Structure and growth pattern of the bizarre hemispheric prominence on the rostrum of the fossil beaked whale Globicetus hiberus (Mammalia,Cetacea, Ziphiidae)

The rostrum of most ziphiids (beaked whales) displays bizarre swollen regions, accompanied with extreme hypermineralisation and an alteration of the collagenous mesh of the bone. The functional significance of this specialization remains obscure. With the voluminous and dense hemispheric excrescence protruding from the premaxillae, the recently described fossil ziphiid Globicetus hiberus is the most spectacular case. This study describes the histological structure and interprets the growth pattern of this unique feature. Histologically, the prominence in Globicetus is made up of an atypical fibro‐lamellar complex displaying an irregular laminar organization and extreme compactness (osteosclerosis). Its development is suggested to have resulted from a protraction of periosteal accretion over the premaxillae, long after the end of somatic growth. Complex shifts in the geometry of this tissue are likely to have occurred during its accretion and no indication of Haversian remodeling could be found. X‐ray diffraction and Raman spectroscopy indicate that the bone matrix in the premaxillary prominence of Globicetus closely resembles that of the rostrum of the extant beaked whale Mesoplodon densirostris: apatite crystals are of common size and strongly oriented, but the collagenous meshwork within bone matrix seems to be extremely sparse. These morphological and structural data are discussed in the light of functional interpretations proposed for the highly unusual and diverse ziphiid rostrum. J. Morphol. 277:1292–1308, 2016. © 2016 Wiley Periodicals, Inc.     

A three-step screening procedure to identify the mode of phloem loading in intact leaves

A three-step screening method was developed to identify the mode of phloem loading in intact leaves. Phloem loading of ¹⁴CO₂-derived photosynthate was challenged by p-chloromercuribenzenesulfonic acid (PCMBS) in leaves of dicotyledons with either a symplasmic (type 1, with intermediary cells as companion cells) or apoplasmic (type 2b, with transfer cells as companion cells) minor-vein configuration. Firstly, photosynthate export as the result of phloem loading was measured by collection of phloem exudate from the petiole. The PCMBS had virtually no effect on photosynthate export in representatives of type-1 families (Lamiaceae, Lythraceae, Onagraceae, Saxifragaceae). In contrast, photosynthate export was strongly reduced by PCMBS in representatives of type-2b families (Asteraceae, Balsaminaceae, Dipsacaceae, Linaceae, Tropaeolaceae, Valerianaceae) and type-2b members of polytypical families (Fabaceae, Scrophulariaceae). Secondly, densitometric measurements of leaf autoradiographs demonstrated that the contrast between the mesophyll and the lower-order veins was hardly affected by PCMBS treatment in type-1 species, whereas PCMBS strongly reduced the contrast in type-2b species. Thirdly, separate ¹⁴C-radioassays of vein and mesophyll tissues confirmed this observation. The three-step procedure thus revealed a strong and consistent reduction of phloem loading by PCMBS in type-2b species which was absent in type-1 species. In conclusion, phloem loading in type-2b species occurs via the apoplast and type-1 species execute an alternative — most likely symplasmic — mode of phloem loading.Abbreviations PCMBS p-chloromercuribenzenesulfonic acid - SE/CC-complex sieve element/companion cell complex We gratefully acknowledge the expert help of Dr. Maarten Terlou, Department of Image Processing and Design, University of Utrecht, in carrying out the densitometric measurements.     

Natural product pectolinarigenin exhibits potent anti-metastatic activity in colorectal carcinoma cells in vitro and in vivo

Colorectal carcinoma (CRC) is one of the most common cancers with high metastatic potential, explaining why identifying new drug candidates that inhibit tumour metastasis is an urgent need. The aim of this study was to evaluate the biological activities of pectolinarigenin (PEC, a natural flavonoid present in Cirsium chanroenicum) in CRC in vitro and in vivo and to determine its underlying mechanism of action. Here, we observed that treatment with PEC could inhibit cell viability and induce apoptosis in cancer cells in a concentration- and time-dependent manner. The occurrence of apoptosis was associated with activation of caspase-3 and Bax and decreased expression of Bcl-2. In addition, PEC markedly impaired CRC cell migration and invasion by downregulating the expression of matrix metalloproteinase (MMP-9) and phosphorylated-Stat3^Tyr705. Moreover, our studies showed that PEC inhibited abdominal metastasis models of murine colorectal cancer. In addition, histological and immunohistochemical analyses revealed a decrease in Ki67-positive cells, MMP9-positive cells and p-Stat3^Tyr705 cells upon treatment with PEC compared to control samples. Furthermore, PEC reduced the number of myeloid-derived suppressor cells (MDSCs) in the blood and tumours, which was accompanied by the increased infiltration of CD8⁺T cells in the blood. Taken together, our findings suggested that PEC could be used as a natural drug to inhibit CRC metastasis.     

