A novel IFNα-induced long noncoding RNA negatively regulates immunosuppression by interrupting H3K27 acetylation in head and neck squamous cell carcinoma.

BACKGROUND: Interferon alpha (IFNα) is a well-established regulator of immunosuppression in head and neck squamous cell carcinoma (HNSCC), while the role of long noncoding RNAs (lncRNAs) in immunosuppression remains largely unknown. METHODS: Differentially expressed lncRNAs were screened under IFNα stimulation using lncRNA sequencing. The role and mechanism of lncRNA in immunosuppression were investigated in HNSCC in vitro and in vivo. RESULTS: We identified a novel IFNα-induced upregulated lncRNA, lncMX1-215, in HNSCC. LncMX1-215 was primarily located in the cell nucleus. Ectopic expression of lncMX1-215 markedly inhibited expression of the IFNα-induced, immunosuppression-related molecules programmed cell death 1 ligand 1 (PD-L1) and galectin-9, and vice versa. Subsequently, histone deacetylase (HDAC) inhibitors promoted the expression of PD-L1 and galectin-9. Binding sites for H3K27 acetylation were found on PD-L1 and galectin-9 promoters. Mechanistically, we found that lncMX1-215 directly interacted with GCN5, a known H3K27 acetylase, to interrupt its binding to H3K27 acetylation. Clinically, negative correlations between lncMX1-215 and PD-L1 and galectin-9 expression were observed. Finally, overexpression of lncMX1-215 suppressed HNSCC proliferation and metastasis capacity in vitro and in vivo. CONCLUSIONS: Our results suggest that lncMX1-215 negatively regulates immunosuppression by interrupting GCN5/H3K27ac binding in HNSCC, thus providing novel insights into immune checkpoint blockade treatment.

Interferon-alpha promotes immunosuppression through IFNAR1/STAT1 signalling in head and neck squamous cell carcinoma.

BACKGROUND: An immunosuppressive microenvironment is critical for cancer initiation and progression. Whether interferon alpha (IFNα) can suppress immune and cancer cells and its involved mechanism still remain largely elusive. METHODS: We examine the expression of interferon alpha/beta receptor-1 (IFNAR1), CD8, CD56 and programmed death ligand 1 (PDL1) in head and neck squamous cell carcinomas (HNSCC). The effect of IFNα on PDL1 and programmed cell death protein 1 (PD1) expression in tumour cells and immune cells was detected in vitro and in vivo. RESULTS: Overexpression of IFNAR1, MX1 and signal transducer and activator of transcription 1 (Stat1) indicated the endogenous IFNα activation in tumour microenvironment, which correlated with immunosuppression status in HNSCC patients. Moreover, IFNα transcriptionally activated the expression of PDL1 through p-Stat1 (Tyr701) and promoted PD1 expression in immune cells through IFNAR1. The inhibition of IFNα signalling enhanced the cytotoxic activity of nature killer cells. At lastastly, we confirmed the upregulation of PDL1 and PD1 in response to IFNα treatment in both xenograft tumour models and patient-derived xenograft models. CONCLUSIONS: Our findings demonstrate that IFNα-induced PDL1 and PD1 expression is a new mechanism of immunosuppression in HNSCC, suggesting that blocking IFNα signalling may enhance the efficacy of immune checkpoint blockade.

Altered expression of TIM-3, LAG-3, IDO, PD-L1, and CTLA-4 during nimotuzumab therapy correlates with responses and prognosis of oral squamous cell carcinoma patients.

BACKGROUND: Since the inhibitory immune checkpoint receptors have been described to benefit the OSCC patients clinically, it is unknown that whether their expression in tumor immune microenvironment (TME) can determine the clinical outcome in response to nimotuzumab therapy. METHODS: We examined the expression patterns of immune checkpoint receptors (including TIM-3, LAG-3, PD-L1, and CTLA-4) and an immunoregulatory enzyme called IDO in 36 OSCC patients during nimotuzumab therapy by immunohistochemistry. Then, we divided the recruited patients into clinical responders and non-responders according to computed tomography (CT) scan and analyzed the relationship between the immunological parameters and clinical outcome. RESULTS: We observed that nimotuzumab therapy significantly increased the expression of TIM-3, LAG-3, IDO, PD-L1, and CTLA-4 in the TME, and the expression of LAG-3 and PD-L1 before nimotuzumab therapy was inversely correlated with the overall survival. In clinical non-responders, we found the expression of TIM-3, LAG-3, IDO, PD-L1, and CTLA-4 was significantly increased during nimotuzumab therapy, and the expression of TIM-3, LAG-3, IDO, PD-L1, and CTLA-4 before nimotuzumab therapy was negatively correlated with the overall survival. However, in clinical responders, neither of those showed significant. CONCLUSIONS: It suggests that these immune checkpoint receptors and IDO could be considered as biomarkers to reflect immune status in the tumor microenvironment during nimotuzumab therapy. Blockade of these immune checkpoint receptors might enhance nimotuzumab-based cancer immunotherapy, thus potentially improving clinical outcomes of OSCC patients.

