Role of Exosomes in Cancer and Aptamer-Modified Exosomes as a Promising Platform for Cancer Targeted Therapy.

Exosomes are increasingly recognized as important mediators of intercellular communication in cancer biology. Exosomes can be derived from cancer cells as well as cellular components in tumor microenvironment. After secretion, the exosomes carrying a wide range of bioactive cargos can be ingested by local or distant recipient cells. The released cargos act through a variety of mechanisms to elicit multiple biological effects and impact most if not all hallmarks of cancer. Moreover, owing to their excellent biocompatibility and capability of being easily engineered or modified, exosomes are currently exploited as a promising platform for cancer targeted therapy. In this review, we first summarize the current knowledge of roles of exosomes in risk and etiology, initiation and progression of cancer, as well as their underlying molecular mechanisms. The aptamer-modified exosome as a promising platform for cancer targeted therapy is then briefly introduced. We also discuss the future directions for emerging roles of exosome in tumor biology and perspective of aptamer-modified exosomes in cancer therapy.

Screening and Application of DNA Aptamers for Heparin-Binding Protein.

Rapid detection of heparin-binding protein (HBP) is essential for timely intervention in sepsis cases. Current detection techniques are usually antibody-based immunological methods, which have certain problems, such as complexity and slow detection, and fall short in meeting the urgency of clinical needs. The application of an aptamer can address these concerns well. In this study, HBP-specific DNA aptamers were screened first. Among which, Apt-01, Apt-02, and Apt-13 had a high affinity for HBP, exhibiting impressive KD values of 3.42, 1.44, and 1.04 nmol/L, respectively. Then, the aptamer of HBP and its partially complementary primer probe were combined to form double-stranded DNA (dsDNA) and synthesize a circular DNA template. The template is complementary to the primer probe, but due to the presence of dsDNA, ExoIII cleaves C2-13 as an RCA primer probe, rendering the template unable to recognize the primer probe and preventing the RCA reaction from proceeding. When the target is present, it competes with the adapter for recognition and releases C2-13, exposing its 3' end. After initiating the RCA at room temperature and reacting with SYBR GreenII at 37 °C for 20 min, fluorescence changes can be observed and quantitatively analyzed at a 530 nm wavelength, achieving quantitative biological analysis. Apt-01 was used to develop a fluorescent biosensor for HBP detection, which exhibited a good linear range (0.01 nmol/L to 10 nmol/L) and detection limit (0.0056 nmol/L). This advancement holds the potential to lay a solid groundwork for pioneering sensitive and specific methods for HBP detection and to significantly enhance the diagnostic processes for sepsis.

A novel electrochemical sandwich-like immunosensor based on carboxyl Ti3C2Tx MXene and rhodamine b/gold/reduced graphene oxide for Listeria monocytogenes.

Listeria monocytogenes (LM) is one of the most common food-borne pathogens and can induce a series of diseases with a high mortality rate to humans; hence, it is very necessary to develop a highly sensitive method for LM detection. Based on this need, a new sandwich-like electrochemical immunosensing platform was developed herein by preparing carboxyl Ti3C2Tx MXene (C-Ti3C2Tx MXene) as the sensing platform and rhodamine b/gold/reduced graphene oxide (RhB/Au/RGO) as the signal amplifier. The high conductivity and large surface area of C-Ti3C2Tx MXene make it a desirable nanomaterial to fix the primary antibody of LM (PAb), while the prepared Au/RGO/RhB nanohybrid is dedicated to assembling the secondary antibody (SAb) of LM, offering an amplified response signal. Through the use of RhB molecule as the signal probe, the experiments showed that the peak currents of RhB increase along with an increase in the concentration of LM from 10 to 105 CFU mL-1, and an extremely low limit of detection (2 CFU mL-1) was obtained on the basis of the proposed immunosensing platform after optimizing various conditions. Hence, it is confirmed that the developed sandwich-like immunosensor based on C-Ti3C2Tx MXene and RhB/Au/Gr has great application in the detection of LM and other analytes.

Association of Serum Amylase Activity and the Copy Number Variation of AMY1/2A/2B with Metabolic Syndrome in Chinese Adults.

