Retracted: Expression of TP53, BCL-2, and VEGFA Genes in Esophagus Carcinoma and its Biological Significance.

The Editors of Medical Science Monitor wish to inform you that the above manuscript has been retracted from publication due to concerns with the credibility and originality of the study, the manuscript content, and the Figure images. Reference: Wei Wei, Yanqin Wang, Xiaoming Yu, Lan Ye, Yuhua Jiang, Yufeng Cheng. Expression of TP53, BCL-2, and VEGFA Genes in Esophagus Carcinoma and its Biological Significance. Med Sci Monit, 2015; 21: 3016-3022. DOI: 10.12659/MSM.894640.

Selective C-H Halogenation of Alkenes and Alkynes Using Flavin-Dependent Halogenases.

Single component flavin-dependent halogenases (FDHs) possess both flavin reductase and FDH activity in a single enzyme. We recently reported that the single component FDH AetF catalyzes site-selective bromination and iodination of a variety of aromatic substrates and enantioselective bromolactonization and iodoetherification of styrenes bearing pendant carboxylic acid or alcohol substituents. Given this inherent reactivity and selectivity, we explored the utility of AetF as catalyst for alkene and alkyne C-H halogenation. We find that AetF catalyzes halogenation of a range of 1,1-disubstituted styrenes, often with high stereoselectivity. Despite the utility of haloalkenes for cross-coupling and other applications, accessing these compounds in a stereoselective manner typically requires functional group interconversion processes, and selective halogenation of 1,1'-disubstituted olefins remains rare. We also establish that AetF and homologues of this enzyme can halogenate terminal alkynes. Mutagenesis studies and deuterium kinetic isotope effects are used to support a mechanistic proposal involving covalent catalysis for halogenation of unactivated alkynes by AetF homologues. These findings expand the scope of FDH catalysis and continue to show the unique utility of single component FDHs for biocatalysis.

Asymmetric catalysis by flavin-dependent halogenases.

In nature, flavin-dependent halogenases (FDHs) catalyze site-selective chlorination and bromination of aromatic natural products. This ability has led to extensive efforts to engineer FDHs for selective chlorination, bromination, and iodination of electron rich aromatic compounds. On the other hand, FDHs are unique among halogenases and haloperoxidases that exhibit catalyst-controlled site selectivity in that no examples of enantioselective FDH catalysis in natural product biosynthesis have been characterized. Over the past several years, our group has established that FDHs can catalyze enantioselective reactions involving desymmetrization, atroposelective halogenation, and halocyclization. Achieving high activity and selectivity for these reactions has required extensive mutagenesis and mitigation of problems resulting from hypohalous acid generated during FDH catalysis. The single-component flavin reductase/FDH AetF is unique among the wild type enzyme we have studied in that it provides high activity and selectivity toward several asymmetric transformations. These results highlight the ability of FDH active sites to tolerate different substrate topologies and suggest that they could be useful for a broad range of oxidative halogenations.

Comparison of 7 T and 3 T vessel wall MRI for the evaluation of intracranial aneurysm wall.