Bone marrow-derived mesenchymal stem cells repair severe acute pancreatitis by secreting miR-181a-5p to target PTEN/Akt/TGF-β1 signaling

BackgroundSevere acute pancreatitis (SAP) is associated with high morbidity and mortality. Bone marrow mesenchymal stem cells (BMSCs) have shown obvious protective effect on SAP. However, little is known about the underlying mechanism. The objective of this study is to unravel the role and regulatory mechanism of miR-181a-5p in BMSCs-mediated pancreatic repair.MethodsBMSCs were isolated from Sprague-Dawley rats and characterized by flow cytometry and Oil Red O staining. Sodium taurocholate- and caerulein-induced models were used as SAP models in vivo and in vitro, respectively. Pancreatic injury were evaluated by H&E and histopathological analysis, as well as by measuring levels of amylase, lipase and cytokines. qRT-PCR and western blotting were performed to detect the level of miR-181a-5p and the protein levels of PTEN/Akt, respectively. ELISA was conducted to detect the levels of TNF-α, IL-1β, IL-6, angiopoietin, IL-4, IL-10 and TGF-β1. The apoptotic rate of AR42 J cells was quantitated by concurrent staining with Annexin-V-FITC and PI.ResultsBMSCs significantly attenuated pancreatic injury in SAP rats by reducing inflammatory infiltration and necrosis, and this effect was abolished by CXCR4 agonist AMD3100. ADM3100 exhibited more severe pancreatic injury and decreased miR-181a-5p levels in the pancreas and serum compared to SAP group. Overexpression of miR-181a-5p in BMSCs (BMSCs-miR-181a-5p) markedly potentiated the protective effect of BMSCs by reducing histological damage and levels of amylase and lipase. Moreover, BMSCs-miR-181a-5p dramatically reduced levels of angiopoietin, TNF-α, IL-1β and IL-6, but induced the levels of IL-4 and IL-10. In caerulein-treated AR42 J cells, co-culturing of BMSCs-miR-181a-5p alleviated caerulein-induced increase of amylase and lipase, and apoptosis via PTEN/Akt/TGF-β1 signaling.ConclusionBMSCs alleviate SAP and reduce inflammatory responses and apoptosis by secreting miR-181a-5p to target PTEN/Akt/TGF-β1 signaling. Hence, BMSCs-miR-181a-5p could serve as potential therapeutic target for SAP.     

Elevated PRC1 in gastric carcinoma exerts oncogenic function and is targeted by piperlongumine in a p53‐dependent manner

Gastric carcinoma is one of the most common malignancies worldwide and the second most frequent cause of cancer‐related death in China. Protein regulator of cytokinesis 1 (PRC1) is involved in cytokinesis and plays key roles in microtubule organization in eukaryotes. This study was aimed to analyse the expression and to investigate the functional role of PRC1 in gastric tumorigenesis. The expression of PRC1 was evaluated by qRT‐PCR, Western blot and immunohistochemistry. The biological function of PRC1 was determined by CCK‐8 proliferation assays, monolayer colony formation, xenografted nude mice and cell invasion assays by shRNA‐mediated knockdown in AGS and HGC27 cells. The regulation of PRC1 expression by piperlongumine was also investigated using dual‐luciferase reporter assay and ChIP‐qPCR analysis. PRC1 was up‐regulated in primary gastric cancers. Overexpression of PRC1 in gastric cancers was associated with poor disease‐specific survival and overall survival. PRC1 knockdown in AGS and HGC27 cell lines suppressed proliferation, reduced monolayer colony formation, inhibited cell invasion and migration ability and induced cell‐cycle arrest and apoptosis. Inhibition of PRC1 also suppressed tumour growth in vivo. We finally confirmed that PRC1 is a novel downstream target of piperlongumine in gastric cancer. Our findings supported the oncogenic role of PRC1 in gastric carcinogenesis. PRC1 might serve as a prognostic biomarker and potential therapeutic target for gastric carcinoma.     

Actin pegs and ultrastructure of presumed sensory receptors of Beroë (Ctenophora)

Summary We have investigated the actin content and ultrastructure of two kinds of presumed sensory projections on the lip epidermis of beroid ctenophores. Transmission electron microscopy showed that conical pegs contain a large bundle of densely packed, parallel microfilaments. Rhodamine-phalloidin brightly stained the pegs, confirming that they contain filamentous actin. Epidermal cells with actin pegs also bear a single long cilium with an onion-root structure, previously described as arising from a different type of cell. The actin peg and onion-root cilium project side-by-side, defining a polarized axis of the cell which is shared by neighboring cells. The onion-root body is surrounded by a flattened membranes sac which lies immediately below the plasma membrane. The perimeter of the membrane sac is encircled by aggregates of dense material. An extra layer of dense material is found along the side of the membrane sac facing the peg; this material often makes direct contact with the adjacent actin filament bundle. Cells with actin pegs and onion-root cilia synapse onto adjacent neurites and secretory gland cells, indicating that one or both types of projections are sensory elements. Since the feeding responses of beroids are reported to depend on chemical and tactile stimuli to the lips, the cells bearing pegs and cilia may function as both mechanoreceptors and chemoreceptors, that is, as double sensory receptors.     

