[A Dual-Aware deep learning framework for identification of glioma isocitrate dehydrogenase genotype using magnetic resonance amide proton transfer modalities].

OBJECTIVE: To propose a Dual-Aware deep learning framework for genotyping of isocitrate dehydrogenase (IDH) in gliomas based on magnetic resonance amide proton transfer (APT) modality data as a means to assist non-invasive diagnosis of gliomas. METHODS: We collected multimodal magnetic resonance imaging (MRI) imaging data of the brain from 118 cases of gliomas, including 68 wild-type and 50 mutant type cases. The delineation of the ROI of brain glioma was completed in all the cases. APT modality imaging does not require contrast agents, and its signal intensity on tumors is positively correlated with tumor malignancy, and the signal intensity on wild-type IDH is higher than that on mutant IDH. For APT modalities, tumor imaging and derived areas are morphologically variable and lack prominent edge contour characteristics compared with other modalities. Based on these characteristics, we propose the Dual-Aware framework, which introduces the Multi-Aware framework to mine multi-scale features, and the Edge Aware module mines the edge features for automatic genotype identification. RESULTS: The introduction of two types of Aware mechanisms effectively improved the identification rate of the model for glioma IDH genotyping. The accuracy and AUC for each modality data were enhanced, and the best performance was achieved on the APT modality with a prediction accuracy of 83.1% and an AUC of 0.822, suggesting its advantages and effectiveness for identifying glioma IDH genotypes. CONCLUSION: The proposed deep learning algorithm model constructed based on the image characteristics of the APT modality is effective for glioma IDH genotyping and identification task and may potentially replace the commonly used T1CE modality to avoid contrast agent injection and achieve non- invasive IDH genotyping.

[Whole-brain parcellation for macaque brain magnetic resonance images based on attention mechanism and multi-modality feature fusion].

OBJECTIVE: We propose a novel deep learning algorithm based on attention mechanism and multimodality feature fusion (DDAM) to achieve whole-brain parcellation of macaque brain magnetic resonance (MR) images. METHODS: We collected multimodality brain MR images of 68 macaques (aged 13 to 36 months) with corresponding ground truth labels. To address the complexity and complementary nature of the multimodality data, we employed a multi- encoder structure to adapt to different modalities and performed feature extraction. In the decoder, an attention mechanism was introduced to construct the Attention-based Multimodality Feature Fusion module (AMFF). Leveraging the rich and complementary information between modalities, AMFF effectively integrated multimodality features of varying scales and complexities to enhance the performance of parcellation. We conducted ablation experiments and statistically analyzed the results. RESULTS: The incorporation of the multi- encoder structure and attention mechanism significantly improved the performance of the network for integrating the multimodality features, and achieved an average DSC of 0.904 and an ASD as low as 0.131 for macaque whole-brain parcellation (P < 0.05). The ablation experiments validated the effectiveness of each component of the DDAM method. CONCLUSION: The proposed DDAM method, with its enhanced ability to extract and integrate multimodality features, can significantly improve the accuracy of whole-brain MR image segmentation.

[The relation between residual ß-cell function and autoimmune status in long-term type 1 diabetes patients].

