Bone Marrow Derived Mesenchymal Stem Cells Incorporate into the Prostate during Regrowth

Prostate cancer recurrence involves increased growth of cancer epithelial cells, as androgen dependent prostate cancer progresses to castrate resistant prostate cancer (CRPC) following initial therapy. Understanding CRPC prostate regrowth will provide opportunities for new cancer therapies to treat advanced disease.Elevated chemokine expression in the prostate stroma of a castrate resistant mouse model, Tgfbr2(fspKO), prompted us to look at the involvement of bone marrow derived cells (BMDCs) in prostate regrowth. We identified bone marrow cells recruited to the prostate in GFP-chimeric mice. A dramatic increase in BMDC recruitment for prostate regrowth occurred three days after exogenous testosterone implantation. Recruitment led to incorporation of BMDCs within the prostate epithelia. Immunofluorescence staining suggested BMDCs in the prostate coexpressed androgen receptor; p63, a basal epithelial marker; and cytokeratin 8, a luminal epithelial marker. A subset of the BMDC population, mesenchymal stem cells (MSCs), were specifically found to be incorporated in the prostate at its greatest time of remodeling. Rosa26 expressing MSCs injected into GFP mice supported MSC fusion with resident prostate epithelial cells through co-localization of β-galactosidase and GFP during regrowth. In a human C4-2B xenograft model of CRPC, MSCs were specifically recruited. Injection of GFP-labeled MSCs supported C4-2B tumor progression by potentiating canonical Wnt signaling. The use of MSCs as a targeted delivery vector for the exogenously expressed Wnt antagonist, secreted frizzled related protein-2 (SFRP2), reduced tumor growth, increased apoptosis and potentiated tumor necrosis.Mesenchymal stem cells fuse with prostate epithelia during the process of prostate regrowth. MSCs recruited to the regrowing prostate can be used as a vehicle for transporting genetic information with potential therapeutic effects on castrate resistant prostate cancer, for instance by antagonizing Wnt signaling through SFRP2

Specific effects of bortezomib against experimental malignant pleural effusion: a preclinical study

BACKGROUND: We have previously shown that nuclear factor (NF)-κB activation of mouse Lewis lung carcinoma (LLC) specifically promotes the induction of malignant pleural effusions (MPE) by these cells. In the present studies we hypothesized that treatment of immunocompetent mice with bortezomib tailored to inhibit cancer cell NF-κB activation and not proliferation specifically inhibits MPE formation by LLC cells. RESULTS: Treatment of LLC cells with low concentrations of bortezomib (100 ng/ml) inhibited NF-κB activation and NF-κB-dependent transcription, but not cellular proliferation. Bortezomib treatment of immunocompetent C57BL/6 mice bearing LLC-induced subcutaneous tumors and MPEs significantly blocked tumor-specific NF-κB activation. However, bortezomib treatment did not impair subcutaneous LLC tumor growth, but was effective in limiting LLC-induced MPE. This specific effect was evidenced by significant reductions in effusion accumulation and the associated mortality and was observed with both preventive (beginning before MPE formation) and therapeutic (beginning after MPE establishment) bortezomib treatment. The favorable impact of bortezomib on MPE was associated with suppression of cardinal MPE-associated phenomena, such as inflammation, vascular hyperpermeability, and angiogenesis. In this regard, therapeutic bortezomib treatment had identical favorable results on MPE compared with preventive treatment, indicating that the drug specifically counteracts effusion formation. CONCLUSIONS: These studies indicate that proteasome inhibition tailored to block NF-κB activation of lung adenocarcinoma specifically targets the effusion-inducing phenotype of this tumor. Although the drug has limited activity against advanced solid lung cancer, it may prove beneficial for patients with MPE

The Energy Computation Paradox and ab initio Protein Folding

The routine prediction of three-dimensional protein structure from sequence remains a challenge in computational biochemistry. It has been intuited that calculated energies from physics-based scoring functions are able to distinguish native from nonnative folds based on previous performance with small proteins and that conformational sampling is the fundamental bottleneck to successful folding. We demonstrate that as protein size increases, errors in the computed energies become a significant problem. We show, by using error probability density functions, that physics-based scores contain significant systematic and random errors relative to accurate reference energies. These errors propagate throughout an entire protein and distort its energy landscape to such an extent that modern scoring functions should have little chance of success in finding the free energy minima of large proteins. Nonetheless, by understanding errors in physics-based score functions, they can be reduced in a post-hoc manner, improving accuracy in energy computation and fold discrimination