PURPOSE: Low serum amylase activity and copy number (CN) variation (CNV) of the salivary amylase gene (AMY1) are reportedly associated with obesity and abnormal glucose metabolism; however, this association remains controversial. We aimed to clarify the relationship between serum amylase activity and the CNV of AMY1/2A/2B with the occurrence of metabolic syndrome (MetS) in Chinese adults. PATIENTS AND METHODS: Anthropometry, metabolic risk factors, and serum amylase activity were assessed in 560 subjects (260 MetS patients; 300 healthy controls). AMY1/2A/2B CNs were evaluated using the highly sensitive droplet digital PCR. RESULTS: The serum total, pancreatic, and salivary amylase activity, but not the AMY1/2A/2B CNs, was significantly lower in MetS patients than that in the control subjects. Patients <45 y had a lower AMY1 CN, compared to that in healthy controls. Low serum amylase activity was significantly associated with high MetS prevalence (p < 0.001). In the receiver operating characteristic curve analysis, serum amylase activity was a significant diagnostic indicator for MetS. The diagnostic value of total amylase was second only to that of γ-glutamyl transpeptidase; it was higher than that of alanine aminotransferase and uric acid. CONCLUSION: Low serum amylase activity was significantly associated with increased risk of MetS in Chinese adults. Therefore, amylase could be a potential biomarker for predicting MetS.

Unzipping Carbon Nanotube Bundles through NH-π Stacking for Enhanced Electrical and Thermal Transport.

Bundling of single-walled carbon nanotubes (SWCNTs) significantly undermines their superior thermal and electrical properties. Realizing stable, homogeneous, and surfactant-free dispersion of SWCNTs in solvents and composites has long been regarded as a key challenge. Here, we report amine-containing aromatic and cyclohexane molecules, which are common chain extenders (CEs) for epoxy curing in industry, can be used to effectively disperse CNTs. We achieve single-tube-level dispersion of SWCNTs in CE solvents, as demonstrated by the strong chirality-dependent absorption and photoluminescence emission. The SWCNT-CE dispersion remains stable under ambient conditions for months. The excellent dispersibility and stability are attributed to the formation of an n-type charge-transfer complex through the NH-π interaction between the amine group of CEs and the delocalized π bond of SWCNTs, which is confirmed by the negative Seebeck coefficient of the CE-functionalized SWCNT films, the red shift of the G band in the Raman spectra, and the NH-π peak in X-ray photoelectron spectroscopy. The high dispersibility of CEs significantly improves the electrical and thermal transport of macroscale CNT assemblies. The sheet resistance of the CE-dispersed SWCNT thin films reaches 161 Ω sq-1 at 80.8% optical transmittance after functional modification by HNO3. Moreover, the CEs cross-link CNTs and epoxy molecules, forming a pathway for phonon transport in CNT/epoxy nanocomposites. The thermal conductivity of the CE-CNT-epoxy composite is enhanced by 1850% compared with the original epoxy, which is the highest enhancement reported to date for CNT/epoxy nanocomposites. The CE-based NH-π interaction provides a new paradigm for the effective and stable dispersion of SWCNTs in a facile and scalable process.

EXT1 methylation promotes proliferation and migration and predicts the clinical outcome of non-small cell lung carcinoma via WNT signalling pathway.

DNA methylation is important for lung cancer prognosis. In this work, it is aimed to seek novel biomarkers with DNA methylation-expression-pathway pattern and explore its underlying mechanism. Prognostic DNA methylation sites and mRNAs were screened in NSCLC data set from TCGA, and further validated using the samples retrospectively collected, and EXT1 was identified as a potential target. Gene body methylation of three CpG sites (cg03276982, cg11592677, cg16286281) on EXT1 was significantly associated with clinical outcome, and the EXT1 gene expression also predicted prognosis. The expression level of EXT1 was also correlated with its DNA methylation level. This observation was further validated in a new data set consist of 170 samples. Knocking down of EXT1 resulted in decreased proliferation and migration. EXT1 targets were analysed using GSEA. It is found that the WNT signalling is the potential downstream target of EXT1. Further analyses revealed that the EXT1 targets the beta-catenin and effect migration rate of NSCLC cell lines. The WNT signalling inhibitor, XAV-939, effectively disrupted the migration promotion effect induced by EXT1. In summary, EXT1 methylation regulates the gene expression, effects the proliferation and migration via WNT pathway and predicted a poor prognosis for NSCLC.

Neuregulin Signaling in the Tumor Microenvironment.