Interferon-alpha enhances the antitumour activity of EGFR-targeted therapies by upregulating RIG-I in head and neck squamous cell carcinoma.

BACKGROUND: The epidermal growth factor receptor (EGFR)-targeted therapies have been tested in the clinic as treatments for head and neck squamous cell carcinoma (HNSCC). Owing to intrinsic or acquired resistance, EGFR-targeted therapies often lead to a low response rate and treatment failure. Interferon-alpha (IFNα) is a chemosensitising agent and multi-functional cytokine with a tumour inhibitory effect. However, the synergic effect of IFNα and EGFR-targeted therapies (erlotinib and nimotuzumab) and their mechanisms in HNSCC remain unclear. METHODS: The interactions between IFNα, erlotinib, and nimotuzumab were evaluated in vitro in HNSCC cells. The synergistic effect of IFNα (20 000 IU per day, s.c.), erlotinib (50 mg kg-1 per day, i.g.) and nimotuzumab (10 mg kg-1 per day, i.p.) was further confirmed in vivo using HNSCC xenografts in nude mice. The upregulation of retinoic-acid inducible gene I (RIG-I) induced by IFNα and EGFR-targeted therapies and its mechanism were detected in vitro and in vivo. RESULTS: IFNα enhances the antitumour effects of erlotinib and nimotuzumab on HNSCC cells both in vitro and in vivo. Importantly, both IFNα and EGFR-targeted therapies promote the expression of RIG-I by activating signal transducers and activators of transcription 1 (STAT1) in HNSCC cells. RIG-I knockdown reduced the sensitivity of HN4 and HN30 cells to IFNα, erlotinib, and nimotuzumab. Moreover, IFNα transcriptionally induced RIG-I expression in HNSCC cells through STAT1. CONCLUSIONS: IFNα enhances the effect of EGFR-targeted therapies by upregulating RIG-I, and its expression may represent a predictor of the effectiveness of a combination treatment including IFNα in HNSCC.

Stabilization of Slug by NF-κB is Essential for TNF-α -Induced Migration and Epithelial-Mesenchymal Transition in Head and Neck Squamous Cell Carcinoma Cells.

BACKGROUND/AIMS: Slug protein, a transcription factor for the induction of epithelial-mesenchymal transition (EMT) and cancer cell invasion and metastasis, is frequently upregulated in human epithelial cancers. However, mutation of this gene in cancer is rare, and the mechanism of its dysregulation remains unknown, especially in head and neck squamous cell carcinoma (HNSCC). METHODS: We examined the role of TNF-α in the stabilization of Slug by immunoprecipitation-westernblot analysis. Migration of HNSCC cells with or without knockdown of Slug gene expression was assayed by a wound healing assay. Immunohistochemical staining analysis was used to measurement Slug levels in both normal and HNSCC tumor tissues. RESULTS: The inflammatory cytokine TNF-α stabilized Slug protein by inhibiting its ubiquitination through the NF-κB pathway. Inhibition of NF-κB or knockdown of p65 abrogated the TNF-α-induced stabilization of Slug. Knockdown of Slug expression inhibited cancer cell migration and EMT characteristics induced by TNF-α. Moreover, increased levels of Slug were found to correlate with lymph node metastasis and predict poor prognosis in patients with HNSCC. CONCLUSIONS: NF-κB-mediated stabilization of Slug underlies the inflammation-induced EMT and metastasis in HNSCC, which may serve as a therapeutic target for metastatic HNSCC.

Ultrasound hyperthermia enhances chemo-sensitivity in oral squamous cell carcinoma by TRIF-mediated pathway.

