Variational calculations for anisotropic solitons in dipolar Bose-Einstein condensates
We present variational calculations using a Gaussian trial function to calculate the ground state of the Gross-Pitaevskii equation and to describe the dynamics of the quasi-two-dimensional solitons in dipolar Bose-Einstein condensates. Furthermore we extend the ansatz to a linear superposition of Gaussians improving the results for the ground state to exact agreement with numerical grid calculations using imaginary time and split-operator method. We are able to give boundaries for the scattering length at which stable solitons may be observed in an experiment. By dynamical calculations with coupled Gaussians we are able to describe the rather complex behavior of the thermally excited solitons. The discovery of dynamically stabilized solitons indicates the existence of such BECs at experimentally accessible temperatures.
pacs:03.75.Lm, 05.30.Jp, 05.45.-a
Since the prediction and the experimental realization of Bose-Einstein condensates (BECs) the field of cold atomic gases has been subject of multiple theoretical and experimental investigations. BECs with long-ranged interaction which can experimentally be realized by the condensation of atoms with a magnetic dipole moment such as are of special interest Griesmaier05a (); Beaufils08 (); Lahaye09 (). To stabilize such condensates, in general optical traps are applied in all three spatial directions. However, it has been shown by Tikhonenkov et al. Tikhonenkov08a () that stable quasi-2d solitons are possible where a trap is applied only in one direction perpendicular to the axis of the aligned atomic dipoles.
Solitons are a nonlinear effect which arises from the dispersion and the nonlinearity cancelling out each other. The solitons suffer from two kinds of instabilities: First, strong attractive particle interactions can cause the collapse of the condensate and second, when the interactions are only weakly attractive or even repulsive the BEC can dissolve in the directions where the external trap is open.
A prerequisite for the experimental realization of the solitons is a detailed theoretical investigation of the parameter ranges where the condensate is stable. The relevant parameters are the trap frequency, the scattering length of the contact interaction, and the excitation energy which allows for an estimation of the temperature range where the solitons can exist. The detailed analysis of the stationary states and the dynamics of solitons based on extended variational calculations is the objective of this article.
In the mean-field approximation the BEC with particle number is described by the extended Gross-Pitaevskii equation (GPE). Introducing “natural” units for mass , action , length , energy , frequency , abbreviating and making use of the scaling properties of the GPE leads to the scaled extended time-dependent GPE in “natural” units
where the tilde is omitted. The dipole moments of the atoms are aligned in direction by an external magnetic field, and is the angle between and the magnetic field axis. In the trap geometry assumed here only a trap in the -direction perpendicular to the magnetic field is present, i.e. .
In Ref. Tikhonenkov08a () the GPE (1) has been solved approximately using a variational approach with a Gaussian type orbital and numerically exact by simulations on a grid. The grid calculations are numerically quite expensive. For a detailed analysis of the parameter space of the quasi-2d solitons we therefore introduce and employ an extended variational method based on coupled Gaussian functions, which has already turned out, for dipolar BECs with an axisymmetric three-dimensional trap, to be a full-fledged alternative to grid simulations Rau10 (); Rau10a (); Rau10b (). In this article the stable ground state of the condensate is computed by imaginary time evolution of an initial wave function, and it is shown that typically three to six coupled Gaussians are sufficient to obtain fully converged results. For a given trap frequency stable solitons exist in a finite range of the scattering length , outside that range the condensate collapses or dissolves.
The dynamics of energetically excited solitons is studied by solving the equations of motions for the variational parameters in real time. The mean-field energy of the ground state is typically only slightly below the energy threshold where the soliton can dissolve. However, the investigation of the dynamics reveals the existence of dynamically stabilized solitons at energies far above that threshold, indicating the possible experimental realization of solitons at temperature or even higher in the limit of the GPE. The transition temperature of a chromium BEC is experimentally given by Griesmaier05a (). Therefore the soliton can be dynamically stabilized in all such BECs.
The paper is organized as follows: In Sec. II we investigate the solitons with the ansatz of a single Gaussian wave packet. The appealing simplicity of this model is that both the stationary states and the dynamics of the solitons can be obtained from the Hamiltonian of a pseudo particle moving in a three-dimensional potential. In Sec. III the variational ansatz will be extended to a linear superposition of Gaussian wave packets (GWPs), and the TDVP will be applied to GWPs. The imaginary time evolution method will be used in Sec. IV for the evaluation of the ground state, and the results will be compared to the calculations with one Gaussian as well as with numerical grid calculations with the split-operator method. The analysis of the real time dynamics allows us to estimate the stability of excited solitons at finite temperatures. Concluding remarks are given in Sec. V.
Ii Variational approach with a single Gaussian
Although the variational ansatz with a single Gaussian function cannot provide quantitatively correct results the simple model already allows us to gain deep insight into the physics of the quasi-2d solitons.
The ansatz with a single Gaussian as a trial function in the TDVP reads
with the complex variational parameters
The parameters determine the real half-widths of the Gaussian function, describes the amplitude used for normalization of the wave function, and is a global phase. The variational ansatz (2) of course strongly simplifies the problem. Nevertheless the investigation of this model yields physical insight and the results for the ground state are, as will be shown, qualitatively correct.
