Chronic p53-independent p21 expression causes genomic instability by deregulating replication licensing

The cyclin-dependent kinase inhibitor p21WAF1/CIP1 (p21) is a cell-cycle checkpoint effector and inducer of senescence, regulated by p53. Yet, evidence suggests that p21 could also be oncogenic, through a mechanism that has so far remained obscure. We report that a subset of atypical cancerous cells strongly expressing p21 showed proliferation features. This occurred predominantly in p53-mutant human cancers, suggesting p53-independent upregulation of p21 selectively in more aggressive tumour cells. Multifaceted phenotypic and genomic analyses of p21-inducible, p53-null, cancerous and near-normal cellular models showed that after an initial senescence-like phase, a subpopulation of p21-expressing proliferating cells emerged, featuring increased genomic instability, aggressiveness and chemoresistance. Mechanistically, sustained p21 accumulation inhibited mainly the CRL4–CDT2 ubiquitin ligase, leading to deregulated origin licensing and replication stress. Collectively, our data reveal the tumour-promoting ability of p21 through deregulation of DNA replication licensing machinery—an unorthodox role to be considered in cancer treatment, since p21 responds to various stimuli including some chemotherapy drugs

The role of sialomucin CD164 (MGC-24v or endolyn) in prostate cancer metastasis

BACKGROUND: The chemokine stromal derived factor-1 (SDF-1 or CXCL12) and its receptor CXCR4 have been demonstrated to be crucial for the homing of stem cells and prostate cancers to the marrow. While screening prostate cancers for CXCL12-responsive adhesion molecules, we identified CD164 (MGC-24) as a potential regulator of homing. CD164 is known to function as a receptor that regulates stem cell localization to the bone marrow. RESULTS: Using prostate cancer cell lines, it was demonstrated that CXCL12 induced both the expression of CD164 mRNA and protein. Functional studies demonstrated that blocking CD164 on prostate cancer cell lines reduced the ability of these cells to adhere to human bone marrow endothelial cells, and invade into extracellular matrices. Human tissue microarrays stained for CD164 demonstrated a positive correlation with prostate-specific antigen levels, while its expression was negatively correlated with the expression of androgen receptor. CONCLUSION: Our findings suggest that CD164 may participate in the localization of prostate cancer cells to the marrow and is further evidence that tumor metastasis and hematopoietic stem cell trafficking may involve similar processes

Citizen science: a new approach to advance ecology, education, and conservation

Citizen science has a long history in the ecological sciences and has made substantial contributions to science, education, and society. Developments in information technology during the last few decades have created new opportunities for citizen science to engage ever larger audiences of volunteers to help address some of ecology’s most pressing issues, such as global environmental change. Using online tools, volunteers can find projects that match their interests and learn the skills and protocols required to develop questions, collect data, submit data, and help process and analyze data online. Citizen science has become increasingly important for its ability to engage large numbers of volunteers to generate observations at scales or resolutions unattainable by individual researchers. As a coupled natural and human approach, citizen science can also help researchers access local knowledge and implement conservation projects that might be impossible otherwise. In Japan, however, the value of citizen science to science and society is still underappreciated. Here we present case studies of citizen science in Japan, the United States, and the United Kingdom, and describe how citizen science is used to tackle key questions in ecology and conservation, including spatial and macro-ecology, management of threatened and invasive species, and monitoring of biodiversity. We also discuss the importance of data quality, volunteer recruitment, program evaluation, and the integration of science and human systems in citizen science projects. Finally, we outline some of the primary challenges facing citizen science and its future.Dr. Janis L. Dickinson was the keynote speaker at the international symposium at the 61th annual meeting of the Ecological Society of Japan. We appreciate the Ministry of Education, Culture, Sports, Science and Technology in Japan for providing grant to Hiromi Kobori (25282044). Tatsuya Amano is financially supported by the European Commission’s Marie Curie International Incoming Fellowship Programme (PIIF-GA-2011- 303221). The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the funding agencies or the Department of the Interior or the US Government.This is the final version of the article. It was first available from Springer via http://dx.doi.org/10.1007/s11284-015-1314-

The potential of antisense oligonucleotide therapies for inherited childhood lung diseases.

Antisense oligonucleotides are an emerging therapeutic option to treat diseases with known genetic origin. In the age of personalised medicines, antisense oligonucleotides can sometimes be designed to target and bypass or overcome a patient's genetic mutation, in particular those lesions that compromise normal pre-mRNA processing. Antisense oligonucleotides can alter gene expression through a variety of mechanisms as determined by the chemistry and antisense oligomer design. Through targeting the pre-mRNA, antisense oligonucleotides can alter splicing and induce a specific spliceoform or disrupt the reading frame, target an RNA transcript for degradation through RNaseH activation, block ribosome initiation of protein translation or disrupt miRNA function. The recent accelerated approval of eteplirsen (renamed Exondys 51™) by the Food and Drug Administration, for the treatment of Duchenne muscular dystrophy, and nusinersen, for the treatment of spinal muscular atrophy, herald a new and exciting era in splice-switching antisense oligonucleotide applications to treat inherited diseases. This review considers the potential of antisense oligonucleotides to treat inherited lung diseases of childhood with a focus on cystic fibrosis and disorders of surfactant protein metabolism

Limited Vegetation Development on a Created Salt Marsh Associated with Over-Consolidated Sediments and Lack of Topographic Heterogeneity

Restored salt marshes frequently lack the full range of plant communities present on reference marshes, with upper marsh species underrepresented. This often results from sites being too low in the tidal frame and/or poorly drained with anoxic sediments. A managed coastal realignment scheme at Abbotts Hall, Essex, UK, has oxic sediments at elevations at which upper marsh communities would be expected. But 7 years after flooding, it continued to be dominated by pioneer communities, with substantial proportions of bare ground, so other factors must hinder vegetation development at these elevations. The poorly vegetated areas had high sediment shear strength, low water and organic carbon content and very flat topography. These characteristics occur frequently on the upper parts of created marshes. Experimental work is required to establish causal links with the ecological differences, but other studies have also reported that reduced plant β-diversity and lower usage by fish are associated with topographic uniformity. Uniformity also leads to very different visual appearance from natural marshes. On the upper intertidal, sediment deposition rate are slow, water velocities are low and erosive forces are weak. So, topographic heterogeneity cannot develop naturally, even if creeks have been excavated. Without active management, these conditions will persist indefinitely

The role of sialomucin CD164 (MGC-24v or endolyn) in prostate cancer metastasis

Abstract Background The chemokine stromal derived factor-1 (SDF-1 or CXCL12) and its receptor CXCR4 have been demonstrated to be crucial for the homing of stem cells and prostate cancers to the marrow. While screening prostate cancers for CXCL12-responsive adhesion molecules, we identified CD164 (MGC-24) as a potential regulator of homing. CD164 is known to function as a receptor that regulates stem cell localization to the bone marrow. Results Using prostate cancer cell lines, it was demonstrated that CXCL12 induced both the expression of CD164 mRNA and protein. Functional studies demonstrated that blocking CD164 on prostate cancer cell lines reduced the ability of these cells to adhere to human bone marrow endothelial cells, and invade into extracellular matrices. Human tissue microarrays stained for CD164 demonstrated a positive correlation with prostate-specific antigen levels, while its expression was negatively correlated with the expression of androgen receptor. Conclusion Our findings suggest that CD164 may participate in the localization of prostate cancer cells to the marrow and is further evidence that tumor metastasis and hematopoietic stem cell trafficking may involve similar processes.http://deepblue.lib.umich.edu/bitstream/2027.42/112493/1/12885_2006_Article_547.pd