Co-administration of fish oil with signal transduction inhibitors has anti-migration effects in breast cancer cell lines, in vitro

Background: There is an urgent need for new therapies to treat cancer metastasis. Fish oil, with high omega 3 fatty acid content, has shown anticancer activity and signal transduction inhibitors have shown anti-metastatic properties. Objective: To provide preliminary in vitro data on the anti-migration potential of signal transduction inhibitors and co-administered fish oil. Methods: MCF-7, TamR and FasR breast cancer cell lines were used to determine the effects of combinations of PD98059, LY294002 and fish oil in growth assays. Modulations of p-Src and COX-2, both mediators of motility and invasion, were then determined by Western blotting and IHC to ascertain effects on migration potential. Results: Migration rates for the three cell lines examined were ranked: FasR>TamR>MCF-7 (p <0.05). Addition of fish oil reduced the number of TamR cells migrating after 48h (p <0.05), while the addition of PD98059 and LY294002 also decreased migratory potential of TamR cells (p <0.05). Addition of PD98059 and LY294002 to TamR cells did not result in a significant decrease in p-Src levels; as was the case when PD98059, LY294002 and 4-hydroxytamoxifen were added to MCF-7 cells. However, the co-administration of fish oil markedly reduced p-Src and COX-2 expression in both cell lines. Conclusion: Co-administration of a commercial fish oil with signal transduction inhibitors results in decreased cell migration via an unknown co-operative mechanism and could constitute a novel approach for the treatment of breast cancer metastasis

Two coupled feedback loops explain random mono-allelic Xist upregulation at the onset of X-chromosome inactivation

In female mammal s, dosage compensation for X-linked genes is ensured through random X-chromosome inactivation, which is initiated by mono-allelic up-regulation of Xist . We use mathematical modeling to identify the regulatory principles required to establish the mono-allelic and female-specific Xist expression pattern and test model predictions experimentally. A cis -acting positive feedback, which in mice is mediated by mutual repression of Xist and its antisense transcript Tsix , together with a trans -acting negative feedba ck are sufficient to explain mono-allelic Xist up-regulation. The model can reproduce data from several mutant, aneuploid and polyploid murine cell lines and explain s Xist expression patterns in other mammalian species. Furthermore, it predicts that transient , reversible bi-allelic Xist expression is not restricted to rabbits and humans but can also occur in mice, which we indeed confirm to occur in mouse embryos. Overall, our study provides a conceptual framework of the molecular mechanisms required to initiate random X-chromosome inactivation

New Langevin and Gradient Thermostats for Rigid Body Dynamics

We introduce two new thermostats, one of Langevin type and one of gradient (Brownian) type, for rigid body dynamics. We formulate rotation using the quaternion representation of angular coordinates; both thermostats preserve the unit length of quaternions. The Langevin thermostat also ensures that the conjugate angular momenta stay within the tangent space of the quaternion coordinates, as required by the Hamiltonian dynamics of rigid bodies. We have constructed three geometric numerical integrators for the Langevin thermostat and one for the gradient thermostat. The numerical integrators reflect key properties of the thermostats themselves. Namely, they all preserve the unit length of quaternions, automatically, without the need of a projection onto the unit sphere. The Langevin integrators also ensure that the angular momenta remain within the tangent space of the quaternion coordinates. The Langevin integrators are quasi-symplectic and of weak order two. The numerical method for the gradient thermostat is of weak order one. Its construction exploits ideas of Lie-group type integrators for differential equations on manifolds. We numerically compare the discretization errors of the Langevin integrators, as well as the efficiency of the gradient integrator compared to the Langevin ones when used in the simulation of rigid TIP4P water model with smoothly truncated electrostatic interactions. We observe that the gradient integrator is computationally less efficient than the Langevin integrators. We also compare the relative accuracy of the Langevin integrators in evaluating various static quantities and give recommendations as to the choice of an appropriate integrator.Comment: 16 pages, 4 figure

Previous reproductive history and post-natal family planning among HIV-infected women in Ukraine

BACKGROUND: Ukraine has the highest antenatal HIV prevalence in Europe. The national prevention of mother-to-child transmission (MTCT) programme has reduced the MTCT rate, but less attention has been given to the prevention of unintended pregnancy among HIV-positive women. Our objectives were to describe the reproductive health, condom use and family planning (FP) practices of HIV-positive childbearing Ukrainian women and to identify factors associated with different methods of post-natal contraception. METHODS: HIV-infected childbearing women, diagnosed before or during pregnancy, were enrolled prospectively in a post-natal cohort study in four regional HIV/AIDS centres in Ukraine from December 2007. Logistic regression models were used to identify factors associated with post-natal FP practices. RESULTS: Data were available for 371 women enrolled by March 2009; 82% (n = 303) were married or cohabiting, 27% (97 of 363) reported a current HIV-negative sexual partner and 69% were diagnosed with HIV during their most recent pregnancy. Overall, 21% (75 of 349) of women were not using contraception post-natally (of whom 80% reported no current sexual activity), 50% (174 of 349) used condoms, 20% (74 of 349) relied solely/partially on coitus interruptus and 4% used hormonal methods or intrauterine device. Among married/cohabiting women, consistent use of condoms in the previous pregnancy [AOR 1.96 (95%CI 1.06–3.62)], having an HIV-positive partner [AOR 0.42 (0.20–0.87)], current sexual activity [AOR 4.53 (1.19–17.3)] and study site were significantly associated with post-natal condom use; 16% of those with HIV-negative partners did not use condoms. Risk factors for non-use of FP were lack of affordability [AOR 6.34 (1.73–23.2)] and inconsistent use of condoms in the previous pregnancy [AOR 7.25 (1.41–37.2)]. CONCLUSIONS: More than 40% of HIV-positive women in this population are at risk of unintended pregnancy and the one in six women in HIV-discordant couples not using barrier methods risk transmitting HIV to their partners. Our study results are limited by the observational nature of the data and the potential for both measured and unmeasured confounding