PD-1/PD-L1 pathway: Basic biology and role in cancer immunotherapy

Over the course of past few years, cancer immunotherapy has been accompanied with promising results. However, preliminary investigations with respect to immunotherapy concentrated mostly on targeting the immune checkpoints, nowadays, emerge as the most efficient strategy to raise beneficial antitumor immune responses. Programmed cell death protein 1 (PD-1) plays an important role in subsiding immune responses and promoting self-tolerance through suppressing the activity of T cells and promoting differentiation of regulatory T cells. PD-1 is considered as an immune checkpoint and protects against autoimmune responses through both induction of apoptosis in antigen-specific T cells and inhibiting apoptosis in regulatory T cells. Several clinical trials exerting PD-1 monoclonal antibodies as well as other immune-checkpoint blockades have had prosperous outcomes and opened new horizons in tumor immunotherapy. Nonetheless, a bulk of patients have failed to respond to these newly emerging immune-based approach and the survival rate was not satisfying. Additional strategies, especially combination therapies, has been initiated and been further promising. Attempts to identify novel and well-suited predictive biomarkers are also sensed. In this review, the promotion of cancer immunotherapy targeting PD-1 immunoinhibitory pathway is discussed.     

Systematic analysis of multigene predictors in gastric cancer exploiting gene expression signature

Gastric cancer (GC) is the second most common cause of cancer death worldwide but could be more curable if diagnosed at an earlier stage. At present, the capability to predict the efficaciousness of molecular diagnosis for GC for each patient remains elusive. The purpose of this study was to identify tumor biomarkers through systems analysis of multigene predictors exploiting the available data resource. In this study, we investigated the top 10% overexpressed genes in GC from five data sets of the Oncomine platform, with 265 GC samples versus 174 normal gastric mucosa samples. Sixteen candidate genes were identified as predictors of GC, of which 14 genes were verified through the comparison of expression levels in specimens from normal (chronic gastritis, 21 samples) and GC groups (38 samples). In addition, unique molecular portraits of diffuse adenocarcinoma (DA), intestinal adenocarcinoma (IA), and mixed adenocarcinoma (MA) were studied through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis, where DA showed higher extracellular matrix alteration while IA and MA showed higher cell-cycle alteration than other types. We also found that the elevated expressions of genes during GC progression were independent of gene mutations, and high core-binding factor subunit β expression is correlated with a high overall survival rate in GC patients. Our research may provide an efficient clinical diagnosis of GC at an early stage with high accuracy and thus help improve the overall survival rate through early therapeutic interventions.     

LINC01342 promotes the progression of ovarian cancer by absorbing microRNA-30c-2-3p to upregulate HIF3A

Ovarian cancer (OC) is a highly prevalent gynecologic malignancy and its mortality is extremely high. Therefore, the development of novel therapeutic approaches for OC is of great significance. In this study, LINC01342 was upregulated in OC tissue in the GSE38666 microarray and in tumor tissue samples collected in our center. The silencing of LINC01342 suppressed the proliferative and metastatic capacities of A2780 and HO8910 cells. Subcellular distribution assays showed that LINC01342 was mainly enriched in the cytoplasm. Subsequently, the downregulation of microRNA-30c-2-3p was proven to be the target of LINC01342. The silencing of microRNA-30c-2-3p enhanced the clonality and migratory capacity of OC cells. Moreover, the silencing of microRNA-30c-2-3p could reverse the inhibited migration and clonality in OC cells caused by LINC01342 knockdown. In addition, hypoxia-inducible factor 3 subunit α (HIF3A) was proven to be the target gene of microRNA-30c-2-3p, which was upregulated. HIF3A was negatively regulated by microRNA-30c-2-3p but positively regulated by LINC01342 in OC cells. An RNA binding protein immunoprecipitation assay showed that microRNA-30c-2-3p, LINC01342, and HIF3A could bind to argonaute RISC catalytic component 2. The overexpression of HIF3A reversed the inhibited migration and clonality in OC cells with LINC01342 knockdown. By analyzing the follow-up data from the enrolled OC patients, the LINC01342 and HIF3A levels were negatively correlated with prognosis, while the microRNA-30c-2-3p level was positively correlated with the same. In short, the upregulated LINC01342 in OC absorbs microRNA-30c-2-3p to release HIF3A. Thus, upregulated HIF3A expression accelerates the progression of OC.