miR-3682-3p directly targets FOXO3 and stimulates tumor stemness in hepatocellular carcinoma via a positive feedback loop involving FOXO3/PI3K/AKT/c-Myc.

BACKGROUND: Cancer stem cells (CSCs) have been implicated in tumorigenesis and tumor recurrence and metastasis are key therapeutic targets in cancer treatment. MicroRNAs display therapeutic potential by controlling the properties of CSCs; however, whether an association exists between miR-3682-3p and CSCs is unknown. AIM: To investigate the mechanism by which miR-3682-3p promotes stemness maintenance in hepatocellular carcinoma (HCC). METHODS: MiR-3682-3p expression in HCC cell lines and 34 pairs of normal and HCC specimens was assayed by quantitative polymerase chain reaction. The functional role of miR-3682-3p was investigated in vitro and in vivo. Dual-luciferase reporter and chromatin immunoprecipitation assays were performed for target asse ssment, and western blotting was utilized to confirm miR-3682-3p/target relationships. RESULTS: We found that miR-3682-3p plays a key role in HCC pathogenesis by promoting HCC cell stemness. The upregulation of miR-3682-3p enhanced CSC spheroid-forming ability, side population cell fractions, and the expression of CSC factors in HCC cells in vitro and the tumorigenicity of transplanted HCC cells in vivo. Furthermore, silencing miR-3682-3p prolonged the survival of HCC-bearing mice. Mechanistically, we found that miR-3682-3p targets FOXO3 and enables FOXO3/ß-catenin interaction, which promotes c-Myc expression through PI3K/AKT; c-Myc, in turn, activates miR-3682-3p, forming a positive feedback loop. Intriguingly, miR-3682-3p expression was induced by hepatitis B virus X protein (HBx) and was involved in HBx-induced tumor stemness-related pathogenesis. CONCLUSION: Our findings reveal a novel mechanism by which miR-3682-3p promotes stemness in HCC stem cells. Silencing miR-3682-3p may represent a novel therapeutic strategy for HCC.

Prognostic significance of in situ and plasma levels of transforming growth factor ß1, -2 and -3 in cutaneous melanoma.

Melanoma is an aggressive type of cutaneous malignancy. Transforming growth factor (TGF)­ß has been demonstrated to be an important mediator of tumor progression. However, to the best of our knowledge, the systemic roles of plasma TGF­ß and TGF­ß in situ have not been investigated in Han Chinese melanoma patients. The results of the present study demonstrated that the in situ and plasma levels of TGF­ß1, TGF­ß2 and TGF­ß3 protein and messenger RNA were significantly elevated in tumor tissues compared with those of normal tissues. The survival rates of the patients which were triple­positive (TGF­ß1+, TGF­ß2+ and TGF­ß3+) were found to be markedly decreased compared to those which were single­ (TGF­ß1+, TGF­ß2+ or TGF­ß3+) or double­positive (TGF­ß1+, TGF­ß2+; TGF­ß2+, TGF­ß3+; or TGF­ß1+, TGF­ß3+). These results may therefore contribute to the use of TGF­ß as a prognostic biomarker, and to the development of novel therapies for melanoma treatment.

Quantum Delayed-Choice Experiment with a Beam Splitter in a Quantum Superposition.

A quantum system can behave as a wave or as a particle, depending on the experimental arrangement. When, for example, measuring a photon using a Mach-Zehnder interferometer, the photon acts as a wave if the second beam splitter is inserted, but as a particle if this beam splitter is omitted. The decision of whether or not to insert this beam splitter can be made after the photon has entered the interferometer, as in Wheeler's famous delayed-choice thought experiment. In recent quantum versions of this experiment, this decision is controlled by a quantum ancilla, while the beam splitter is itself still a classical object. Here, we propose and realize a variant of the quantum delayed-choice experiment. We configure a superconducting quantum circuit as a Ramsey interferometer, where the element that acts as the first beam splitter can be put in a quantum superposition of its active and inactive states, as verified by the negative values of its Wigner function. We show that this enables the wave and particle aspects of the system to be observed with a single setup, without involving an ancilla that is not itself a part of the interferometer. We also study the transition of this quantum beam splitter from a quantum to a classical object due to decoherence, as observed by monitoring the interferometer output.

