Fiber depolymerization

Depolymerization is, by definition, a crucial process in the reversible assembly of various biopolymers. It may also be an important factor in the pathology of sickle cell disease. If sickle hemoglobin fibers fail to depolymerize fully during passage through the lungs then they will reintroduce aggregates into the systemic circulation and eliminate or shorten the protective delay (nucleation) time for the subsequent growth of fibers. We study how depolymerization depends on the rates of end- and side-depolymerization, kend and kside, which are, respectively, the rates at which fiber length is lost at each end and the rate at which new breaks appear per unit fiber length. We present both an analytic mean field theory and supporting simulations showing that the characteristic fiber depolymerization time View the MathML source depends on both rates, but not on the fiber length L, in a large intermediate regime 1 much less-than ksideL2/kend much less-than (L/d)2, with d the fiber diameter. We present new experimental data which confirms that both mechanisms are important and shows how the rate of side depolymerization depends strongly on the concentration of CO, acting as a proxy for oxygen. Our theory remains rather general and could be applied to the depolymerization of an entire class of linear aggregates, not just sickle hemoglobin fibers

In Situ Geophysical Exploration by Humans in Mars Analog Environments

We carried out three geophysical experiments in Mars analog environments in order to better understand the challenges future astronauts will face when conducting similar surveys on Mars or the Moon. The experiments included a passive seismometer deployment and a time-domain electromagnetic survey at the Flashline Mars Arctic Research Station (FMARS) on Devon Island, Canada and a seismic refraction survey in southeastern Utah at the Mars Desert Research Station (MDRS). FMARS is located on the rim of the 23 Ma Haughton Crater in a polar desert environment. MDRS is located in an area with sedimentary plateaus and canyons of Jurassic to Cretaceous age. Both facilities were built by The Mars Society to help develop key knowledge about human Mars exploration. Crews of six spend 2-4 weeks in the habitats and conduct eld research on simulated extravehicular activities (EVAs) wearing mock spacesuits. The work reported here was conducted in July 2009 at FMARS and February 2010 at MDRS

RHIC heavy ion operations performance

The Relativistic Heavy Ion Collider (RHIC) completed its fifth year of operation in 2005, colliding copper ion beams with ps=200 GeV/u and 62.4 GeV/u[1]. Previous heavy ion runs have collided gold ions at ps=130 GeV/u, 200 GeV/u, and 62.4 GeV/u[2], and deuterons and gold ions at ps=200 GeV/u[3]. This paper discusses operational performance statistics of this facility, including Cu- Cu delivered luminosity, availability, calendar time spent in physics stores, and time between physics stores. We summarize the major factors affecting operations efficiency, and characterize machine activities between physics stores

PDGFRα up-regulation mediated by sonic hedgehog pathway activation leads to BRAF inhibitor resistance in melanoma cells with BRAF mutation

Control of BRAF(V600E) metastatic melanoma by BRAF inhibitor (BRAF-I) is limited by intrinsic and acquired resistance. Growth factor receptor up-regulation is among the mechanisms underlying BRAF-I resistance of melanoma cells. Here we demonstrate for the first time that PDGFRα up-regulation causes BRAF-I resistance. PDGFRα inhibition by PDGFRα-specific short hairpin (sh)RNA and by PDGFRα inhibitors restores and increases melanoma cells' sensitivity to BRAF-I in vitro and in vivo. This effect reflects the inhibition of ERK and AKT activation which is associated with BRAF-I resistance of melanoma cells. PDGFRα up-regulation is mediated by Sonic Hedgehog Homolog (Shh) pathway activation which is induced by BRAF-I treatment. Similarly to PDGFRα inhibition, Shh inhibition by LDE225 restores and increases melanoma cells' sensitivity to BRAF-I. These effects are mediated by PDGFRα down-regulation and by ERK and AKT inhibition. The clinical relevance of these data is indicated by the association of PDGFRα up-regulation in melanoma matched biopsies of BRAF-I +/- MEK inhibitor treated patients with shorter time to disease progression and less tumor regression. These findings suggest that monitoring patients for early PDGFRα up-regulation will facilitate the identification of those who may benefit from the treatment with BRAF-I in combination with clinically approved PDGFRα or Shh inhibitors

Blocking the formation of radiation–induced breast cancer stem cells

The goal of adjuvant (post-surgery) radiation therapy (RT) for breast cancer (BC) is to eliminate residual cancer cells, leading to better local tumor control and thus improving patient survival. However, radioresistance increases the risk of tumor recurrence and negatively affects survival. Recent evidence shows that breast cancer stem cells (BCSCs) are radiation-resistant and that relatively differentiated BC cells can be reprogrammed into induced BCSCs (iBCSCs) via radiation-induced re-expression of the stemness genes. Here we show that in irradiation (IR)-treated mice bearing syngeneic mammary tumors, IR-induced stemness correlated with increased spontaneous lung metastasis (51.7%). However, IR-induced stemness was blocked by targeting the NF-κB- stemness gene pathway with disulfiram (DSF)and Copper (Cu2+). DSF is an inhibitor of aldehyde dehydrogenase (ALDH) and an FDA-approved drug for treating alcoholism. DSF binds to Cu2+ to form DSF-Cu complexes (DSF/Cu), which act as a potent apoptosis inducer and an effective proteasome inhibitor, which, in turn, inhibits NF-κB activation. Treatment of mice with RT and DSF significantly inhibited mammary primary tumor growth (79.4%) and spontaneous lung metastasis (89.6%) compared to vehicle treated mice. This anti-tumor efficacy was associated with decreased stem cell properties (or stemness) in tumors. We expect that these results will spark clinical investigation of RT and DSF as a novel combinatorial treatment for breast cancer

Mutation analysis of BRAF and KIT in circulating melanoma cells at the single cell level

信州大学博士（医学）・学位論文・平成25年3月31日授与（甲第945号）・境澤 香里BACKGROUND: The availability of molecular-targeted therapies for the treatment of melanoma has emphasised the need to identify mutations in target genes such as BRAF and KIT. Circulating tumour cells (CTC) are present in the peripheral blood of a significant proportion of cancer patients. METHODS: High molecular weight melanoma-associated antigen (HMW-MAA) was used to isolate melanoma cells from peripheral blood as it is selectively expressed at high levels on melanomas. The HMW-MAA-positive cells were isolated using immunomagnetic beads. After removing CD45(+) cells, CTC were identified by staining with MART-1-and gp100-specific antibodies (HMW-MAA(+), CD45(-), MART-1/gp100(+)). Single, isolated CTC were then subjected to BRAF and KIT mutational analysis. RESULTS: CTC (HMW-MAA(+), CD45(-), MART-1/gp100(+)) were isolated from the blood of 11 patients and BRAF and KIT were sequenced in nine and four patients, respectively. The BRAF sequences identified in the CTC were inconsistent with those identified in autologous melanoma tumours in three patients and the KIT sequences were inconsistent in three patients. In addition, polyclonal BRAF mutations were identified in one patient and concomitant mutations in BRAF and KIT were identified in another patient. CONCLUSION: Melanoma cells show clonal heterogeneity. Therefore, CTC genotyping may be crucial for successful molecular-targeted therapy. British Journal of Cancer (2012) 106, 939-946. doi:10.1038/bjc.2012.12 www.bjcancer.com Published online 26 January 2012 (C) 2012 Cancer Research UKArticleBRITISH JOURNAL OF CANCER. 106(5):939-946 (2012)journal articl