The mean-field energy and the chemical potential are
respectively. The expectation values with the wave function given in Eq. (2) read
for the kinetic term,
for the trapping potential,
for the scattering potential, and
for the dipolar potential with and . The term
denotes an elliptic integral of second kind in “Carlson’s form” which can be evaluated with a fast and stable approximation algorithm Carlson94a (); Carlson95a () more efficiently than the integral representation given in Tikhonenkov08a ().
ii.1 Hamiltonian form of the equations of motion
The ground state of the GPE can in principle be obtained by minimizing the mean-field energy in Eq. (4). Alternatively, the TDVP can be applied to derive equations of motion for the variational parameters in Eq. (3). The equations of motion can be used to investigate the dynamics of the soliton, and the stationary states of the system can be found by searching for the fixed points of these equations. The stable fixed point with the lowest mean-field energy denotes the ground state.
For the ansatz of a single Gaussian the system can be transformed to the descriptive form of a Hamiltonian system by the coordinate transformation
The Hamiltonian in the coordinates
has the conventional form . It can be shown that Hamilton’s equations
lead to the same equations of motion as the TDVP applied to the variational parameters in Eq. (3).
The potential is visualized in Fig. 1.
The isopotential surfaces close to the stable fixed point have ellipsoidal form. At the trap energy the potential gets open. The unstable fixed point at smaller values of than the local minimum is given by the saddle point where the surrounding isosurfaces have hyperbolic form. In Fig. 1(c) the potential at a smaller scattering length close to the bifurcation point is shown. The local minimum and the saddle point approach one another and coincide at the critical scattering length .
ii.2 Stationary states and linear stability
The fixed points of the system can now be easily calculated by a nonlinear root search for and in Hamilton’s equations (13). In Fig. 2 the mean-field energy and the chemical potential of the stable ground state and of an excited unstable state are shown as a function of the scattering length.
The two branches emerge in a tangent bifurcation at the critical scattering length . In Fig. 2(c) the width parameters corresponding to the ground state show, that with increasing scattering length the soliton gets very broad and finally dissolves.
To analyze the stability of the solution of the GPE the eigenvalues of the six-dimensional Jacobi matrix
or equivalently in the canonical coordinates the eigenvalues of the three-dimensional real symmetric Hesse matrix of the potential are calculated. The results are shown in Fig. 3.
The eigenvalues appear in pairs of different sign and are all pure imaginary for the stable state. The linear stability for different trap frequencies shows qualitatively similar behavior.
ii.3 Dynamics with a frozen Gaussian
Hamilton’s equations (13) describe the dynamics of the soliton with the potential . The systematic investigation and visualization of the dynamics of a Hamiltonian system with three degrees of freedom is a nontrivial task. However, the force in the direction is dominated by the strong harmonic trap potential. If therefore is sufficiently large at least for the ground state of the condensate takes nearly the value of the harmonic oscillator ground state. As a further simplification of the problem we therefore restrict the dynamics to the plane given by the condition
which corresponds to a frozen Gaussian ansatz in the direction. For the plane is marked in Fig. 1(b).
The dynamics of the wave function (2) with fixed parameters , is described in the canonical coordinates and by the two-dimensional potential
which is illustrated in Fig. 4.
To describe the dynamics of this two-dimensional system it is convenient to analyze Poincaré surfaces of section (PSOS). An adequate choice of the PSOS shown in Fig. 4 is using the rotated coordinates and momenta
with and the crossing condition . For constant energy different initial conditions are integrated. The border of the allowed energy range is given by
In Fig. 5(a) a PSOS at an energy close to the ground state is shown. The motion is completely regular and an elliptic fixed point of the Poincaré map is present, which belongs to the antisymmetric periodic oscillation of the condensate. The symmetric oscillation is not visible in the PSOS for the surface of section being almost parallel to it. Increasing the energy towards , the turning points of the periodic oscillations in Fig. 4 move to larger values of and (for the symmetric oscillation only one turning point, for the antisymmetric both). For they lie at infinity, i.e. the soliton dissolves. In the Poincaré map the resonant tori decay according to the Poincaré-Birkhoff therorem building the same number of elliptic and hyperbolic fixed points in the Poincaré map. The closer to the bifurcation point the scattering length is, the lower the energy is, where this takes place. This can be seen especially in Fig. 5. Further increasing of the energy leads to regions of chaotic oscillations while the elliptic fixed point moves outwards to larger values of .
In the picture with a frozen Gaussian the solitons dissolve at energy in agreement with Tikhonenkov08a (); Santos09 (). If this were always true it would imply that in an experiment with realistic parameters (e.g., a condensate with 10000 particles at and ) the solitons must be cooled down to temperatures of about because the energy gap between the ground state and the threshold is very small (for a more detailed discussion see Sec. IV.1). However, a dynamical stabilization of the solitons at energies is possible as will be discussed for an ansatz with a single Gaussian in the next Section II.4 and for coupled Gaussians in Sec. IV.2.
ii.4 Three-dimensional dynamics
In the frozen Gaussian approximation any excitation energy of the soliton must be completely deposited in the motion, which leads to the dissolving of the soliton at the low threshold . In this section we demonstrate that for the fully three-dimensional dynamics with the ansatz (2) a large amount of excitation energy can be stored in the motion dominated by the one-dimensional harmonic trap.
An example trajectory for trap frequency , scattering length , and with mean-field energy far above the threshold at is presented in Fig. 6.