Objective: We aimed to investigate the autoimmune status of long-term type 1 diabetes mellitus (T1DM) patients with residual ß-cell function. Methods: The residual ß-cell function of long-term (disease duration≥10 years) autoimmune T1DM patients from the T1DM Integrated Management Clinic of the Second Xiangya Hospital was assessed by serum C-peptide levels. Patients with fasting or 2-hour postprandial C-peptide levels over the lower sensitivity limit of detection (16.7 pmol/L) were grouped as C-peptide-positive, and others were grouped as C-peptide-negative. We screened and enrolled all the C-peptide-positive patients (n=19). C-peptide-negative patients with matched sex, age, duration, BMI (n=19) and healthy controls (n=19) were recruited at the same time. The frequencies of CD4+T cell (Th1/Th2/Th17/Treg) and B cell (MZB/FoB/B10) subsets, the expression of PD-1/PD-L1 on T and B lymphocytes, and the levels of T1DM related cytokines including IFN-γ, TNF-α, IL-1ß, IL-1RA, IL-4, IL-6, IL-10, IL-12p40, IL-12p70, IL-23 and IP-10 were tested. We compared these parameters in patients with different levels of ß-cell function. Results: In healthy controls, C-peptide-negative and C-peptide-positive patients, the frequencies M (Q1, Q3) of Th1 cells were 9.93% (7.45%, 15.20%), 14.90% (11.70%, 18.00%) and 10.20% (6.93%, 15.80%) (P=0.015), and the frequencies M (Q1, Q3) of Treg cells were 3.52% (2.92%, 5.68%),2.88% (1.64%, 3.22%) and 3.12% (2.81%, 4.81%) (P=0.005), and the frequencies M(Q1,Q3) of PD-1+B cells were 4.69% (2.64%, 6.37%), 2.11% (1.45%, 3.63%) and 4.20% (2.53%, 6.01%) (P=0.003), respectively. The levels of IL-6 M(Q1,Q3)were 26.43(18.06, 33.35) ng/L, 42.97 (25.52, 66.30) ng/L, and 22.07 (14.85, 34.45) ng/L (P=0.006), and the levels of IP-10 M(Q1,Q3) were 107.39 (76.19, 126.07) ng/L, 188.82 (131.27, 348.18) ng/L and 128.26 (114.31, 136.50) ng/L (P<0.001) in healthy controls, C-peptide-negative and C-peptide-positive patients, respectively. Compared with C-peptide-positive patients, the frequency of Th1 cells and the levels of IL-6 and IP-10 cytokines were higher, while the frequencies of Treg cells and PD-1+B cells were lower in C-peptide-negative patients (all P<0.05). Conclusions: Long-term T1DM patients with residual ß-cell function had lower frequency of Th1 cells, lower levels of IL-6, IP-10 cytokines, and higher frequencies of Treg and PD-1+B cells, which indicated a pronounced autoimmune tolerance.

Fetoscopy-guided bipolar cord coagulation in selective fetal reduction with complicated monochorionic diamniotic twins: a prospective cohort study.

OBJECTIVE: To assess the feasibility of fetoscopy-guided bipolar umbilical cord coagulation for selective fetal reduction in complicated monochorionic diamniotic (MCDA) twin pregnancies. METHODS: MCDA twins undergoing fetoscopy-guided bipolar cord coagulation (BCC) were enrolled prospectively between December 2015 to March 2020 in a fetal medicine center. RESULTS: Twenty-three cases undergoing fetoscopy-guided BCC were finally analyzed, including 11 cases for type 2 selective intrauterine growth restriction, 4 cases for twin-twin transfusion syndrome, and 8 cases for a severe discordant anomaly. The overall survival rate was 78.3% (18/23). CONCLUSIONS: Fetoscopy-guided BCC is effective for selective fetal reduction in complicated monochorionic twin pregnancies.

[Efficacy of a recombinant bovine basic fibroblast growth factor gel for the treatment of moderate dry eye: a multicenter randomized double-blind parallel controlled clinical trial].