Neuregulins, members of the largest subclass of growth factors of the epidermal growth factor family, mediate a myriad of cellular functions including survival, proliferation, and differentiation in normal tissues through binding to receptor tyrosine kinases of the ErbB family. However, aberrant neuregulin signaling in the tumor microenvironment is increasingly recognized as a key player in initiation and malignant progression of human cancers. In this chapter, we focus on the role of neuregulin signaling in the hallmarks of cancer, including cancer initiation and development, metastasis, as well as therapeutic resistance. Moreover, role of neuregulin signaling in the regulation of tumor microenvironment and targeting of neuregulin signaling in cancer from the therapeutic perspective are also briefly discussed.

Conversions of aryl carboxylic acids into aryl nitriles using multiple types of Cu-mediated decarboxylative cyanation under aerobic conditions.

Here, we used malononitrile or AMBN as a cyanating agent to develop efficient and practical protocols for Cu-mediated decarboxylative cyanations, under aerobic conditions, of aryl carboxylic acids bearing nitro and methoxyl substituents at the ortho position as well as of heteroaromatic carboxylic acids. These protocols involved economical methods to synthesize value-added aryl nitriles from simple and inexpensive raw materials. Further diversification of the 2-nitrobenzonitrile product was performed to highlight the practicality of the protocols.

Knockdown of CYP24A1 Aggravates 1α,25(OH)2D3-Inhibited Migration and Invasion of Mouse Ovarian Epithelial Cells by Suppressing EMT.

Epithelial-mesenchymal transition (EMT) bestows cancer cells with motile and invasive properties. But for ovarian tissues, EMT plays a physiological role in the postovulatory repair of ovary surface epithelial (OSE) cells. Accumulating data indicated that 1α,25(OH)2D3 decreased both the migration and invasion of various cancer cells by suppressing EMT. However, it remains unclear whether 1α,25(OH)2D3 inhibits the process of EMT during different stages of oncogenic transformation in mouse OSE (MOSE) cells. In present study, a spontaneous malignant transformation model of MOSE cells at three sequential stages (early, intermediate and late) was established in vitro first and then subjected to 1α,25(OH)2D3 treatment to investigate the effect of 1α,25(OH)2D3 on the oncogenic transformation of MOSE cells. We found that 1α,25(OH)2D3 significantly reduced the proliferation and invasion of late malignant transformed MOSE (M-L cells) cells by inhibiting EMT both in vitro and in vivo, but not in intermediate transformed (M-I) cells. Importantly, we found that the levels of CYP24A1 in M-I cells were dramatically higher than that in M-L cells following treatment with 1α,25(OH)2D3. Furthermore, we demonstrated that, in both M-I and M-L cells with CYP24A1 knockdown, 1α,25(OH)2D3 suppressed the proliferation and invasion, and reduced the expression of N-cadherin, Vimentin, ß-catenin and Snail. In addition, knockdown of CYP24A1 suppressed EMT by increasing E-cadherin while decreasing N-cadherin, Vimentin, ß-catenin and Snail. These findings provide support for inhibiting CYP24A1 as a potential approach to activate the vitamin D pathway in the prevention and therapy of ovarian cancer.

Mesenchymal stem cell-derived exosomes protect beta cells against hypoxia-induced apoptosis via miR-21 by alleviating ER stress and inhibiting p38 MAPK phosphorylation.

BACKGROUND: Hypoxia is a major cause of beta cell death and dysfunction after transplantation. The aim of this study was to investigate the effect of exosomes derived from mesenchymal stem cells (MSCs) on beta cells under hypoxic conditions and the potential underlying mechanisms. METHODS: Exosomes were isolated from the conditioned medium of human umbilical cord MSCs and identified by WB, NTA, and transmission electron microscopy. Beta cells (ßTC-6) were cultured in serum-free medium in the presence or absence of exosomes under 2% oxygen conditions. Cell viability and apoptosis were analysed with a CCK-8 assay and a flow cytometry-based annexin V-FITC/PI apoptosis detection kit, respectively. Endoplasmic reticulum stress (ER stress) proteins and apoptosis-related proteins were detected by the WB method. MiRNAs contained in MSC exosomes were determined by Illumina HiSeq, and treatment with specific miRNA mimics or inhibitors of the most abundant miRNAs was used to reveal the underlying mechanism of exosomes. RESULTS: Exosomes derived from MSC-conditioned culture medium were 40-100 nm in diameter and expressed the exosome markers CD9, CD63, CD81, HSP70, and Flotillin 1, as well as the MSC markers CD73, CD90, and CD105. Hypoxia significantly induced beta cell apoptosis, while MSC exosomes remarkably improved beta cell survival. The WB results showed that ER stress-related proteins, including GRP78, GRP94, p-eIF2α and CHOP, and the apoptosis-related proteins cleaved caspase 3 and PARP, were upregulated under hypoxic conditions but were inhibited by MSC exosomes. Moreover, the p38 MAPK signalling pathway was activated by hypoxia and was inhibited by MSC exosomes. The Illumina HiSeq results show that MSC exosomes were rich in miR-21, let-7 g, miR-1246, miR-381, and miR-100. After transfection with miRNA mimics, the viability of beta cells under hypoxia was increased significantly by miR-21 mimic, and the p38 MAPK and ER stress-related proteins in beta cells were downregulated. These changes were reversed after exosomes were pretreated with miR-21 inhibitor. CONCLUSIONS: Exosomes derived from MSCs could protect beta cells against apoptosis induced by hypoxia, largely by carrying miR-21, alleviating ER stress and inhibiting p38 MAPK signalling. This result indicated that MSC exosomes might improve encapsulated islet survival and benefit diabetes patients.