In (a) and (b) the expectation values
are drawn as functions of time. The slow oscillations in and generate the Lissajous type motion of the quasi-2d soliton visualized in Fig. 6(c). The fast oscillation in results dominantly from the external harmonic trap. The calculations with a single Gaussian thus indicate that a rather highly excited soliton may be dynamically stabilized and does not dissolve in contrast to the calculations with a frozen Gaussian Tikhonenkov08a (); Santos09 (). However, it must be clarified (in Sec. IV.2) whether the dynamical stabilization is also possible with coupled Gaussians.
Iii Ansatz with coupled Gaussians
Though the ansatz made in Sec. II offers a descriptive analysis of the soliton, comparison with calculations where the GPE is solved numerically on a grid show that the results for the ground state only hold qualitatively. As it will be shown, the results for the dynamics of the soliton are qualitatively different as well. To gain quantitatively correct results the ansatz for the trial function has to be modified. As shown in Rau10a (); Rau10b () the condensate wavefunction can be well described by a superposition of Gaussians. We therefore apply the TDVP to coupled Gaussian wave packets McLachlan1964a (); Heller75a (); Fab09a (); Fab09b (). The ground state will be determined by the imaginary time evolution (ITE) with the norm conservation embedded in the TDVP as a constraint.
In this section we elaborate the theory and derive the formulae for the computations with coupled Gaussians. The results for the stationary states and the dynamics of the solitons are presented in Sec. IV.
iii.1 Time-dependent variational principle for GWPs
In this article the TDVP provides the basis for the solution of the time-dependent GPE. Its application to GWPs was originally introduced by Heller heller:4979 (); Heller81a () for the description of atomic and molecular quantum dynamics and later on applied to BEC Rau10a (); Rau10b (). For the convenience of the reader we here shortly recapitulate this method.
is to be minimized with respect to . Afterwards it is set . The wave function shall be parameterized by the variational parameters . The variation of in Eq. (20) carries over to the variation of and and results in
for the wave function being constant. Because the variational parameters are complex quantities both brackets in Eq. (21) have to vanish separately. This yields
which can be written shortly as
where is an hermitian positive definite matrix. The linear system (23) has to be solved for every time step to integrate the equations of motion .
We now choose a linear superposition of Gaussians as the trial function
where are complex diagonal matrices of dimension and denotes the relative phases and the amplitude of the Gaussians, respectively. The Gaussians are fixed at the origin. The time evolution can be considered as the motion in an effective time-dependent harmonic potential
The dynamics of the GWPs are now determined by the TDVP, which variationally fits the effective time-dependent harmonic potential coefficients to the underlying potential. Splitting the Hamiltonian and operating on the trial wave function (24) yields
The parameters are scalars and the matrices are diagonal matrices. The equations of motion then read
The coefficients and have to be calculated from the TDVP
Combining the coefficients and in a complex vector the set of equations (29) can be written as
The positive definite hermitian matrix includes in contrast to Eq. (23) the kinetic operator. Eq. (30) has to be solved for every time step and the resulting vector has then to be inserted in Eq. (27).
In the numerical integration of the equations of motion (27) (e.g. with a standard algorithm like Runge-Kutta), the quadratic term can lead to the numerical overflow heller:4979 (). It is therefore reasonable to split up the matrices into two matrices and according to . For the case of diagonal matrices , and are diagonal, too. Hence the splitting can be done component-by-component. This leads to
where and are taken as initial values.
iii.2 Constraints in the TDVP
The most important reason for the introduction of constraints is the conservation of the norm in the imaginary time evolution (cf. Sec. III.4). Apart from that inequality constraints can be used to avoid matrix singularities which arise from overcrowding the basis set Fabcic08a (). In principle constraints can be introduced combined in the -dimensional vector . The constraints are embedded then by a set of Lagrangian multiplicators
where is a real matrix. To find the minimum of
has to be calculated which yields the system of equations
In the special case of Gaussian wave packets the equations of motion (split into real and imaginary part and combining the variational parameters to can be written in the form
where consists of the terms linear in and the constant terms are absorbed in the vector . The constraints combined in yield
The set of linear equations (34) then reads
Solving this system of linear equations and inserting the result vector in Eq. (27) enables one to integrate the equations of motion.
iii.3 Energy functional
To gain the mean-field energy of the soliton the time-dependent variational parameters of the GWPs are used in the evaluation of the integrals in the energy functional. The energy functional for coupled Gaussians reads
With the integrals in (39) yield
with the abbreviations
The additional integrals in the TDVP , and are obtained easily from the integrals in the energy functional.
iii.4 Imaginary time evolution
In principle the ground state of the system of coupled Gaussians could be obtained by a nonlinear root search in the equations of motion. Since complex initial values are required, it is difficult to find the fixed points this way for a large number of Gaussians . The imaginary time evolution represents an alternative for the determination of the ground state.
In the linear Schrödinger equation the transformation leads to an exponential damping of the excited states and converges to the ground state for . The method can be applied to the nonlinear GPE as well. In imaginary time the norm is not conserved any more. This is crucial in the nonlinear GPE because the decay of the norm has the meaning of particle losses. To avoid the norm decay we implement the norm conservation as a constraint
in the TDVP as elaborated above. Supposing a general complex rotation of the time with the equations of motion can be written in the general form
where the abreviative notation in can be understood as follows: Every entry is an submatrix . If all elements of , otherwise . The vectors , , and contain the real and imaginary parts of the coefficients of the effective potential. The entries in are vectors with the index running from to . One special case is the real time evolution , and the other special case the imaginary time evolution , . The gradient vector in Eq. (36) is given by
with which one obtains and .