Objective: To compare the clinical efficacy of a recombinant bovine basic fibroblast growth factor (rb-bFGF) gel and a gel matrix in the treatment of moderate dry eye. Methods: It was a prospective random double-blind controlled study. One hundred patients diagnosed as moderate dry eye in Eye Institute and Affiliated Xiamen Eye Center of Xiamen University, Union Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology, Beijing Tongren Hospital, Capital Medical University, Eye & ENT Hospital of Fudan University and Zhongshan Ophthalmic Center from August 2015 to April 2019 were divided into two groups: experimental group and control group. Two groups of patients were allocated to receive either a rb-bFGF gel or a gel matrix 4 times per day for 4 weeks. Subjective symptoms, break-up time of the tear film (BUT), Schirmer Ⅰ test (SⅠt) and corneal fluorescein sodium staining were assessed at baseline, 2 and 4 weeks after treatment. Bulbar impression cytology was evaluated at baseline and 4 weeks after treatment. Irritation of the rb-bFGF gel and the gel matrix was estimated after treatment. T test, Wilcoxon signed-rank test or Mann-Whitney U test was used for quantitative data, and Chi-square test was used for enumerative data. Results: Eighty-four subjects were included for statistical analyses after the exclusion of 16 subjects who were lost for followup, with an age of 43±14 years. There were 42 cases in the experimental group and the control group, respectively. There was no statistically significant difference between the two groups in demographic baseline characteristics before treatment (P>0.05). The total score of subjective symptoms was 7.17±3.60 and 5.95±3.25 at 2 and 4 weeks after therapy in the experimental group, which were lower than 9.48±3.88 before treatment (t=6.226, 6.563; both P<0.05); in the control group, it was 7.01±3.25 and 6.32±3.85 at 2 and 4 weeks after treatment, with a significant reduction in comparison with that before treatment (9.15±3.58; t=4.693, 4.726; both P<0.05). The median (lower quartile, upper quartile) BUT was 4.00 (2.40, 5.00) s and 4.64 (3.00, 5.00) s at 2 and 4 weeks after therapy in the experimental group, which were longer than 3.72 (2.00, 4.39) s before treatment (Z=-2.485, -3.152; both P<0.05). The BUT was 4.41 (2.79, 5.12) s at 2 weeks after therapy in the control group, which was of no statistical difference compared with 3.89 (2.09, 4.25) s before treatment (Z=-1.953, P>0.05). The BUT was 5.21 (3.00, 5.02) s at 4 weeks after therapy in the control group, which was longer than that before treatment (Z=-2.485, P<0.05). The SⅠt score was 7.31 (3.75, 10.00) mm and 8.50 (4.00, 11.00) mm at 2 and 4 weeks after therapy in the experimental group, which were significantly higher than 6.69 (2.00, 8.13) mm before treatment (Z=-2.031, -2.236; both P<0.05); in the control group, it was 6.82 (2.00, 8.25) mm and 6.86 (3.00, 9.25) mm at 2 and 4 weeks after therapy, which were not significantly increased compared with 6.50 (2.00, 7.75) mm before treatment (Z=-0.179, -1.161; both P>0.05). The corneal fluorescein sodium staining points were 5.00 (2.00, 5.00) and 3.71 (0.00, 5.00) at 2 and 4 weeks after therapy in the experimental group, which were significantly lower than 7.10 (5.00, 7.00) before treatment (t=-2.895, -4.639; both P<0.05); those in the control group were 5.52 (0.00, 7.00) and 6.19 (0.75, 6.25) at 2 and 4 weeks after treatment, with a significant reduction in comparison with 8.90 (5.00, 10.50) before treatment (t=-2.776, -1.991; both P<0.05). The differences in the average total score of subjective symptoms, BUT, SIt, and corneal fluorescein sodium staining points between both groups were not statistically significant at each time point. The impression cytology grade was decreased from 1.72 (1.00, 2.00) before treatment to 0.94 (0.00, 2.00) at 4 weeks after therapy in the experimental group (Z=-2.803, P<0.05). The staining grade of conjunctival imprinted cells in the control group was 1.42 (1.00, 2.00) at 4 weeks, which showed no statistical significance compared with 1.56 (1.00, 2.00) before treatment (Z=1.195, P>0.05). The impression cytology grade was significantly reduced in the experimental group compared with the control group at 4 weeks after treatment (Z=-3.308, P<0.05). The number of goblet cells was 10.90 (5.00, 20.00) at 4 weeks after therapy in the experimental group, which was significantly higher than 6.30 (5.00, 8.00) before treatment (Z=-2.383, P<0.05); in the control group, it was 8.36 (4.00, 12.00) at 4 weeks after treatment, with no significant increase in comparison with that before treatment [7.55 (5.00, 11.00)] (Z=-0.095, P>0.05). The number of goblet cells was not significantly increased in the experimental group compared with the control group at 4 weeks after treatment (Z=-1.162, P>0.05). Most patients indicated that the drug was non-irritating, and no patient had intolerable irritation affecting daily lives at 4 weeks after therapy; there was no difference between the two groups (Z=-0.290, P>0.05). Conclusions: Both the rb-bFGF gel and the gel matrix can effectively improve the symptoms and signs of moderate dry eye. However, compared with the gel matrix, the rb-bFGF gel shows obvious advantages in promoting conjunctival epithelial cell repair and increasing the number of goblet cells. (Chin J Ophthalmol, 2021, 57: 930-938).

[Analysis of the effect of microwave ablation in the treatment of small liver cancer].