BACKGROUND: Hyperthermia is currently used as an alternative to surgery or in combination with chemotherapy and/or radiation therapy in the treatment of oral squamous cell carcinoma. However, little has been known about the change in chemo-sensitivity after hyperthermia and the mechanism underlie it in oral squamous cell carcinoma. METHODS: The aim of this study was to explore the influence of chemo-sensitivity of CAL-27 and SCC-4 cells by histoculture drug response assay after the animal model treated by the ultrasound hyperthermia. Then, we conducted a microarray between xenograft after hyperthermia at 42°C for 45 minutes and that with no treatment. We further confirmed the expression of TRIF in hyperthermia by immunohistochemistry, RT-PCR and Western blot. RESULTS: The chemo-sensitivity to five kinds of drugs demonstrated ultrasound hyperthermia performed in 42°C for 45 minutes would reach the highest inhibition rate in CAL-27 and SCC-4 cells. The microarray dataset revealed that 847 mRNA were upregulated and 1031 were downregulated. GO and pathway analyses indicated that they play an important role in translational initiation, nucleoplasm, and poly (A) RNA binding in the hyperthermia process. We further confirmed the expression of TRIF was downregulated in hyperthermia along with inactivation of NF-κB pathway. CONCLUSIONS: The experiments confirms the rationality of synchronous combination of hyperthermia and chemotherapy and may provide a better treatment that the use of sensitivity testing in such cases may lead to individualized, more effective therapy.

Retracted: Effects of Nano-Hydroxyapatite/Polyetheretherketone-Coated, Sandblasted, Large-Grit, and Acid-Etched Implants on Inflammatory Cytokines and Osseointegration in a Peri-Implantitis Model in Beagle Dogs.

The article is withdrawn by the authors request.

Effect of Choukroun Platelet-Rich Fibrin Combined With Autologous Micro-Morselized Bone on the Repair of Mandibular Defects in Rabbits.

PURPOSE: The aim of this study was to explore the effect of Choukroun platelet-rich fibrin (PRF) combined with autologous micro-morselized bone on the repair of mandibular defects in rabbits. MATERIALS AND METHODS: Thirty-six healthy New Zealand rabbits were selected for the present study. After models of mandibular defects were established, rabbits were randomly divided into Choukroun PRF, autologous micro-morselized bone (autologous), Choukroun PRF combined with autologous bone (combined) and model groups. After the rabbits were sacrificed at 2, 8, and 12 weeks postoperatively, their bone formation was assessed by x-ray and scanning electron microscopy, and the histologic changes of the mandibular defect area were detected by hematoxylin and eosin staining. Cone-beam computed tomography was used to observe the size of the change of the mandibular defect area. Bone mineral density (BMD) was analyzed by dual-energy x-ray absorptiometry. RESULTS: The bone defect in the combined group showed better repair, increased bone mineral content, and denser callus than the other groups, and the defect area was filled with mature trabecular bone. In the Choukroun PRF and autologous groups, the defect area was smaller and filled with osteoporotic trabecular bone. A clear mandibular defect area was still observed in the model group. Compared with the other groups, the combined group showed more bone regeneration, more fibrous tissue regeneration, and greater bone maturity at all time points. The combined group had the highest BMD, there was no relevant difference in BMD between the Choukroun PRF and autologous groups, and the model group had the lowest BMD. BMD in all 4 groups increased with time. CONCLUSION: These findings indicate that Choukroun PRF combined with autologous micro-morselized bone can substantially improve the repair of mandibular defects in rabbits, and the effect is superior to Choukroun PRF or autologous micro-morselized bone alone.

Effects of Nano-Hydroxyapatite/Polyetheretherketone-Coated, Sandblasted, Large-Grit, and Acid-Etched Implants on Inflammatory Cytokines and Osseointegration in a Peri-Implantitis Model in Beagle Dogs.

