Treatment of Progressive Hemifacial Atrophy by Cartilage Graft and Free Adipofascial Flap Combined with Three-Dimensional Planning.

BACKGROUND: Progressive hemifacial atrophy (PHA) is a rare disease characterized by progressive atrophy of skin, soft tissue, muscles, and underlying bone structures. For severe PHA patients with obvious bone deformities, skeletal framework reconstruction is needed in addition to soft-tissue augmentation. The authors propose a new combinatorial surgical method using rib cartilage graft and free adipofascial flap for restoring facial symmetry. To improve the surgical accuracy, preoperative three-dimensional planning and printing was used. METHODS: Twelve patients with severe facial atrophy were included in the authors' study. Three-dimensional facial image analyses were performed preoperatively to quantify the facial asymmetry. Rib cartilages were harvested and sculptured to the appropriate shape created by three-dimensional planning and fixed to the atrophic bone. The circumflex scapular artery-based adipofascial flap was transplanted to repair soft-tissue deficiency. A residual small monitor flap was left with the adipofascial flap. A revision surgery was performed to perfect the repair if the contour was suboptimal 6 months postoperatively. RESULTS: The adipofascial flaps survived in all 12 patients. All patients achieved good healing without complications. At 1 more year after surgery, the rib cartilage was still in position and rarely absorbed. The morphologic and volumetric difference between the affected side and the unaffected side was improved significantly postoperatively. All patients were satisfied with the results, and no more additional operations were required. CONCLUSION: The combinatorial surgery of rib cartilage graft and free adipofascial flap in the setting of three-dimensional planning and printing can be a good choice in restoring facial symmetry in severe cases of PHA. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Long-term Safety and Effectiveness of Hyaluronic Acid Fillers Correcting Nasolabial Folds in Chinese Patients.

Background: Soft-tissue fillers, specifically hyaluronic acid fillers, can reduce many signs of aging by treating the associated loss of subcutaneous fat and midfacial contour deficiencies. The objective of this study was to investigate whether the effectiveness and safety of Belotero Volume Lidocaine (BVL) compared with Restylane (RES, control) is noninferior in the treatment of severe nasolabial folds (NLFs) in Chinese patients. Methods: This was a prospective, randomized, controlled, split-face clinical study. Overall, 220 Chinese patients of both sexes with symmetrical NLFs of severe intensity (grade 4) on the Wrinkle Severity Rating Scale (WSRS) were treated with both fillers. Treatment outcomes were assessed by the WSRS, and other scales, at multiple time points up to 18 months postinjection. The co-primary effectiveness outcomes were based on the blinded evaluator ratings of NLFs according to the WSRS scale after 6 and 12 months. Adverse events were assessed during the whole study and patients' pain sensation at three time points after injection. Results: Noninferiority of BVL versus control based on the WSRS was demonstrated at month 6 and month 12. Response rates were slightly higher for BVL than control at all time points, and BVL had a sustained effect until month 18. Pain sensation scores were significantly lower for BVL compared with control. The incidence rates of treatment-related AEs were low and very similar for both treatments. Conclusions: This study demonstrates that BVL is a safe, long-lasting, and effective treatment to correct severe NLFs in Chinese patients while being noninferior to the control device.

Keloid Core Factor CTRP3 Overexpression Significantly Controlled TGF-ß1-Induced Propagation and Migration in Keloid Fibroblasts.