Objective: To explore the clinical effect of microwave ablation in the treatment of early small liver cancer (≤3 cm). Methods: 103 cases with small liver cancer (tumor number < 3 and maximum tumor diameter < 3 cm) who underwent microwave ablation from November 2016 to November 2018 were retrospectively collected. The rate of residual lesions, recurrence rate one-year after the operation, and surgical complications were observed and grouped according to tumor size (< 2 cm and≥2 cm group) and tumor numbers (solitary and 2 ~ 3 lesion groups). The therapeutic effects of each group were compared and analyzed. Results: The tumor residual rate and one-year recurrence rate of small liver cancer after microwave ablation were 11.7% and 35.0%, respectively. The post-ablation syndrome incidence rate was 52.4%, with no serious adverse events. Compared with tumors < 2 cm, patients with≥2 cm had a higher postoperative residual rate (χ(2) = 7.651, P = 0.006), and the one-year recurrence rate of more solitary nodular tumors was lower (χ(2) = 10.125, P = 0.001). Conclusion: Microwave ablation is a safe and effective treatment for early small liver cancer, and it is more effective for small solitary nodules (< 2 cm).

[A tissue recovery-based brain tumor image registration method].

We propose an algorithm for registration between brain tumor images and normal brain images based on tissue recovery. U-Net is first used in BraTS2018 dataset to segment the brain tumors, and PConv-Net is then used to simulate the generation of missing normal tissues in the tumor region to replace the tumor region. Finally, the normal brain image is registered to the tissue recovery brain image. We evaluated the effectiveness of this method by comparing the registration results of the repaired image and the tumor image corresponding to the surrounding tissues of the tumor area. The experimental results showed that the proposed method could reduce the effect of pathological variation, achieve a high registration accuracy, and effectively simulate and generate normal tissues to replace the tumor regions, thus improving the registration effect between brain tumor images and normal brain images.

Prognostic potentials of miRNA-19a-3p and PDCD5 in nasopharynx carcinoma.

OBJECTIVE: To determine expressions of MicroRNA-19a-3p (miRNA-19a-3p) and PDCD5 in nasopharyngeal carcinoma (NPC) tissues, and their prognostic potentials in NPC. PATIENTS AND METHODS: Expressions of miRNA-19a-3p and PDCD5 in NPC tissues and controls were determined by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). The correlation between expressions of miRNA-19a-3p and PDCD5 in NPC was evaluated by Pearson correlation test. Furthermore, potential influences of miRNA-19a-3p and PDCD5 on clinical features of NPC patients were assessed. Through 5-year follow-up, survival analysis in NPC patients was conducted by Kaplan-Meier method. Finally, factors influencing prognosis of NPC were determined using the Cox regression model. RESULTS: MiRNA-19a-3p was upregulated and PDCD5 was downregulated in NPC tissues. Pearson correlation test uncovered a negative correlation between expression levels of miRNA-19a-3p and PDCD5 in NPC tissues. MiRNA-19a-3p level was correlated with N classification and clinical stage in NPC patients, while PDCD5 level was correlated with T classification, pathological grade and clinical stage. Survival analysis showed poor prognosis in NPC patients expressing high level of miRNA-19a-3p or low level of PDCD5. Cox regression analysis illustrated that N2+3 classification, clinical stage III+IV, high level of miRNA-19a-3p and low level of PDCD5 were independent risk factors for the prognosis of NPC. CONCLUSIONS: MiRNA-19a-3p is upregulated and PDCD5 is downregulated in NPC tissues. High level of miRNA-19a-3p and low level of PDCD5 are unfavorable for the prognosis of NPC.

[Quantitative study on the development of fetal ventricles and cisterna magna in second and third trimesters with MRI].