BACKGROUND This study explored the effects of nano-hydroxyapatite/polyetheretherketone (n-HA/PEEK)- coated sandblasted, large-grit, and acid-etched (SLA) implants on inflammatory cytokines and osseointegration in peri-implantitis model beagle dogs. MATERIAL AND METHODS Peri-implantitis models were established. Eight beagle dogs were randomly and evenly assigned into SLA tied, SLA + n-HA/PEEK tied, SLA untied, or SLA + n-HA/PEEK untied groups. A special periodontal probe was used to detect the plaque index (PLI), probing depth (PD), and modified Sulcus Bleeding Index (mSBI). Gingival crevicular fluid was collected and an ELISA kit was utilized to detect IL-1, IL-6, and IL-17 levels. The colony-forming units were counted and the maximum shear strength of implants was tested using the axial pullout test. HE staining was used to detect the inflammation of peri-implant bone tissues. Osseointegration was observed through toluidine blue staining. Bone-to-implant contact (BIC) was obtained through histological observation and the mineral apposition rate (MAR) was calculated after immune fluorescent double staining. RESULTS The SLA tied group demonstrated higher levels of PLI, PD, mSBI, IL-1, IL-6, and IL-17 and a higher degree of inflammation than the SLA + n-HA/PEEK tied group. The tied groups also displayed similar results over the untied groups at the same time point. The maximum shear strength, BIC, and MAR in the SLA tied group were significantly lower than in the SLA + n-HA/PEEK tied group. CONCLUSIONS Our findings demonstrate that SLA + n-HA/PEEK implants can promote osseointegration and relieve the inflammation response of peri-implantitis in beagle dogs.

Risk Factors for Pedicle Flap Complications in 251 Elderly Chinese Patients Who Underwent Oral and Maxillofacial Reconstruction.

PURPOSE: To determine risk factors for pedicle flap complications in elderly patients undergoing oral and maxillofacial reconstruction. PATIENTS AND METHODS: The authors designed and implemented a retrospective cohort study and enrolled a sample of patients at least 75 years old who underwent resection of oral and maxillofacial tumors and pedicle flap reconstruction from January 2004 through December 2013. The primary predictor variable was reconstructive technique grouped into 5 types of pedicle flap. The difference among groups was tested with the χ(2) test and t test. The primary outcome variable was the presence of flap complication, which was divided into minor and major groups. Other variables were grouped into the following sets: demographic, operative, and adjuvant treatments. Univariate, bivariate, and regression statistics were computed and statistical significance was set at a P value less than .05. RESULTS: The study sample was composed of 251 patients with a mean age of 78 years and 62.95% were men. Of these, 68.13% had various preoperative systemic diseases. With regard to flap type, 120 underwent reconstruction with a pectoralis major myocutaneous flap, 5 with a submental island flap, 4 with a submandibular gland flap, 13 with a platysma myocutaneous flap, and 109 with a sternocleidomastoid flap. TNM stage (negative correlation) and smoking (positive correlation) correlated with flap type. There were 48 complications, of which 32 were minor and 16 were major; flap failure was observed in only 1 patient. Risk factors associated with complications were types of pedicle flap, age, heart score, hypertension, diabetes, postoperative hypoproteinemia, and drug-induced liver injury. CONCLUSION: The pedicle flap is suitable and safe for the reconstruction of defects caused by the ablation of oral and maxillofacial tumors in elderly patients. Preoperative evaluation of positive risk factors, including type of surgery and systemic conditions, is very important for the selection of an appropriate flap for such patients.

Use of the buccal fat pad in the immediate reconstruction of palatal defects related to cancer surgery with postoperative radiation therapy.

PURPOSE: To evaluate the use of the buccal fat pad (BFP) in the immediate reconstruction of oncologic palate defects and the influence of postoperative radiotherapy on reconstruction. PATIENTS AND METHODS: Patients who were diagnosed with moderate- to high-grade malignancies of the palate underwent partial maxillectomy. The BFP was used as a pedicled flap to reconstruct the defects. All patients received postoperative radiotherapy 4 to 5 weeks after surgery. RESULTS: Eighteen patients (9 men and 9 women; age range, 37 to 81 yr) underwent surgery and subsequent radiotherapy. The size of all defects ranged from 7.5 to 19.2 cm2. Adequate closure of the defects was achieved during surgery and all flaps were epithelialized within 3 weeks after surgery, with no complications of dehiscence or flap failure. Furthermore, there were no complications derived from postoperative radiotherapy. CONCLUSIONS: This study suggests that BFP grafting is an effective and reliable method for the reconstruction of small to medium-size palate defects. Furthermore, postoperative radiotherapy does not influence the success of reconstruction.

Application of modified Karapandzic flaps in large lower lip defect reconstruction.