With this method the norm is conserved during the numerical integration for rather long times. However for very long times a small drift in the norm is present due to the numerical error of the integration. The ITE of a system of 10 coupled Gaussians is shown in Fig. 7.
If the relative accuracy of the integrater is chosen coarse, the mean-field energy does not decay monotonously but for long times it converges to the same value as an integration with a fine relative accuracy thus a coarse accuracy can be chosen for the sake of time. The ITE is very robust to the initial choice of the wave function. This also holds for large numbers of Gaussians coupled, where the nonlinear root search often fails. However, only the stable ground state is accessible with this method.
Iv Results with coupled Gaussians
Applying the variational ansatz with coupled Gaussians to the wave functions of dipolar condensates we are now able to obtain quantitatively correct ranges of the parameters where stable quasi-2d solitons can exist. For an experimental realization of solitons with chromium atoms realistic trap frequencies are typically a few hundred Hertz for condensates with about to particles. These values roughly correspond to an interval of . We therefore focus our calculations on two values for the scaled trap frequency, viz. and .
iv.1 Stationary ground state
In Figs. 8(a) and 9(a) the mean-field energy as a function of the scattering length is plotted for up to 6 coupled Gaussians. For comparison the calculation using a nonlinear root search for one Gaussian as discussed in Sec. II.2 is displayed, as well. The mean-field energy and also the chemical potential [see Figs. 8(b) and 9(b)] converge with increasing number of Gaussians . The detailed convergence properties of the calculations with increasing number of Gaussians are illustrated in Fig. 10, where calculations for up to 12 Gaussians are shown at constant scattering length .
The ground state energy converges fast with the number of Gaussians and the corrections above a number of about 5 Gaussians can be neglected. The small energy differences between the variational and the grid calculations in Fig. 9(a) may be due to the finite grid size, which is limited by an acceptable computation time.
In the calculations with a single Gaussian a stable and an unstable state are created in a tangent bifurcation at a scattering length . Using coupled Gaussians the critical scattering length where the condensate collapses is shifted to higher values, e.g., from to at trap frequency and from to at trap frequency . The ITE can only provide the stable ground state but no unstable states which are certainly also involved in the bifurcation. For dipolar condensates in an axisymmetric trap a complicated bifurcation scenario has been revealed Rau10 (); Rau10b (), and it will be an interesting future task to study bifurcations of the soliton states in more detail.
The corrections to the calculations with a single Gaussian decrease with growing scattering lengths. This can be understood when looking at the spatial size of the soliton [cf. Fig. 2(c)]. For large expansion of the condensate the nonlinear interaction terms in the GPE are small and thus the mean-field energy is dominated by the ground state energy of the harmonic trap in the direction. Above a certain threshold value for the scattering length the soliton is no longer bound but dissolves. The thresholds at, e.g., for and for obtained with a single Gaussion (see Fig. 2) are only very slightly shifted to higher values when using coupled Gaussians.
The extended variational approach allows us to compute for each trap frequency an accurate lower and upper critical value of the scattering length, i.e., a range where stable solitons in dipolar BECs can exist. However, in an experiment thermal excitations of the soliton may cause the dissolving of the soliton, and therefore it is also necessary to determine an energy or temperature limit for the existence of stable solitons. As a dissolving condensate without any interaction must have at least the zero point energy of the harmonic trap in the direction the difference between this threshold and the mean-field energy of the ground state,
can be taken for a very conservative estimation of the temperature at which the soliton should survive thermal excitations. In Figs. 8(c) and 9(c) that temperature is plotted as a function of the scattering length for two condensates with and particles. With this conservative estimate a soliton at, e.g., trap frequency and scattering length must be cooled down to about . However, solitons may exist at much higher temperatures when they are dynamically stabilized as discussed in Sec. II.4 for the ansatz with a single Gaussian. We now extend that discussion to the ansatz with coupled Gaussians.
iv.2 Dynamics with coupled Gaussians
The ansatz with a single Gaussian used to describe the dynamics of the solitons in Sec. II.4 and especially the further simplification with a frozen Gaussian in Sec. II.3 are basically mathematical model systems, and the results obtained with these models have to be seen from an academic point of view. For a realistic description it is necessary to investigate the dynamics of the solitons with the extended ansatz (24) of coupled Gaussians which has shown to significantly improve the results for the ground state in Sec. IV.1. Of special interest is to search for the existence of dynamically stabilized solitons at energies above the threshold . To this aim the equations of motion (27) are integrated with the initial wave function chosen appropriately to yield the desired mean-field energy.
The condensate wave function (24) with coupled Gaussians is parametrized by real time-dependent variational parameters. For the visualization of the wave function we use the reduced set of parameters
which are related to the extension of the soliton in the three spatial dimensions and can be directly compared with the results for a single Gaussian using the coordinates in Eq. (19).