Objective: To analyze the changes of growth and development of normal fetal ventricles and cisterna magna with gestational age(GA) and the correlation with fetal gender in the second and third trimester,and establish the MR prenatal diagnosis reference standards. Methods: A total of 633 fetuses (mean GA (27.0±4.1) weeks (18.9-40.6 weeks))without central nervous system abnormalities were retrospectively collected from the Obstetrics and Gynecology Hospital of Fudan University from June 2012 to August 2017. The lateral ventricle trigonometric width (LVTW), third ventricle width (TVW), fourth ventricle width (FVW), anterior-posterior diameter of the fourth ventricle(APDFV), cavum septum pellucidum width (CSPW) and cisterna magna width (CMW) were obtained in the standard measure planes on MR image.The correlation between the biometrics and GA and the correlation between the biometrics and fetal gender were analyzed respectively, and the normal reference values of the biometrics were calculated. Spearman correlation analysis, Pearson correlation analysis,linear regression analysis, independent samples t-test and paired samples t-test were used for statistic analysis. Results: (1)Fetal LLVTW,RLVTW,TVW,CSPW and CMW in second and third trimesters were correlated with GA at medium and low levels(the correlation coefficient r were 0.311, 0.277, 0.207, 0.226, 0.295, respectively, all P<0.01). FVW and APDFV were statistically correlated with GA, and the linear regression equations were as follows: y=0.022×GA-0.043 (adjusted R(2)=0.642); y=0.018×GA-0.159 (adjusted R(2)=0.690). (2)Fetal LLVTW,RLVTW,FVW,APDFV and CSPW were not correlated with fetal gender in second and third trimesters(r=-0.078,-0.057,-0.087,-0.004 and 0.024, P=0.124,0.258,0.085,0.931 and 0.618, all P>0.05). TVW and CMW were statistically correlated with fetal gender(r=-0.310, -0.180, P=0.000, 0.006, all P<0.05). (3) The mean values of LLVTW and RLVTW were (0.71±0.13) cm and (0.68±0.13) cm, respectively, and significant difference was found between them(t=3.180, P=0.002). The mean value of CSPW was (0.59±0.15) cm. And the mean values of male and female fetuses for TVW and CMW were (0.17±0.05) cm, (0.16±0.06) cm and (0.68±0.15) cm, (0.58±0.15) cm, respectively. The corresponding prenatal MRI diagnostic criteria were as follows: LLVTW 1.1 cm, RLVTW 1.0 cm, CSPW 1.0 cm, TVW 0.3 cm, CMW (male 1.1 cm, female 1.0 cm). Conclusions: The normal fetal ventricles and cisterna magna are increased with the GA in the second and third trimesters. TVW and CMW are related to fetal gender. The establishment of normal reference values of fetal ventricles and cisterna magna based on GA and fetal gender are conducive to enhance the accuracy of MRI prenatal diagnosis.

Grading meningiomas using mono-exponential, bi-exponential and stretched exponential model-based diffusion-weighted MR imaging.

AIM: To prospectively evaluate and compare the potential of various diffusion metrics obtained from mono-exponential model (MEM), bi-exponential model (BEM), and stretched exponential model (SEM)-based diffusion-weighted imaging (DWI) in the grading of meningiomas. MATERIAL AND METHODS: Consecutive 93 patients with histopathologically confirmed meningiomas received DWI of multiple b-values. Apparent diffusion coefficient (ADC), pure molecular diffusion (D), pseudo-diffusion coefficient (D*), perfusion fraction (f), water molecular diffusion heterogeneity index (alpha), and distributed diffusion coefficient (DDC) were calculated and compared between low-grade and high-grade meningiomas. Receiver operating characteristic and multivariable stepwise logistic regression analyses were performed to evaluate the diagnostic performance of different parameters. RESULTS: The mean and normalised ADC, D, f, and DDC values were significantly lower in high-grade meningiomas than those in low-grade meningiomas (all p<0.05). The AUCs of D and DDC were significantly higher than that of f in the differentiation (all p<0.05). D was the only variable that could be used to independently differentiate high-grade and low-grade meningiomas (p<0.001). CONCLUSION: Different models of DWI, including MEM, BEM, and SEM, are useful in the differentiating high-grade and low-grade meningiomas; however, D obtained from BEM is the most promising diffusion parameter for predicting the grade of meningiomas.

Capture Deformation Twinning in Mg during Shock Compression with Ultrafast Synchrotron X-Ray Diffraction.

Deformation twinning plays a vital role in accommodating plastic deformation of hexagonal-close-packed (hcp) metals, but its mechanisms are still unsettled under high strain rate shock compression. Here we investigate deformation twinning in shock-compressed Mg as a typical hcp metal with in situ, ultrafast synchrotron x-ray diffraction. Extension twinning occurs upon shock compression along ⟨112[over ¯]0⟩ and ⟨101[over ¯]0⟩, but only upon release for loading along ⟨0001⟩. Such deformation mechanisms are a result of the polarity of deformation twinning, which depends on directionality and relative magnitude of resolved shear stress and may be common for Mg and its alloys in a wide range of strain rates.

Ventilation strategy and anesthesia management in patients with severe tracheal stenosis undergoing urgent tracheal stenting.

