MMP14 regulates the lineage progression of hypertrophic chondrocytes

It is traditionally believed that chondrocytes and osteoblasts are two separate lineages with hypertrophic chondrocytes (HCs) being the terminal stage of chondrocyte differentiation, culminating in apoptosis. However, we have shown that HCs can contribute to the full osteoblast (Obs) lineage in vivo. MMP14 is a transmembrane matrix metalloproteinase responsible for matrix remodeling that is highly expressed at the chondro‐osseous junction which coincides with the transition from HCs to Obs. Knockout of Mmp14 in mice results in impaired endochondral ossification. To test whether loss of MMP14 has an impact on the HC to Obs transition, we have employed a genetic recombination approach to track and compare the fate of HCs in wild‐type and Mmp14 conditional and total null mutants. Both complete and conditional deletion of MMP14 activity results in increased number of HC‐descendent cells in the trabecular bone. Surprisingly, conditional knockout of Mmp14 in HC‐descendent cells results in increased trabecular bone formation. Our results suggest that MMP14 in general negatively regulates HC to Obs transition.postprin

Calycosin and Formononetin Induce Endothelium-Dependent Vasodilation by the Activation of Large-Conductance Ca2+-Activated K+ Channels (BKCa)

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Berberine induces autophagic cell death and mitochondrial apoptosis in liver cancer cells: The cellular mechanism

Extensive studies have revealed that berberine, a small molecule derived from Coptidis rhizoma (Huanglian in Chinese) and many other plants, has strong anti-tumor properties. To better understand berberine-induced cell death and its underlying mechanisms in cancer, we examined autophagy and apoptosis in the human hepatic carcinoma cell lines HepG2 and MHCC97-L. The results of this study indicate that berberine can induce both autophagy and apoptosis in hepatocellular carcinoma cells. Berberine-induced cell death in human hepatic carcinoma cells was diminished in the presence of the cell death inhibitor 3-methyladenine, or following interference with the essential autophagy gene Atg5. Mechanistic studies showed that berberine may activate mitochondrial apoptosis in HepG2 and MHCC97-L cells by increasing Bax expression, the formation of permeable transition pores, cytochrome C release to cytosol, and subsequent activation of the caspases 3 and 9 execution pathway. Berberine may also induce autophagic cell death in HepG2 and MHCC97-L cells through activation of Beclin-1 and inhibition of the mTOR-signaling pathway by suppressing the activity of Akt and up-regulating P38 MAPK signaling. This is the first study to describe the role of Beclin-1 activation and mTOR inhibition in berberine-induced autophagic cell death. These results further demonstrate the potential of berberine as a therapeutic agent in the emerging list of cancer therapies with novel mechanisms. © 2010 Wiley-Liss, Inc.postprin

Impact of G 2 checkpoint defect on centromeric instability

Centromeric instability is characterized by dynamic formation of centromeric breaks, deletions, isochromosomes and translocations, which are commonly observed in cancer. So far, however, the mechanisms of centromeric instability in cancer cells are still poorly understood. In this study, we tested the hypothesis that G 2 checkpoint defect promotes centromeric instability. Our observations from multiple approaches consistently support this hypothesis. We found that overexpression of cyclin B1, one of the pivotal genes driving G 2 to M phase transition, impaired G 2 checkpoint and promoted the formation of centromeric aberrations in telomerase-immortalized cell lines. Conversely, centromeric instability in cancer cells was ameliorated through reinforcement of G 2 checkpoint by cyclin B1 knockdown. Remarkably, treatment with KU55933 for only 2.5 h, which abrogated G 2 checkpoint, was sufficient to produce centromeric aberrations. Moreover, centromeric aberrations constituted the major form of structural abnormalities in G 2 checkpoint-defective ataxia telangiectasia cells. Statistical analysis showed that the frequencies of centromeric aberrations in G 2 checkpoint-defective cells were always significantly overrepresented compared with random assumption. As there are multiple pathways leading to G 2 checkpoint defect, our finding offers a broad explanation for the common occurrence of centromeric aberrations in cancer cells. © 2011 Macmillan Publishers Limited All rights reserved.postprin

