A single administration of combination therapy inhibits breast tumour progression in bone and modifies both osteoblasts and osteoclasts

We have previously shown that repeated sequential administration of doxorubicin, followed 24 h later by zoledronic acid, inhibits tumour growth in models of established breast cancer bone metastasis. As breast cancer patients only receive zoledronic acid every 3-4 weeks, the aim of the current study was to establish the anti-tumour and bone effects of a single administration of doxorubicin/zoledronic acid combination therapy in a bone metastasis model. MDA-MB-231-GFP cells were injected i.c. in 6-week-old nude mice. On day 2, animals received PBS, doxorubicin (2 mg/kg i.v.), zoledronic acid (100 μg/kg s.c.) or doxorubicin followed 24 h later by zoledronic acid. Anti-tumour effects were assessed on days 15/23 by quantification of apoptotic and proliferating cells and changes in expression of genes implicated in apoptosis, proliferation and bone turnover. Bone effects were assessed by μCT analysis, bone histomorphometry and measurement of serum markers. A tumour-free control group was included. Combination treatment reduced bone tumour burden compared to single agent or PBS control and increased levels of tumour cell apoptosis on day 15, but this was no longer detectable on day 23. Animals receiving zoledronic acid had increased bone density, without evidence of tumour-induced lesions. Bone histomorphometry showed that zoledronic acid caused a decrease in osteoblast and osteoclast numbers and an increase in osteoclast size, in both tumour-free and tumour-bearing animals. Our data show that although zoledronic acid modifies the bone microenvironment through effects on both osteoblasts and osteoclasts, this does not result in a significant anti-tumour effect in the absence of doxorubicin. © 2012 Elsevier GmbH. All rights reserved

A randomised double-blind comparison of intravenous pamidronate and clodronate in the hypercalcaemia of malignancy

In conjunction with rehydration, the bisphosphonates are the treatment of choice for hypercalcaemia of malignancy. Single infusions of either pamidronate or clodronate are usually effective, but a direct comparison of the two agents given at the highest doses commonly used has not been performed. Forty-one patients (15 breast, 12 squamous carcinomas, four lymphomas, four bladder, two prostate and four others) with hypercalcaemia of malignancy (corrected serum calcium > 2.7 mmol l-1) persisting after 48 h of saline rehydration were randomly allocated to receive a 4 h intravenous (i.v.) infusion of either pamidronate 90 mg or clodronate 1500 mg. No other systemic anti-cancer treatment was prescribed. There were no significant differences in the post-hydration serum calcium values (mean 3.17 mmol l-1 for pamidronate and 3.06 mmol l-1 for clodronate), tumour type or frequency of bone metastases between the two treatments. One patient on each treatment died within 2 days and was not assessable for response. A total of 19/19 (100%) patients achieved normocalcaemia following pamidronate and 16/20 (80%) with clodronate. The median time to achieve normocalcaemia was 4 days (range 2-14) for pamidronate and 3 days (range 2-6) with clodronate. The median duration of normocalcaemia was 28 days (range 10-28+ days) after pamidronate and 14 days after clodronate (range 7-21 days) (P 28 days respectively. Two patients experienced fever after pamidronate but no significant toxicity was observed with either treatment. We conclude that both agents are effective in the management of hypercalcaemia of malignancy. At the doses studied, the effects of pamidronate are more complete and longer lasting than those of clodronate

Zircon U-Pb geochronology of the Mount Givens Granodiorite: Implications for the genesis of large volumes of eruptible magma

The Mount Givens Granodiorite, a large pluton in the central Sierra Nevada batholith, California, is similar in area to zoned intrusive suites yet is comparatively chemically and texturally homogenous. New zircon U-Pb geochronology indicates that the pluton was constructed over at least 7 Ma from 97.92 ± 0.06 Ma to 90.87 ± 0.05 Ma. Combining the new geochronology with the exposed volume of the pluton yields an estimated magma flux of <0.001 km3/a. The geochronologic data are at odds with the previously speculated links between plutons such as the Mount Givens Granodiorite and large-volume homogeneous ignimbrites (often termed monotonous intermediates). Existing data indicate that large plutons accumulate at rates of ≤0.001 km3/a, 1-2 orders of magnitude less than fluxes calculated for dated monotonous intermediates. If monotonous intermediates are remobilized, erupted plutons accumulated at rates comparable to dated examples, they should preserve a record of zircon growth of up to 10 Ma. Alternatively, the long history of zircon growth recorded in plutons may be erased during the processes of reheating and remobilization that precede supervolcano eruption. However, zircon dissolution modeling, based on hypothetical temperature-time histories for preeruptive monotonous intermediates, indicates that rejuvenation events would not sufficiently dissolve zircon. We suggest that eruptions of monotonous intermediates occur during high magmatic flux events, leaving little behind in the intrusive rock record, whereas low fluxes favor pluton accumulation

