Point-NAS: A Novel Neural Architecture Search Framework for Point Cloud Analysis.

Recently, point-based networks have exhibited extraordinary potential for 3D point cloud processing. However, owing to the meticulous design of both parameters and hyperparameters inside the network, constructing a promising network for each point cloud task can be an expensive endeavor. In this work, we develop a novel one-shot search framework called Point-NAS to automatically determine optimum architectures for various point cloud tasks. Specifically, we design an elastic feature extraction (EFE) module that serves as a basic unit for architecture search, which expands seamlessly alongside both the width and depth of the network for efficient feature extraction. Based on the EFE module, we devise a searching space, which is encoded into a supernet to provide a wide number of latent network structures for a particular point cloud task. To fully optimize the weights of the supernet, we propose a weight coupling sandwich rule that samples the largest, smallest, and multiple medium models at each iteration and fuses their gradients to update the supernet. Furthermore, we present a united gradient adjustment algorithm that mitigates gradient conflict induced by distinct gradient directions of sampled models and supernet, thus expediting the convergence of the supernet and assuring that it can be comprehensively trained. Pursuant to the provided techniques, the trained supernet enables a multitude of subnets to be incredibly well-optimized. Finally, we conduct an evolutionary search for the supernet under resource constraints to find promising architectures for different tasks. Experimentally, the searched Point-NAS with weights inherited from the supernet realizes outstanding results across a variety of benchmarks. i.e., 94.2% and 88.9% overall accuracy under ModelNet40 and ScanObjectNN, 68.6% mIoU under S3DIS, 63.6% and 69.3% mAP@0.25 under SUN RGB-D and ScanNet V2 datasets.

Erratum: CD151 promotes Colorectal Cancer progression by a crosstalk involving CEACAM6, LGR5 and Wnt signaling via TGFß1: Erratum.

[This corrects the article DOI: 10.7150/ijbs.53657.].

DDTC Suppresses Ovarian Cancer Development via the PI3K/AKT/mTOR Signaling Pathway.

In prior research, 6,12-diphenyl-3,9-diazatetraasterane-1, 5, 7, 11-tetracarboxylate (DDTC) has been shown to be an effective inhibitor of the growth of the SKOV3 and A2780 ovarian cancer (OC) cell lines. Flow cytometry analyses indicated that DDTC was able to suppress P-CNA expression at the protein level within OC cells, while RNA-seq indicated that DDTC treatment was associated with marked changes in gene expression profiles within A2780 cells. Molecular docking analyses suggested that DDTC has the potential to readily dock with key signaling proteins including PI3K, AKT, and mTOR. In line with these findings, DDTC treatment inhibited the growth of xenograft tumors in a mouse model system. Such treatment was also associated with reduced p-PI3K/PI3K, p-AKT/AKT, p-mTOR/mTOR, and CyclinD1 (CCND1) expressions and with the increased expression of PTEN in vitro and in vivo. Together, these results suggest that DDTC is capable of readily inhibiting OC development at least in part via targeting and modulating signaling via the PI3K/AKT/mTOR axis.

Evaluation of the Prognostic Relevance of Differential Claudin Gene Expression Highlights Claudin-4 as Being Suppressed by TGFß1 Inhibitor in Colorectal Cancer.