Cyclin D1 overexpression supports stable EBV infection in nasopharyngeal epithelial cells

Undifferentiated nasopharyngeal carcinomas (NPCs) are commonly present with latent EBV infection. However, events regulating EBV infection at early stages of the disease and the role of EBV in disease pathogenesis are largely undefined. Genetic alterations leading to activation of cyclin D1 signaling in premalignant nasopharyngeal epithelial (NPE) cells have been postulated to predispose cells to EBV infection. We previously reported that loss of p16, a negative regulator of cyclin D1 signaling, is a frequent feature of NPC tumors. Here, we report that early premalignant lesions of nasopharyngeal epithelium overexpress cyclin D1. Furthermore, overexpression of cyclin D1 is closely associated with EBV infection. Therefore we investigated the potential role of cyclin D1 overexpression in dysplastic NPE cells in vitro. In human telomerase reverse transcriptase-immortalized NPE cells, overexpression of cyclin D1 or a p16-resistant form of CDK4 (CDK4(R24C)) suppressed differentiation. This suppression may have implications for the close association of EBV infection with undifferentiated NPC. In these in vitro models, we found that cellular growth arrest and senescence occurred in EBV-infected cell populations immediately after infection. Nevertheless, overexpression of cyclin D1 or a p16-resistant form of CDK4 or knockdown of p16 in the human telomerase reverse transcriptase-immortalized NPE cell lines could counteract the EBV-induced growth arrest and senescence. We conclude that dysregulated expression of cyclin D1 in NPE cells may contribute to NPC pathogenesis by enabling persistent infection of EBV.published_or_final_versio

High Diversity of Genogroup I Picobirnaviruses in Mammals

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The Impact of the Oncotype DX Breast Cancer Assay on Treatment Decisions for Women With Estrogen Receptor-Positive, Node-Negative Breast Carcinoma in Hong Kong

Background The Oncotype DX Breast Cancer Assay is validated to assess risk of distant recurrence and likelihood of chemotherapy (CT) benefit in estrogen receptor-positive ESBC in various populations. In Hong Kong, > 80% of breast cancers are early stage breast cancer (ESBC) and > 60% of these women receive CT. This prospective study measured changes in CT type and recommendations, as well as physician impression of assay impact in a homogenous Chinese population. Methods Consecutive patients with estrogen receptor-positive, T1-3 N0-1mi M0 ESBC were offered enrollment. After surgery, physicians discussed treatment options with patients, then ordered the assay, then reassessed treatment recommendation considering assay results. Changes in treatment recommendation, CT utilization, physician confidence, and physician rating of influence on their treatment recommendations were measured. Results A total of 146 evaluable patients received pre- and post-testing treatment recommendations. CT recommendations (including changes in intensity of CT) were changed for 34 of 146 patients (23.3%; 95% confidence interval, 16.7%-31.0%); change in intensity occurred in 7 of 146 (4.8%). There were 27 changes in treatment recommendations of adding or removing CT altogether (18.5% change; 95% confidence interval, 12.6%-25.8%). CT recommendations decreased from 52.1% to 37.7%, a net absolute reduction of 14.4% (P < .001; 27.6% net relative reduction). Pre-assay, 96% of physicians agreed/strongly agreed that they were confident in their treatment recommendation; post-assay, 90% of physicians agreed/strongly agreed with the same statement. Thirty percent of physicians agreed/strongly agreed that the test had influenced their recommendation, similar to the proportion of changed recommendations. Conclusions The Oncotype DX Assay appears to influence physician ESBC adjuvant treatment recommendations in Hong Kong.published_or_final_versio

Berberine suppresses tumorigenicity and growth of nasopharyngeal carcinoma cells by inhibiting STAT3 activation induced by tumor associated fibroblasts