For energies close to the ground state energy periodic oscillations can be found. The parameters of the turning points of the periodic oscillations show a rather complicated behavior when the mean-field energy is increased. The different periodic oscillations vanish in multiple bifurcations close to the ground state energy. Above no periodic oscillations were found. However increasing the energy above yields oscillations of the soliton which do not destroy it. Applying a frozen Gaussian approximation yields stable oscillations only slightly above this limit. But allowing oscillations in all spatial directions stabilizes the condensate and gives rise to an oscillating soliton as shown in Fig. 11 for a trajectory at trap frequency , scattering length , and mean-field energy .


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- Research article
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Parthenolide and costunolide reduce microtentacles and tumor cell attachment by selectively targeting detyrosinated tubulin independent from NF-κB inhibition
Breast Cancer Research volume 15, Article number: R83 (2013)
Detyrosinated tubulin, a post-translational modification of α-tubulin and a hallmark of stable microtubules, has gained recent attention given its association with tumor progression, invasiveness, and chemoresistance. We also recently reported that epithelial-to-mesenchymal transition (EMT) promotes tubulin detyrosination through tubulin tyrosine ligase (TTL) suppression. Furthermore, detyrosinated tubulin-enriched membrane protrusions, termed microtentacles (McTN), facilitate tumor cell reattachment to endothelial layers. Given the induction of EMT associated with inflammation and cancer progression, we tested anti-inflammatory nuclear factor-kappaB (NF-κB) inhibitors on a panel of human breast carcinoma cells to examine their effects on detyrosinated tubulin to identify more specific tubulin-directed anti-cancer treatments.
Using metastatic human breast carcinoma cells MDA-MB-157, MDA-MB-436, and Bt-549, we measured the impact of NF-κB inhibitors parthenolide, costunolide, and resveratrol on detyrosinated tubulin using protein expression analysis and immunofluorescence. A luciferase reporter assay and a viability screen were performed to determine if the effects were associated with their NF-κB inhibitory properties or were a result of apoptosis. Real-time monitoring of cell-substratum attachment was measured utilizing electrical impedance across microelectronic sensor arrays. We compared the selectivity of the NF-κB inhibitors to specifically target detyrosinated tubulin with traditional tubulin-targeted therapeutics, paclitaxel and colchicine, throughout the study.
Sesquiterpene lactones, parthenolide and costunolide, selectively decrease detyrosinated tubulin independent of their inhibition of NF-κB. Live-cell scoring of suspended cells treated with parthenolide and costunolide show reduction in the frequency of microtentacles and inhibition of reattachment. Structural analysis shows that parthenolide and costunolide can decrease detyrosinated microtubules without significantly disrupting the overall microtubule network or cell viability. Paclitaxel and colchicine display indiscriminate disruption of the microtubule network.
Our data demonstrate that selective targeting of detyrosinated tubulin with parthenolide and costunolide can reduce McTN frequency and inhibit tumor cell reattachment. These actions are independent of their effects on NF-κB inhibition presenting a novel anti-cancer property and therapeutic opportunity to selectively target a stable subset of microtubules in circulating tumor cells to reduce metastatic potential with less toxicity in breast cancer patients.
Microtubules have long been a target for cancer therapy given their critical and diverse cellular functions in intracellular transport and metabolism, as well as cell shape, signaling, migration, polarization and division . Despite the attractiveness of microtubules as cancer targets, the clinical effectiveness and tolerance of microtubule-directed agents are limited, largely due to toxicity, broad and/or undetermined mechanisms of action, inherent or acquired resistance and tubulin mutations that reduce drug binding . Alterations in tubulin-binding sites, microtubule associated proteins (MAPs) and microtubule dynamics have all been implicated as mechanisms for tumorigenesis, chemoresistance and metastasis . To improve and advance the therapeutic benefits of microtubule-targeted compounds for cancer treatment, research has focused on combination therapy, discovering novel tubulin or tubulin-associated drug targets and elucidating more specific drug mechanisms. More importantly, better characterization of microtubule function, regulation and role in cancer progression and chemoresistance continue to advance the development of clinically-applicable, novel tubulin-directed chemotherapies.
Microtubules can undergo phases of growth and shrinkage by modulating dynamic instability; however, stabilization of a subset of microtubules is necessary for cell motility  and morphogenetic events . Selective stabilization occurs prior to changes in cell behavior , indicating that stabilization is an early causative event rather than a result of alterations in cell behavior. These stable microtubules are enriched in detyrosinated tubulin, a reversible post-translational modification on the C-terminus of α-tubulin, regulated by the enzymatic activity of tubulin tyrosine ligase (TTL) and an ill-defined tubulin carboxypeptidase (TCP). Detyrosination has been shown to be a consequence of microtubule stability and the precise function of this post-translational modification on microtubule dynamics and regulation is still unclear. Early insight into microtubule stability suggests that stable microtubules enriched in detyrosinated tubulin are more resistant to microtubule antagonists . In addition to its implications for chemoresistance, research has shown that increased detyrosinated tubulin is associated with poor cancer prognosis  and may arise from suppressed TTL activity during tumor growth which prevents re-tyrosination [8, 9]. Moreover, TTL-/- cells exhibit decreased microtubule sensitivity to depolymerizing drugs as well as microtubule overgrowth and persistence at the cell’s leading edge , potentially contributing to abnormal cell behavior. We have recently reported that epithelial-to-mesenchymal transition (EMT) promotes α-tubulin detyrosination by downregulating expression of TTL and that detyrosinated tubulin accumulates at invasive tumor fronts in patient samples . Furthermore, we have shown that microtentacles (McTNs), tubulin-based, dynamic membrane protrusions that occur at high frequencies in detached metastatic cell lines, are enriched in detyrosinated tubulin and facilitate tumor cell reattachment and cell-cell adhesion [11, 12]. This evidence highlights the importance of the tubulin tyrosination cycle in cancer progression and reveals detyrosinated tubulin as a novel microtubule target in the metastatic cascade.