Ekpyrotic collapse with multiple fields

A scale invariant spectrum of isocurvature perturbations is generated during collapse in the scaling solution in models where two or more fields have steep negative exponential potentials. The scale invariance of the spectrum is realised by a tachyonic instability in the isocurvature field. We show that this instability is due to the fact that the scaling solution is a saddle point in the phase space. The late time attractor is identified with a single field dominated ekpyrotic collapse in which a steep blue spectrum for isocurvature perturbations is found. Although quantum fluctuations do not necessarily to disrupt the classical solution, an additional preceding stage is required to establish classical homogeneity.Comment: 13 pages, 1 figur

Metric gravity theories and cosmology:II. Stability of a ground state in f(R) theories

A fundamental criterion of viability of any gravity theory is existence of a stable ground-state solution being either Minkowski, dS or AdS space. Stability of the ground state is independent of which frame is physical. In general, a given theory has multiple ground states and splits into independent physical sectors. All metric gravity theories with the Lagrangian being a function of Ricci tensor are dynamically equivalent to Einstein gravity with a source and this allows us to study the stability problem using methods developed in GR. We apply these methods to f(R) theories. As is shown in 13 cases of Lagrangians the stability criterion works simply and effectively whenever the curvature of the ground state is determined. An infinite number of gravity theories have a stable ground state and further viability criteria are necessary.Comment: A modified and expanded version of a second part of the paper which previously appeared as gr-qc/0702097v1. The first, modified part is now published as gr-qc/0702097v2 and as a separate paper in Class. Qu. Grav. The present paper matches the published versio

LONG TERM IN VIVO KINEMATICS OF THE OVINE STIFLE JOINT FOLLOWING ANTERIOR CRUCIATE LIGAMENT TRANSECTION

INTRODUCTION Osteoarthritis (OA) is a degenerative joint disease involving the breakdown of articular cartilage, which is common after injury or with aging1. Following knee injury, sheep develop OA at a slightly accelerated rate compared to humans but with some similar patterns2. In an ovine knee injury model3,4, altered gait mechanics and degradation of the cartilage has been observed 20 weeks post anterior cruciate ligament (ACL) transection (Tx) surgery; however, potential alterations in gait at 40 weeks post ACL Tx surgery remain to be determined. Therefore, the objective of this study was to investigate the in vivo kinematics of the ovine stifle joint over time (20 weeks and 40 weeks) following ACL Tx. METHODS Force Plate Testing. Three skeletally mature 3 to 4-year-old female Suffolk-cross sheep (average weight 77.1kg) were led across an embedded force platform (Kistler Instrumente, Winterthur, Switzerland) until 20 hind limb hoof strikes were recorded at 1200 Hz. Peak hind limb vertical ground reaction force was determined prior to surgical plate implantation, and then serially prior to each kinematic data collection. Surgical Procedure. All sheep had a bone plate implanted onto each of the proximomedial aspect of the tibia and the distolateral aspect of the femur of their right hind limb, four weeks prior to kinematic testing. Kinematic Collection and Bone Digitization. On the day of kinematic testing, a stainless steel post was attached to each plate and an instrumented spatial linkage (ISL) mounted between them. The ISL consisted of six rotational encoders providing a measurement of position and orientation in six degrees of freedom (6-DOF) to its motion throughout gait. The in vivo kinematics of the stifle joint were measured while the sheep walked on a treadmill at 2 mph (0.89 m/s). Each sheep then underwent arthroscopic ACL Tx surgery on their right hind limb. The in vivo gait kinematics were measured again over time at 20 and 40 weeks post ACL Tx. Following kinematic testing at 40 weeks, the animals were euthanized. A coordinate measuring machine was used to measure anatomic landmarks on the bone with respect to the ISL in order to create an anatomically relevant coordinate system. Analysis. Data are presented as mean ± SD. RESULTS Figure 1: The 6-DOF in vivo gait kinematics of the ovine stifle joint, intact (black), 22 weeks post ACL Tx (red), and 40 weeks post ACL Tx (blue). DISCUSSION AND CONCLUSIONS These data indicate that the in vivo kinematics of the ovine stifle joint do change over time following ACL Tx. The kinematic changes appear to be more drastic after 22 weeks, and do not entirely return back to pre-injury mechanics in all rotations and translations after 40 weeks. As shown in Figure 1, the medial-lateral as well as posterior-anterior translation of the joint is progressively altered post ACL Tx over time. Rotationally, the internal-external kinematic curve at 22 weeks is dissimilar to the intact motion, however by 40 weeks a recovery towards the intact measurement is seen as the animal compensates for the injury. In the future, principal component analysis will be utilized to compare these gait changes. In conclusion, the transection of the ACL causes long-term changes in the in vivo kinematics of the joint. Alterations of the kinematics may result in degradation of cartilage due to abnormal loading of the joint and overall damage in the joint due to compensation of the instability post ACL Tx, which is a painful and destructive condition