Tissue engineering a surrogate niche for metastatic cancer cells

In breast and prostate cancer patients, the bone marrow is a preferred site of metastasis. We hypothesized that we could use tissue-engineering strategies to lure metastasizing cancer cells to tissue-engineered bone marrow. First, we generated highly porous 3D silk scaffolds that were biocompatible and amenable to bone morphogenetic protein 2 functionalization. Control and functionalized silk scaffolds were subcutaneously implanted in mice and bone marrow development was followed. Only functionalized scaffolds developed cancellous bone and red bone marrow, which appeared as early as two weeks post-implantation and further developed over the 16-week study period. This tissue-engineered bone marrow microenvironment could be readily manipulated in situ to understand the biology of bone metastasis. To test the ability of functionalized scaffolds to serve as a surrogate niche for metastasis, human breast cancer cells were injected into the mammary fat pads of mice. The treatment of animals with scaffolds had no significant effect on primary tumor growth. However, extensive metastasis was observed in functionalized scaffolds, and the highest levels for scaffolds that were in situ manipulated with receptor activator of nuclear factor kappa-B ligand (RANKL). We also applied this tissue-engineered bone marrow model in a prostate cancer and experimental metastasis setting. In summary, we were able to use tissue-engineered bone marrow to serve as a target or "trap" for metastasizing cancer cells

New contribution to dimension five operators on proton decay in anomaly mediation scenario

In supergravity, effective superpotential relevant to dimension five operators on proton decay processes also leads to supersymmetry breaking terms among sfermions, dimension four operators. These dimension four operators induce the dimension five operators through 1-loop diagrams dressed by gauginos. We find that, in a class of models with the anomaly mediation, the 1-loop contributions can be comparable to those at the tree level. Therefore, such operators have a great impact on proton decay rate. Depending on a universal phase of gaugino masses and soft mass spectrum, the proton decay rate can be enhanced or suppressed.Comment: 8 pages, no figure. A few minor changes have been mad

The ABC7 regimen: a new approach to metastatic breast cancer using seven common drugs to inhibit epithelial-to-mesenchymal transition and augment capecitabine efficacy.

Breast cancer metastatic to bone has a poor prognosis despite recent advances in our understanding of the biology of both bone and breast cancer. This article presents a new approach, the ABC7 regimen (Adjuvant for Breast Cancer treatment using seven repurposed drugs), to metastatic breast cancer. ABC7 aims to defeat aspects of epithelial-to-mesenchymal transition (EMT) that lead to dissemination of breast cancer to bone. As add-on to current standard treatment with capecitabine, ABC7 uses ancillary attributes of seven already-marketed noncancer treatment drugs to stop both the natural EMT process inherent to breast cancer and the added EMT occurring as a response to current treatment modalities. Chemotherapy, radiation, and surgery provoke EMT in cancer generally and in breast cancer specifically. ABC7 uses standard doses of capecitabine as used in treating breast cancer today. In addition, ABC7 uses 1) an older psychiatric drug, quetiapine, to block RANK signaling; 2) pirfenidone, an anti-fibrosis drug to block TGF-beta signaling; 3) rifabutin, an antibiotic to block beta-catenin signaling; 4) metformin, a first-line antidiabetic drug to stimulate AMPK and inhibit mammalian target of rapamycin, (mTOR); 5) propranolol, a beta-blocker to block beta-adrenergic signaling; 6) agomelatine, a melatonergic antidepressant to stimulate M1 and M2 melatonergic receptors; and 7) ribavirin, an antiviral drug to prevent eIF4E phosphorylation. All these block the signaling pathways ? RANK, TGF-beta, mTOR, beta-adrenergic receptors, and phosphorylated eIF4E ? that have been shown to trigger EMT and enhance breast cancer growth and so are worthwhile targets to inhibit. Agonism at MT1 and MT2 melatonergic receptors has been shown to inhibit both breast cancer EMT and growth. This ensemble was designed to be safe and augment capecitabine efficacy. Given the expected outcome of metastatic breast cancer as it stands today, ABC7 warrants a cautious trial

Modified reaction centers from Rhodobacter sphaeroides R26

Incubation of photosynthetic reaction centers from Rhodobacter sphaeroides R26 with exogenous 132-OH-bacteriochlorophyll ap or aGG according to Scheer et al. (1987) results in the exchange of endogenous bacteriochlorophyll ap. The exchange amounts to less-than-or-equals, slant 50% according to HPLC analysis, corresponding to a complete replacement of the ‘monomeric’ bacteriochlorophylls, bm and bl, by exogenous pigment. The absorption spectra show small, but distinct changes in the Qx-region of the bacteriochlorophylls, and bleaching of the modified reaction centers is retained. The corresponding binding sites must be accessible from the exterior, and allow for the introduction of a polar residue at C-132. This is supported by the observation of side reactions of the endogenous ‘monomeric’ bacteriochlorophylls within the reaction center pigments, e.g. epimerization and hydroxylation at C-132

Influence of Introgression and Geological Processes on Phylogenetic Relationships of Western North American Mountain Suckers (Pantosteus, Catostomidae)