SUMO1 genetic polymorphisms may contribute to the risk of nonsyndromic cleft lip with or without palate: a meta-analysis.

OBJECTIVE: We conducted the present meta-analysis to investigate whether single-nucleotide polymorphisms (SNPs) in the SUMO1 gene contribute to the risk of nonsyndromic cleft lip with or without palate (NSCL/P). METHOD: The Web of Science (1945-2013), the Cochrane Library Database (Issue 12, 2013), PubMed (1966-2013), EMBASE (1980-2013), CINAHL (1982-2013), and the Chinese Biomedical Database (CBM) (1982-2013) were searched without language restrictions. Meta-analysis was performed with the use of the STATA statistical software. RESULTS: Six studies with a total of 1381 NSCL/P patients and 2054 control subjects were included. Twenty-seven functional polymorphisms in the SUMO1 gene were assessed. Our results indicated that SUMO1 genetic polymorphisms were correlated with an increased risk of NSCL/P. Subgroup analysis by the SNP type indicated that 4 functional polymorphisms (rs12470401 T>C, rs16838917 A>G, rs12470529 A>G, and rs7572505 A>G) in the SUMO1 gene might be strongly correlated with NSCL/P risk. Furthermore, ethnicity-stratified analysis demonstrated that SUMO1 genetic polymorphisms were closely related to an increased risk of NSCL/P among both Asians and Caucasians. CONCLUSION: Our findings provide empirical evidence that SUMO1 genetic polymorphisms might be strongly involved in the etiology of NSCL/P, especially for rs12470401 T>C, rs16838917 A>G, rs12470529 A>G, and rs7572505 A>G polymorphisms.

CD24 expression predicts poor prognosis for patients with cutaneous malignant melanoma.

Cutaneous malignant melanoma represents the major cause of mortality among skin cancers. Metastasis-associated protein CD24 is a small, heavily glycosylated cell surface protein that is overexpressed in various human malignancies. The present study was designed to determine the roles of CD24 in cutaneous malignant melanoma. The levels of CD24 mRNA and protein in cutaneous malignant melanoma tissues were detected by RT-PCR, Western blot and IHC. In patient samples, the levels of CD24 mRNA and protein were higher in cancer tissues than that in normal tissues. CD24 expression decreased the survival time of the patients with melanoma. Taken together, these results suggest that CD24 may be used as a new drug target for cutaneous malignant melanoma.

Distinct roles of different fragments of PDCD4 in regulating the metastatic behavior of B16 melanoma cells.

Melanoma is an aggressive cutaneous malignancy. In this study, we demonstrated that the levels of the programmed cell death 4 (PDCD4) protein and mRNA were lower in tumor tissues compared with normal tissues. In order to further investigate the effects of PDCD4 and its fragments in B16 melanoma cells, we established B16 clones with expression of different PDCD4 fragments. Intact PDCD4, PDCD4∆164­469 and PDCD4∆327-440 expression, respectively, decreased proliferation and migration and increased apoptosis in B16 cells in vitro. We found that intact PDCD4, PDCD4∆164-469 or PDCD4∆327-440 can inhibit the activity of MMP-2 and the expression of CXCR4. However, PDCD4∆164-275 showed no effects on B16 cells. These results may prove helpful for the development of novel therapies for melanoma treatment.

CSMD1 exhibits antitumor activity in A375 melanoma cells through activation of the Smad pathway.