Hesperetin reverses P­glycoprotein­mediated cisplatin resistance in DDP­resistant human lung cancer cells via modulation of the nuclear factor­κB signaling pathway.

Lung cancer is the leading cause of cancer­associated mortality worldwide. Cisplatin (DDP) is a first­line chemotherapeutic drug for the treatment of lung cancer; however, the majority of patients develop resistance to DDP. P­glycoprotein (P­gp), also referred to as multidrug resistance (MDR) protein 1, is associated with an MDR phenotype, which results in failure of cancer chemotherapy; thus, identifying effective MDR pump inhibitors may improve the outcomes of patients who develop resistance to treatment. Hesperetin is a derivative of hesperidin, which is extracted from tangerine peel and exhibits multiple antitumor properties. In the present study, human lung adenocarcinoma A549 and A549/DDP cells were treated with different concentrations of hesperetin and DDP, respectively. Furthermore, rhodamine 123 efflux assays, Cell Counting Kit­8 assays, immunofluorescence, reverse transcription­quantitative PCR and western blot analysis were used to elucidate the mechanisms underlying the effects of hesperetin On A549/DDP cells. Additionally, a xenograft model of lung cancer in nude mice was established to explore the effects of hesperetin on A549/DDP cell growth in vivo. The results demonstrated that hesperetin sensitized A549/DDP cells to DDP. In vivo, hesperetin pretreatment significantly inhibited tumor growth. Mechanistically, hesperetin markedly decreased the expression of P­gp and increased the intracellular accumulation of the P­gp substrate, rhodamine 123, in A549/DDP cells. In addition, pretreatment of A549/DDP cells with hesperetin significantly inhibited nuclear factor (NF)­κB (p65) activity and its nuclear translocation. Taken together, the results of the present study suggest that hesperetin reversed P­gp­mediated MDR by decreasing P­gp expression in A549/DDP cells, which was associated with inhibition of the NF­κB signaling pathway. These findings may provide the basis for the use of hesperetin clinically to reverse MDR.

ABAT and ALDH6A1, regulated by transcription factor HNF4A, suppress tumorigenic capability in clear cell renal cell carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is a malignancy characterized by metabolic reprogramming. ABAT and ALDH6A1 are metabolic enzymes. In this study, we aim to investigate the associations of ABAT and ALDH6A1 with the malignancy of ccRCC cells. METHODS: The gene expression levels of ABAT and ALDH6A1 in ccRCC were analyzed from gene expression microarray datasets and RNA sequencing data. Clinical information was analyzed from The Cancer Genome Atlas (TCGA) data. The distributions of ABAT and ALDH6A1 in ccRCC clinical tissues were screened by reverse transcription-quantitative polymerase chain reaction (RT-QPCR) and immunohistochemical assays. The effect of overexpression of ABAT or ALDH6A1 was measured by detecting the cell viability, migration ability, and the ratio of lactate and nicotinamide adenine dinucleotide phosphate (NADPH). Chromatin immunoprecipitation (ChIP) and luciferase reporter assays were carried out to investigate the transcript regulation of HNF4A in ABAT and ALDH6A1. RESULTS: Remarkable downregulated ABAT and ALDH6A1 expression levels were observed in ccRCC patients and low expression of ABAT and ALDH6A1 was correlated with poor survival. Overexpression of ABAT or ALDH6A1 significantly attenuated cell proliferation and migration, and impaired lactate production. In ABAT increased ccRCC cells, the ratio of NADPH/NADP+ was reduced. Finally, we demonstrated that ABAT and ALDH6A1 were directly regulated by a tumor suppressor, HNF4A. CONCLUSIONS: These observations identified HNF4A-regulated low-expressed ABAT and ALDH6A1 as promising diagnostic and prognostic biomarkers for ccRCC.