Purpose: Keloid is a type of benign fibrous proliferative tumor characterized by excessive scarring. C1q/TNF-related protein 3 (CTRP3) has been proven to possess antifibrotic effect. Here, we explored the role of CTRP3 in keloid. In the current research, we examined the influence of CTRP3 on keloid fibroblasts (KFs) and investigated the potential molecular mechanism. Methods: KF tissue specimens and adjacent normal fibroblast (NF) tissues were collected cultured from 10 keloid participants. For the TGF-ß1 stimulation group, KFs were processed with human recombinant TGF-ß1. Cell transfection of pcDNA3.1-CTRP3 or pcDNA3.1 was performed. The siRNA of CTRP3 (si-CTRP3) or negative control siRNA (si-scramble) was transfected into KFs. Results: CTRP3 was downregulated in keloid tissues and KFs. CTRP3 overexpression significantly controlled TGF-ß1-induced propagation and migration in KFs. Col I, α-SMA, and fibronectin mRNA and protein levels were enhanced by TGF-ß1 stimulation, whereas they were inhibited by CTRP3 overexpression. In contrast, CTRP3 knockdown exhibited the opposite effect. In addition, CTRP3 attenuated TGF-ß receptors TRI and TRII in TGF-ß1-induced KFs. Furthermore, CTRP3 prevented TGF-ß1-stimulated nuclear translocation of smad2 and smad3 and suppressed the expression levels of p-smad2 and p-smad3 in KFs. Conclusion: CTRP3 exerted an antifibrotic role through inhibiting proliferation, migration, and ECM accumulation of KFs via regulating TGF-ß1/Smad signal path.

Circular RNA_0061587 is associated with the tumorigenesis of neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is a kind of common neurogenetic disorder associated with various developmental deficits. Circular RNAs (circRNAs) have been frequently verified to be crucial modulators in human diseases. However, the functions of circRNAs on the occurrence of NF1 remain largely obscure. In our study, RT-qPCR was applied to analyze circ_0061,587 expression and we noticed that circ_0061,587 expression was overtly elevated in human NF1-associated malignant peripheral nerve sheath tumor (MPNST) cell lines. Meanwhile, the results of loss-of-function assays revealed that silencing of circ_0061,587 hampered the proliferation, migration, and invasion but stimulated the apoptosis of human NF1-associated MPNST cells. In addition, mechanism assays were implemented to unveil the possible regulatory mechanism behind circ_0061,587. As a result, circ_0061,587 sequestered microRNA-485-5p (miR-485-5p) to modulate the expression of RUNX family transcription factor 1 (RUNX1) and annexin A11 (ANXA11). Finally, rescue experiments confirmed that circ_0061,587 boosted the malignant behaviors of human NF1-associated MPNST cells through up-regulating RUNX1 and ANXA11. In conclusion, circ_0061,587 functioned as an oncogene in NF1-associated MPNST cells and this study might provide novel insights for the diagnosis and treatment of NF1.

Exosomes from adipose-derived mesenchymal stem cells promote survival of fat grafts by regulating macrophage polarization via let-7c.

The rate of fat graft survival is a critical aspect of successful surgery and has been a matter of concern for over 20 years. Owing to their anti-inflammatory effects and regenerative property, adipose-derived mesenchymal stem cells (AD-MSCs) have been adapted for clinical application in fat grafting, although the mechanism underlying their action remains unclear. Recently, exosomes derived from MSCs were suggested as a better alternative, and these exosomes have also been applied in diverse clinical therapies. Accumulating evidence suggests that MSCs modulate macrophage differentiation via exosome secretion, and the connection between macrophage regulation and the rate of fat graft survival has been established. Here, we identified that let-7c, the key factor in the regulatory process, is shuttled by AD-MSC-derived exosomes to downregulate the transcription factor CCAAT/enhancer-binding protein (C/EBP)-δ. The downregulation of C/EBP-δ resulted in the attenuation of pro-inflammatory M1 macrophages and elevation of anti-inflammatory M2 macrophages. These results suggest that AD-MSC-derived exosomes promote the survival of fat grafts by regulating macrophage polarization via let-7c. This is the first study to elucidate the mechanism underlying the promotion of the fat graft survival rate by AD-MSCs and to evaluate the immunotherapeutic potential of AD-MSC-derived exosomes in fat grafting.

Modified Buried Vertical Mattress Suture Versus Buried Intradermal Suture: A Prospective Split-Scar Study.