Goserelin, as an ovarian protector during (neo)adjuvant breast cancer chemotherapy, prevents long term altered bone turnover

Background: The Ovarian Protection Trial In Premenopausal Breast Cancer Patients “OPTION” trial (NCT00427245) was a prospective, multicenter, randomised, open label study evaluating the frequency of primary ovarian insufficiency (POI) at 12 months in women randomised to 6–8 cycles of (neo)adjuvant chemotherapy (CT) þ/ goserelin (G). Here we report the results of a secondary endpoint analysis of the effects of CTþ/-G on markers of bone turnover. Methods: Serum for bone alkaline phosphatase (BALP) and urine for N-terminal telopeptide (NTX) were collected at baseline, 6, 12, 18, 24 and 36 months. Changes in median levels of bone turnover markers were evaluated for the overall population, according to age stratification at randomisation (r40 vs 440 years) and with exploratory analysis according to POI rates at 12 months. Results: In the overall population, there was a significant increase in NTX at 6 months compared to baseline in patients treated with CTþG (40.81 vs 57.82 p¼0.0074) with normalisation of levels thereafter. BALP was significantly increased compared to baseline at 6 months and 12 months in those receiving CTþG, but normalised thereafter. BALP remained significantly higher compared to baseline at 12, 24 and 36 months in patients receiving CT, resulting in a significant difference between treatment groups at 36 months (CTþG 5.845 vs CT 8.5 p¼0.0006). These changes were predominantly seen in women 440 years. Women with POI at 12 months showed altered bone formation compared to baseline levels for a longer duration than women who maintained menses. Conclusion: Addition of G to CT increases bone turnover during treatment with normalisation after cessation of treatment suggesting G may offer sufficient ovarian protection against CT induced POI to negate longstanding altered bone turnover associated with POI

Designing of a Fleet-Leader Program for Carbon Composite Overwrapped Pressure Vessels

Composite Overwrapped Pressure Vessels (COPVs) are often used for storing pressurant gases on board spacecraft when mass saving is a prime requirement. Substantial weight savings can be achieved compared to all metallic pressure vessels. For example, on the space shuttle, replacement of all metallic pressure vessels with Kevlar COPVs resulted in a weight savings of about 30 percent. Mass critical space applications such as the Ares and Orion vehicles are currently being planned to use as many COPVs as possible in place of all-metallic pressure vessels to minimize the overall mass of the vehicle. Due to the fact that overwraps are subjected to sustained loads during long periods of a mission, stress rupture failure is a major concern. It is, therefore, important to ascertain the reliability of these vessels by analysis, since it is practically impossible to show by experimental testing the reliability of flight quality vessels. Also, it is a common practice to set aside flight quality vessels as "fleet leaders" in a test program where these vessels are subjected to slightly accelerated operating conditions so that they lead the actual flight vessels both in time and load. The intention of fleet leaders is to provide advanced warning if there is a serious design flaw in the vessels so that a major disaster in the flight vessels can be averted with advance warning. On the other hand, the accelerating conditions must be not so severe as to be prone to false alarms. The primary focus of the present paper is to provide an analytical basis for designing a viable fleet leader program for carbon COPVs. The analysis is based on a stress rupture behavior model incorporating Weibull statistics and power-law sensitivity of life to fiber stress level