The relationship between EMT, inflammation and cancer progression has received considerable attention in the last several years . Given our recent discovery that EMT promotes detyrosination of α-tubulin in combination with data linking chronic inflammation and associated nuclear factor-kappaB (NF-κB) activation to the induction of an EMT [14, 15], we decided to test anti-inflammatory compounds to determine their impact on tubulin detyrosination and McTN occurrence. Parthenolide and costunolide, members of the natural compound sesquiterpene lactone group, have been well-characterized as inhibitors of the NF-κB pathway and effective anti-inflammatory drugs but are less recognized for their microtubule-interfering properties [16, 17]. A recent report, however, uncovered parthenolide’s ability to inhibit TCP activity to restore functional tyrosinated tubulin levels and reduce detyrosination . Parthenolide and costunolide could possibly interfere with microtubules through their potent NF-κB inhibitory properties. There is conflicting evidence suggesting that depolymerization of microtubules can decrease translocation of active NF-κB into the nucleus or induce NF-κB activity and transactivation of NF-κB-dependent genes [19, 20]. Additionally, microtubule stabilizers such as Taxol may promote NF-κB activation  or have no effect . Despite the conflicting data, it is apparent that interfering with microtubule dynamics can affect transcription factor activity. Therefore, the question remains whether the ability of parthenolide and costunolide to reduce stable, detyrosinated tubulin in metastatic breast cancer cells occurs through a mechanism that is dependent or independent of their NF-κB inhibitory properties.
Our past research has used broad microtubule and actin disrupting agents as tools to determine the structure and function of McTNs. These tools have been useful to define McTNs as tubulin-based and distinguish McTNs from actin-based membrane structures, but have limited value when translated to the clinic due to their toxicity and severe disruption of the entire microtubule array. The primary focus of the current report is to identify novel therapeutic candidates that move beyond indiscriminate targeting of microtubules, enabling reductions in McTNs and the reattachment proficiencies of metastatic breast cancer cell lines by specifically targeting detyrosinated tubulin. We also investigate whether the effects of parthenolide and costunolide on detyrosination are related to their NF-κB inhibitory activity or if a separate mechanism is responsible and reveals multi-faceted targets for these anti-cancer therapies.
Cell culture and chemical compounds
Bt-549 and MDA-MB-436 were maintained at 37°C in (D)MEM (Mediatech, Inc., Manassas, VA) in 5% CO2 while MDA-MB-157 was cultured in L-15 media (Life Technologies, Carlsbad, CA) at 37°C without CO2. Cells were obtained by American Type Culture Collection (Manassas, VA, USA) and growth media was supplemented with 10% fetal bovine serum (FBS) and penicillin-streptomycin (100 μg/ml). Parthenolide (Parth), resveratrol (ResV), colchicine (Col), and paclitaxel (Taxol;Tax) were obtained from Sigma (St. Louis, MO, USA). Costunolide (Cost) was purchased from Chromadex (Santa Ana, CA, USA). Recombinant human TNF-α was from PeproTech (Rocky Hill, NJ, USA). This study did not require approval from an ethics committee.
Cells were treated for six hours in growth media using a concentration range containing vehicle (0.1% dimethyl sulfoxide (DMSO)), Parth, Cost, ResV, Col or Tax. Cells were harvested as previously described . Total protein (12 μg) was separated by SDS-PAGE on 4% to 12% NuPage MES Bis-Tris gels (Life Technologies). Membranes were blocked in 5% milk/Tris-buffered saline - Tween (TBST) for one hour at room temperature followed by an overnight incubation at 4°C in polyclonal detyrosinated α-tubulin (1:1000; abCam, Cambridge, MA) poly (ADP-ribose) polymerase (PARP; H-250, Santa Cruz Biotechnology; 1:1000), or monoclonal α-tubulin DM1A (1:5000; Sigma) in 2.5% milk/TBST. Secondary antibodies to immunoglobulin G-horse radish peroxidase (IgG-HRP) were used (1:10000; Jackson ImmunoResearch, West Grove, PA). Densitometry was performed using ImageJ.
Cells were transduced with NF-κB -luciferase reporter adenovirus (Ad-NF-κB -Luc; 1 × 106 PFU/ml) obtained from Vector Biolabs (Philadelphia, PA, USA) for 24 hours. Cells were then split into a microplate to ensure uniform cell density. Following four hours of drug treatment, cells were stimulated with TNF-α (100 ng/ml) for one hour remaining in the presence of drug. D-Luciferin (Caliper Life Sciences, Alameda, CA; 200 μg/ml) was added and luminescence was detected on a Berthold LB 940 Mirthras. All values are shown as mean ± SD of triplicate samples.
Cells were seeded into 96-well microplates and treated in triplicate for six hours. CellTiter 96 AQueous One Solution (Promega, Madison, WI) was followed according to the manufacturer’s protocol to determine cell viability. Absorbance was measured using a Biotek Synergy HT Multidetection Microplate Reader. All values are shown as mean ± SD of triplicate samples.