BACKGROUND: The modified buried vertical mattress suture (MBVMS) is believed to provide excellent outcomes by relieving the tension on wound edges. However, clinical data on the topic remain sparse and inadequate. OBJECTIVE: To compare the cosmetic results of the MBVMS and the buried intradermal suture (BIS) in chest wounds using a split-scar model. MATERIALS AND METHODS: Twenty patients participated in the study. One randomly selected half of each chest wound was closed with the MBVMS; the other half was closed with the BIS. Immediately, postoperatively, the maximum degree of wound eversion was obtained. After 3 months, the wound complication rates were recorded, and the aesthetic appearance of each scar was evaluated by the Patient and Observer Scar Assessment Scale (POSAS), the Vancouver Scar Scale (VSS), the visual analog scale (VAS), and scar width. RESULTS: The MBVMS yielded a greater mean postoperative eversion height and width (p < .05); lower POSAS, VSS, and VAS scores (p < .05); and a narrower scar width (p < .05) than did the BIS. CONCLUSION: Compared with the BIS, the MBVMS provided significantly increased wound eversion immediately, postoperatively, and improved aesthetic outcomes at the end of the 3-month follow-up period.

Cutaneous neurofibroma cells with active YAP promotes proliferation of macrophages resulting in increased accumulation of macrophages by modulating CCL5 and TGF­ß1.

Cutaneous neurofibromas (cNFs) are present in the majority of patients with neurofibromatosis type 1 (NF1), and results in disfigurements of the body, which is associated with psychological distress. A hallmark feature of cNF is the infiltration of inflammatory cells, among which macrophages are an important component of the microenvironment. Loss of neurofibromin (Nf1) expression results in activation of the PI3K and MAPK signaling pathways; however, the therapeutic effects of specific inhibitors targeting these pathways are not satisfactory. The present study showed increased macrophage infiltration accompanied by activation of effectors of the Hippo signaling pathway. Additionally, it was shown that XMU­MP­1 enhanced macrophage accumulation, in vivo and in vitro, by elevating the levels of C­C motif chemokine ligand 5 (CCL5) and transforming growth factor (TGF)­ß1 expression. However, neither CCL5 nor TGF­ß1 ablation alone were able to effectively reverse the XMU­MP­1­induced upregulation of macrophage accumulation, whereas concurrent ablation of these two genes significantly decreased macrophage accumulation. EdU staining and flow cytometry suggested that activated Yes­associated protein 1 promoted proliferation rather than inhibiting apoptosis in macrophage cells, and this may underlie the increase in the accumulation of macrophages. Both CCL5/C­C motif chemokine receptor 5 and TGF­ß1/TGFß1 receptor served crucial roles in modulating macrophage proliferation, which ultimately contributed to macrophage accumulation. The function of the Hippo pathway in the development of cNF development and its potency as a therapeutic target merit further investigation.

Infiltrating Macrophages Induced Stem-cell-like Features Through PI3K/AKT/GSK3ß Signaling to Promote Neurofibroma Growth.

BACKGROUND: Inflammation plays an important role in promoting neurofibroma progression, and macrophages are key inflammatory cells in neurofibroma. AIM OF THIS STUDY: We attempted to clarify the detailed mechanism of infiltrating macrophages promoting neurofibroma progression. METHODS: We performed IHC and Western blot assays to detect the expression levels of OCT3/4, Nanog and SOX2 in tissues and cells. A colony/sphere formation assay was used to analyze cell stemness. MTT, colony formation assay and xenograft tumor model were used to detect cell growth. The transwell system was used to examine macrophage infiltration. RESULTS: We demonstrated increased macrophage infiltration in neurofibroma tissues accompanied by increased stem cell-like markers. Moreover, Nf1-mutated SW10 cells possessed a stronger capacity to recruit macrophages, which in turn facilitated neurofibroma growth. Mechanistically, the infiltrating macrophages induced neurofibroma cell stem cell transition by modulating PI3K/AKT/GSK3ß signaling, which then enhanced neurofibroma cell viability in vivo and in vitro. CONCLUSION: Our results revealed a new mechanism of infiltrating macrophages contributing to neurofibroma progression, and targeting this newly identified signaling may help to treat neurofibroma.

AR facilitates YAP-TEAD interaction with the AM promoter to enhance mast cell infiltration into cutaneous neurofibroma.