Background: Claudins (CLDNs) are a family of closely related transmembrane proteins that have been linked to oncogenic transformation and metastasis across a range of cancers, suggesting that they may be valuable diagnostic and/or prognostic biomarkers that can be used to evaluate patient outcomes. However, CLDN expression patterns associated with colorectal cancer (CRC) remain to be defined. Methods: The mRNA levels of 21 different CLDN family genes were assessed across 20 tumor types using the Oncomine database. Correlations between these genes and patient clinical outcomes, immune cell infiltration, clinicopathological staging, lymph node metastasis, and mutational status were analyzed using the GEPIA, UALCAN, Human Protein Atlas, Tumor Immune Estimation Resource, STRING, Genenetwork, cBioportal, and DAVID databases in an effort to clarify the potential functional roles of different CLDN protein in CRC. Molecular docking analyses were used to probe potential interactions between CLDN4 and TGFß1. Levels of CLDN4 and CLDN11 mRNA expression in clinical CRC patient samples and in the HT29 and HCT116 cell lines were assessed via qPCR. CLDN4 expression levels in these 2 cell lines were additionally assessed following TGFß1 inhibitor treatment. Results: These analyses revealed that COAD and READ tissues exhibited the upregulation of CLDN1, CLDN2, CLDN3, CLDN4, CLDN7, and CLDN12 as well as the downregulation of CLDN5 and CLDN11 relative to control tissues. Higher CLDN11 and CLDN14 expression as well as lower CLDN23 mRNA levels were associated with poorer overall survival (OS) outcomes. Moreover, CLDN2 and CLDN3 or CLDN11 mRNA levels were significantly associated with lymph node metastatic progression in COAD or READ lower in COAD and READ tissues. A positive correlation between the expression of CLDN11 and predicted macrophage, dendritic cell, and CD4+ T cell infiltration was identified in CRC, with CLDN12 expression further being positively correlated with CD4+ T cell infiltration whereas a negative correlation was observed between such infiltration and the expression of CLDN3 and CLDN15. A positive correlation between CLDN1, CLDN16, and neutrophil infiltration was additionally detected, whereas neutrophil levels were negatively correlated with the expression of CLDN3 and CLDN15. Molecular docking suggested that CLDN4 was able to directly bind via hydrogen bond with TGFß1. Relative to paracancerous tissues, clinical CRC tumor tissue samples exhibited CLDN4 and CLDN11 upregulation and downregulation, respectively. LY364947 was able to suppress the expression of CLDN4 in both the HT29 and HCT116 cell lines. Conclusion: Together, these results suggest that the expression of different CLDN family genes is closely associated with CRC tumor clinicopathological staging and immune cell infiltration. Moreover, CLDN4 expression is closely associated with TGFß1 in CRC, suggesting that it and other CLDN family members may represent viable targets for antitumor therapeutic intervention.

Therapy Strategy of CD47 in Diffuse Large B-Cell Lymphoma (DLBCL).

At present, the use of the common chemotherapy regimen CHOP/R-CHOP for diffuse large B-cell lymphoma (DLBCL) has some shortcomings, especially for relapsed and refractory DLBCL. CD47 is now considered as a prominent target in cancer therapies, and CD47 blockade mainly inhibits the CD47-SIRPα axis to prevent tumor immune escape. Here, we evaluated the effects of the latest CD47 antibodies reported and the correlations of closely related genes with CD47 in this disease. In the future, therapeutic strategies for DLBCL will focus on multitarget antibody combined treatment and multigene joint attacks.

The Mechanism of Xiaoyao San in the Treatment of Ovarian Cancer by Network Pharmacology and the Effect of Stigmasterol on the PI3K/Akt Pathway.

PURPOSE: This study was aimed at exploring the regulatory mechanism of Xiaoyao San (XYS) and its main compound, Stigmasterol, in the biological network and signaling pathway of ovarian cancer (OC) through network pharmacology-based analyses and experimental validation. METHODS: The active compounds and targets of XYS were studied by the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). The GeneCards and OMIM databases were used to screen common targets of XYS in the treatment of OC. Combined with the STRING database and Cytoscape 3.6.0, the core compounds and targets of XYS were obtained. GO and KEGG pathway enrichment analyses of core target genes were carried out by using the Metascape and DAVID databases. Molecular docking has been achieved by using the AutoDock Vina program to discuss the interaction of the core targets and compounds of XYS in the treatment of OC. The effect of Stigmasterol on proliferation and migration were assessed by CCK8 and wound healing assay. Western blot and qRT-PCR were used to analyze the protein and mRNA expressions of PI3K, Akt, and PTEN after treatment of Stigmasterol. RESULTS: A total of 113 common targets of XYS for the treatment of OC were obtained from 975 targets related to OC and 239 targets of XYS's effect. The main compounds of XYS include Quercetin, Naringenin, Isorhamnetin, and Stigmasterol, which mainly regulate the targets such as TP53, Akt1, and MYC and PI3K/Akt, p53, and cell cycle signal pathways. At the same time, molecular docking showed that Stigmasterol and Akt1 had good docking conformation. Stigmasterol inhibited OC cell proliferation and migration in vitro and reduced the protein and mRNA expressions of the PI3K/Akt signaling pathway. CONCLUSION: Stigmasterol as the one of the main compounds of XYS suppresses OC cell activities through the PI3K-Akt signaling pathway.

CD151 promotes Colorectal Cancer progression by a crosstalk involving CEACAM6, LGR5 and Wnt signaling via TGFß1.

