROUND: Conventional blepharoptosis repair methods distort the normal anatomy of levator aponeurosis and often cause a visible depressed scar in the upper eyelid. METHODS: The levator aponeurosis was dissected as a flap from the pretarsal tissue in mono-eyelid Asian patients who had mild to moderate congenital blepharoptosis. The flap base was advanced and repositioned on the tarsus. The margin of the distal flap was interposed and fused with orbicularis oculi muscles. Postoperative evaluation included ptosis correction, symmetry, and overall cosmetic outcomes. RESULTS: A total of 162 eyes on 97 patients were corrected using our method. Follow-up time ranged from 8 to 24 months (mean 12.4). In mild ptosis eyelids, out of 58 eyelids, 36.2% (21 eyelids), 56.9% (33), and 6.9% (4) required adequate correction, normal correction, and undercorrection, respectively, whereas in moderate ptosis, the results were 34.6% (36 eyelids), 53.9% (56), and 11.5% (12), respectively. For symmetry, 58.8% (57 cases), 32.0% (31), and 9.2% (9) resulted in good, fair, and poor outcomes, respectively. For cosmetic outcomes, 82.8% (48 eyelids), 15.5% (9), and 1.7% (1) of mild ptosis cases achieved good, moderate, and poor results in mild ptosis cases, whereas the results were 77.9% (81 eyes), 20.2% (21), and 1.9% (2), respectively, in moderate ptosis cases. The only complication among all cases was postoperative swelling. CONCLUSIONS: We presented a new blepharoplasty for ptosis repair that allows both satisfactory ptosis correction and cosmetic outcomes in mild to moderate congenital blepharoptosis.

Pre-culture of adipose-derived stem cells and heterologous acellular dermal matrix: paracrine functions promote post-implantation neovascularization and attenuate inflammatory response.

Heterologous acellular dermal matrix (ADM) has good biocompatibility and sufficient strength for clinical use for the repair of defects, tissue filling, and resurfacing of deep wounds. However, ADM tissue has such a compact structure that it can easily result in delayed vascularization after implantation. Moreover, in spite of the low immunogenicity of heterologous ADM, it can still cause varying degrees of inflammation in the host. These two drawbacks limit the efficacy and scope of clinical applications for heterologous ADM. Adipose-derived stem cells (ADSCs) have multiple effects on promoting vascularization and regulating immunological responses through paracrine signaling. Pre-culturing heterologous ADM with ADSCs may address these problems; however, it is unknown if ADSCs can exert their paracrine functions within a heterologous ADM microenvironment. This study examined the effect of porcine ADM (PADM) on the paracrine function of rat ADSCs (rADSCs) and showed that the expression of genes associated with inflammatory regulation, pro-angiogenesis factors, and stemness increased when rADSCs were seeded on PADM compared to rADSCs seeded on microplates. This indicates that PADM can provide a beneficial microenvironment for ADSCs to exert their paracrine function. After pre-culture, in vivo implanted rADSC-PADM exhibited improved vascularization and mitigated inflammatory response compared to untreated PADM. This study is the first to report that ADM can provide a suitable microenvironment for ADSCs and that pre-culturing improved the ADM implantation quality in vivo. These results suggest that it could be possible to apply heterologous ADM more effectively and broadly for repair and reconstruction treatments.