Abundant mast cell infiltration and disease initiation at puberty are hallmark features of cutaneous neurofibroma (cNF). However, the association between mast cell infiltration and steroid hormones in cNF remains unclear. Here, we determined that androgen receptor (AR) expression is positively associated with mast cell density in cNF tissues. Moreover, both in vitro cell experiments and in vivo mouse models verified that activated AR promoted mast cell infiltration and that AR inhibition reduced mast cell infiltration. Analyses in cell models and xenograft tumours both demonstrated that AR upregulated Yes associate  protein 1 (YAP)-adrenomedullin (AM) signalling. Clinical samples from cNF patients further verified that AR was positively related to YAP and AM. Mechanistic analysis revealed that AR accelerates AM transcription via enhancing YAP- TEA domain transcription factor (TEAD) binding to the AM promoter. Consequently, the upregulated AM enhanced mast cell recruitment. Interruption of the YAP-TEAD interaction or inhibition of AM could impair mast cell accumulation induced by active AR, which indicated that this newly found signalling pathway may provide novel targets for cNF treatment.

Activation of PLCγ/AKT/IκBα/p65 signaling increases inflammation in mast cells to promote growth of cutaneous neurofibroma.

AIM: Cutaneous neurofibroma (cNF), a hallmark feature of neurofibromatosis type 1 (NF1), results in psychological and physical damage to patients. Considering the important role of mast cells in neurofibroma development, the aim of this study was to elucidate the underlying mechanism of the interaction between cNF cells and mast cells. MAIN METHODS: SW10 cells with Nf1 knocked down were used as a cNF cell model. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and colony formation assays, as well as a mouse xenograft tumor model, were used to assess the cNF tumor growth in vivo and in vitro. ELISAs and IHC were used to examine the inflammatory activity of mast cells. KEY FINDINGS: We demonstrated that cNF cells activated mast cells, which in turn promoted the cNF cell growth, while suppression of the inflammatory activity of cNF-associated mast cells reversed their stimulating effect on the growth of cNF cells. Mechanistic studies revealed that SW10 cells upregulated PLCγ/AKT/IκBα/p65 signaling in mast cells, thereby increasing inflammation. Moreover, PLCγ modulated the AKT/IκBα/p65 signaling activity and played a critical role in the interaction of mast cells and cNF cells. Knockdown of PLCγ in mast cells diminished their cNF cell-induced inflammatory activity and subsequently reduced the cNF cell growth in vivo and in vitro. SIGNIFICANCE: This study revealed a novel interaction between mast cells and cNF cells, suggesting a potential strategy for treating cNF by targeting the newly recognized signaling pathway.

Tailored Microform Cleft Lip Repair: Personalizing Small Incisions, Orbicularis Reconstruction, and Rhinoplasty.

BACKGROUND: In the last decade, many surgeons have reported their perspectives on microform cleft lip repair, including techniques for incision placement and size, philtral reconstruction, and nasal base reconstruction. This interest demonstrates continued controversy in the repair of microform cleft lip. METHODS: This is a retrospective cohort of patients from 2010 to 2016. The authors included patients with microform cleft lip repaired by our described technique who had both preoperative photographs, as well as photographs taken at >1-year follow-up. Patient outcomes were assessed through anthropometric measurements and also subjectively by 3 senior residents of plastic surgery. RESULTS: The inclusion criteria yielded 36 microform cleft lip patients. Most patients were satisfied with their results. Regarding subjective assessment, the scar appearance and symmetry was fairly good. Objective measurements indicated excellent symmetry, with the cleft side achieving 92.58% of the height and measurements of the non-cleft side. CONCLUSIONS: Our method of combining labial muscle reconstruction through a personalized, small incision effectively corrects microform cleft lip deformity with minimal scar burden.

Activated androgen receptor accelerates angiogenesis in cutaneous neurofibroma by regulating VEGFA transcription.