Pazopanib as salvage therapy in metastatic renal cell carcinoma with hypercalcemic crisis and renal insufficiency: a case report and literature review.

A hypercalcemic crisis in renal cell carcinoma (RCC) is an extremely rare and life-threatening condition for advanced RCC patients. It is considered nearly intractable for treatment and a poor-risk category by Memorial Sloan Kettering Cancer Center (MSKCC) criteria. In our case, best supportive care was regularly administered according to the related guidelines and consensuses but with little high-quality, prospective clinical trial data to support the therapeutic strategy. Indeed, determining the individual etiological treatment for a given patient can be challenging. Here, we present a typical case with hypercalcemic crisis, reduced renal function (chronic kidney disease, CKD4), and poor performance status. The patient, who was treated with pazopanib of an individual lower dose of 200 mg daily as salvage therapy, had significantly improved quality of life (QOL) and prolonged progression-free survival (PFS) and overall survival (OS). These are the first results of their kind to be reported of a clinical benefit being generally observed with single doses of 800 mg. How to individually control the primary disease and concurrently relieve the symptoms in clinic to improve QOL and prolong the patient's PFS and OS is worthy of exploration.

Icariin induces apoptosis of human lung adenocarcinoma cells by activating the mitochondrial apoptotic pathway.

Lung cancer is the largest cause of morbidity and mortality among tumor diseases. Traditional first-line chemotherapeutic drugs are frequently accompanied by serious side effects when used to treat tumors, thus, novel drugs with reduced toxic effects may improve a patients' quality of life. Icariin, an extract of herba epimedii, has been demonstrated to exhibit multiple antitumor effects with low toxicity. In the present study, cell cycle analysis, apoptosis assays, DAPI staining, CCK8 assays, xenograft tumor models, mitochondrial membrane potential analysis, western blotting and reverse transcription-quantitative PCR were performed to determine the molecular mechanism underlying icariin activity in the human lung adenocarcinoma cell lines, A549 and H1975. The results showed that icariin reduced proliferation of A549 and H1975 cells in a time- and dose-dependent manner in vitro to a greater degree than the control BEAS-2B cells, and this was associated with increased apoptosis, but not with cell cycle progression. In vivo experiments showed that icariin treatment significantly decreased proliferation of H1975 cells in a xenograft mouse model. Mechanistically, icariin activated the mitochondrial pathway by inhibiting the activation of the PI3K-Akt pathway-associated kinase, Akt, resulting in the activation of members of the caspase family of proteins, and thus inducing apoptosis of A549 cells. Taken together, the results revealed that icariin has anti-cancer properties in lung cancer in vitro and in vivo without any noticeable toxic effects on normal lung epithelial cells. Icariin in combination with conventional anti-cancer agents may be an effective therapeutic strategy for treatment of lung carcinoma.

LAT, HOXD3 and NFE2L3 identified as novel DNA methylation-driven genes and prognostic markers in human clear cell renal cell carcinoma by integrative bioinformatics approaches.