PURPOSE: Reconstruction of a lower lip defect with a Karapandzic flap often leads to greater rounding of the commissure. The aim of this study was to provide a new design of bilateral Karapandzic flap for large lower lip defect reconstruction. MATERIALS AND METHODS: In this case-series retrospective study, a modification of the Karapandzic lip reconstruction technique was used with an additional incision to obtain more tissue. The esthetic outcome of the reconstruction was assessed using a 4-point scale with regard to the shape of the commissure, lip symmetry, appearance of the scar, and lip projection. Functional outcome was assessed by speech, preservation of oral competence, lip sensation, facial expression, diet, and denture usage. RESULTS: Seventeen patients (13 male, 4 female; age range, 52 to 82 yr) with squamous cell carcinoma in the lower lip underwent single-stage lip reconstruction. Lip defects after tumor resection ranged from 50 to 90% of the lower lips. All patients achieved oral competence, without leading to greater rounding of the commissure. The esthetic outcome was considered good to excellent in 88% of cases and reconstruction did not lead to functional impairments in speech, oral competence, lip sensation, facial expression, diet, or denture usage. CONCLUSIONS: The modified bilateral Karapandzic flap is a reliable technique to reconstruct large lip defects without leading to rounding of the commissure. With this technique, good esthetic and functional outcomes can be achieved.

A data-mining study on the prediction of head injury in traffic accidents among vulnerable road users with varying body sizes and head anatomical characteristics.

Body sizes and head anatomical characteristics play the major role in the head injuries sustained by vulnerable road users (VRU) in traffic accidents. In this study, in order to study the influence mechanism of body sizes and head anatomical characteristics on head injury, we used age, gender, height, and Body Mass Index (BMI) as characteristic parameters to develop the personalized human body multi-rigid body (MB) models and head finite element (FE) models. Next, using simulation calculations, we developed the VRU head injury dataset based on the personalized models. In the dataset, the dependent variables were the degree of head injury and the brain tissue von Mises value, while the independent variables were height, BMI, age, gender, traffic participation status, and vehicle speed. The statistical results of the dataset show that the von Mises value of VRU brain tissue during collision ranges from 4.4 kPa to 46.9 kPa at speeds between 20 and 60 km/h. The effects of anatomical characteristics on head injury include: the risk of a more serious head injury of VRU rises with age; VRU with higher BMIs has less head injury in collision accidents; height has very erratic and nonlinear impacts on the von Mises values of the VRU's brain tissue; and the severity of head injury is not significantly influenced by VRU's gender. Furthermore, we developed the classification prediction models of head injury degree and the regression prediction models of head injury response parameter by applying eight different data mining algorithms to this dataset. The classification prediction models have the best accuracy of 0.89 and the best R2 value of 0.85 for the regression prediction models.

Stabilization of EREG via STT3B-mediated N-glycosylation is critical for PDL1 upregulation and immune evasion in head and neck squamous cell carcinoma.

Dysregulated Epiregulin (EREG) can activate epidermal growth factor receptor (EGFR) and promote tumor progression in head and neck squamous cell carcinoma (HNSCC). However, the mechanisms underlying EREG dysregulation remain largely unknown. Here, we showed that dysregulated EREG was highly associated with enhanced PDL1 in HNSCC tissues. Treatment of HNSCC cells with EREG resulted in upregulated PDL1 via the c-myc pathway. Of note, we found that N-glycosylation of EREG was essential for its stability, membrane location, biological function, and upregulation of its downstream target PDL1 in HNSCC. EREG was glycosylated at N47 via STT3B glycosyltransferases, whereas mutations at N47 site abrogated N-glycosylation and destabilized EREG. Consistently, knockdown of STT3B suppressed glycosylated EREG and inhibited PDL1 in HNSCC cells. Moreover, treatment of HNSCC cells with NGI-1, an inhibitor of STT3B, blocked STT3B-mediated glycosylation of EREG, leading to its degradation and suppression of PDL1. Finally, combination of NGI-1 treatment with anti-PDLl therapy synergistically enhanced the efficacy of immunotherapy of HNSCC in vivo. Taken together, STT3B-mediated N-glycosylation is essential for stabilization of EREG, which mediates PDL1 upregulation and immune evasion in HNSCC.

Fe3O4 Nanoparticles That Modulate the Polarisation of Tumor-Associated Macrophages Synergize with Photothermal Therapy and Immunotherapy (PD-1/PD-L1 Inhibitors) to Enhance Anti-Tumor Therapy.

