Search

Background: Infantile hemangioma (IH) arises as a result of dysregulation of both angiogenesis and vasculogenesis. The deubiquitylase OTUB1 (OTU domain, ubiquitin aldehyde binding 1) has been reported to play an essential role in multiple cancers; however, its function in the progression of IH and the underlying mechanisms regulating angiogenesis remain unclear. Methods: Transwell assays, EdU assays, and tube formation assays were performed to investigate the biological behavior of IH in vitro. IH animal models were established to estimate the progression of IH in vivo. Mass spectrometric analysis were conducted to detect the downstream of OTUB1 and ubiquitination sites of transforming growth factor beta induced (TGFBI). Half-life assays and ubiquitination test were performed to investigate the interaction between TGFBI and OTUB1. Extracellular acidification rate assays were employed to estimate the glycolysis level in IH. Results: The expression of OTUB1 was obviously increased in proliferating IH as compared to the involuting and involuted IH tissues. Through in vitro experiments, the knockdown of OTUB1 inhibited the proliferation, migration and tube formation of human hemangioma endothelial cells, while the overexpression of OTUB1 promoted the proliferation, migration and angiogenic abilities of human hemangioma endothelial cells. The knockdown of OTUB1 significantly suppressed IH progression in vivo. Furthermore, TGFBI was predicted as a functional downstream target of OTUB1 in IH by mass spectrometry. Mechanistically, OTUB1 interacted with and deubiquitylated TGFBI on the K22 and K25 residues, which was demonstrated to be independent of the catalytic activity of OTUB1. The inhibitory effects of OTUB1 knockdown on cell proliferation, migration and tube formation ability of human hemangioma endothelial cells were reversed by TGFBI overexpression. Further, we found that OTUB1 mediated glycolysis by regulating TGFBI in infantile hemangioma. Conclusions: OTUB1 deubiquitinates TGFBI in a catalytic-independent manner and promotes angiogenesis in infantile hemangioma by regulating glycolysis. Targeting OTUB1 might be an effective therapeutic strategy for inhibiting IH progression and tumor angiogenesis.

Infantile hemangioma (IH) is the most common benign tumor in infancy. Propranolol, a nonselective β-adrenergic receptor blocker, is now the first-line therapy for IH. Recently, low sensitivity to propranolol therapy has become one major reason for the failure of IH treatment. However, the exact underlying mechanisms are yet to be fully elucidated. Here, we reported that pyruvate kinase isoform M2 (PKM2), an essential glycolytic enzyme, played a critical role in regulating the progression of IH and the therapeutic resistance of propranolol treatment. Shikonin reversed the propranolol resistance in hemangioma-derived endothelial cells and in hemangioma animal models. Moreover, shikonin combined with propranolol could induce excessive reactive oxygen species (ROS) accumulation and lead to autophagic dysfunction, which is essential for the enhanced therapeutic sensitivity of propranolol treatment. Taken together, our results indicated that PKM2 has a significant role in hemangiomas progression and therapeutic resistance; it could be a safe and effective therapeutic strategy for those hemangiomas with poor propranolol sensitivity combined with shikonin.

The fibula osteocutaneous flap is the most commonly used flap to repair jaw defects, which can be used for composite soft and hard tissue reconstruction. Traditionally, the skin paddle of the fibula osteocutaneous flap is based on perforators from the peroneal artery, which is affifixed to the posterior crural septum between the peroneus and the soleus. The anatomy is relatively constant, and the perforators of skin paddle variation encounter in clinical occasionally. The authors report a case of reconstruction of mandible and soft tissue with fibula osteocutaneous flap after extensive radical resection of squamous cell carcinoma of the mouth floor. In this case, the authors raised a skin paddle based on the anterior tibial perforator of peroneal artery from the anterolateral intermuscular septum between the peroneus and the anterior calf muscles, which successfully rescued the traditional perforator absence and avoided exploration for a second donor site.

Metabolic reprogramming is reported to be one of the hallmarks of cancer, which is an adaptive mechanism by which fast-growing cancer cells adapt to their increasing energy demands. Recently, extracellular vesicles (EVs) known as exosomes have been recognized as crucial signaling mediators in regulating the tumor microenvironment (TME). Meanwhile, the TME is a highly heterogeneous ecosystem incorporating cancer cells, fibroblasts, adipocytes, endothelial cells, mesenchymal stem cells, and extracellular matrix. Accumulated evidence indicates that exosomes may transfer biologically functional molecules to the recipient cells, which facilitate cancer progression, angiogenesis, metastasis, drug resistance, and immunosuppression by reprogramming the metabolism of cancer cells and their surrounding stromal cells. In this review, we present the role of exosomes in the TME and the underlying mechanism of how exosomes exacerbate tumor development through metabolic reprogramming. In addition, we will also discuss the potential role of exosomes targeting metabolic process as biomarkers for tumor diagnosis and prognosis, and exosomes-mediated metabolic reprogramming as potential targets for cancer therapy. Furthermore, a better understanding of the link between exosomes and metabolic reprogramming, and their impact on cancer progression, would provide novel insights for cancer prevention and treatment in the future.

This study is aimed at determining the optimal sinus augmentation approach considering the poor bone condition in the zone of atrophic posterior maxilla. A series of simplified maxillary segment models varying in residual bone height (RBH) and bone quality were established. A 10 mm standard implant combined with two types of maxillary sinus augmentation methods was applied with the RBH, which was less than 10 mm in the maxilla. The maximal equivalent von Mises (EQV) stress in residual bone was evaluated. Bone quality had an enormous impact on the stress magnitude of supporting bone. Applying sinus augmentation combined with grafts was suitable for stress distribution, and high-stiffness graft performed better than low-stiffness one. For 7 mm and 5 mm atrophic maxilla, nongrafted maxillary sinus augmentation was feasible in D3 bone. Poor bone quality was a negative factor for the implant in the region of atrophic posterior maxilla, which could be improved by grafts. Meanwhile, the choice of maxillary sinus augmentation approaches should be determined by the RBH and quality.