Pulmonary Nodule Classification Using a Multiview Residual Selective Kernel Network.

Lung cancer is one of the leading causes of death worldwide and early detection is crucial to reduce the mortality. A reliable computer-aided diagnosis (CAD) system can help facilitate early detection of malignant nodules. Although existing methods provide adequate classification accuracy, there is still room for further improvement. This study is dedicated to investigating a new CAD scheme for predicting the malignant likelihood of lung nodules in computed tomography (CT) images in light of a deep learning strategy. Conceived from the residual learning and selective kernel, we investigated an efficient residual selective kernel (RSK) block to handle the diversity of lung nodules with various shapes and obscure structures. Founded on this RSK block, we established a multiview RSK network (MRSKNet), to which three anatomical planes in the axial, coronal, and sagittal directions were fed. To reinforce the classification efficiency, seven handcrafted texture features with a filter-like computation strategy were explored, among which the homogeneity (HOM) feature maps are combined with the corresponding intensity CT images for concatenation input, leading to an improved network architecture. Evaluated on the public benchmark Lung Image Database Consortium and Image Database Resource Initiative (LIDC-IDRI) challenge database with ten-fold cross validation of binary classification, our experimental results indicated high area under receiver operating characteristic (AUC) and accuracy scores. A better compromise between recall and specificity was struck using the suggested concatenation strategy comparing to many state-of-the-art approaches. The proposed pulmonary nodule classification framework exhibited great efficacy and achieved a higher AUC of 0.9711. The association of handcrafted texture features with deep learning models is promising in advancing the classification performance. The developed pulmonary nodule CAD network architecture is of potential in facilitating the diagnosis of lung cancer for further image processing applications.

Src-IL-18 signaling regulates the secretion of atrial natriuretic factor in hypoxic beating rat atria.

BACKGROUND: Interleukin (IL)-18 is produced mainly in the heart and can be associated with the development of cardiac hypertrophy that leads to cardiac dysfunction. However, the effects of hypoxia on IL-18 expression and atrial natriuretic factor (ANF) secretion remain largely unknown. AIM: The aim of this study was to assess the effect of hypoxia on IL-18 production and its role in ANF secretion by using an isolated perfused beating rat atrial model. METHODS: The level of ANF in the perfusates was determined by radioimmunoassay, and the protein levels of Src, IL-18 and its receptors (IL-18-Rα and IL-18-Rß), Rho guanine nucleotide exchange factor (RhoGEF) and RhoA, activating transcription factor 3 (ATF3), T cell factor (TCF) 3 and 4, and lymphoid enhancer factor (LEF) 1 in atrial tissue samples were detected by Western blotting. RESULTS: Hypoxia significantly upregulated the expression of the non-receptor tyrosine kinase Src, and this effect was blocked by endothelin-1 receptor type A (BQ123) and type B (BQ788) antagonists. Hypoxia also enhanced the expression of RhoGEF and RhoA concomitantly with the upregulation of IL-18, IL-18-Rα and IL-18-Rß. The hypoxia-induced RhoGEF and RhoA were abolished by Src inhibitor 1 (SrcI), and the protein levels of IL-18 and its two receptors were also blocked by SrcI. Moreover, the hypoxia-induced expression levels of ATF3, TCF3, TCF4 and LEF1 were repealed by IL-18 binding protein, and the hypoxia-promoted secretion of ANF was also obviously attenuated by this binding protein. CONCLUSIONS: These findings imply that Src-IL-18 signaling is involved in the release of ANF in hypoxic beating rat atria.

NOX4/Src regulates ANP secretion through activating ERK1/2 and Akt/GATA4 signaling in beating rat hypoxic atria.