Background: Abnormal DNA methylation of is one of the important mechanisms leading to tumor pathogenesis. The purpose of this study was to explore differentially methylated genes that may drive the development of renal clear cell carcinoma through a comprehensive analysis of the TCGA database. Materials and methods: Methylation data and RNA-seq data for clear cell renal cell carcinoma were downloaded from The Cancer Genome Atlas (TCGA). Differentially methylated genes and the differential genes associated with survival were then screened by MethylMix R package and univariate Cox proportional-hazards model, respectively. Their common genes were then intersected and obtained for further analysis. Correlation of gene expression and methylation levels, gene set enrichment analysis (GSEA) enrichments, survival curve, and ROC curve plotting for DNA methylation-driven genes were finally performed. The methylation alterations of the three genes were validated via two GEO datasets (GSE70303 and GSE113501), and the genes expression level was verified through two GEO datasets (GSE6344 and GSE53757). Results: Three novel DNA methylation-driven genes LAT, HOXD3 and NFE2L3 were identified in clear cell renal cell carcinoma. Expression analysis further revealed that hypomethylation levels of LAT and NFE2L3 showed higher gene expression levels, while HOXD3 exhibited opposite methylation-expression pattern. The CpG sites of LAT (cg16462073), HOXD3 (cg24000528) and NFE2L3 (cg16882373) that may affect respective gene expressions were also identified. For the survival analysis, we found that hypomethylation and over-expression of LAT and NFE2L3 were correlated with poor survival, while hypermethylation and low-expression HOXD3 was correlated with poor survival of clear cell renal cell carcinoma patients. In addition, GSEA KEGG analysis and biological processes of these genes were also enriched for functional analysis. Kaplan-Meier survival and ROC analyses of these genes showed an average risk score of 0.9140593, AUC = 0.692, which suggested a good clinical application value. Finally, the opposite methylation-expression pattern of these three genes were verified in GEO datasets. Conclusions: In this study, we successfully exhibited the potential DNA methylation-driven genes LAT, HOXD3, and NFE2L3 involved in clear cell renal cell carcinoma. Moreover, gene functions and prognostic risk models were also elucidated, which facilitated the expansion of the current study on the role of methylation in the pathology process of clear cell renal cell carcinoma.

Integrative gene expression profiling reveals that dysregulated triple microRNAs confer paclitaxel resistance in non-small cell lung cancer via co-targeting MAPT.

BACKGROUND: Paclitaxel has shown significant anti-tumor activity against non-small cell lung cancer (NSCLC); however, resistance to paclitaxel frequently occurs and represents a significant clinical problem and its underlying molecular mechanism remains elusive. METHODS: Long-term treatment of culture cell with paclitaxel was carried out to mimic the development of acquired drug resistance in NSCLC. Cell proliferation and clonogenic assay and apoptosis evaluation were carried out to determine the efficacy of paclitaxel on NSCLC cells. Western blot analyses were performed to determine the expression and activation of proteins. Apoptosis enzyme-linked immunosorbent assay was used to quantify cytoplasmic histone-associated DNA fragments. Microarray analyses were applied to explore both mRNA and miRNA expression profiles in NSCLC cells followed by integrative analysis. qRT-PCR was carried out to verify the differentially expressed mRNAs and miRNAs. RESULTS: The expression of 652 genes was shown to be changed at least 2-fold in paclitaxel-resistant NSCLC (H460_TaxR) cells with 511 upregulated and 141 downregulated as compared with that in parental H460 cells. The differentially expressed genes were functionally enriched in regulating the cell proliferation, cell death, and response to endogenous stimulus, and clustered in pathways such as cancer and signaling by the G protein-coupled receptor (GPCR). Moreover, 43 miRNAs were shown to be differentially expressed in H460_TaxR cells with 15 upregulated and 28 downregulated as compared with parental H460 cells. A total of 289 pairs of miRNA-potential target gene were revealed in H460_TaxR cells by bioinformatics analysis. Furthermore, integrative analysis of miRNAs and gene expression profiles revealed that dysregulated miR-362-3p, miR-766-3p, and miR-6507-3p might confer paclitaxel resistance in NSCLC via targeting MAPT simultaneously. CONCLUSION: Our findings suggested that specific manipulation of MAPT-targeting miRNAs may be a novel strategy to overcome paclitaxel resistance in patients with NSCLC especially large-cell lung carcinoma.

miR-192/215-5p act as tumor suppressors and link Crohn's disease and colorectal cancer by targeting common metabolic pathways: An integrated informatics analysis and experimental study.

MicroRNAs have emerged as key regulators involved in a variety of biological processes. Previous studies have demonstrated that miR-192/215 participated in progression of Crohn's disease and colorectal cancer. However, their concrete relationships and regulation networks in diseases remain unclear. Here, we used bioinformatics methods to expound miR-192/215-5p macrocontrol regulatory networks shared by two diseases. For data mining and figure generation, several miRNA prediction tools, Human miRNA tissue atlas, FunRich, miRcancer, MalaCards, STRING, GEPIA, cBioPortal, GEO databases, Pathvisio, Graphpad Prism 6 software, etc . are extensively applied. miR-192/215-5p were specially distributed in colon tissues and enriched biological pathways were closely associated with human cancers. Emerging role of miR-192/215-5p and their common pathways in Crohn's disease and colorectal cancer was also analyzed. Based on results derived from multiple approaches, we identified the biological functions of miR-192/215-5p as a tumor suppressor and link Crohn's disease and colorectal cancer by targeting triglyceride synthesis and extracellular matrix remodeling pathways.

