Copper deficit as a potential pathogenic factor of reduced bone mineral density and severe tooth wear

SUMMARY: The study evaluated if men and women with severe tooth wear were at increased risk of general bone loss. Enamel biopsies obtained from 50 subjects aged 47.5 ± 5 years showed decreased copper content, which was associated with reduced spine bone mineral density, suggesting deficits of this trace element contributing to bone demineralization, enamel attrition, and deteriorated quality of mineralized tissues. INTRODUCTION: The objective of this cross-sectional study was to assess associations between enamel trace minerals and bone mineral density (BMD) in severe tooth wear. We hypothesized that similar factors contributed to both the excessive abrasion of dental enamel and reduced BMD in subjects with tooth wear. METHODS: Fifty patients aged 47.5 ± 5 years with severe tooth wear and 20 age-, sex-, and body mass index (BMI)-matched healthy volunteers with normal dental status were studied regarding dietary intakes of trace elements, serum and salivary copper (Cu), zinc (Zn), and calcium (Ca) concentrations, and serum PTH, osteocalcin, and hydroxyvitamin D levels. Tooth wear was determined using clinical examination based on standard protocol according to Smith and Knight. In all subjects, acid biopsies of the maxillary central incisors were carried out to assess mineral composition of the enamel. Atomic absorption spectroscopy with an air/acetylene flame was used to measure Ca and Zn, and graphite furnace atomic absorption spectroscopy was used to analyze Cu content. BMD was examined using dual energy X-ray absorptiometry. RESULTS: Tooth wear patients had reduced lumbar spine, but not femoral, BMD relative to controls (p < 0.001). No differences were found in enamel Ca concentration and Zn content was slightly higher in tooth wear patients than in controls whereas Cu content was significantly decreased in the patients: 19.59 ± 16.4 vs 36.86 ± 26.1 μg/l (p = 0.01) despite similar levels of Cu in serum and saliva. The differences were independent of serum 25-OH-D, osteocalcin concentrations or PTH either. CONCLUSION: Severe tooth wear is associated with reduced spinal BMD. Enamel in adult individuals with severe tooth wear is low in copper content. Therefore, further work is needed to determine whether copper plays a role in bone pathophysiology in these patients

An elastoplastic theory of dislocations as a physical field theory with torsion

We consider a static theory of dislocations with moment stress in an anisotropic or isotropic elastoplastical material as a T(3)-gauge theory. We obtain Yang-Mills type field equations which express the force and the moment equilibrium. Additionally, we discuss several constitutive laws between the dislocation density and the moment stress. For a straight screw dislocation, we find the stress field which is modified near the dislocation core due to the appearance of moment stress. For the first time, we calculate the localized moment stress, the Nye tensor, the elastoplastic energy and the modified Peach-Koehler force of a screw dislocation in this framework. Moreover, we discuss the straightforward analogy between a screw dislocation and a magnetic vortex. The dislocation theory in solids is also considered as a three-dimensional effective theory of gravity.Comment: 38 pages, 6 figures, RevTe

New hints towards a precision medicine strategy for IDH wild-type glioblastoma.

Glioblastoma represents the most common primary malignancy of the central nervous system in adults and remains a largely incurable disease. The elucidation of disease subtypes based on mutational profiling, gene expression and DNA methylation has so far failed to translate into improved clinical outcomes. However, new knowledge emerging from the subtyping effort in the IDH-wild-type setting may provide directions for future precision therapies. Here, we review recent learnings in the field, and further consider how tumour microenvironment differences across subtypes may reveal novel contexts of vulnerability. We discuss recent treatment approaches and ongoing trials in the IDH-wild-type glioblastoma setting, and propose an integrated discovery stratagem incorporating multi-omics, single-cell technologies and computational approaches

Tau Neutrinos Favored over Sterile Neutrinos in Atmospheric Muon Neutrino Oscillations

The previously published atmospheric neutrino data did not distinguish whether muon neutrinos were oscillating into tau neutrinos or sterile neutrinos, as both hypotheses fit the data. Using data recorded in 1100 live-days of the Super-Kamiokande detector, we use three complementary data samples to study the difference in zenith angle distribution due to neutral currents and matter effects. We find no evidence favoring sterile neutrinos, and reject the hypothesis at the 99% confidence level. On the other hand, we find that oscillation between muon and tau neutrinos suffices to explain all the results in hand.Comment: 9 pages with 2 figures, submitted to PR

Constraints on Neutrino Oscillations Using 1258 Days of Super-Kamiokande Solar Neutrino Data

We report the result of a search for neutrino oscillations using precise measurements of the recoil electron energy spectrum and zenith angle variations of the solar neutrino flux from 1258 days of neutrino-electron scattering data in Super-Kamiokande. The absence of significant zenith angle variation and spectrum distortion places strong constraints on neutrino mixing and mass difference in a flux-independent way. Using the Super-Kamiokande flux measurement in addition, two allowed regions at large mixing are found.Comment: 6 pages, 4 figures, submitted to PR