BACKGROUND: Stenting of airway stenosis is a common procedure in specialized centers. The aim of this study was to summarize our clinical experience in ventilation strategy and anesthesia management of patients undergoing urgent tracheal stenting. METHODS: Clinical data of 22 patients with severe tracheal stenosis who underwent urgent endoscopic placement of a tracheal stent during a 2-year period were retrospectively reviewed. The efficacy and safety of different ventilation strategies and veno-arterial extracorporeal membrane oxygenation (ECMO), individualized based on the cause and location of tracheal narrowing, were evaluated. RESULTS: Sufficient ventilation was successfully established in all patients; ECMO was used in five patients with stenosis in the mid-trachea who were unable to tolerate conventional intubation; a laryngeal mask airway (LMA) was used in five patients with post-intubation tracheal stenosis; a cuffed tracheal tube was used in eight patients with lower tracheal stenosis; and low-frequency jet ventilation in rigid bronchoscopy was used in four patients with mid- or lower tracheal stenosis. Tracheal stents were successfully placed and there were significant improvements in dyspnea. There were significant increases in the partial pressure of carbon dioxide in patients ventilated with the LMA and cuffed tracheal tube. There was no hypoxia during the operative period. CONCLUSION: Establishment of effective airway ventilation in patients with severe tracheal stenosis should be based on the cause, location, and severity of tracheal narrowing. Veno- arterial ECMO may be considered in patients with severe stenosis, if they are judged unable to tolerate conventional ventilation or jet ventilation.

New insights into mitogenomic phylogeny and copy number in eight indigenous sheep populations based on the ATP synthase and cytochrome c oxidase genes.

The origins and phylogeny of different sheep breeds has been widely studied using polymorphisms within the mitochondrial hypervariable region. However, little is known about the mitochondrial DNA (mtDNA) content and phylogeny based on mtDNA protein-coding genes. In this study, we assessed the phylogeny and copy number of the mtDNA in eight indigenous (population size, n=184) and three introduced (n=66) sheep breeds in China based on five mitochondrial coding genes (COX1, COX2, ATP8, ATP6 and COX3). The mean haplotype and nucleotide diversities were 0.944 and 0.00322, respectively. We identified a correlation between the lineages distribution and the genetic distance, whereby Valley-type Tibetan sheep had a closer genetic relationship with introduced breeds (Dorper, Poll Dorset and Suffolk) than with other indigenous breeds. Similarly, the Median-joining profile of haplotypes revealed the distribution of clusters according to genetic differences. Moreover, copy number analysis based on the five mitochondrial coding genes was affected by the genetic distance combining with genetic phylogeny; we also identified obvious non-synonymous mutations in ATP6 between the different levels of copy number expressions. These results imply that differences in mitogenomic compositions resulting from geographical separation lead to differences in mitochondrial function.

miR-141 Inhibits Proliferation and Migration of Colorectal Cancer SW480 Cells.

BACKGROUND: This study was designed to determine the molecular function of miR-141 and the underlying mechanisms in colorectal cancer (CRC). MATERIALS AND METHODS: SW480 cells in which miR-141 was up- or down-regulated were established. Reverse transcription, quantitative polymerase chain reaction and Western blotting were used to examine the microRNA and protein expression. Cell-cycle progression was analyzed by flow cytometry. Proliferation marker Ki-67 was evaluated by immunofluorescence. Transwell assay was conducted to determine the migration rates of cells. Subcutaneous xenograft models were used to examine the effect of miR-141 on tumorigenicity. Human mitogen-activated protein kinase (MAPK) and receptor tyrosine kinase (RTK) pathway phosphorylation array assays were used to interrogate MAPK and RTK pathway activation. RESULTS: miR-141 directly targeted zinc finger E-box-binding homeobox 1/2 (ZEB1/2). We first determined the expression levels of ZEB1 and ZEB2 in miR-141-expressing cells and miR-141-knockdown cells and found that inhibition of miR-141 significantly increased the expression of ZEB2. In vitro study revealed that miR-141 overexpression inhibited the expression of Ki-67. Furthermore, overexpression of miR-141 led to a significant reduction in the proliferation of SW480 cells via induction of cell-cycle arrest at the G1 stage. In contrast, inhibition of miR-141 markedly promoted the proliferation of SW480 cells by promoting cell-cycle progression. Moreover, overexpression of miR-141 significantly inhibited SW480 cell migration in vitro. In addition, overexpression of miR-141 significantly reduced tumor size and weight, and inhibited the growth of SW480 cell-derived tumor in nude mice. Notably, overexpression of miR-141 also suppressed the liver metastasis of SW480 cells in nude mice. Using RTK and MAPK arrays, we found increased phosphorylation of hepatocyte growth factor receptor (HGFR/c-MET) following inhibition of miR-141, but phosphorylation of P53, AKT, ERK1/2, P38 and mTOR, etc., in SW480 cells was not affected by miR-141. CONCLUSION: Our results suggest that miR-141 functions as a tumor suppressor through ZEB2 and HGFR in CRC cells.