Introduction: Traditional surgical resection, radiotherapy, and chemotherapy have been the treatment options for patients with head and neck squamous cell carcinoma (HNSCC) over the past few decades. Nevertheless, the five-year survival rate for patients has remained essentially unchanged, and research into treatments has been relatively stagnant. The combined application of photothermal therapy (PTT) and immunotherapy for treating HNSCC has considerable potential. Methods: Live-dead cell staining and CCK-8 assays proved that Fe3O4 nanoparticles are biocompatible in vitro. In vitro, cellular experiments utilized flow cytometry and immunofluorescence staining to verify the effect of Fe3O4 nanoparticles on the polarisation of tumor-associated macrophages. In vivo, animal experiments were conducted to assess the inhibitory effect of Fe3O4 nanoparticles on tumor proliferation under the photothermal effect in conjunction with BMS-1. Tumour tissue sections were stained to observe the effects of apoptosis and the inhibition of tumor cell proliferation. The histological damage to animal organs was analyzed by hematoxylin and eosin (H&E) staining. Results: The stable photothermal properties of Fe3O4 nanoparticles were validated by in vitro cellular and in vivo animal experiments. Fe3O4 photothermal action not only directly triggered immunogenic cell death (ICD) and enhanced the immunogenicity of the tumor microenvironment but also regulated the expression of tumor-associated macrophages (TAMs), up-regulating CD86 and down-regulating CD206 to inhibit tumor growth. The PD-1/PD-L1 inhibitor promoted tumor suppression, and reduced tumor recurrence and metastasis. In vivo studies demonstrated that the photothermal action exhibited a synergistic effect when combined with immunotherapy, resulting in significant suppression of primary tumors and an extension of survival. Conclusion: In this study, we applied Fe3O4 photothermolysis in a biomedical context, combining photothermolysis with immunotherapy, exploring a novel pathway for treating HNSCC and providing a new strategy for effectively treating HNSCC.

Tongue reconstruction with tongue base island advancement flap.

Reconstruction of a medium-sized defect of the tongue remains a challenge if aesthetic impairment is to be avoided. In this study, 19 tongue base island advancement flaps were developed to reconstruct medium-sized defects after the tongue squamous cell carcinoma ablations: 13 cases were T1N0M0, and 6 cases were T2N0∼1M0. The largest size amounts to 5.4 × 4.8 cm (length × width), with a mean of 4.6 × 4.4 cm. The tongue base island advancement flap reduces the volume of the tongue base without causing function impairment of the tongue. All patients recovered with good objective and subjective speech and swallowing and aesthetics. No patient developed local recurrence or lymphatic metastasis. The technique of tongue base advancement flap is ideal for functional and aesthetic repair of medium-sized tongue defects after cancer ablation.

Surgical approaches for tongue base schwannoma.

Schwannomas (neurilemmomas) are benign nerve sheath tumor originating from Schwann cells. They are well circumscribed and rarely infiltrate and metastasize. Schwannomas of the head and neck commonly occur in the tongue followed by the palate, floor of mouth, buccal mucosa, and mandible. Tongue base schwannomas could extend to the pharyngeal cavity or the floor of the mouse, and it is difficult to differentiate between tumors of the lingual, hypoglossal, and glossopharyngeal nerves.Surgical treatment of tongue base schwannomas is difficult because of limited operative exposure. Although mandibulotomy with lip splitting could obtain good exposure, surgeons might strike a balance between exposure obtaining and morbidity following because there are intricate neurovascular anatomical relationships in this region, and mandibulotomy with lip splitting would cause significant morbidity. Surgical approach options are important for tongue base schwannoma removal. From March 2008 to March 2010, 8 patients were clinically and pathologically diagnosed with tongue base schwannomas in our department, and all underwent surgical treatment. In our experience, transoral approach was used for tongue base schwannomas extending to the floor of the mouse and suprahyroid pharyngotomy approach for those extending to the pharyngeal cavity. Follow-up was made until now. One patient who experienced transoral excision still experienced numbness in the region of the lateral tongue tip, and the other 7 patients had no postoperative long-term complications.

IDENTIFIABLE BOUNDED COMPONENT ANALYSIS VIA MINIMUM VOLUME ENCLOSING PARALLELOTOPE.