OBJECTIVES: To compare the visibility of intracranial aneurysm wall and thickness quantification between 7 and 3 T vessel wall imaging and evaluate the association between aneurysm size and wall thickness. METHODS: Twenty-nine patients with 29 unruptured intracranial aneurysms were prospectively recruited for 3D T1-weighted vessel wall MRI at both 3 T and 7 T with 0.53 mm (3 T) and 0.4 mm (7 T) isotropic resolution, respectively. Two neuroradiologists independently evaluated wall visibility (0-5 Likert scale), quantified the apparent wall thickness (AWT) using a semi-automated full-width-half-maximum method, calculated wall sharpness, and measured the wall-to-lumen contrast ratio (CRwall/lumen). RESULTS: Twenty-four patients with 24 aneurysms were included in this study. 7 T achieved significantly better aneurysm wall visibility than 3 T (3.6 ± 1.1 vs 2.7 ± 0.8, p = 0.003). AWT measured on 3 T and 7 T had a good correlation (averaged r = 0.63 ± 0.19). However, AWT on 3 T was 15% thicker than that on 7 T (0.52 ± 0.07 mm vs 0.45 ± 0.05 mm, p < 0.001). Wall sharpness on 7 T was 57% higher than that on 3 T (1.95 ± 0.32 mm-1 vs 1.24 ± 0.15 mm-1, p < 0.001). CRwall/lumen on 3 T and 7 T was comparable (p = 0.424). AWT on 7 T was positively correlated with aneurysm size (saccular: r = 0.58, q = 0.046; fusiform: r = 0.67, q = 0.049). CONCLUSIONS: 7 T provides better visualization of intracranial aneurysm wall with higher sharpness than 3 T. 3 T overestimates the wall thickness relative to 7 T. Aneurysm wall thickness is positively correlated with aneurysm size. 7 T MRI is a promising tool to evaluate aneurysm wall in vivo. KEY POINTS: • 7 T provides better visualization of intracranial aneurysm wall with higher sharpness than 3 T. • 3 T overestimates the wall thickness comparing with 7 T. • Aneurysm wall thickness is positively correlated with aneurysm size.

The Single-Component Flavin Reductase/Flavin-Dependent Halogenase AetF is a Versatile Catalyst for Selective Bromination and Iodination of Arenes and Olefins.

Flavin-dependent halogenases (FDHs) natively catalyze selective halogenation of electron rich aromatic and enolate groups. Nearly all FDHs reported to date require a separate flavin reductase to supply them with FADH2 , which complicates biocatalysis applications. In this study, we establish that the single component flavin reductase/flavin dependent halogenase AetF catalyzes halogenation of a diverse set of substrates using a commercially available glucose dehydrogenase to drive its halogenase activity. High site selectivity, activity on relatively unactivated substrates, and high enantioselectivity for atroposelective bromination and bromolactonization was demonstrated. Site-selective iodination and enantioselective cycloiodoetherification was also possible using AetF. The substrate and reaction scope of AetF suggest that it has the potential to greatly improve the utility of biocatalytic halogenation.

Xanthohumol Attenuates Lipopolysaccharide-Induced Depressive Like Behavior in Mice: Involvement of NF-κB/Nrf2 Signaling Pathways.

Depression is the most common psychiatric disorder associated with brain and immune system abnormalities. In recent years, xanthohumol (Xn) a bioactive prenylated flavonoid has received ample attention for its polypharmacological effects, therefore, here we aimed to explore the protective effects of Xn against the LPS-induced depressive-like symptoms mediated by inflammation and oxidative stress. We tested the effect of Xn against LPS-induced behavioural changes in mice by means of forced swimming test (FST), tail suspention test (TST), sucrose preference test (SPT) and open field test (OPT). Examined the neuroinflammation and oxido-nitrosative stress (O&NS) markers and analyze Nrf2 and NF-κB signalling pathways in the hippocampus. Our results indicated that peripheral repeated administration of lipopolysaccharides (LPS) (1 mg/kg, intra peritoneally) induced depressive-like behavior, neuroinflammation and O&NS in mice. Pretreatment with Xn (10 and 20 mg/kg, intra gastrically) reverse the behavioural impairments prophylactically as obvious in the FST and TST without effecting locomotion, however only 20 mg dose improve anhedonic behavior as observed in SPT. Similarly, Xn pretreatment in dose-dependent manner prevented the LPS induced neuro-inflammation and O&NS. Immunofluorescence analysis showed that Xn reduced activated gliosis via attenuation of Iba-1 and GFAP in hippocampus. In addition, Xn considerably reduced the expression of phospho-NF-κB and cleaved caspase-3 while enhanced Nrf2 and HO-1 expression in the hippocampus. To the best of our knowledge, this is the first study to examine the underlying beneficial prophylactic effects of the Xn in neuroinflammation and O&NS mediating depressive-like behaviors.

Wall enhancement of intracranial saccular and fusiform aneurysms may differ in intensity and extension: a pilot study using 7-T high-resolution black-blood MRI.