Live cell imaging and microtentacle scoring
GFP-membrane targeted AcGFP1-Mem plasmid (Clontech, Mountain View, CA) was used to generate a custom adenovirus (Ad-GFP-Mem; Vector BioLabs) for McTN scoring and population imaging. Cells were transduced for 24 hours and then treated with drug for 6 hours prior to detachment. Detailed methods for live cell imaging and McTN scoring were previously described . Single Ad-GFP-Mem+cells were scored blindly for McTNs at 15 to 30 minutes while suspended in an ultra-low attachment plate (Corning, Corning, NY) in the respective drug-containing growth media. Images were collected using an Olympus CKX41 inverted fluorescent microscope (Melville, NY, USA) and analysis was performed using Olympus MicroSuite Five software. Cell images were collected following detachment as grayscale images and subsequently color inverted for better visualization contrast. The original images were contrasted equivalently using ImageJ.
Cells were drug treated on glass coverslips for six hours then fixed in 3.7% formaldehyde/PBS. Fixed cells were permeabilized (0.25% Triton X-100/PBS, 10 minutes), and blocked for one hour (PBS/5% bovine serum albumin (BSA)/0.5% NP40). Immunostaining was performed overnight at 4°C (PBS/2% BSA/0.5% NP40) using polyclonal detyrosinated α-tubulin (abCam) and monoclonal α-tubulin DM1A (Sigma). Image acquisition was captured on an Olympus FV1000 laser scanning confocal microscope (Olympus, Center Valley, PA, USA).
Cell-electrode impedance attachment assay
Real-time monitoring of cell-substratum attachment was measured utilizing the xCELLigence RTCA SP real-time cell sensing device (ACEA Biosciences, San Diego, CA). Cells were pretreated for six hours, trypsinized and counted. Cells (20,000) were seeded into 96-well microelectronic sensored standard plates (E-plates) containing the respective drug. Briefly, attachment is measured from the interaction of cells with the electrodes and represented as a change in cell index (CI), an arbitrary unit derived from the relative change in electrical impedance across microelectronic sensor arrays. The electrical impedance was captured every three minutes for an experimental duration of 3.5 hours. The attachment rate is expressed as the CI, or the change in electrical impedance at each timepoint. Values are expressed as the +/- SD of the triplicate wells. Three independent trials were conducted.
Parthenolide and costunolide decrease detyrosinated tubulin in human breast carcinoma cells
Human breast carcinoma cell lines, MDA-MB-157, Bt-549 and MDA-MB-436 were treated with anti-inflammatory or microtubule-targeting drugs to determine their effect on detyrosinated tubulin. These cell lines were selected based on their metastatic properties as well as our previous research demonstrating high McTN frequencies and detyrosination of α-tubulin . Following six hours of treatment, all cell lines show a significant dose-dependent decrease in detyrosinated tubulin in the presence of 10 to 25 μM of Parth and Cost (Figure 1A and B) (Bt-549: Parth10 (P <0.001), Parth25 (P < .001); Cost5 (P <0.05), Cost10 (P <0.05), Cost25 (P <0.001)), (MDA-MB-157: Parth10 (P <0.001), Parth25 (P <0.001); Cost10 (P <0.001), Cost25 (P <0.05)). The absence of PARP cleavage indicates that this concentration range did not reduce detyrosinated tubulin as a result of apoptosis. Treatment with ResV, a non-sesquiterpene lactone NF-κB inhibitor (Figure 1A and B), did not show a significant decrease (MDA-MB-157 and Bt-549 = P >0.5) in detyrosinated tubulin suggesting that the effects of Parth and Cost on detyrosinated tubulin are independent of their NF-κB inhibitory properties. Traditional microtubule-targeting drugs were included to show the effect on detyrosinated tubulin when microtubules are either destabilized (Col) or stabilized (Tax). The six-hour timepoint was chosen based on prior reports that have shown that the NF-κB inhibitory effects of Parth, Cost and ResV are realized within a three- to eight-hour window [22, 23] as well as a time course of Parth and Cost in the experimental cell lines to determine when detyrosinated tubulin was significantly reduced [see Additional file 1: Figure S1]. Comparison of the drug structures shows strong similarity between Parth and Cost, which differ only in an epoxide group, while the other compounds are structurally dissimilar (Figure 1B).
Previous research using a novel high-throughput cell-based immunoluminescence assay has shown that Parth, but not Cost, can prevent accumulation of detyrosinated tubulin purportedly through TCP inhibition following a two hour treatment duration; however, these experiments were conducted in HeLa cells which have undetectable levels of detyrosinated microtubules (13). We report here that both Parth and Cost can significantly reduce detyrosinated tubulin in multiple invasive breast carcinomas with abundant detyrosinated microtubules. Our observation that Cost can reduce detyrosinated tubulin similarly to Parth may indicate that breast cancer cell lines with increased detyrosination levels are more susceptible to inhibition, or that extending treatment beyond two hours is required to realize the inhibitory action of Cost [see Additional file 1: Figure S1].