Chemotherapy following radium-223 dichloride treatment in ALSYMPCA

BACKGROUND Radium-223 prolongs overall survival in patients with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases, regardless of prior docetaxel. Whether or not chemotherapy can be safely administered following radium-223 treatment is of clinical importance. An exploratory analysis of prospectively collected data, from the ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) patient subgroup who received chemotherapy after radium-223 or placebo treatment, was conducted to evaluate the safety and efficacy of chemotherapy following radium-223. METHODS In ALSYMPCA, CRPC patients with symptomatic bone metastases and no visceral metastases were randomized 2:1 to receive six injections of radium-223 (50 kBq/kg IV) or placebo plus best standard of care, stratified by prior docetaxel, baseline alkaline phosphatase, and current bisphosphonate use. In this exploratory analysis, chemotherapy agents administered following study treatment were identified; timing and duration were calculated. Hematologic safety was reviewed, and overall survival analyzed. RESULTS Overall, 142 radium-223 and 64 placebo patients received subsequent chemotherapy; most common were docetaxel (70% radium-223, 72% placebo) and mitoxantrone (16% radium-223, 20% placebo). The majority of patients (61% radium-223, 58% placebo) had received prior docetaxel. Radium-223 patients started subsequent chemotherapy later than placebo patients; chemotherapy duration was similar between groups. In radium-223 and placebo patients receiving subsequent chemotherapy, median hematologic values (hemoglobin, neutrophils, and platelets) remained nearly constant up to 18 months following start of chemotherapy, regardless of prior docetaxel treatment. A low percentage of patients in both groups had grades 3–4 hematologic values (<10%). Platelet count decline, from last measurement before chemotherapy, was numerically greater in radium-223 versus placebo patients. Median overall survivals from start of chemotherapy were 16.0 and 15.8 months following radium-223 and placebo, respectively. CONCLUSIONS Chemotherapy following radium-223, regardless of prior docetaxel, is feasible and appears to be well tolerated in patients with CRPC and symptomatic bone metastases

FERMION ZERO MODES AND BLACK-HOLE HYPERMULTIPLETS WITH RIGID SUPERSYMMETRY

The gravitini zero modes riding on top of the extreme Reissner-Nordstrom black-hole solution of N=2 supergravity are shown to be normalizable. The gravitini and dilatini zero modes of axion-dilaton extreme black-hole solutions of N=4 supergravity are also given and found to have finite norms. These norms are duality invariant. The finiteness and positivity of the norms in both cases are found to be correlated with the Witten-Israel-Nester construction; however, we have replaced the Witten condition by the pure-spin-3/2 constraint on the gravitini. We compare our calculation of the norms with the calculations which provide the moduli space metric for extreme black holes. The action of the N=2 hypermultiplet with an off-shell central charge describes the solitons of N=2 supergravity. This action, in the Majumdar-Papapetrou multi-black-hole background, is shown to be N=2 rigidly supersymmetric.Comment: 18 pages, LaTe

Charge Density Wave-Assisted Tunneling Between Hall Edge States

We study the intra-planar tunneling between quantum Hall samples separated by a quasi one-dimensional barrier, induced through the interaction of edge degrees of freedom with the charge density waves of a Hall crystal defined in a parallel layer. A field theory formulation is set up in terms of bosonic (2+1)-dimensional excitations coupled to (1+1)-dimensional fermions. Parity symmetry is broken at the quantum level by the confinement of soliton-antisoliton pairs near the tunneling region. The usual Peierls argument allows to estimate the critical temperature $T_c$, so that for $T > T_c$ mass corrections due to longitudinal density fluctuations disappear from the edge spectrum. We compute the gap dependence upon the random global phase of the pinned charge density wave, as well as the effects of a voltage bias applied across the tunneling junction.Comment: Additional references + 1 figure + more detailed discussions. To be published in Phys. Rev.

Ab initio calculation of the neutron-proton mass difference

The existence and stability of atoms rely on the fact that neutrons are more massive than protons. The measured mass difference is only 0.14\% of the average of the two masses. A slightly smaller or larger value would have led to a dramatically different universe. Here, we show that this difference results from the competition between electromagnetic and mass isospin breaking effects. We performed lattice quantum-chromodynamics and quantum-electrodynamics computations with four nondegenerate Wilson fermion flavors and computed the neutron-proton mass-splitting with an accuracy of $300$ kilo-electron volts, which is greater than $0$ by $5$ standard deviations. We also determine the splittings in the $\Sigma$, $\Xi$, $D$ and $\Xi_{cc}$ isospin multiplets, exceeding in some cases the precision of experimental measurements.Comment: 57 pages, 15 figures, 6 tables, revised versio