Nicotinamide adenine dinucleotide phosphate oxidases (NOXs) are the major enzymatic source of reactive oxygen species (ROS). NOX2 and NOX4 are expressed in the heart but its role in hypoxia-induced atrial natriuretic peptide (ANP) secretion is unclear. This study investigated the effect of NOX on ANP secretion induced by hypoxia in isolated beating rat atria. The results showed that hypoxia significantly upregulated NOX4 but not NOX2 expression, which was completely abolished by endothelin-1 (ET-1) type A and B receptor antagonists BQ123 (0.3 µM) and BQ788 (0.3 µM). ET-1-upregulated NOX4 expression was also blocked by antagonists of secreted phospholipase A2 (sPLA2; varespladib, 5.0 µM) and cytosolic PLA2 (cPLA2; CAY10650, 120.0 nM), and ET-1-induced cPLA2 expression was inhibited by varespladib under normoxia. Moreover, hypoxia-increased ANP secretion was evidently attenuated by the NOX4 antagonist GLX351322 (35.0 µM) and inhibitor of ROS N-Acetyl-D-cysteine (NAC, 15.0 mM), and hypoxia-increased production of ROS was blocked by GLX351322. In addition, hypoxia markedly upregulated Src expression, which was blocked by ET receptors, NOX4, and ROS antagonists. ET-1-increased Src expression was also inhibited by NAC under normoxia. Furthermore, hypoxiaactivated extracellular signal-regulated kinase 1/2 (ERK1/2) and protein kinase B (Akt) were completely abolished by Src inhibitor 1 (1.0 µM), and hypoxia-increased GATA4 was inhibited by the ERK1/2 and Akt antagonists PD98059 (10.0 µM) and LY294002 (10.0 µM), respectively. However, hypoxia-induced ANP secretion was substantially inhibited by Src inhibitor. These results indicate that NOX4/Src modulated by ET-1 regulates ANP secretion by activating ERK1/2 and Akt/GATA4 signaling in isolated beating rat hypoxic atria.

Synthesis and biological evaluation of 3-aryl-quinolin derivatives as anti-breast cancer agents targeting ERα and VEGFR-2.

SERMs are a series of important small molecular compounds to modulate estrogen receptor, such as tamoxifen. Although these drugs have showed great benefits in the treatment of breast cancer, the risk of endometrial cancer and endocrine resistance restrict their use. The reasonable designing of multi-target drugs can decrease the side effects and improve the tolerance of antineoplastic agents Studies have identified that VEGFR-2 plays a pivotal role in tumor angiogenesis and drug resistance. Besides, a combination of Tamoxifen and low dose of a VEGFR-2 inhibitor was reported to maximize therapeutic efficacy as well as to retard SERM resistant tumor growth. In this work, a series of 3-aryl-quinolin derivatives were designed to target to ERα and VEGFR-2 to eliminate the disadvantages of SERMs. We identified that compounds 12f and 13f displayed highly ERα binding affinities as well as relative intensity VEGFR-2 inhibitory activities. Moreover, this two compounds exhibited excellent anti-proliferative activities against MCF-7 and HUVEC cell lines with low micromolar IC50 (1-8 µM). A further study confirmed that compound 13f can reduce the expression of PgR mRNA, arrest cell cycle in MCF-7 breast cancer cells, and restrain the cell migration. Overall, based on the biological activities data, 13f can be chosen as a potential anti-cancer lead compound for further studying.

HIF-1α-l-PGDS-PPARγ regulates hypoxia-induced ANP secretion in beating rat atria.

Lipocalin-type prostaglandin D synthase (L-PGDS) and peroxisome proliferator activated receptor γ (PPARγ) play important roles in cardiovascular diseases. Nevertheless, effects of hypoxia-inducible factor 1α (HIF-1α) on L-PGDS and PPARγ protein levels and its role in hypoxia-induced atrial natriuretic peptide (ANP) secretion are unclear. In perfused beating rat atria, we observed that hypoxia significantly increased HIF-1α protein levels and stimulated ANP secretion, while upregulating L-PGDS. Hypoxia-induced ANP secretion was clearly attenuated by HIF-1α antagonist 2-methoxyestradiol, downregulating both HIF-1α and L-PGDS protein levels. It was also attenuated by L-PGDS antagonists, AT-56 and HQL-49, downregulating L-PGDS protein levels. In addition, hypoxia-induced ANP secretion was accompanied by increased PPARγ protein levels and was strongly attenuated by PPARγ antagonist GW9662. Hypoxia-induced increase in atrial PPARγ protein levels were dramatically inhibited by both 2-methoxyestradiol and AT-56. These results indicated that hypoxia promotes ANP secretion, at least in part, by activating HIF-1α-l-PGDS-PPARγ signaling in beating rat atria.

Wavefront aberrations and retinal image quality in different lenticular opacity types and densities.