PURPOSE: To evaluate and compare wall enhancement patterns in saccular and fusiform intracranial aneurysms using high-resolution black-blood MRI at 7 T. METHODS: Thirty-one patients with 32 unruptured intracranial aneurysms (21 saccular and 11 fusiform) underwent 7-T black-blood MRI. Aneurysm wall enhancement (AWE) was categorized as follows: no wall enhancement (NWE), focal wall enhancement (FWE), and uniform wall enhancement (UWE). The degree of enhancement was scored as follows: 0 (no enhancement), 1 (signal intensity (SI) of the aneurysm wall less than that of the pituitary infundibulum), and 2 (equal to that of the pituitary infundibulum). The chi-squared test was used to compare the AWE pattern and degree between saccular and fusiform aneurysms. RESULTS: In saccular aneurysms, 12/21 (57%) enhanced. Of these, 9 showed FWE (5 grade 1 and 4 grade 2), and 3 showed UWE (2 grade 1 and 1 grade 2). In fusiform aneurysms, 11/11 (100%) enhanced. Of these, 1 showed FWE and 10 showed UWE. All fusiform aneurysms had grade-2 enhancement. Fusiform aneurysms had more extensive and higher SI AWE than saccular aneurysms (p < 0.01) despite having a similar size (6.9 ± 3.0 mm vs. 8.0 ± 2.9, p = 0.23). For saccular aneurysm, larger aneurysm size was correlated with higher degree of enhancement with Pearson's r = 0.64 (p = 0.002). CONCLUSION: Intracranial fusiform aneurysms had enhancement of higher SI and that covered a more extensive area than saccular aneurysms, which might indicate differences in vessel wall pathology. KEY POINTS: • Intracranial aneurysm wall enhancement can be reliably characterized by 7-T black-blood MRI. • AWE in intracranial fusiform aneurysms presents over a larger surface area and with greater signal intensity as compared with that in saccular aneurysms, which might indicate differences in pathology. • Stronger signal intensity of AWE correlates with the aneurysm size in saccular aneurysms.

Prediction of Aneurysm Stability Using a Machine Learning Model Based on PyRadiomics-Derived Morphological Features.

Background and Purpose- Discrimination of the stability of intracranial aneurysms is critical for determining the treatment strategy, especially in small aneurysms. This study aims to evaluate the feasibility of applying machine learning for predicting aneurysm stability with radiomics-derived morphological features. Methods- Morphological features of 719 aneurysms were extracted from PyRadiomics, of which 420 aneurysms with Maximum3DDiameter ranging from 4 mm to 8 mm were enrolled for analysis. The stability of these aneurysms and other clinical characteristics were reviewed from the medical records. Based on the morphologies with/without clinical features, machine learning models were constructed and compared to define the morphological determinants and screen the optimal model for predicting aneurysm stability. The effect of clinical characteristics on the morphology of unstable aneurysms was analyzed. Results- Twelve morphological features were automatically extracted from PyRadiomics implemented in Python for each aneurysm. Lasso regression defined Flatness as the most important morphological feature to predict aneurysm stability, followed by SphericalDisproportion, Maximum2DDiameterSlice, and SurfaceArea. SurfaceArea (odds ratio [OR], 0.697; 95% CI, 0.476-0.998), SphericalDisproportion (OR, 1.730; 95% CI, 1.143-2.658), Flatness (OR, 0.584; 95% CI, 0.374-0.894), Hyperlipemia (OR, 2.410; 95% CI, 1.029-5.721), Multiplicity (OR, 0.182; 95% CI, 0.082-0.380), Location at middle cerebral artery (OR, 0.359; 95% CI, 0.134-0.902), and internal carotid artery (OR, 0.087; 95% CI, 0.030-0.211) were enrolled into the final prediction model. In terms of performance, the area under curve of the model reached 0.853 (95% CI, 0.767-0.940). For unstable aneurysms, Compactness1 (P=0.035), Compactness2 (P=0.036), Sphericity (P=0.035), and Flatness (P=0.010) were low, whereas SphericalDisproportion (P=0.034) was higher in patients with hypertension. Conclusions- Morphological features extracted from PyRadiomics can be used for aneurysm stratification. Flatness is the most important morphological determinant to predict aneurysm stability. Our model can be used to predict aneurysm stability. Unstable aneurysm is more irregular in patients with hypertension.