Metformin alters DNA methylation genome-wide via the H19/SAHH axis.

The molecular mechanisms underlying the antineoplastic properties of metformin, a first-line drug for type 2 diabetes, remain elusive. Here we report that metformin induces genome-wide alterations in DNA methylation by modulating the activity of S-adenosylhomocysteine hydrolase (SAHH). Exposing cancer cells to metformin leads to hypermethylation of tumor-promoting pathway genes and concomitant inhibition of cell proliferation. Metformin acts by upregulating microRNA let-7 through AMPK activation, leading to degradation of H19 long noncoding RNA, which normally binds to and inactivates SAHH. H19 knockdown activates SAHH, enabling DNA methyltransferase 3B to methylate a subset of genes. This metformin-induced H19 repression and alteration of gene methylation are recapitulated in endometrial cancer tissue samples obtained from patients treated with antidiabetic doses of metformin. Our findings unveil a novel mechanism of action for the drug metformin with implications for the molecular basis of epigenetic dysregulation in cancer. This novel mechanism of action also may be occurring in normal cells.

Methylation differences and expression profiles of the caprine DIO3 gene.

DIO3 gene encoding type 3 iodothyronine deiodinase is an imprinted gene, located in the DLK1-DIO3 (delta-like 1 homolog-type 3 iodothyronine deiodinase) imprinted domain, and is potentially involved in degrading excessive amounts of thyroid hormone to protect embryogenesis. However, the underlying regulatory mechanism of the imprinted DIO3 gene expression during fetal and neonatal development in goats has not been elucidated. In this study, we explored the DNA methylation patterns of the caprine DIO3 intragenic CpG island and quantified gene expression level in six tissues from Chinese Nanjiang Yellow 3-day old kids. The expression of the DIO3 gene was determined using quantitative reverse transcription-polymerase chain reactions (qRT-PCRs), while the identification of methylation patterns was determined using bisulfite-sequencing PCRs. Modest, and non-significant (P > 0.05), methylation patterns were noted for the DIO3 CpG island methylation in the brain, heart, liver, kidney, lung, and longissimus dorsi tissues (ranging from 26.48 to 34.92%). The expression level of the DIO3 mRNA was significantly higher (P < 0.05) in the liver tissue than in the other five tissues. Pearson's correlation analysis revealed that there was no significant relationship between methylation and gene expression (P > 0.05), which indicated that the expression of the caprine DIO3 gene was likely modified by other regulatory elements. This study identified DNA methylation and expression patterns of the DIO3 gene in goats and provided insights into further regulatory mechanisms of expression and imprinting in the DLK1-DIO3 domain.

Association between downexpression of MiR-203 and poor prognosis in non-small cell lung cancer patients

Background and aim: Although miR-203 has been proposed as a relevant biomarker for several cancers, the validated prognostic significance of miR-203 in lung cancer remains obscure. Thus, we aimed to identify the relationship between miR-203 expression and clinicopathological significance in non-small cell lung cancer (NSCLC) patients in the current study. Methods: The expression of miR-203 in 125 cases of NSCLC and their paired adjacent non-cancerous tissues was evaluated by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Simultaneously, the correlation of miR-203 expression with a variety of clinicopathological factors and patient survival was analyzed. Functionally, in vitro effects of miR-203 on proliferation and viability were explored in lung cancer H460, A549, H1299, PC9 and H292 cells, as assessed by MTS tetrazolium assay and fluorimetric resorufin viability assay, respectively. Results: The relative level of miR-203 was 6.12 ± 6.25 in NSCLC tissues, remarkably downregulated than that of their paired non-tumorous lung tissues (7.88 ± 5.56, P = 0.019). The area under curve (AUC) of low expression of miR-203 to diagnose NSCLC was 0.622 (95 % CI 0.552–0.692, P = 0.001). MiR-203 expression was negatively correlated to lymphatic metastasis (r = -0.334, P < 0.001), tumor size (r = -0.407, P < 0.001) and clinical TNM stages (r = -0.298, P = 0.001). Furthermore, the survival of the low miR-203 expression group was 4.88 ± 4.38 months, markedly shorter than that of the high expression group (23.35 ± 1.12 months, P < 0.001). The level of miR-203 was an independent prognostic indicator of NSCLC using univariate analysis. MiR-203 mimic could suppress the cell growth of five lung cancer cell lines tested to different degrees in vitro. Conclusions: MiR-203 could become a prognostic predictor in NSCLC and may be a new target for the molecular therapy of NSCLC patients (AU)