Intense geological activity caused major topographic changes in Western North America over the past 15 million years. Major rivers here are composites of different ancient rivers, resulting in isolation and mixing episodes between river basins over time. This history influenced the diversification of most of the aquatic fauna. The genus Pantosteus is one of several clades centered in this tectonically active region. The eight recognized Pantosteus species are widespread and common across southwestern Canada, western USA and into northern Mexico. They are typically found in medium gradient, middle-elevation reaches of rivers over rocky substrates. This study (1) compares molecular data with morphological and paleontological data for proposed species of Pantosteus, (2) tests hypotheses of their monophyly, (3) uses these data for phylogenetic inferences of sister-group relationships, and (4) estimates timing of divergence events of identified lineages. Using 8055 base pairs from mitochondrial DNA protein coding genes, Pantosteus and Catostomus are reciprocally monophyletic, in contrast with morphological data. The only exception to a monophyleticPantosteus is P. columbianus whose mtDNA is closely aligned with C. tahoensis because of introgression. Within Pantosteus, several species have deep genetic divergences among allopatric sister lineages, several of which are diagnosed and elevated to species, bringing the total diversity in the group to 11 species. Conflicting molecular and morphological data may be resolved when patterns of divergence are shown to be correlated with sympatry and evidence of introgression

Weak and Electromagnetic Nuclear Decay Signatures for Neutrino Reactions in SuperKamiokande

We suggest the study of events in the SuperKamiokande neutrino data due to charged- and neutral-current neutrino reactions followed by weak and/or electromagnetic decays of struck nuclei and fragments thereof. This study could improve the prospects of obtaining evidence for $\tau$ production from $\nu_\mu \to \nu_\tau$ oscillations and could augment the data sample used to disfavor $\nu_\mu \to \nu_{sterile}$ oscillations.Comment: 7 pages, latex, to appear in Phys. Rev. Let

Gauge Unification in Higher Dimensions

A complete 5-dimensional SU(5) unified theory is constructed which, on compactification on the orbifold with two different Z_2's (Z_2 and Z_2'), yields the minimal supersymmetric standard model. The orbifold accomplishes SU(5) gauge symmetry breaking, doublet-triplet splitting, and a vanishing of proton decay from operators of dimension 5. Until 4d supersymmetry is broken, all proton decay from dimension 4 and dimension 5 operators is forced to vanish by an exact U(1)_R symmetry. Quarks and leptons and their Yukawa interactions are located at the Z_2 orbifold fixed points, where SU(5) is unbroken. A new mechanism for introducing SU(5) breaking into the quark and lepton masses is introduced, which originates from the SU(5) violation in the zero-mode structure of bulk multiplets. Even though SU(5) is absent at the Z_2' orbifold fixed point, the brane threshold corrections to gauge coupling unification are argued to be negligibly small, while the logarithmic corrections are small and in a direction which improves the agreement with the experimental measurements of the gauge couplings. Furthermore, the X gauge boson mass is lowered, so that proton decay to e^+ \pi^0 is expected with a rate within about one order of magnitude of the current limit. Supersymmetry breaking occurs on the Z_2' orbifold fixed point, and is felt directly by the gauge and Higgs sectors, while squarks and sleptons acquire mass via gaugino mediation, solving the supersymmetric flavor problem.Comment: 21 pages, Latex, references added, final versio

Erythropoietin supports the survival of prostate cancer, but not growth and bone metastasis

Erythropoietin (Epo) is used in clinical settings to enhance hematopoietic function and to improve the quality of life for patients undergoing chemotherapy by reducing fatigue and the need for transfusions. However, several meta‐analyses have revealed that Epo treatments are associated with an increased risk of mortality in cancer patients. In this study, we examined the role of Epo in prostate cancer (PCa) progression, using in vitro cell culture systems and in vivo bone metastatic assays. We found that Epo did not stimulate the proliferation of PCa cell lines, but did protect PCa cells from apoptosis. In animal models of PCa metastasis, no evidence was found to support the hypothesis that Epo enhances metastasis. Together, these findings suggest that Epo may be useful for treating severe anemia in PCa patients without increasing metastatic risk. J. Cell. Biochem. 114: 2471–2478, 2013. © 2013 Wiley Periodicals, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/100159/1/jcb24592.pd

Signatures of Nucleon Disappearance in Large Underground Detectors

For neutrons bound inside nuclei, baryon instability can manifest itself as a decay into undetectable particles (e.g., $\it n \to \nu \nu \bar{\nu}$), i.e., as a disappearance of a neutron from its nuclear state. If electric charge is conserved, a similar disappearance is impossible for a proton. The existing experimental lifetime limit for neutron disappearance is 4-7 orders of magnitude lower than the lifetime limits with detectable nucleon decay products in the final state [PDG2000]. In this paper we calculated the spectrum of nuclear de-excitations that would result from the disappearance of a neutron or two neutrons from $^{12}$C. We found that some de-excitation modes have signatures that are advantageous for detection in the modern high-mass, low-background, and low-threshold underground detectors, where neutron disappearance would result in a characteristic sequence of time- and space-correlated events. Thus, in the KamLAND detector [Kamland], a time-correlated triple coincidence of a prompt signal, a captured neutron, and a $\beta^{+}$ decay of the residual nucleus, all originating from the same point in the detector, will be a unique signal of neutron disappearance allowing searches for baryon instability with sensitivity 3-4 orders of magnitude beyond the present experimental limits.Comment: 13 pages including 6 figures, revised version, to be published in Phys.Rev.