CD151 impacts various signaling pathways in different cancers, and promotes colorectal cancer (CRC) cell malignancy by yet undefined mechanisms. This study aimed to comprehensively assess CD151's function in CRC. CD151 levels were significantly higher in CRC tissues and cells compared with controls in the tissue microarray. Cell viability, migration and invasion were suppressed by CD151 downregulation in CRC cells. Consistently, mouse xenografts were inhibited by CD151 silencing. RNA-seq revealed that multiple genes were significantly altered by CD151 knockdown in cultured CRC cells and xenografts. Particularly, transforming growth factor ß1 (TGFß1), carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) and leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) alongside CD151 were downregulated both in vitro and in vivo. Co-immunoprecipitation and mass spectrometry results were validated by qRT-PCR and immunoblot. Moreover, pull-down assay and immunofluorescence confirmed the associations of TGFß1, CEACAM6 and LGR5 with CD151. This study demonstrated CEACAM6, LGR5 and Wnt pathway suppression by CD151 silencing might occur through TGFß1 regulation, offering a comprehensive view of CD151's roles in colorectal carcinogenesis. Our findings provide an insight into the CD151-involved signaling network in CRC oncogenesis, which could be utilized to design novel targeted therapies against CD151-based signaling in treatment for CRC.

6,12-Diphenyl-3, 9-diazatetraasterane-1, 5, 7, 11-tetracarboxylate Inhibits Proliferation, Migration and Promotes Apoptosis in Ovarian Cancer Cells.

6,12-Diphenyl-3,9-diazatetraasterane-1, 5, 7, 11-tetracarboxylate (DDTC) has been synthesized by the photodimerization of 4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate. The potential of theercvantitumor activity and mechanism were investigated in vitro using MTT assay in human lung cancer cell line A549, ovarian cancer cell lines SKOV3 and A2780, breast cancer cell line MCF-7, gastric cancer cell line BGC-823, colon cancer cell line HT29, prostate cancer cell line DU145, and liver cancer cell line SMMC7721. The results show that DDTC can inhibit the growth of ovarian cancer SKOV3 and A2780 cells. The best IC50 value is approximately 5.29 ± 0.38 and 4.29 ± 0.39 µM, respectively. DDTC induced the cell cycle arrest in the G2 phase by flow cytometric analysis. The migration and invasion of ovarian cancer SKOV3 and A2780 cells were inhibited by DDTC. DDTC could increase the expression protein level of E-cadherin in A2780 cells and ascend the expression protein and mRNA levels of E-cadherin in SKOV3 cells. DDTC could also decrease the protein and mRNA expression of EMT (epithelial-to-mesenchymal transition) markers of N-cadherin and Vimentin. mRNA and protein expression level of checkpoint kinase 1 (Chk1) were significantly increased and expressions of cyclin-dependent kinase (CDK1) and cell division cycle 25a (Cdc25a) were decreased in the SKOV3 and A2780 cell lines. Moreover, DDTC induced apoptosis by the cleavage and activation of caspase 3 and caspase 9.

The Epigenetic Modification of Epigallocatechin Gallate (EGCG) on Cancer.

Among the major components of green tea, epigallocatechin-3-gallate (EGCG) is the most effective for its anti-cancer characteristics. The bulk of studies provide the mechanisms of suppressive function of EGCG are involved in alteration of cancer cell cycle, development, and apoptosis through activation/inhibition of several signal pathways. Another mechanism that explains the multiple effects exerted by EGCG in cancer is the epigenetic change by DNA methylation or methyltransferases, histone acetylation or deacetylases, and no coding RNAs (micoRNAs). Furthermore, decontrolled expression of miRNA transcription has been tested to be directly regulated by oncogenic and tumor-suppressor transcription factors. Recently, several proteins have been identified as miRNA direct interactors by EGCG. However, the mechanisms explaining the action of miRNA being modulated by EGCG have not been completely understood yet. This review summarizes the state of epigenetic change being modulated by EGCG in a variety of cancers and oncogenic and tumor-suppressor transcription factors.

IgG4 and IgE co-positive group found in idiopathic orbital inflammatory disease.

AIM: To reveal the cytokines involved in idiopathic orbital inflammatory disease (IOID) and the relationship between Th17 cells, IgE and IOID pathogenesis. METHODS: Whole blood samples were processed immediately after collection and serological IgG4, IgG, and IgE antibodies were tested using ELISA. IOID and orbital cavernous hemangioma (CH) tissue samples underwent Bio-Plex multiplex cytokine detection. Hematoxylin-Eosin (HE) staining of all paraffin samples suggested the histological features of IOIDs, and expressions of IgG4 and IL-17A in affected tissues were detected by immunohistochemistry. RESULTS: Among 40 IOID plasma samples, 52.5% (21/40) were positive for IgG4 and 25% (10/40) were positive for IgE. Overlapped IgG4 or IgE positive samples accounted for 22.5% (9/40). Therefore, IOID samples were separated into three groups. The IgE+/IgG4+ group had a relevantly lower level of pro-inflammatory cytokine expression. IL-4 (Th2 cell related), IL-10 and TGF-ß1 (Treg cell immunity related) were elevated in all three groups. Some of the Th17 cell related cytokines (i.e. IL-17A/F, IL-25, IL-23, and IL-33) displayed higher expression levels in the IgE-/IgG4- group compared to the other two groups. CONCLUSION: We discovered an IgG4-IgE co-positive group as well as Th17 cell immune involvement in IgG4-IgE co-negative subgtroup in IOID for the first time. The pathogenesis of IOID could differ from different subgroups according to the IgG4 and IgE detection. Therefore, we recommend that, Treatment stratagy should be made according to the clinical assessment of IgG4-IgE and Th17 profile detection.