Study on real-time force feedback for a master-slave interventional surgical robotic system.

In robot-assisted catheterization, haptic feedback is important, but is currently lacking. In addition, conventional interventional surgical robotic systems typically employ a master-slave architecture with an open-loop force feedback, which results in inaccurate control. We develop herein a novel real-time master-slave (RTMS) interventional surgical robotic system with a closed-loop force feedback that allows a surgeon to sense the true force during remote operation, provide adequate haptic feedback, and improve control accuracy in robot-assisted catheterization. As part of this system, we also design a unique master control handle that measures the true force felt by a surgeon, providing the basis for the closed-loop control of the entire system. We use theoretical and empirical methods to demonstrate that the proposed RTMS system provides a surgeon (using the master control handle) with a more accurate and realistic force sensation, which subsequently improves the precision of the master-slave manipulation. The experimental results show a substantial increase in the control accuracy of the force feedback and an increase in operational efficiency during surgery.

A cooperation of catheters and guidewires-based novel remote-controlled vascular interventional robot.

Remote-controlled vascular interventional robots (RVIRs) are being developed to increase the overall accuracy of surgical operations and reduce the occupational risks of intervening physicians, such as radiation exposure and chronic neck/back pain. Several RVIRs have been used to operate catheters or guidewires accurately. However, a lack of cooperation between the catheters and guidewires results in the surgeon being unable to complete complex surgery by propelling the catheter/guidewire to the target position. Furthermore, it is a significant challenge to operate the catheter/guidewire accurately and detect their proximal force without damaging their surfaces. In this study, we introduce a novel method that allows catheters and guidewires to be operated simultaneously in complex surgery. Our method accurately captures force measurements and enables precisely controlled catheter and guidewire operation. A prototype is validated through various experiments. The results demonstrate the feasibility of the proposed RVIR to operate a catheter and guidewire accurately, detect the resistance forces, and complete complex surgical operations in a cooperative manner.

Operating force information on-line acquisition of a novel slave manipulator for vascular interventional surgery.

Vascular interventional surgery has its advantages compared to traditional operation. Master-slave robotic technology can further improve the operation accuracy, efficiency and safety of this complicated and high risk surgery. However, on-line acquisition of operating force information of catheter and guidewire remains to be a significant obstacle on the path to enhancing robotic surgery safety. Thus, a novel slave manipulator is proposed in this paper to realize on-line sensing of guidewire torsional operating torque and axial operation force during robotic assisted operations. A strain sensor is specially designed to detect the small scale torsional operation torque with low rotational frequency. Additionally, the axial operating force is detected via a load cell, which is incorporated into a sliding mechanism to eliminate the influence of friction. For validation, calibration and performance evaluation experiments are conducted. The results indicate that the proposed operation torque and force detection device is effective. Thus, it can provide the foundation for enabling accurate haptic feedback to the surgeon to improve surgical safety.

Transverse microvibrations-based guide wires drag reduction evaluation for endovascular interventional application.

When conducting endovascular interventional surgery, doctors usually experience high viscous resistance resulting from direct contact with blood when operating the guide wire in blood vessels, which reduces the operational efficiency. Improper operation can cause vascular injuries and greatly reduce surgical safety, sometimes leading to the death of the patient. This paper presents a new method that applies transverse microvibrations at the proximal end of a conventional passive guide wire to reduce viscous resistance. The effect of the proposed method in reducing the viscous resistance in the fluid is studied. The influences of the tube diameter, medium density, and applied vibration frequency on the viscous force are investigated. Finally, for endovascular therapy, a mathematical model of the viscous force of the guide wire based on the proposed method is established in the environment of human blood vessels to predict the magnitude of the viscous force exerted on the guide wire and analyze the drag reduction effect of the proposed method. The effectiveness of the proposed method in drag reduction and its feasibility in improving surgical safety are experimentally demonstrated. The experimental results indicate that the proposed method can assist the doctor during complicated and variable operation conditions.