Background: Cortidis rhizoma (Huanglian) and its major therapeutic component, berberine, have drawn extensive attention in recent years for their anti-cancer properties. Growth inhibitory effects of berberine on multiple types of human cancer cells have been reported. Berberine inhibits invasion, induces cell cycle arrest and apoptosis in human cancer cells. The anti-inflammatory property of berberine, involving inhibition of Signal Transducer and Activator of Transcription 3 (STAT3) activation, has also been documented.Methods: In this study, we have examined the effects of berberine on tumorigenicity and growth of nasopharyngeal carcinoma (NPC) cells and their relationship to STAT3 signaling using both in vivo and in vitro models.Results: Berberine effectively inhibited the tumorigenicity and growth of an EBV-positive NPC cell line (C666-1) in athymic nude mice. Inhibition of tumorigenic growth of NPC cells in vivo was correlated with effective inhibition of STAT3 activation in NPC cells inside the tumor xenografts grown in nude mice. In vitro, berberine inhibited both constitutive and IL-6-induced STAT3 activation in NPC cells. Inhibition of STAT3 activation by berberine induced growth inhibition and apoptotic response in NPC cells. Tumor-associated fibroblasts were found to secret IL-6 and the conditioned medium harvested from the fibroblasts also induced STAT3 activation in NPC cells. Furthermore, STAT3 activation by conditioned medium of tumor-associated fibroblasts could be blocked by berberine or antibodies against IL-6 and IL-6R.Conclusions: Our observation that berberine effectively inhibited activation of STAT3 induced by tumor-associated fibroblasts suggests a role of berberine in modulating the effects of tumor stroma on the growth of NPC cells. The effective inhibition of STAT3 activation in NPC cells by berberine supports its potential use in the treatment of NPC. © 2013 Tsang et al.; licensee BioMed Central Ltd

Convergent Evolution in Aquatic Tetrapods: Insights from an Exceptional Fossil Mosasaur

Mosasaurs (family Mosasauridae) are a diverse group of secondarily aquatic lizards that radiated into marine environments during the Late Cretaceous (98–65 million years ago). For the most part, they have been considered to be simple anguilliform swimmers – i.e., their propulsive force was generated by means of lateral undulations incorporating the greater part of the body – with unremarkable, dorsoventrally narrow tails and long, lizard-like bodies. Convergence with the specialized fusiform body shape and inferred carangiform locomotory style (in which only a portion of the posterior body participates in the thrust-producing flexure) of ichthyosaurs and metriorhynchid crocodyliform reptiles, along with cetaceans, has so far only been recognized in Plotosaurus, the most highly derived member of the Mosasauridae. Here we report on an exceptionally complete specimen (LACM 128319) of the moderately derived genus Platecarpus that preserves soft tissues and anatomical details (e.g., large portions of integument, a partial body outline, putative skin color markings, a downturned tail, branching bronchial tubes, and probable visceral traces) to an extent that has never been seen previously in any mosasaur. Our study demonstrates that a streamlined body plan and crescent-shaped caudal fin were already well established in Platecarpus, a taxon that preceded Plotosaurus by 20 million years. These new data expand our understanding of convergent evolution among marine reptiles, and provide insights into their evolution's tempo and mode

Factors affecting exhaled nitric oxide measurements: the effect of sex

<p>Abstract</p> <p>Background</p> <p>Exhaled nitric oxide (F_ENO) measurements are used as a surrogate marker for eosinophilic airway inflammation. However, many constitutional and environmental factors affect F_ENO, making it difficult to devise reference values. Our aim was to evaluate the relative importance of factors affecting F_ENO in a well characterised adult population.</p> <p>Methods</p> <p>Data were obtained from 895 members of the Dunedin Multidisciplinary Health and Development Study at age 32. The effects of sex, height, weight, lung function indices, smoking, atopy, asthma and rhinitis on F_ENO were explored by unadjusted and adjusted linear regression analyses.</p> <p>Results</p> <p>The effect of sex on F_ENO was both statistically and clinically significant, with F_ENO levels approximately 25% less in females. Overall, current smoking reduced F_ENO up to 50%, but this effect occurred predominantly in those who smoked on the day of the F_ENO measurement. Atopy increased F_ENO by 60%. The sex-related differences in F_ENO remained significant (p < 0.001) after controlling for all other significant factors affecting F_ENO.</p> <p>Conclusion</p> <p>Even after adjustment, F_ENO values are significantly different in males and females. The derivation of reference values and the interpretation of F_ENO in the clinical setting should be stratified by sex. Other common factors such as current smoking and atopy also require to be taken into account.</p