Pd-Catalyzed Decarboxylative Ortho-Halogenation of Aryl Carboxylic Acids with Sodium Halide NaX Using Carboxyl as a Traceless Directing Group.

A highly regioselective Pd-catalyzed carboxyl directed decarboxylative ortho-C-H halogenation of cheap o-nitrobenzoic acids with NaX (X = I, Br) under aerobic conditions has been established. The utility of the method has been demonstrated by the gram-scale reaction and derivatization of the product. Experimental results have confirmed Pd and Bi played critical roles in the transformation and indicated the transformation might proceed via 2-halo-6-nitrobenzoic acid derivative intermediate.

Valproic acid exhibits anti-tumor activity selectively against EGFR/ErbB2/ErbB3-coexpressing pancreatic cancer via induction of ErbB family members-targeting microRNAs.

BACKGROUND: Deregulated ErbB signaling plays an important role in tumorigenesis of pancreatic cancer. However, patients with pancreatic cancer benefit little from current existed therapies targeting the ErbB signaling. Here, we explore the potential anti-tumor activity of Valproic acid against pancreatic cancer via targeting ErbB family members. METHODS: Cell viability assay and apoptosis evaluation were carried out to determine the efficacy of VPA on pancreatic cancer cells. Western blot analyses were performed to determine the expression and activation of proteins. Apoptosis enzyme-linked immunosorbent assay was used to quantify cytoplasmic histone associated DNA fragments. Lentiviral expression system was used to introduce overexpression of exogeneous genes or gene-targeting short hairpin RNAs (shRNAs). qRT-PCR was carried out to analyze the mRNAs and miRNAs expression levels. Tumor xenograft model was established to evaluate the in vivo anti-pancreatic cancer activity of VPA. RESULTS: VPA preferentially inhibited cell proliferation/survival of, and induced apoptosis in EGFR/ErbB2/ErbB3-coexpressing pancreatic cancer cells within its clinically achievable range [40~100 mg/L (0.24~0.6 mmol/L)]. Mechanistic investigations revealed that VPA treatment resulted in simultaneous significant down-regulation of EGFR, ErbB2, and ErbB3 in pancreatic cancer cells likely via induction of ErbB family members-targeting microRNAs. Moreover, the anti-pancreatic cancer activity of VPA was further validated in tumor xenograft model. CONCLUSIONS: Our data strongly suggest that VPA may be added to the treatment regimens for pancreatic cancer patients with co-overexpression of the ErbB family members.

Prognostic values of GMPS, PR, CD40, and p21 in ovarian cancer.

Early detection and prediction of prognosis and treatment responses are all the keys in improving survival of ovarian cancer patients. This study profiled an ovarian cancer progression model to identify prognostic biomarkers for ovarian cancer patients. Mouse ovarian surface epithelial cells (MOSECs) can undergo spontaneous malignant transformation in vitro cell culture. These were used as a model of ovarian cancer progression for alterations in gene expression and signaling detected using the Illumina HiSeq2000 Next-Generation Sequencing platform and bioinformatical analyses. The differential expression of four selected genes was identified using the gene expression profiling interaction analysis (http://gepia.cancer-pku.cn/) and then associated with survival in ovarian cancer patients using the Cancer Genome Atlas dataset and the online Kaplan-Meier Plotter (http://www.kmplot.com) data. The data showed 263 aberrantly expressed genes, including 182 up-regulated and 81 down-regulated genes between the early and late stages of tumor progression in MOSECs. The bioinformatic data revealed four genes (i.e., guanosine 5'-monophosphate synthase (GMPS), progesterone receptor (PR), CD40, and p21 (cyclin-dependent kinase inhibitor 1A)) to play an important role in ovarian cancer progression. Furthermore, the Cancer Genome Atlas dataset validated the differential expression of these four genes, which were associated with prognosis in ovarian cancer patients. In conclusion, this study profiled differentially expressed genes using the ovarian cancer progression model and identified four (i.e., GMPS, PR, CD40, and p21) as prognostic markers for ovarian cancer patients. Future studies of prospective patients could further verify the clinical usefulness of this four-gene signature.