STX140, but not paclitaxel, inhibits mammary tumour initiation and progression in C3(1)/SV40 T/t-antigen transgenic mice.

Despite paclitxael's clinical success, treating hormone-refractory breast cancer remains challenging. Paclitaxel has a poor pharmacological profile, characterized by a low therapeutic index (TIX) caused by severe dose limiting toxicities, such as neutropenia and peripheral neuropathy. Consequently, new drugs are urgently required. STX140, a compound previously shown to have excellent efficacy against many tumors, is here compared to paclitaxel in three translational in vivo breast cancer models, a rat model of peripheral neuropathy, and through pharmacological testing. Three different in vivo mouse models of breast cancer were used; the metastatic 4T1 orthotopic model, the C3(1)/SV40 T-Ag model, and the MDA-MB-231 xenograft model. To determine TIX and pharmacological profile of STX140, a comprehensive dosing regime was performed in mice bearing MDA-MD-231 xenografts. Finally, peripheral neuropathy was examined using a rat plantar thermal hyperalgesia model. In the 4T1 metastatic model, STX140 and paclitaxel significantly inhibited primary tumor growth and lung metastases. All C3(1)/SV40 T-Ag mice in the control and paclitaxel treated groups developed palpable mammary cancer. STX140 blocked 47% of tumors developing and significantly inhibited growth of tumors that did develop. STX140 treatment caused a significant (P<0.001) survival advantage for animals in early and late intervention groups. Conversely, in C3(1)/SV40 T-Ag mice, paclitaxel failed to inhibit tumor growth and did not increase survival time. Furthermore, paclitaxel, but not STX140, induced significant peripheral neuropathy and neutropenia. These results show that STX140 has a greater anti-cancer efficacy, TIX, and reduced neurotoxicity compared to paclitaxel in C3(1)/SV40 T-Ag mice and therefore may be of significant benefit to patients with breast cancer

Hierarchical Hough all-sky search for periodic gravitational waves in LIGO S5 data

We describe a new pipeline used to analyze the data from the fifth science run (S5) of the LIGO detectors to search for continuous gravitational waves from isolated spinning neutron stars. The method employed is based on the Hough transform, which is a semi-coherent, computationally efficient, and robust pattern recognition technique. The Hough transform is used to find signals in the time-frequency plane of the data whose frequency evolution fits the pattern produced by the Doppler shift imposed on the signal by the Earth's motion and the pulsar's spin-down during the observation period. The main differences with respect to previous Hough all-sky searches are described. These differences include the use of a two-step hierarchical Hough search, analysis of coincidences among the candidates produced in the first and second year of S5, and veto strategies based on a $\chi^2$ test.Comment: 7 pages, 2 figures, Amaldi08 proceedings, submitted to JPC

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Safety of a Sustainably Produced, Bioengineered, Nature-Identical Salidroside Compound

Bioactive phytochemicals such as salidroside have been studied to understand the beneficial effects of Rhodiola rosea, an herbaceous plant used in traditional medicine to increase energy and treat a variety of health issues. However, Rhodiola plants are often slow-growing, and many are endangered in their native habitats. Thus, there is a need for safe, alternative supplies of key phytochemicals from Rhodiola. The salidroside subject of this safety study is a synthetic biology product from fermentation of a bioengineered E. coli that produces salidroside. Here, we present comprehensive test results that support the safety of salidroside manufactured via a patented sustainable bioengineering manufacturing process. In vitro bacterial reverse mutation assays with the bioengineered salidroside show no mutagenicity in any of the concentrations tested. In vivo toxicity studies in rats show no adverse effects from the salidroside product. Based on the results of these studies, we conclude that the bioengineered salidroside discussed here is not genotoxic and demonstrates a no-observed-adverse-effect level (NOAEL) at least 2000 mg/kg bw/day in male and female Sprague&ndash;Dawley rats. This study supports that the salidroside compound produced using bioengineered E. coli is a viable alternative to salidroside produced from harvested Rhodiola plants for use as a dietary supplement, food ingredient, or potentially as a pharmaceutical product

The chemical structure of STX140.

<p>The chemical structure of STX140.</p

Experimental design for the use of STX140 and paclitaxel <i>in vivo</i> in C3(1)/SV40 Tag transgenic mice.

<p>Two different studies were performed. In the early intervention study, animals were treated at 12 weeks of age for 15 weeks; mice were euthanized if tumor length reached 1.5 cm in any direction. The late intervention experiment was initiated when the tumor burden was greater than 100 mm³ and dosing of STX140 was continuous until humane endpoints reached.</p

Anatomopathological analysis of brain, spinal cord and sciatic nerve from nude mice treated with STX140 or paclitaxel.

<p>Anatomopathological analysis of brain, spinal cord and sciatic nerve from nude mice treated with STX140 or paclitaxel.</p