In this paper, we revisit bounded component analysis (BCA) and formulate it as a geometric problem of finding the minimum volume enclosing parallelotope (MVEP) of a set of data points in the Euclidean space. A parallelotope is an affine transformation of the standard box, also known as the L∞-norm ball. An immediate benefit of the novel formulation is that the bounds on the supports of the latent components can be arbitrary, unlike most existing BCA works that assume the bounds are symmetric around zero. The main contribution is that the MVEP solution exactly recovers the latent components, up to the inherent (and inconsequential) permutation, shift, and scaling ambiguities, if the groundtruth components satisfy a so-called "sufficiently scattered" condition in the standard box. This is a great improvement to the existing result that requires all vertices of the box are contained in the data set, which requires exponentially many data points, or that of ICA, which essentially requires infinite amount of data points to guarantee exact recovery. We also present a new learning algorithm to solve the (NP-hard) MVEP problem based on Frank-Wolfe, and show numerically that the performance is surprisingly effective.

A fast methodology for generating skeletal FEM with detailed human geometric features based on CPD and RBF algorithms.

Due to the significant effects of the human anatomical characteristics on the injury mechanism of passenger in traffic accidents, it is necessary to develop human body FEM (Finite Element Model) with detailed anatomical characteristics. However, traditional development of a human body FEM is an extremely complicated process. In particular, the meshing of human body is a huge and time-consuming project. In this paper, a new fast methodology based on CPD (Coherent Point Drift) and RBF (Radial Basis Function) was proposed to achieve the rapid developing the FEM of human bone with detailed anatomical characteristics. In this methodology, the mesh morphing technology based the RBF was used to generate FEM mesh in the geometry extracted from the target CT (Computed Tomography) data. In order to further improve the accuracy and speed of mesh morphing, the target geometric feature points required in the mesh morphing process were realized via the rapid and automatic generation based on the point-cloud registration technology of the CPD algorithm. Finally, this new methodology was used to generate a 3-year-old ribcage FEM consisting of a total of 27,728 elements with mesh size 3-5 mm based on the THUMS (Total Human Model for Safety) adult model. In the entire process of generating this new ribcage model, it only took about 2.7 s. The average error between the new FEM and target geometries was only about 2.7 mm. This indicated that the new FEM well described the detailed anatomical characteristics of target geometry, thus importantly revealing that the mesh quality of the new FEM was basically similar to that of source FEM.

A functional study of zinc-titanium coatings and exploration of the intrinsic correlation between angiogenesis and osteogenesis.

With the development of implant applications, osseointegration has become a criterion for implant success. A good blood supply is essential for successful osseointegration. To improve the pro-angiogenic ability of the implants, in this experiment we introduced zinc into the titanium coating. The physical morphology, biocompatibility, pro-angiogenic ability, and osteogenic effect of the zinc-containing titanium coatings were investigated. The pro-angiogenic effect of zinc ions was determined, and the intrinsic link between angiogenesis and osteogenesis under the effect of zinc ions was investigated. Zinc-containing titanium coating was prepared using a micro-arc oxidation (MAO) technique. The physical properties of the coating materials were determined by analyzing the microstructure, roughness, hydrophilic properties, constituent elements, and ionic release of the coating. The biocompatibility of the coating materials was examined using apoptosis and proliferation assays of human umbilical vein endothelial cells (HUVECs). The pro-angiogenic function and osteogenic ability of the zinc-containing coating were investigated by CD31 immunofluorescence staining and quantitative polymerase chain reaction (q-PCR) assay. The optimal concentration of zinc ions for pro-angiogenesis was screened by ion assay. Conditioned media (CM) were prepared for the experiments. The intrinsic link between angiogenesis and osteogenesis was determined by q-PCR to detect the expression of genes related to HUVECs and BMSCs after culture in CM. The prepared Zn-containing micro-arc oxide coatings were shown to have good physical properties, stable Zn2+ release ability, and biocompatibility, as well as good angiogenic and osteogenic potential. In addition, ion experiments confirmed that 60 µM Zn2+ exhibited the best angiogenic effect; more importantly, a mutual promotion between angiogenesis and osteogenesis regeneration in the Zn2+ microenvironment was also found. The introduction of Zn2+ improved the implants' functionality and laid the foundation for the clinical application of Zn2+ pro-angiogenesis.