Systematic review of the evidence relating FEV1 decline to giving up smoking

<p>Abstract</p> <p>Background</p> <p>The rate of forced expiratory volume in 1 second (FEV₁) decline ("beta") is a marker of chronic obstructive pulmonary disease risk. The reduction in beta after quitting smoking is an upper limit for the reduction achievable from switching to novel nicotine delivery products. We review available evidence to estimate this reduction and quantify the relationship of smoking to beta.</p> <p>Methods</p> <p>Studies were identified, in healthy individuals or patients with respiratory disease, that provided data on beta over at least 2 years of follow-up, separately for those who gave up smoking and other smoking groups. Publications to June 2010 were considered. Independent beta estimates were derived for four main smoking groups: never smokers, ex-smokers (before baseline), quitters (during follow-up) and continuing smokers. Unweighted and inverse variance-weighted regression analyses compared betas in the smoking groups, and in continuing smokers by amount smoked, and estimated whether beta or beta differences between smoking groups varied by age, sex and other factors.</p> <p>Results</p> <p>Forty-seven studies had relevant data, 28 for both sexes and 19 for males. Sixteen studies started before 1970. Mean follow-up was 11 years. On the basis of weighted analysis of 303 betas for the four smoking groups, never smokers had a beta 10.8 mL/yr (95% confidence interval (CI), 8.9 to 12.8) less than continuing smokers. Betas for ex-smokers were 12.4 mL/yr (95% CI, 10.1 to 14.7) less than for continuing smokers, and for quitters, 8.5 mL/yr (95% CI, 5.6 to 11.4) less. These betas were similar to that for never smokers. In continuing smokers, beta increased 0.33 mL/yr per cigarette/day. Beta differences between continuing smokers and those who gave up were greater in patients with respiratory disease or with reduced baseline lung function, but were not clearly related to age or sex.</p> <p>Conclusion</p> <p>The available data have numerous limitations, but clearly show that continuing smokers have a beta that is dose-related and over 10 mL/yr greater than in never smokers, ex-smokers or quitters. The greater decline in those with respiratory disease or reduced lung function is consistent with some smokers having a more rapid rate of FEV₁decline. These results help in designing studies comparing continuing smokers of conventional cigarettes and switchers to novel products.</p

Mechanical properties and thermal expansion behaviour in leucite containing materials

The effect of a change in sodium content and thermal history on a leucite composition material produced by a coprecipitation process was studied. Five materials with formulae of (K( 1− x ),Na x ) 2 O-Al 2 O 3 -4SiO 2 ( x = 0.0, 0.2, 0.4, 0.6, 0.8) were investigated for differences in phases, thermal expansion, and strength. Strengths of up to 175 MPa were obtained for a leucite composition material ( x = 0.0). Sodium was effective in lowering the thermal expansion coefficients of these materials. Leucite was linked to higher flexural strengths, but was present only in those specimens which were sintered at 1200 °C. Leucite was not present in those specimens sintered at 1100 °C or lower. Porosity was present in all specimens sintered at 1000 °C or higher.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44726/1/10853_2004_Article_BF00356582.pd

Allometry and Ecology of the Bilaterian Gut Microbiome

Classical ecology provides principles for construction and function of biological communities, but to what extent these apply to the animal-associated microbiota is just beginning to be assessed. Here, we investigated the influence of several well-known ecological principles on animal-associated microbiota by characterizing gut microbial specimens from bilaterally symmetrical animals (Bilateria) ranging from flies to whales. A rigorously vetted sample set containing 265 specimens from 64 species was assembled. Bacterial lineages were characterized by 16S rRNA gene sequencing. Previously published samples were also compared, allowing analysis of over 1,098 samples in total. A restricted number of bacterial phyla was found to account for the great majority of gut colonists. Gut microbial composition was associated with host phylogeny and diet. We identified numerous gut bacterial 16S rRNA gene sequences that diverged deeply from previously studied taxa, identifying opportunities to discover new bacterial types. The number of bacterial lineages per gut sample was positively associated with animal mass, paralleling known species-area relationships from island biogeography and implicating body size as a determinant of community stability and niche complexity. Samples from larger animals harbored greater numbers of anaerobic communities, specifying a mechanism for generating more-complex microbial environments. Predictions for species/abundance relationships from models of neutral colonization did not match the data set, pointing to alternative mechanisms such as selection of specific colonists by environmental niche. Taken together, the data suggest that niche complexity increases with gut size and that niche selection forces dominate gut community construction

Nuclear astrophysics with radioactive ions at FAIR

The nucleosynthesis of elements beyond iron is dominated by neutron captures in the s and r processes. However, 32 stable, proton-rich isotopes cannot be formed during those processes, because they are shielded from the s-process flow and r-process, β-decay chains. These nuclei are attributed to the p and rp process. For all those processes, current research in nuclear astrophysics addresses the need for more precise reaction data involving radioactive isotopes. Depending on the particular reaction, direct or inverse kinematics, forward or time-reversed direction are investigated to determine or at least to constrain the desired reaction cross sections. The Facility for Antiproton and Ion Research (FAIR) will offer unique, unprecedented opportunities to investigate many of the important reactions. The high yield of radioactive isotopes, even far away from the valley of stability, allows the investigation of isotopes involved in processes as exotic as the r or rp processes