Accumulating evidence has demonstrated the significant progression of cutaneous neurofibroma (cNF) without necrosis during puberty. However, the molecular events involved in this process remain unclear. The alteration of the steroid hormone levels during puberty has led to the investigation of the expression levels of the androgen receptor (AR). A positive correlation between AR expression and microvessel density has been reported in human cNF tissues in combination with enhanced endothelial cell tube formation in vitro. In addition, activated AR signaling can promote neurofibroma cell growth in vivo and in vitro and tube formation in vitro. In the present study, AR was shown to bind directly to the promoter of vascular endothelial growth factor A (VEGFA), a key factor involved in angiogenesis, and to sequentially induce its expression. Furthermore, the AR inhibitor, MDV3100, downregulated VEGFA expression and abolished endothelial cell recruitment and tube formation. Taken collectively, the findings of this study revealed that AR signaling enhanced tumor growth and angiogenesis in cNF by regulating VEGFA transcription. However, whether AR can be regarded a therapeutic target for cNF requires further investigation.

Different suturing techniques in thoracic incision: protocol for a feasibility randomised controlled trial.

INTRODUCTION: Based on the principles of the ideal skin closure technique, we previously described a suture technique (wedge-shaped excision and modified buried vertical mattress suture (WE-MBVMS)) that could provide excellent outcomes for the most demanding surfaces. However, adequate clinical comparative evidence supporting improved outcomes is lacking. Thus, the purpose of this protocol is to establish the feasibility of conducting a fully randomised controlled trial (RCT) comparing the clinical effectiveness of WE-MBVMS with a buried intradermal suture (BIS) in closing thoracic incision. METHODS AND ANALYSIS: This study is a feasibility RCT of WE-MBVMS and BIS in patients undergoing surgery for costal cartilage harvesting. Seventy-eight participants are expected to participate in the study and will be randomised in a ratio of 1:1 to WE-MBVMS or BIS. Trial feasibility will be assessed by the number of participants assessed for eligibility, recruitment rates, reasons for ineligibility or non-participation, time for interventions, withdrawal and retention at all follow-up points (3, 6 and 12 months), follow-up rates and reasons for withdrawing from the trial. In addition, clinical data regarding the cosmetic results of scars will be collected to inform the sample size for a fully powered RCT. ETHICS AND DISSEMINATION: This study has been approved by The First Affiliated Hospital of Xi'an Jiaotong University Institutional Review Board (XJTU1AF2017LSK-120). The findings will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ChiCTR-INR-17013335; Pre-results.

[The development and recent status of the craniomaxillofacial surgery in China during past three decades].

The authors made a profound review on the development and the recent status of craniomaxillofacial surgery in China during past three decades. The emphases were placed on the following aspects: the modifications of the reconstructive procedure and minimal invasive mode, the researches on molecular genetic characteristics of the congenital craniofacial malformations, the clinical applications of three-dimensional digital computer-aided techniques (including three-dimensional printing and prefabricated template for precious osteotomies), the craniomaxillofacial defects reconstructing by using the distraction osteogenesis and osseous integrated titanium implant and prothesis, etc. Finally, the authors outlooked prospectively the future trends of the craniomaxillofacial surgery.

Silibinin Induced Human Glioblastoma Cell Apoptosis Concomitant with Autophagy through Simultaneous Inhibition of mTOR and YAP.

Silibinin, also known as silybin, is the major flavonolignan isolated from Silybum marianum. Although previous reports demonstrated that silibinin exhibits significant tumor suppressor activities in various cancers by promoting cell apoptosis, it was also shown to trigger autophagy to counteract apoptosis induced by exogenous stresses in several types of cells. However, there is no report to address the role of silibinin induced autophagy in human A172 and SR glioblastoma cells. Our study showed that silibinin treatment not only inhibited the metabolic activities of glioblastoma cells but also promoted their apoptosis through the regulation of caspase 3 and PARP-1 in concentration- and time-dependent manners. Meanwhile, silibinin induced autophagy through upregulation of microtubule-associated protein a light chain 3- (LC3-) II. And autophagy inhibition with chloroquine, a lysosomotropic agent, significantly enhanced silibinin induced glioblastoma cell apoptosis. Moreover, silibinin dose-dependently downregulated the phosphorylation levels of mTOR at Ser-2448, p70S6K at Thr-389, and 4E-BP1 at Thr-37/46. Furthermore, the expression of YAP, the downstream effector of Hippo signal pathway, was also suppressed by silibinin. These results suggested that silibinin induced glioblastoma cell apoptosis concomitant with autophagy which might be due to simultaneous inhibition of mTOR and YAP and silibinin induced autophagy exerted a protective role against cell apoptosis in both A172 and SR cells.