In this work, we studied the effects of CUB and Sushi multiple domains 1 gene (CSMD1) expression in A375 melanoma cells in vivo and in vitro. CSDM1 expression decreased proliferation and migration, and increased apoptosis and G(1) arrest in A375 cells in vitro. Expression of CSDM1 in established xenografted tumors decreased tumor size and weight, and decreased the density of intratumor microvessels. The survival rate of mice with tumors expressing CSMD1 was significantly higher than mice with tumors that did not express CSDM1. These results confirm the role of CSDM1 as a tumor suppressor gene in melanoma cells. Furthermore, we found that CSMD1 can interact with Smad3, activate Smad1, Smad2, and Smad3, and increase the expression of Smad4. These results might prove helpful for the development of novel therapies for melanoma treatment.

Oxymatrine inhibits collagen synthesis in keloid fibroblasts via inhibition of transforming growth factor-ß1/Smad signaling pathway.

BACKGROUND: Keloids are benign dermal tumors characterized by fibroblastic proliferation and excessive accumulation of collagen. Oxymatrine (OMT) is an alkaloid extracted from the Chinese herb Sophora japonica with capacities of anti-fibrosis. OBJECTIVE: To evaluate the effects of OMT on collagen production and to explore its mechanisms. METHODS: OMT was applied to human keloid fibroblasts in vitro. Collagen, transforming growth factor (TGF)-ß1, TGF-ß receptor, and Smads were analyzed by Western Blot, reverse transcription polymerase chain reaction, and immunofluorescence. RESULTS: We found that both collagen synthesis and Smad3 production were significantly suppressed in a dose-dependent administration of OMT. However, expression of TGF-ß1, TGF-ß receptor1, TGF-ß receptor2, Smad4, and Smad7 was unchanged. We also found that OMT reversed phosphorylation and nuclear translocation of Smad3 induced by TGF-ß1. CONCLUSIONS: OMT inhibited collagen synthesis, which might be associated with TGF-ß/Smad signaling pathway. These findings suggest that OMT may be a promising candidate to prevent keloid and other fibrotic diseases.

[Clinical application of unimportant branches of facial nerve to repair important ones].

PURPOSE: To study the feasibility and clinical effect of repairing important branches of facial nerve (zygomatic and marginal mandibular branches) with unimportant ones (upper buccal and cervical branches). METHODS: The defect of zygomatic and marginal mandibular branches was repaired with upper buccal and cervical branches, respectively. After the length of facial nerve defect was measured, the distal part of the upper buccal and cervical branches with peripheral tissue was used to repair the defect. Under operating microscope, nerve anastomosis was performed with 9-0 suture. 5 cases suffering from defect of marginal mandibular branches were repaired with cervical branches, and 7 cases with defect of zygomatic branches were repaired with upper buccal branches. RESULTS: In 5 cases suffering from defect of marginal mandibular branches, 2 cases recovered in 3 months, and 3 cases recovered in 6 months; In 7 cases suffering from defect of zygomatic branches, all recovered in 3-4 months. CONCLUSION: Repair of defect of zygomatic and marginal mandibular branches with upper buccal and cervical branches is feasible and the result is acceptable.

[Entire restoration of deformities caused by naso-orbito-ethmoidal complex and adjacent craniomaxillofacial fracture].

OBJECTIVE: To introduce the therapy of malformation caused by naso-orbito-ethmoidal (NOE) complex and adjacent craniomaxillofacial fracture. METHODS: Seventy-six cases with NOE complex and adjacent craniomaxillofacial fracture underwent surgical replacement and internal fixation, using several cosmetically favorable incisions. At the same time, nasal reconstruction was performed to correct nasal deformities and defect through the coronal access during the exposure for the treatment of the NOE fracture. If larger nasal fragments were present, they were reduced and fixed by microplates or wires. If there was lack of septal support, dorsal nasal bone grafting was used to reestablish the height and anterior projection of the nose. Synthetic material (Medpor) was chosen for restoration of the orbital defects. Transnasal reduction was used for canthopexy. RESULTS: After 3 - 6 months follow-up, the outcomes of these patients were satisfactory functionally and esthetically. Posttraumatic nasal malformation and enophthalmos were corrected in most cases, and residual enophthalmos occurred in 3 cases, diplopia in 2 cases, insufficient prominence in 5 cases which underwent secondary correction with good results. Transnasal reduction of canthal realignment in the type III fracture was also satisfactory. There was no complication in this group. CONCLUSIONS: Comprehensive pre-operative evaluation of the patient and careful examinations should be taken to workout an appropriate operation plan. Simultaneous restoration for this type of complicated fracture is critical to obtain good results.