Operation evaluation in-human of a novel remote-controlled vascular interventional robot.

Remote-controlled vascular interventional robots (RVIRs) are being developed to increase the accuracy of surgical operations and reduce the number of occupational risks sustained by intervening physicians, such as radiation exposure and chronic neck/back pain. However, complex control of the RVIRs improves the doctor's operation difficulty and reduces the operation efficiency. Furthermore, incomplete sterilization of the RVIRs will increase the risk of infection, or even cause medical accidents. In this study, we introduced a novel method that provides higher operation efficiency than a previous prototype and allows for complete robot sterilization. A prototype was fabricated and validated through laboratory setting experiments and an in-human experiment. The results illustrated that the proposed RVIR has better performance compared with the previous prototype, and preliminarily demonstrated that the proposed RVIR has good safety and reliability and can be used in clinical surgeries.

Aberrant Expression of microRNA-9 Contributes to Development of Intracranial Aneurysm by Suppressing Proliferation and Reducing Contractility of Smooth Muscle Cells.

BACKGROUND MiR-9 is reportedly involved with many diseases, such as acute myeloid leukemia and liver oncogenesis. In the present study we investigated the molecular mechanism, including the potential regulator and signaling pathways, of MYOCD, which is the gene that in humans encodes the protein myocardin. MATERIAL AND METHODS We searched the online miRNA database (www.mirdb.org) with the "seed sequence" located within the 3'-UTR of the target gene, and then validated MYOCD to be the direct gene via luciferase reporter assay system, and further confirmed it in cultured cells by using Western blot analysis and realtime PCR. RESULTS We established the negative regulatory relationship between miR-9 and MYOCD via studying the relative luciferase activity. We also conducted realtime PCR and Western blot analysis to study the mRNA and protein expression level of MYOCD between different groups (intracranial aneurysm vs. normal control) or cells treated with scramble control, miR-9 mimics, MYOCD siRNA, and miR-9 inhibitors, indicating the negative regulatory relationship between miR-9 and MYOCD. We also investigated the relative viability of smooth muscle cells when transfected with scramble control, miR-9 mimics, MYOCD siRNA, and miR-9 inhibitors to validate that miR-9 t negatively interferes with the viability of smooth muscle cells. We then investigated the relative contractility of smooth muscle cells when transfected with scramble control, miR-9 mimics, MYOCD siRNA, and miR-9 inhibitors, and the results showed that miR-9 weakened contractility. CONCLUSIONS Our findings show that dysregulation of miR-9 is responsible for the development of IA via targeting MYOCD. miR-9 and its direct target, MYOCD, might novel therapeutic targets in the treatment of IA.

Endovascular Treatment of 147 Cases of Cavernous Carotid Aneurysms: A Single-Center Experience.

BACKGROUND: Cavernous carotid aneurysms (CCAs) are characterized by pain and neuro-ophthalmologic deficits. The optimal treatment remains unclear, especially for asymptomatic CCAs. This study investigated the efficacy of endovascular treatment for CCAs in our center. METHODS: Data obtained from patients who underwent endovascular treatment for CCAs from July 2011 to July 2014 were reviewed. A retrospective analysis was conducted regarding the general condition, clinical presentation, aneurysm characteristics, therapeutic strategy, and prognosis of CCA patients. RESULTS: One hundred forty-seven patients who exhibited 155 CCAs were included, which comprised 46 asymptomatic and 101 symptomatic CCA cases. Forty-eight cases presented with headache, 5 cases presented with subarachnoid hemorrhage, 20 cases presented with diplopia, 38 cases presented with cranial nerve palsy, and 27 cases presented with ischemic stroke. The mean aneurysm sizes were 15.3 ± 12.2 and 8.1 ± 7.1 mm in the symptomatic and asymptomatic groups, respectively. Different treatments were administered: coil occlusion (n = 15), stent/balloon-assisted coil occlusion (n = 123), and parent artery occlusion (PAO) (n = 17). The PAO-treated group exhibited the highest aneurysm occlusion rate. Follow-up data were available for 131 cases, which included 86 symptomatic and 45 asymptomatic cases. There were no deaths. Among the symptomatic patients, 40.7% improved, 58.1% remained stable, and 1.2% worsened; 12 patients exhibited regrowth and 6 patients had repeated endovascular treatment. The asymptomatic patients remained stable, including 5 patients who exhibited regrowth and 2 patients who had repeated endovascular treatment. CONCLUSION: Endovascular treatment is safe and effective for CCAs and should be considered in patients with minimal complications, as well as in asymptomatic patients with stable symptoms.