No disponible

Swimming exercise ameliorates neurocognitive impairment induced by neonatal exposure to isoflurane and enhances hippocampal histone acetylation in mice.

Isoflurane-induced neurocognitive impairment in the developing rodent brain is well documented, and regular physical exercise has been demonstrated to be a viable intervention for some types of neurocognitive impairment. This study was designed to investigate the potential protective effect of swimming exercise on both neurocognitive impairment caused by repeated neonatal exposure to isoflurane and the underlying molecular mechanism. Mice received 0.75% isoflurane exposures for 4h on postnatal days 7, 8, and 9. From the third month after anesthesia, the mice were subjected to regular swimming exercise for 4weeks, followed by a contextual fear condition (CFC) trial. We found that repeated neonatal exposure to isoflurane reduced freezing behavior during CFC testing and deregulated hippocampal histone H4K12 acetylation. Conversely, mice subjected to regular swimming exercise showed enhanced hippocampal H3K9, H4K5, and H4K12 acetylation levels, increased numbers of c-Fos-positive cells 1h after CFC training, and less isoflurane-induced memory impairment. We also observed increases in histone acetylation and of cAMP-response element-binding protein (CREB)-binding protein (CBP) during the swimming exercise program. The results suggest that neonatal isoflurane exposure-induced memory impairment was associated with dysregulation of H4K12 acetylation, which may lead to less hippocampal activation following learning tasks. Swimming exercise was associated with enhanced hippocampal histone acetylation and CBP expression. Exercise most likely ameliorated isoflurane-induced memory impairment by enhancing hippocampal histone acetylation and activating more neuron cells during memory formation.

Association between downexpression of MiR-203 and poor prognosis in non-small cell lung cancer patients.

BACKGROUND AND AIM: Although miR-203 has been proposed as a relevant biomarker for several cancers, the validated prognostic significance of miR-203 in lung cancer remains obscure. Thus, we aimed to identify the relationship between miR-203 expression and clinicopathological significance in non-small cell lung cancer (NSCLC) patients in the current study. METHODS: The expression of miR-203 in 125 cases of NSCLC and their paired adjacent non-cancerous tissues was evaluated by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Simultaneously, the correlation of miR-203 expression with a variety of clinicopathological factors and patient survival was analyzed. Functionally, in vitro effects of miR-203 on proliferation and viability were explored in lung cancer H460, A549, H1299, PC9 and H292 cells, as assessed by MTS tetrazolium assay and fluorimetric resorufin viability assay, respectively. RESULTS: The relative level of miR-203 was 6.12 ± 6.25 in NSCLC tissues, remarkably downregulated than that of their paired non-tumorous lung tissues (7.88 ± 5.56, P = 0.019). The area under curve (AUC) of low expression of miR-203 to diagnose NSCLC was 0.622 (95 % CI 0.552-0.692, P = 0.001). MiR-203 expression was negatively correlated to lymphatic metastasis (r = -0.334, P < 0.001), tumor size (r = -0.407, P < 0.001) and clinical TNM stages (r = -0.298, P = 0.001). Furthermore, the survival of the low miR-203 expression group was 4.88 ± 4.38 months, markedly shorter than that of the high expression group (23.35 ± 1.12 months, P < 0.001). The level of miR-203 was an independent prognostic indicator of NSCLC using univariate analysis. MiR-203 mimic could suppress the cell growth of five lung cancer cell lines tested to different degrees in vitro. CONCLUSIONS: MiR-203 could become a prognostic predictor in NSCLC and may be a new target for the molecular therapy of NSCLC patients.