Genes and pathways associated with the occurrence of malignancy in benign lymphoepithelial lesions.

There is increasing evidence concerning the occurrence of malignant lymphoma among people suffering from Mikulicz disease, also termed benign lymphoepithelial lesion (BLEL) and immunoglobulin G4­associated disease. However, the underlying molecular mechanism of the malignant transformation remains unclear. The present study aimed to investigate the gene expression profile between BLEL and malignant lymphoepithelial lesion (MLEL) conditions using tissue microarray analysis, to identify genes and pathways which may be associated with the risk of malignant transformation. Comparing gene expression profiles between BLEL tissues (n=13) and MLEL (n=14), a total of 1,002 differentially expressed genes (DEGs) were identified including 364 downregulated and 638 upregulated DEGs in BLEL. The downregulated DEGs in BLEL were frequently associated with immune­based functions, immune cell differentiation, proliferation and survival, and metabolic functions, whereas the upregulated DEGs were primarily associated with organ, gland and tissue developmental processes. The B cell receptor signaling pathway, the transcription factor p65 signaling pathway, low affinity immunoglobulin γ Fc region receptor II­mediated phagocytosis, the high affinity immunoglobulin ε receptor subunit γ signaling pathway and Epstein­Barr virus infection, and pathways in cancer, were the pathways associated with the downregulated DEGs. The upregulated DEGs were associated with three pathways, including glutathione metabolism, salivary secretion and mineral absorption pathways. These results suggested that the identified signaling pathways and their associated genes may be crucial for understanding the molecular mechanisms underlying malignant transformation from BLEL, and they may be considered to be markers for predicting malignancy among the BLEL group.

A meta-analysis of transcatheter device closure of perimembranous ventricular septal defect.

BACKGROUND: While transcatheter device closure of ventricular septal defects (VSDs) is gaining popularity, concerns remain about adverse events; particularly heart block in peri-membranous VSDs (pmVSDs). The aim of this study is to ascertain outcomes of transcatheter device closure of pmVSDs through a meta-analysis of current literature. METHODS: A PubMed and Scopus search for studies in English on device closure of pmVSDs published till end-February 2017 was performed. Exclusion criteria included case series already included in multi-centre studies, sample size <5, and VSD acquired following myocardial infarction. Pooled estimates of success and complications was obtained using the random effects model. RESULTS: A total of 54 publications comprising 6762 patients with pmVSDs were included. The mean age of patients ranged from 1.6 to 37.4years. The pooled estimate of successful device implantation is 97.8% (95% CI: 96.8 to 98.6). The most common complication is residual shunt (15.9%; 95% CI: 10.9 to 21.5). Other complications include arrhythmias (10.3%; 95% CI: 8.3 to 12.4) and valvular defects (4.1%; 95% CI: 2.4 to 6.1). The pooled estimate of complete atrioventricular block (cAVB) is 1.1% (95% CI: 0.5 to 1.9). CONCLUSION: Our meta-analysis suggests that device closure of pmVSDs is a safe and effective procedure. The complication of cAVB is low but significant. The risk is expected to further reduce with newer devices which are less stiff with improved profiles. Further studies validating this will be useful in formulating guidelines for device closure of pmVSDs.

TLR7 and TLR8 agonist resiquimod (R848) differently regulates MIF expression in cells and organs.