To investigate wavefront aberrations in the entire eye and in the internal optics (lens) and retinal image qualities according to different lenticular opacity types and densities. Forty-one eyes with nuclear cataract, 33 eyes with cortical cataract, and 29 eyes with posterior subcapsular cataract were examined. In each group, wavefront aberrations in the entire eye and in the internal optics and retinal image quality were measured using a raytracing aberrometer. Eyes with cortical cataracts showed significantly higher coma-like aberrations compared to the other two groups in both entire eye and internal optic aberrations (P = 0.012 and P = 0.007, respectively). Eyes with nuclear cataract had lower spherical-like aberrations than the other two groups in both entire eye and internal optics aberrations (P < 0.001 and P < 0.001, respectively). In the nuclear cataract group, nuclear lens density was negatively correlated with internal spherical aberrations (r = -0.527, P = 0.005). Wavefront technology is useful for objective and quantitative analysis of retinal image quality deterioration in eyes with different early lenticular opacity types and densities. Understanding the wavefront optical properties of different crystalline lens opacities may help ophthalmic surgeons determine the optimal time to perform cataract surgery.

Novel SERMs based on 3-aryl-4-aryloxy-2H-chromen-2-one skeleton - A possible way to dual ERα/VEGFR-2 ligands for treatment of breast cancer.

There is considerable interest in developing new SERMs as multifunctional agents in women's health. Development of dual selective estrogen receptor modulators/VEGFR-2 inhibitors (SERMs/V-2I) has been an attractive strategy for the discovery of new breast cancer therapeutic agents. Our previous efforts led to the preparation of a series of 3-aryl-4-anilino-2H-chromen-2-ones endowed with potent estrogen receptor binding affinity and anti-proliferative efficacy. In this study, various structurally related 3-aryl-4-anilino/aryloxy-2H-chromen-2-one analogues were rationally designed, synthesized and evaluated as a new chemo-type of dual ERα and VEGFR-2 inhibitors. Most of the derivatives exhibited potent activities in both enzymatic and cellular assays. SAR investigation revealed that introducing of bioisosteric O atom at the C-4 position of coumarin scaffold is beneficial to improve the inhibitory potency, especially in ERα binding affinity assay. Furthermore, most of the piperidyl substituted compounds showed better inhibitory activity against MCF-7 and Ishikawa cells than lead compounds BL-18d, tamoxifen and Vandetanib. Optimization of the hit compound, identified in an ERα binding affinity assay, led to compound 42d, exhibiting an IC50 for ERα binding affinity of 2.19 µM while retaining an excellent inhibition on VGFR-2 as well as a potent suppression on the growth of angiogenesis-related cells. In RT-PCR assay, 42d exerted significantly antiestrogenic property via suppressing the expression of progesterone receptor (PgR) mRNA in MCF-7 cells, which was consistent with the ERα antagonistic property of a selective estrogen receptor modulator. Further mechanism investigation demonstrated that compound 42d could inhibit the activation of VEGFR-2 and subsequent signaling transduction of Raf-1/MAPK/ERK pathway in MCF-7 cells. All these results together with molecular modeling studies open a new avenue for the development of multifunctional agents targeting ERα and VEGFR-2 in the therapy of some breast cancers.

Peroxisome proliferator-activated receptor γ is essential for secretion of ANP induced by prostaglandin D2 in the beating rat atrium.

Prostaglandin D2 (PGD2) may act against myocardial ischemia-reperfusion (I/R) injury and play an anti-inflammatory role in the heart. Although the effect of PGD2 in regulation of ANP secretion of the atrium was reported, the mechanisms involved are not clearly identified. The aim of the present study was to investigate whether PGD2 can regulate ANP secretion in the isolated perfused beating rat atrium, and its underlying mechanisms. PGD2 (0.1 to 10 µM) significantly increased atrial ANP secretion concomitantly with positive inotropy in a dose-dependent manner. Effects of PGD2 on atrial ANP secretion and mechanical dynamics were abolished by AH-6809 (1.0 µM) and AL-8810 (1.0 µM), PGD2 and prostaglandin F2α (PGF2α) receptor antagonists, respectively. Moreover, PGD2 clearly upregulated atrial peroxisome proliferator-activated receptor gamma (PPARγ) and the PGD2 metabolite 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2, 0.1 µM) dramatically increased atrial ANP secretion. Increased ANP secretions induced by PGD2 and 15d-PGJ2 were completely blocked by the PPARγ antagonist GW9662 (0.1 µM). PD98059 (10.0 µM) and LY294002 (1.0 µM), antagonists of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) and phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) signaling, respectively, significantly attenuated the increase of atrial ANP secretion by PGD2. These results indicated that PGD2 stimulated atrial ANP secretion and promoted positive inotropy by activating PPARγ in beating rat atria. MAPK/ERK and PI3K/Akt signaling pathways were each partially involved in regulating PGD2-induced atrial ANP secretion.