Solar 8B and hep Neutrino Measurements from 1258 Days of Super-Kamiokande Data

Solar neutrino measurements from 1258 days of data from the Super-Kamiokande detector are presented. The measurements are based on recoil electrons in the energy range 5.0-20.0MeV. The measured solar neutrino flux is 2.32 +- 0.03(stat.) +0.08-0.07(sys.)*10^6cm^{-2}s^{-1}, which is 45.1+-0.5(stat.)+1.6-1.4(sys.)% of that predicted by the BP2000 SSM. The day vs night flux asymmetry is 0.033+-0.022(stat.)+0.013-0.012(sys.). The recoil electron energy spectrum is consistent with no spectral distortion (\chi^2/d.o.f. = 19.0/18). The seasonal variation of the flux is consistent with that expected from the eccentricity of the Earth's orbit (\chi^2/d.o.f. = 3.7/7). For the hep neutrino flux, we set a 90% C.L. upper limit of 40 *10^3cm^{-2}s^{-1}, which is 4.3 times the BP2000 SSM prediction.Comment: 7 pages, 5 figures, submitted to PRL (part of this paper

Stem cell-associated heterogeneity in Glioblastoma results from intrinsic tumor plasticity shaped by the microenvironment

The identity and unique capacity of cancer stem cells (CSC) to drive tumor growth and resistance have been challenged in brain tumors. Here we report that cells expressing CSC-associated cell membrane markers in Glioblastoma (GBM) do not represent a clonal entity defined by distinct functional properties and transcriptomic profiles, but rather a plastic state that most cancer cells can adopt. We show that phenotypic heterogeneity arises from non-hierarchical, reversible state transitions, instructed by the microenvironment and is predictable by mathematical modeling. Although functional stem cell properties were similar in vitro, accelerated reconstitution of heterogeneity provides a growth advantage in vivo, suggesting that tumorigenic potential is linked to intrinsic plasticity rather than CSC multipotency. The capacity of any given cancer cell to reconstitute tumor heterogeneity cautions against therapies targeting CSC-associated membrane epitopes. Instead inherent cancer cell plasticity emerges as a novel relevant target for treatment.publishedVersio

Minnelide effectively eliminates CD133+ side population in pancreatic cancer

BACKGROUND: Pancreatic Ductal Adenocarcinoma (PDAC) is a devastating disease hallmarked by limited patient survival. Resistance to chemotherapy, a major cause of treatment failure in PDAC patients, is often attributed to Cancer Stem Cells (CSCs). Pancreatic CSCs are a small subset of quiescent cells within a tumor represented by surface markers like CD133. These cells are responsible not only for tumor recurrence, but also poor prognosis based on their “stem-like” characteristics. At present, conventional therapy is directed towards rapidly dividing PDAC cells and thus fails to target the CSC population. METHODS: MIA PaCa-2, S2-013 and AsPC-1 were treated with 12.5 nM triptolide (12 T cells) for 7 days. The surviving cells were recovered briefly in drug-free growth media and then transferred to Cancer Stem cell Media (CSM). As a control, untreated cells were also transferred to CSM media (CSM). The 12 T and CSM cells were tested for stemness properties using RNA and protein markers. Low numbers of CSM and 12 T cells were implanted subcutaneously in athymic nude mice to study their tumorigenic potential. 12 T and CSM cells were sorted for CD133 expression and assayed for their colony forming ability and sphere forming ability. Invasiveness of 12 T cells, CSM and MIA PaCa-2 were compared using Boyden chamber assays. RESULTS: Treated 12 T cells displayed increased expression of the surface marker CD133 and the drug transporter ABCG2 compared to untreated cells (CSM cells). Both 12 T and CSM cells formed subcutaneous tumors in mice confirming their tumor-initiating properties. When tested for invasion, 12 T cells had increased invasiveness compared to CSM cells. CD133(+) cells in both CSM and 12 T showed greater colony and sphere forming ability compared to CD133(−) cells from each group. Consistent with these data, when injected subcutaneously in mice, CD133(−) cells from CSM or 12 T did not form any tumors whereas CD133(+) cells from both groups showed tumor formation at a very low cell number. Despite pre-exposure to triptolide in 12 T CD133(+) cells, treatment of tumors formed by these cells with Minnelide, a triptolide pro-drug, showed significant tumor regression. CONCLUSION: Our results indicated that triptolide enhanced and enriched the “stemness” in the PDAC cell lines at a low dose of 12.5 nM, but also resulted in the regression of tumors derived from these cells. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12943-015-0470-6) contains supplementary material, which is available to authorized users