Mineralization of pH-Sensitive Doxorubicin Prodrug in ZIF-8 to Enable Targeted Delivery to Solid Tumors

The zeolitic imidazolate framework (ZIF-8), composed of zinc ion and dimethylimidazole, is widely used in drug delivery because of the easy fabrication process and the good biosafety. However, ZIF-8 suffers from low affinity to nonelectric-rich drugs and does not have surface functional groups. Here, to deliver doxorubicin (DOX) with ZIF-8 to specific target sites, DOX was first modified with a pH-sensitive linker containing two carboxyl groups to form the inactive prodrug CAD and subsequently seeded inside ZIF-8 by a 5 min mineralization process. CAD has high affinity to ZIF-8 because of the carboxyl groups and can anchor to the ZIF-8 surface to enable the surface modification with folic acid for tumor targeting. Moreover, the DOX release is precisely controlled by three steps of acidic pH response, with the dissociation of the FA layer, the breakdown of the ZIF-8 structure, and the cleavage of the pH-sensitive linker in prodrug. This novel "prodrug-ZIF-8" strategy has opened a new horizon in drug delivery

Epimorphin Regulates Bile Duct Formation via Effects on Mitosis Orientation in Rat Liver Epithelial Stem-Like Cells

Understanding how hepatic precursor cells can generate differentiated bile ducts is crucial for studies on epithelial morphogenesis and for development of cell therapies for hepatobiliary diseases. Epimorphin (EPM) is a key morphogen for duct morphogenesis in various epithelial organs. The role of EPM in bile duct formation (DF) from hepatic precursor cells, however, is not known. To address this issue, we used WB-F344 rat epithelial stem-like cells as model for bile duct formation. A micropattern and a uniaxial static stretch device was used to investigate the effects of EPM and stress fiber bundles on the mitosis orientation (MO) of WB cells. Immunohistochemistry of liver tissue sections demonstrated high EPM expression around bile ducts in vivo. In vitro, recombinant EPM selectively induced DF through upregulation of CK19 expression and suppression of HNF3α and HNF6, with no effects on other hepatocytic genes investigated. Our data provide evidence that EPM guides MO of WB-F344 cells via effects on stress fiber bundles and focal adhesion assembly, as supported by blockade EPM, β1 integrin, and F-actin assembly. These blockers can also inhibit EPM-induced DF. These results demonstrate a new biophysical action of EPM in bile duct formation, during which determination of MO plays a crucial role

An immune-related gene prognostic risk index for pancreatic adenocarcinoma

ObjectiveOur goal is to construct an immune-related gene prognostic risk index (IRGPRI) for pancreatic adenocarcinoma (PAAD), and to clarify the immune and molecular features in IRGPRI-defined PAAD subgroups and the benefit of immune checkpoint inhibitors (ICIs) therapy.MethodThrough differential gene expression analysis, weighted gene co-expression network analysis (WGCNA), and univariate Cox regression analysis, 16 immune-related hub genes were identified using the Cancer Genome Atlas (TCGA) PAAD dataset (n = 182) and immune gene set. From these genes, we constructed an IRGPRI with the Cox regression method and the IRGPRI was verified based on the Gene Expression Omnibus (GEO) dataset (n = 45). Then, we analyzed the immune and molecular features and the benefit of ICI therapy in IRGPRI-defined subgroups.ResultsFive genes, including S100A16, CD40, VCAM1, TNFRSF4 and TRAF1 were used to construct IRGPRI. As with the results of the GEO cohort, the overall survival (OS) was more favorable in low IRGPRI patients versus high IRGPRI patients. The composite results pointed out that low IRGPRI was associated with immune response-related pathways, high level of CTLA4, low KRAS and TP53 mutation rate, more infiltration of activated memory CD4+ T cells, CD8+ T cells, and more benefits from ICIs therapy. In comparison, high IRGPRI was associated with cancer-related pathways, low expression of CTLA4, high KRAS and TP53 mutation rate, more infiltration of M2 macrophages, and less benefit from ICIs therapies.ConclusionThis IRGPRI is an encouraging biomarker to define the prognosis, immune and molecular features, and benefits from ICIs treatments in PAAD

Rap2B promotes proliferation, migration and invasion of human breast cancer through calcium-related ERK1/2 signaling pathway

Rap2B, a member of GTP-binding proteins, is widely upregulated in many types of tumors and promotes migration and invasion of human suprarenal epithelioma. However, the function of Rap2B in breast cancer is unknown. Expression of Rap2B was examined in breast cancer cell lines and human normal breast cell line using Western blot analysis. Using the CCK-8 cell proliferation assay, cell cycle analysis, and transwell migration assay, we also elucidated the role of Rap2B in breast cancer cell proliferation, migration, and invasion. Results showed that the expression of Rap2B is higher in tumor cells than in normal cells. Flow cytometry and Western blot analysis revealed that Rap2B elevates the intracellular calcium level and further promotes extracellular signal-related kinase (ERK) 1/2 phosphorylation. By contrast, calcium chelator BAPTM/AM and MEK inhibitor (U0126) can reverse Rap2B-induced ERK1/2 phosphorylation. Furthermore, Rap2B knockdown inhibits cell proliferation, migration, and invasion abilities via calcium related-ERK1/2 signaling. In addition, overexpression of Rap2B promotes cell proliferation, migration and invasion abilities, which could be neutralized by BAPTM/AM and U0126. Taken together, these findings shed light on Rap2B as a therapeutic target for breast cancer

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Molecular characteristics, recombinant expression and activity detection of OsGSTL1 from rice

The mRNA of OsGSTL1 was detected in the roots and leaves of rice plants at seedling and tillering stages, and their roots, leaves and panicles at the heading stage. The full-length open reading frame of OsGSTL1 cDNA was 732 bp and encoded a putative polypeptide of 243 amino acids with a calculated molecular mass of 27.30 kDa and a theoretical pI of 5.50. The protein sequences of OsGSTL1 exhibited typical feature of the lambda class GST, which contained the conserved domain "GST_C_Lambda" in C-terminal alpha helical domain and a highly conserved Cys42 in active center. In silico predictions showed that the OsGSTL1 protein was strongly hydrophilic. The phylogenetic analysis revealed OsGSTL1 belonged to monocots subgroup and was closer to IN2-1 of Z. may. The OsGSTL1 gene was cloned into pYTV vector and was introduced into yeast strain PEP4. Western blot analysis showed that the exogenous OsGSTL1 was expressed in the transformed yeast. The GST activity of the crude extracts of yeast showed that the OsGSTL1 transgenic yeast had higher levels of GST activities than the control yeasts. These findings suggested that the OsGSTL1 was a glutathione S-transferase and could play an important role during the growth and development processes in rice