Since its first description in 1966, macrophage migration inhibitory factor (MIF) was found to play a critical role in inflammatory and immune responses as well as in disease pathogenesis especially in tumor pathogenesis and cancer progression. MIF is expressed in different cell types and is associated with many disease severity and tumor pathogenesis. Here, we investigated the influence of TLR7 and TLR8 agonist resiquimod (R848), an immune response inducer used as a prophylactic agent for several infectious diseases as well as anticancer agents and vaccine adjuvant on MIF expression in cells and organs. Humans, mice and rats cell lines from different tissues (blood, retinal, nasopharynx, brain and liver) and C57BL/6J mice organs (brain, liver and spleen) were used for this investigation. In vitro, R848 induced MIF gene overexpression except in brain and liver cells. Furthermore, it enhanced cells ability to release soluble MIF and differently regulated mRNA expression of MIF-related receptors (CD74, CXCR4, CXCR2 and CD44). Its influence on MIF gene expression and MIF proteins release was more consistent in cancer cells. In vivo, a strong positive expression of MIF was observed in different regions in brain and spleen in response to R848 treatment; however in liver, increased MIF expression was observed in hepatocytes only. On the other hand, R848 treatment had induced a slight enhancement of MIF concentration in the plasma of C57BL/6J mice. Taken together, these data suggest that R848 differently regulates MIF mRNA expression depending on organ types and could influence MIF concentration in cellular microenvironment.

A systematic review and meta-analysis of outcomes of transcatheter stent implantation for the primary treatment of native coarctation.

BACKGROUND/OBJECTIVES: The treatment of native coarctation of aorta (CoA) has evolved since surgery performed in 1944, followed by transcatheter balloon angioplasty and recently, widely adopted stent implantation. Despite good results demonstrated with stent implantation, a systematic review and meta-analysis (SRMA) looking at the efficacy and safety of the intervention, particularly in younger population is yet to be done. We aimed to obtain pooled estimates of the success and complication rates after transcatheter stent implantation in the treatment of native CoA based on SRMA. METHODS: We searched literature published until 31 Dec. 2015, reporting outcomes of transcatheter stent implantation in the treatment of native CoA. The pooled estimates were obtained using the random effect model. RESULTS: Seventeen reports comprising 561 patients were included. Fourteen studies reported 100% success rate, the lowest was 77%, the largest study reported 81% using a definition of systolic pressure difference of less than 15mmHg. The pooled estimate of overall success rate was 98% (95% CI: 94.5-100.0; I2=65%, heterogeneity test p<0.001). Six out of 17 studies reported zero complication. Two studies, however, reported complications in almost half of the cohort. The pooled estimate of rate of complications was 10% (95% CI: 5.1-15.5; I2=72%, heterogeneity test p<0.001). Three studies comprising only children, 62, with mean age of 11.1 (4-19) years reported high mean success rate at 98% with only 1 failure. CONCLUSIONS: There is a high success rate with a small complication rate with stent implantations for native CoA even as the treatment is brought to younger age group.

A systematic review on the efficacy and safety of transcatheter device closure of ventricular septal defects (VSD).

BACKGROUND: Advances in interventional techniques now allow for transcatheter treatment of some ventricular septal defects (VSD), although there remain concerns about adverse events. We performed a systematic review to look at outcomes and complications associated with transcatheter closure of VSD. METHOD: A PubMed search for series in English on device closure of VSD from 2003 to June 2012 was performed. We excluded small series that were included in multicenter studies and patients who had acquired VSD following myocardial infarction. The random effects model was used to obtain pooled estimates of success and complications. RESULTS: A total of 37 publications comprising 4,406 patients with VSD (perimembranous = 3,758, muscular = 419, intracristal = 47, doubly committed subarterial = 36, multiple = 16, postsurgical = 123, unclassified = 7) were included in this analysis. The age of patients ranged from 3 days to 84 years. The pooled estimate of successful device implantation was 96.6% (95% CI: 95.7-97.5). The most common complication is residual shunt (pooled estimated 25.5%; 95% CI: 18.9-32.1). Others included valvular defects (pooled estimate 4.9%; 95% CI: 3.4-6.4) and arrhythmias (pooled estimate 10.6%; 95% CI: 8.4-12.7). DISCUSSION AND CONCLUSION: Our analysis suggests that transcatheter device closure of VSD is safe and yields good results. The limitations of this study are difficulties in analyzing different devices individually, and segregating the different VSD types. Further stratification by type of VSD, age of patients, and prevention of complications is needed before this can be recommended for routine treatment.

[1-(4-Chloro-phen-yl)-5-hy-droxy-3-phenyl-1H-pyrazol-4-yl](thio-phen-2-yl)methanone.

In the title compound, C(20)H(13)ClN(2)O(2)S, the chloro-phenyl, phenyl and thienoyl rings are oriented at dihedral angles 17.84 (7), 53.13 (8) and 34.03 (8)°, respectively, to the central pyrazole ring. An intra-molecular O-H⋯O hydrogen bond occurs. In the crystal, pairs of bifurcated O-H⋯O hydrogen bonds link mol-ecules into inversion dimers with R(2) (2)(12) graph-set motifs.