Gallic acid increases atrial natriuretic peptide secretion and mechanical dynamics through activation of PKC.

AIMS: Gallic acid (GA) protects against myocardial ischemia-reperfusion (I/R) injury, prevents cardiac hypertrophy and fibrosis, and has anti-inflammatory activity in the heart. However, its effects in regulating atrial natriuretic peptide (ANP) secretion are unknown. The aim of this study was to determine the function of GA in regulating ANP secretion and atrial dynamics in rat atria. KEY FINDINGS: GA (0.01, 0.05, and 0.1µmol/L) significantly increased atrial ANP secretion and induced positive inotropy dose-dependently. GA (0.1µmol/L) also increased plasma level of ANP and hemodynamics in rats. These effects were accompanied by upregulation of atrial protein kinase C subtypes ß and ε (PKCß and PKCε), which was completely blocked by LY333531 and EAVSLKPT, antagonists of protein PKCß and PKCε, respectively. GA-induced ANP secretion was also attenuated by Gö6983 but not rottlerin, antagonists of PKCα and PKCδ, and the positive inotropy was reversed by Gö6983. U-73122, a phospholipase C (PLC) antagonist, mitigated the effects of GA on ANP secretion and mechanical dynamics and downregulated Phospho-PLCß at Ser537 (pPLCß S537), Phospho-PLCß at Ser1105 (pPLCß S1105), PKCß and PKCε levels, whereas KN62, an inhibitor of Ca2+/calmodulin-dependent kinase II, was not modified the GA-induced ANP secretion and suppressed GA-induced mechanical dynamics. SIGNIFICANCE: GA promotes ANP secretion and effects positive inotropy with regard to mechanical dynamics through the activation of PLC-PKC signaling in rat atria.

Design, synthesis and evaluation of 6-aryl-indenoisoquinolone derivatives dual targeting ERα and VEGFR-2 as anti-breast cancer agents.

The estrogen receptors have played important roles in breast cancer development and progression. Selective estrogen receptor modulators, such as Tamoxifen, have showed great benefits in the treatment and prevention of breast cancer. But the disadvantages of induction of endometrial cancer and drug resistance have limited their use. Multiple ligand which act at multiple biomolecular targets may exert favorable advantages of improved efficacy with lower incidence of side effects. In this work, we described the synthesis and evaluation of a series of 6-aryl-indenoisoquinolone derivatives as dual ERα and VEGFR-2 inhibitors. These compounds presented good ERα binding affinity and ERα antagonistic activity, as well as potent VEGFR-2 inhibitory potency. They also possessed excellent anti-proliferative activities against MCF-7, MDA-MB-231, Ishikawa and HUVEC cell lines. Further investigation of selective compound 21c showed that it was able to inhibit the activation of VEGFR-2 and the signaling transduction of Raf-1/MAPK/ERK pathway in MCF-7 cells.

Marginal ectropion induced by conjunctival ingrowth after levator resection surgery.

BACKGROUND: Levator resection surgery is commonly performed to correct ptosis, and a large number of postoperative complications are well known. This report presents a previously unreported complication of marginal ectropion after levator resection surgery for congenital ptosis. METHODS: The three patients with upper eyelid marginal ectropion in this observational case series previously had undergone levator resection surgery for congenital ptosis. The patients' medical records and clinical photographs were reviewed retrospectively. The patients underwent reoperations for ectropion correction. Unusual tissues identified during the surgery were excised and processed for histopathologic analysis. RESULTS: The patients presented with upper eyelid marginal ectropion and had a history of levator resection surgery for congenital ptosis on the same eye. Ingrown tissues were observed during the second operations for ectropion correction in all three patients. Histopathologic analysis was performed for two of the patients, confirming that the tissue consisted of mucosa. The ectropions were corrected after surgical removal of the ingrown tissues. CONCLUSIONS: Marginal ectropion can occur after levator resection surgery. In this study, the ectropion was attributed to mucosal ingrowth, a complication not previously reported. To improve the surgical outcomes, surgeons should be aware of this complication. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Periorbital globe fixation after severe extraocular muscle injury.

Endoscopic sinus surgery is a popular surgical treatment for chronic sinus disease. Despite improved surgical techniques, postoperative orbital complications can occur, including extraocular muscle injury. We report the case of a 62-year-old woman who suffered from medial rectus muscle transection after transnasal endoscopic ethmoidectomy. She was successfully managed with periorbital globe fixation.