Inhibition of ocular neovascularization by co-inhibition of VEGF-A and PLGF.

BACKGROUND/AIMS: Age-related macular degeneration (AMD) appears to be a disease with increasing incidence in Western countries and may develop into acquired blindness. Choroidal neovascularization (CNV) is the most frequent cause for AMD, and is commonly induced by regional inflammation. Past studies have highlighted vascular endothelial growth factor A (VEGF-A) as a major trigger for CNV. However, studies on the associated angiogenic factors other than VEGF-A are lacking. METHODS: Here, we used a well-established laser burn (LB)-induced experimental CNV mouse model to study the molecular mechanisms underlying the development of CNV after ocular injury. We analyzed vessel density by lectin labeling. We isolated macrophages, endothelial cells and other cell types by flow cytometry, and analyzed levels of different angiogenic factors in these populations. We used antisera against VEGF-A (aVEGF) and/or antisera against placental growth factor (PLGF; aPLGF) to antagonize CNV. We used an antibody-driven toxin to selectively eliminate macrophages to evaluate the role of macrophages in CNV. We also examined expression of PLGF in macrophage subtypes. RESULTS: The choroidal vessel density increased significantly 7 days after LB. LB increased significantly the levels of VEGF-A and PLGF in mouse eyes. Treatment with aVEGF significantly blunted increases in vessel density by LB. Treatment with aPLGF alone did not significantly reduce increases in vessel density. However, aPLGF significantly increased the inhibitory effects of aVEGF on vessel density increases. While VEGF-A was produced by endothelial cells, macrophages and other types at similar levels, PLGF seemed to be predominantly produced by macrophages. Selective macrophage depletion significantly reduced CNV. M2, but M1 macrophages produced high levels of PLGF. CONCLUSIONS: Together, our data suggest a previously unappreciated role of PLGF in coordination with VEGF-A to regulate CNV during ocular injury. Our study highlights macrophages and their production of PLGF as novel targets for CNV therapy.

Androgen receptor signaling regulates growth of glioblastoma multiforme in men.

Although glioblastoma multiforme (GBM) is the most malignant primary human brain cancer with surprisingly high incidence rate in adult men than in women, the exact mechanism underlying this pronounced epidemiology is unclear. Here, we showed significant upregulated androgen receptor (AR) expression in the GBM tissue compared to the periphery normal brain tissue in patients. An expression of AR was further detected in all eight examined human GBM cell lines. To figure out whether AR signaling may play a role in GBM, we used high AR-expressing U87-MG GBM line for further study. We found that activation of transforming growth factor ß (TGFß) receptor signaling by TGFß1 in GBM significantly inhibited cell growth and increased apoptosis. Moreover, application of active AR ligand 5α-dihydrotestosterone (DHT) significantly decreased the effect of TGFß1 on GBM growth and apoptosis, suggesting that AR signaling pathway may contradict the effect of TGFß receptor signaling in GBM. However, neither total protein nor the phosphorylated protein of SMAD3, a major TGFß receptor signaling downstream effector in GBM, was affected by DHT, suggesting that AR activation may not affect the SMAD3 protein production or phosphorylation of TGFß receptor and SMAD3. Finally, immunoprecipitation followed by immunoblot confirmed binding of pAR to pSMAD3, which may prevent the DNA binding of pSMAD3 and subsequently prevent its effect on cell growth in GBM. Taken together, our study suggests that AR signaling may promote tumorigenesis of GBM in adult men by inhibiting TGFß receptor signaling.

The predictive value and potential mechanisms of miRNA-328 and miRNA-378 for brain metastases in operable and advanced non-small-cell lung cancer.