Lipoamide Inhibits NF1 Deficiency-induced Epithelial-Mesenchymal Transition in Murine Schwann Cells.

BACKGROUND AND AIMS: Neurofibromatosis type I (NF1) is one of the most common neurocutaneous syndromes characterized by development of adult neurofibromas which is mainly made up of Schwann cells. The disease is generally accepted to be caused by inactivation mutation of Nf1 gene. And Nf1 deficiency had been reported to lead to ROS overproduction and epithelial-mesenchymal transition (EMT) phenotype. This study was designed to investigate whether excessive ROS conferred to Nf1 deficiency-induced EMT in Schwann cells. METHODS: Colony formation, wound healing assay and transwell assay was used to evaluate the effects of stable Nf1 knockdown in SW10 Schwann cells. Western blot and ROS assay was conducted to explore the molecular mechanisms of Nf1 inactivation in tumorigenesis. Animal experiments were performed to assess the inhibitory effects of lipoamide, which is the neutral amide of α-lipoic acid and functions as a potent antioxidant to scavenge ROS, on Nf1-deficiency tumor growth in vivo. RESULTS: Nf1 knockdown enhanced the cellular capacities of proliferation, migration and invasion, promoted ROS generation, decreased the expression of epithelial surface marker E-cadherin, and up-regulated several EMT-associated molecules in Schwann cells. Moreover, lipoamide dose-dependently inhibited not only Nf1 deficiency-induced EMT but also spontaneous EMT. Furthermore, lipoamide markedly suppresses tumor growth in a mouse model of NF1-associated neurofibroma. CONCLUSIONS: Our results clearly reveal that ROS overproduction is responsible for Nf1 deficiency-induced EMT and plays a crucial role in NF1 tumor growth. The findings presented herein shed light on the potential of antioxidant therapy to prevent the progression of NF1-associated neurofibroma.

Growth Factor-Reinforced ECM Fabricated from Chemically Hypoxic MSC Sheet with Improved In Vivo Wound Repair Activity.

MSC treatment can promote cutaneous wound repair through multiple mechanisms, and paracrine mediators secreted by MSC are responsible for most of its therapeutic benefits. Recently, MSC sheet composed of live MSCs and their secreted ECMs was reported to promote wound healing; however, whether its ECM alone could accelerate wound closure remained unknown. In this study, Nc-ECM and Cc-ECM were prepared from nonconditioned and CoCl2-conditioned MSC sheets, respectively, and their wound healing properties were evaluated in a mouse model of full-thickness skin defect. Our results showed that Nc-ECM can significantly promote wound repair through early adipocyte recruitment, rapid reepithelialization, enhanced granulation tissue growth, and augmented angiogenesis. Moreover, conditioning of MSC sheet with CoCl2 dramatically enriched its ECM with collagen I, collagen III, TGF-ß1, VEGF, and bFGF via activation of HIF-1α and hence remarkably improved its ECM's in vivo wound healing potency. All the Cc-ECM-treated wounds completely healed on day 7, while Nc-ECM-treated wounds healed about 85.0% ± 8.6%, and no-treatment wounds only healed 69.8% ± 9.6% (p < 0.05). Therefore, we believe that such growth factor-reinforced ECM fabricated from chemically hypoxic MSC sheet has the potential for clinical translation and will lead to a MSC-derived, cost-effective, bankable biomaterial for wound management.

Evaluation of xenogeneic extracellular matrix fabricated from CuCl2-conditioned mesenchymal stem cell sheets as a bioactive wound dressing material.