[Application of iliac cancellous and chondral bone to repair the cleft of alveolar process and the nasal deformity at the same time].

OBJECTIVE: To study a new method of simultaneous repair of alveolar cleft and the deformity of the nose and lip. METHODS: 42 patients with cleft of alveolar process were included in this study. We filled the cleft of alveolar process with iliac cancellous bone and covered the depression of piriform aperture and the nasal side with iliac cartilage. Simultaneously, we corrected the nasal deformity using V-Y plasty of a mucosa-cartilage compound flap at the nasal vestibule. RESULTS: In the patients aged 9 approximately 11 years, the mean height of the repaired alveolar process was 86.7%; the mean thickness was 89.6%; the contour and function of the alveolar process was grade I or II. The canine erupted at the place of bone grafting. The depression of the piriform aperture and alae nasi was repaired. The contour of the nares was symmetrical. In the patients over 12 years, the mean height of the alveolar process was 70.1%; the mean thickness was 71.7%; the contour and function of the alveolar process was grade II or III. The deflexion of nasal dorsum and nasal dome was not ameliorated in 2 patients of 18 years old. CONCLUSIONS: The application of iliac cancellous and chondral bone to simultaneously repair cleft of alveolar process and the nasal deformity is an ideal plastic method. It can recover the height of alveolar process and the continuity of dental arch, ameliorate the nasal deformity, and redress the deflexion of nasal dorsum and nasal end. It can also eliminate the psychological obstacle of the patients at an early stage.

[Application of facial canal dissection for recovery of facial nerve after operation of parotid carcinoma].

OBJECTIVE: To study the recovery method of facial nerve function and to compare the clinical effect after operation of parotid carcinoma, which invades stylomastoid foramen and peripheral bone in deep lobe. METHODS: Three operation methods were taken: (1) The tumor, parotid, invasive facial nerve and bone around the tumor were resected with transplantation of facial nerve. (2) Tumor parotid and facial nerve were resected without transplantation of facial nerve. (3) Tumor and parotid were dislocated from facial nerve, keeping the continuity of facial nerve. RESULTS: For the first method, facial nerve function of 68.2% patients came back to the patients without facial paralysis before operation, while facial nerve function of 16.7% patients came back to the patients with facial paralysis before operation. There was obvious difference between them (P < 0.05). To the patients with facial paralysis before operation, the first and the second method were taken. The ratio of local control was 33.3% and 10.0% respectively. And survival for 5 years were 25.0% and 10.0% respectively. There was no obvious difference between the two methods (P > 0.05). To the patients without facial paralysis before operation, three methods of operation were taken. The ratio of local control was 77.3%, 48.0% and 33.3% respectively. And survival for 5 years were 86.4%, 52.0% and 41.7% respectively. There was obvious difference between the first method and the other two (P < 0.05). There was no obvious difference between the second and the third methods (P > 0.05). CONCLUSION: Facial canal dissection in operation of parotid carcinoma with recovery of facial nerve can not only resect tumor completely, but also fit for development of functional surgery. It is an ideal method for surgery operation.

[Effect of intraoperative radiation therapy on enzyme histochemistry of expression muscle of guinea pigs after injury of facial nerve].