OBJECTIVE: The incidence of brain metastases greatly varies in patients with non-small-cell lung cancer, and molecular markers are considered to predict brain metastases. Therefore, this study sought to identify the predictive value and potential mechanisms of miRNA-328 and miRNA-378 for brain metastases in non-small-cell lung cancer. METHODS: Patients who received a curable surgery for their lung cancer were screened according to our criteria. Formalin-fixed paraffin-embedded samples from the patients were examined for the expression of miRNA-328 and miRNA-378 using real-time polymerase chain reaction and the expression of N-cadherin, E-cadherin, vascular endothelial growth factor, protein kinase Cα and S100B were investigated using immunohistochemical staining. RESULTS: In total, 86 patients were screened for this study and 23 patients were diagnosed with brain metastases during the follow-up period. Comparing patients with and without brain metastases, the expression of miRNA-328 and miRNA-378 in tumor tissues were significantly different (P = 6.2 × 10(-5) and P = 2.8 × 10(-5), respectively). For the patients with brain metastases, the expression of miRNA-328 and miRNA-378 in tumor tissues compared with para-carcinoma tissues were also significantly different (P = 2.2 × 10(-5) and P = 1.6 × 10(-5), respectively). For patients with brain metastases, the association between miRNA-328 and protein kinase Cα was significant (r = 0.591, P = 0.003), but that between miRNA-378 and protein kinase Cα was not significant (r = 0.259, P = 0.232). CONCLUSIONS: The expression of miRNA-328 and miRNA-378 in tumor tissues can be used to predict brain metastases in patients with non-small-cell lung cancer. miRNA-328 might promote brain metastases by regulating the expression of protein kinase Cα. However, the mechanisms of miRNA-378 to promote brain metastases should be studied in the future.

Reversal of Chemoresistance in Human Lung Cancer Cell Line A549/Taxol by Synthetic Second Mitochondria-Derived Activator of Caspase Peptide.

BACKGROUND: Chemoresistance is a leading cause of treatment failure in advanced lung cancer, including that with the extensively prescribed taxol. Recently, a series of structurally unique second mitochondria-derived activators of caspase (Smac) that act as antagonists of inhibitor of apoptosis proteins (IAPs) have been discovered, exhibiting the ability of inducing enhanced apoptosis of various cancer cell types when combined with chemotherapy. In the present study, we synthesized the second mitochondria-derived activator of caspase peptide (Smac-N7 for short) and explored its capacity in combination with taxol in vitro. METHODS: The sensitivity assay and reversal ability of Smac-N7 were tested by MTT. Flow cytometry was used to analyze apoptosis of cells with Annexin V/PI double staining technique. Cell cloning ability was performed to reflect its biological behavior in each group. RESULTS: Concentrations with inhibitory rates < 10% were selected as the reversal value of Smac-N7 peptide using MTT. The reversal folds were 2.52, 3.26, 3.67, and 5.4 in taxol + Smac-N7 (0.0390625, 0.078125, 0.15625, 0.3125 µg/mL, respectively), and concentrations of Smac-N7 and reversal folds appeared in an obvious positive correlation (r(s) = 1, p = 0.000). Apoptosis analyzed at 48 hours by flow cytometry showed the apoptotic rates in taxol and 0.0390625, 0.078125, 0.15625, and 0.3125 µg/mL Smac-N7 + taxol groups were 15.4 ± 1.09%, 20.8% ± 2.18%, 28.4% ± 4.17%, 37.64% ± 6.41%, and 46.6% ± 7.76%, respectively. Concentrations of Smac-N7 appeared to have negative correlations with PE and SF (r(s) = -1, p < 0.05), which showed that the cells' cloning ability in 0.3125 µg/mL Smac-N7 + taxol group was worse than that of other groups. CONCLUSIONS: When combined with taxol, 0.3125 µg/mL Smac-N7 peptide may significantly increase taxol-induced apoptosis in chemoresistant A549/taxol lung cells at 48 hours, and is potentially useful as a reversal agent in lung cancer therapy.