The extracellular matrix has drawn considerable interest in tissue engineering not only acts as a bioactive three-dimensional scaffold but also regulates cell behaviors through providing biochemical signals. Extracellular matrix-based biomaterials, mainly derived from xenogeneic tissues, have shown positive outcomes in promoting cutaneous wound healing. However, such extracellular matrices only contain low doses of growth factors, which limit their therapeutic efficiency. Recent reports demonstrated that cell sheets made from mesenchymal stem cell can accelerate wound repair through enhanced re-epithelialization and angiogenesis, but its clinical translation is hindered by several limitations, such as the risk of aberrant immune responses and cost implications. In this study, acellular extracellular matrices were prepared from CuCl2-conditioned mesenchymal stem cell sheets and their in vivo wound healing properties were evaluated in a mouse model of full-thickness skin defect. We found that extracellular matrices derived from CuCl2-conditioned mesenchymal stem cell sheets have a compact surface with thick solid-like cross-sectional structure. Moreover, CuCl2 dramatically enriched the extracellular matrices with collagen I, collagen III, transforming growth factor-ß1, vascular endothelial growth factor, and basic fibroblast growth factor via hypoxia-inducible factor-1α activation. And as a consequence, the resulting extracellular matrices showed markedly improved in vivo wound healing potency through early adipocyte mobilization, enhanced granulation tissues formation, rapid re-epithelialization, and augmented angiogenesis. Therefore, we consider that the extracellular matrix derived from CuCl2-conditioned mesenchymal stem cell sheets has the potential for clinical translation and may lead to a novel strategy for wound management.

Epigenomic landscape of 5-hydroxymethylcytosine reveals its transcriptional regulation of lncRNAs in colorectal cancer.

BACKGROUND: DNA methylation at the 5 position of cytosine (5mC) can be converted to 5-hydroxymethylcytosine (5hmC) by the ten-eleven translocation family. The loss of global levels of 5hmC has been regarded as a hallmark in various cancers. 5-hydroxymethylcytosine is distributed at protein-coding gene bodies and promoters; however, the role and distribution of 5hmC at long non-coding RNAs (lncRNAs) is not clear. We investigated the distribution and regulatory roles of 5hmC for lncRNAs in colorectal cancer (CRC). METHODS: We integrated genome-wide profiles of 5hmC, 5mC, transcriptome and histone marks in CRC patients and examined the 5hmC-based clinical outcomes in patients. RESULTS: 5-hydroxymethylcytosine was distributed at lncRNA loci and positively correlated with lncRNA transcription. Dysreulated CRC lncRNAs were regulated by 5hmC directly or through abnormal activities of typical and super-enhancers and promoters modified by 5hmC. In addition, 5hmC was involved in long-range chromatin interactions at lncRNA loci. Finally, lncRNAs regulated by differential 5hmC marks were correlated with different clinical outcomes and tumour status in patients. CONCLUSIONS: 5-hydroxymethylcytosine is critical in regulating the transcription of lncRNA and serve as novel biomarkers for clinical prognosis in CRC.

A novel subtype classification and risk of breast cancer by histone modification profiling.

Breast cancer has been classified into several intrinsic molecular subtypes on the basis of genetic and epigenetic factors. However, knowledge about histone modifications that contribute to the classification and development of biologically distinct breast cancer subtypes remains limited. Here we compared the genome-wide binding patterns of H3K4me3 and H3K27me3 between human mammary epithelial cells and three breast cancer cell lines representing the luminal, HER2, and basal subtypes. We characterized thousands of unique binding events as well as bivalent chromatin signatures unique to each cancer subtype, which were involved in different epigenetic regulation programs and signaling pathways in breast cancer progression. Genes linked to the unique histone mark features exhibited subtype-specific expression patterns, both in cancer cell lines and primary tumors, some of which were confirmed by qPCR in our primary cancer samples. Finally, histone mark-based gene classifiers were significantly correlated with relapse-free survival outcomes in patients. In summary, we have provided a valuable resource for the identification of novel biomarkers of subtype classification and clinical prognosis evaluation in breast cancers.