PURPOSE: To explore the mechanism of facial nerve recovery after radiotherapy by simulating surgical treatment of parotid gland carcinoma with reserving facial nerve and studying the ability of aerobic metabolism, transmission of neurotransmitter, variation of ultrastructure of motor end and mitochondrion after radiotherapy during operation. METHODS: Animal models of treatment group(15Gy) and lethal dose group(17Gy) were established. Succinic dehydrogenase(SDH) and acetylcholine lipase(AchE) of orbicularis oris were measured after radiotherapy. Student's t test was used for statistical analysis. RESULTS: The activity of SDH and AchE declined after radiotherapy. There was significant difference between treatment group and lethal dose group. One month later, there was a significant improvement in the activity of SDH and AchE in treatment group, while that of lethal dose group continued to decline. CONCLUSION: After radiotherapy during parotid gland surgery, the activity of SDH and AchE, transmission of neurotransmitter, and the ability of aerobic metabolism decreased. The ultrastructure of motor end and mitochondrion was destroyed. The variation returned to preoperative levels in treatment group, while did not in lethal dose group.

[Application the sternocleidomastoid muscle-great auricular nerve flap in radical parotidectomy].

OBJECTIVE: To study a new method for repair of facial depression and facial nerve defect after parotid carcinoma resection. METHODS: 12 patients with parotid carcinoma and peripheral bone invasion were treated using facial nerve canal dissection and radical resection of the tumor, the parotid gland and the involved facial nerve and bone, including the mastoid, stylomastoid foramen, styloid process and the rear part of the mandible. A sternocleidomastoid muscle flap was elevated and transferred to repair the facial depression. The great annular nerve in the flap was anastomosed with the severed end of the facial nerve in the canal. RESULTS: The depressed deformity of the parotid area was well corrected in 9 patients. The aesthetic results were compromised in 2 patients because of tumor recurrence and reoperation. The depressed deformity was not corrected in 1 patient because of infection. Postoperatively, the function of the facial nerve recovered to a normal level. The recovery time ranged from 12 to 20 weeks ,with an average of 16.3 weeks. The local control rate of tumor was improved. CONCLUSIONS: Immediate transplantation of the sternocleidomastoid muscle-great auricular nerve flap and facial nerve canal dissection in radical parotidectomy can repair the depressed deformity of the parotid area, restore facial nerve function,and decrease tumor recurrence. The method is an ideal operation with functional recovery.

[The effect of autogenous vein cuff and injection of cerebral cell growth peptide on the recovery of injured facial nerve].

OBJECTIVE: To study the effect of autogenous vein cuff and injection of cerebral cell growth peptide on the recovery of the injured facial nerve. METHODS: The injured facial nerve was anastomosed and covered with an autogenous vein cuff. Cerebral cell growth peptide was then injected to it. The different repairing methods were evaluated and compared with electromyography and observing functional recovery of the mimetic muscles. RESULTS: The new repairing method accelerated the recovery of the injured facial nerve. The recovery period of mimetic muscle function was significant shorter than the traditional method (P < 0.01). The recovery period of I-stage repairing was significant shorter than that of II--stage repairing (P < 0.01). The conduction velocity of the repaired facial nerves had no obvious differences between the new repairing method and the traditional method (P > 0.05). CONCLUSION: Application of the autogenous vein cuff to cover the nerve anastomosis and injection of cerebral cell growth peptide is a promising method for facial nerve repairing.

[Restoration of deformities caused by complex fracture of the orbit region and adjacent cranio-maxillofacial fracture].

OBJECTIVE: In order to improve the diagnosis and treatment of the complex fracture of the orbit region and adjacent cranio-maxillofacial fracture. METHODS: 73 cases with blowout fracture of the orbit and adjacent cranio-maxillofacial fracture in recent years were retrospectively analyzed and comparied with different methods of treatment. All cases had undertaken CT examinations. RESULTS: The positive rate of the CT examinations with blowout fracture of the orbit and adjacent cranio-maxillofacial region were 100%. Operating repositioning, rigid fixation and artificial material placement were used to treat this kind of deformities. CONCLUSIONS: With the progress of modern photographic methods, blowout fracture of the orbit and adjacent cranio-maxillofacial fracture can be diagnosed clearly and help the operation procedure. Operations with reduction, rigid fixation and filling materials can be used to restore this kind of fracture and appearance.