Tubulin detyrosination is independent of the NF-κB pathway
Since normal cells are not generally as sensitive as tumor cells to sesquiterpene lactones due to low basal NF-κB activity, these compounds may target cancers in which the NF-κB pathway is constitutively activated. Studies have also shown that NF-κB activity has been associated with the polymerization state of microtubules. Therefore, we used an NF-κB reporter assay to determine if the effects of Parth and Cost on detyrosinated tubulin are related to their anti-inflammatory properties. Parth and Cost effectively inhibit TNF-α-induced NF-κB activation (Figure 2A, Additional file 2: Figure S2A) at the concentrations that reduce detyrosinated tubulin (Figure 1A). ResV also inhibited NF-κB (Figure 2A, Additional file 2: Figure S2A) but did not affect detyrosinated tubulin (Figure 1A), highlighting that the reduction in detyrosinated tubulin is independent of NF-κB inhibition. Tax increased detyrosinated tubulin but did not inhibit or synergistically increase TNF-α activation of NF-κB in all cell lines. Interestingly, Col decreased detyrosinated tubulin but caused a moderate increase in the NF-κB activation in all lines, suggesting that microtubule depolymerization may activate NF-κB as previously reported. Furthermore, the drug concentrations used did not affect viability (Figure 2B, Additional file 2: Figure S2B). These results indicate that the effects on detyrosinated tubulin are independent of NF-κB activation, revealing novel anticancer properties of these two sesquiterpene lactones.
Parthenolide and costunolide decrease detyrosinated tubulin without compromising the overall microtubule network
While detyrosinated microtubules have been implicated in tumor aggressiveness, exclusive targeting of this post-translational modification with effective small molecule compounds has been a greater challenge. The majority of current anti-tubulin agents bind directly to tubulin and affect microtubule dynamics, ultimately impairing cellular functions to an extent that inhibits proliferation and triggers apoptosis. While this is the desired outcome for cancer cells, the side effects can lead to toxicity in non-target cells resulting in clinical limitations. Therefore, immunofluorescence was performed to investigate the structural impact of Parth and Cost on detyrosinated microtubules relative to the overall microtubule network. The vehicle treatment (0.1% DMSO) did not affect the elaborate filamentous detyrosinated tubulin that was observed in nearly every cell in the population (Figure 3A and B). ResV did not affect either detyrosinated tubulin or the microtubule network. The microtubule destabilizing drug Col significantly disrupted the detyrosinated microtubules while also destroying the overall microtubule array. Tax increased cellular levels and bundling, and altered the organization of detyrosinated microtubules while also affecting the microtubule network. Tax also caused cell shrinkage in both lines. Interestingly, Parth and Cost decreased detyrosinated microtubules without disrupting the overall microtubule network, demonstrating that these compounds have more targeted effects on stabilized microtubules than either Col or Tax. These results, in combination with the western blot, show that Parth and Cost selectively decrease detyrosinated microtubules.
Parthenolide and costunolide decrease microtentacle (McTN) frequency
Our previous research has identified detyrosinated α-tubulin as a structural component of McTNs observed in detached cells. Additionally, increased McTN frequency has been correlated with invasiveness in a panel of breast tumor cell lines . Based on Parth and Cost’s ability to selectively reduce detyrosinated tubulin, we investigated their effects on McTN frequency using a panel of invasive human breast carcinoma cells with high McTN frequency. Following six hours of treatment, cells infected with a membrane-targeted GFP were detached in drug-containing media and McTNs were scored blindly. Parth and Cost significantly (all lines: P <0.001) reduced McTN frequency to a greater extent than Col (Figure 4A; Additional file 3: Figure S3A). ResV and Tax did not change McTN frequency compared to the vehicle control (Figure 4A and B, Additional file 3: Figure S3A and B). Live-cell imaging of the detached population illustrates the considerable reduction in McTNs in the presence of Parth and Cost (Figure 4B, Additional file 3: Figure S3B).
Parthenolide and costunolide reduce tumor cell attachment
We previously showed that McTNs facilitate cell attachment to ECM and to an endothelial layer . Additionally, mesenchymal cells with increased detyrosinated tubulin and McTNs attach at a faster rate than their epithelial counterpart . Given the significant reductions in McTN frequencies and selective targeting of detyrosinated tubulin by Parth and Cost, we compared the reattachment efficiency of each line in the presence of drug using real-time electrical impedance monitoring. Each cell line was pretreated for six hours and then plated into media containing the respective drug in specialized E-plates with sensor electrode arrays. Real-time attachment monitoring shows that Parth and Cost inhibited cells from reattaching in all lines while ResV and Tax attached similarly to the vehicle control (Figure 5; Additional file 4: Figure S4 and Additional file 5: Figure S5). Interestingly, Col treatment decreased attachment in Bt-549 and MDA-MB-436 more strongly than in MDA-MB-157, illustrating differences in cell sensitivity. These results suggest that Parth and Cost reduced attachment by affecting detyrosinated tubulin, a major structural component of McTNs.
Metastasis causes 90% of deaths from solid tumors; therefore, novel chemotherapeutic strategies that go beyond primary tumor treatment and inhibit metastatic dissemination are critical. Since cancer cells can be shed from primary tumors that remain below the threshold of detection  and microtubules can influence the metastatic cascade, the effects of microtubule-directed compounds on circulating tumor cells are a crucial area for investigation. Interestingly, treatment with a tubulin depolymerizing agent prevents circulating colon carcinoma cells from attaching to the microvascular endothelium in vivo, highlighting a microtubule-dependent mechanism for circulating tumor cell retention in distant tissues . Recent patient studies have further shown a rapid increase of circulating tumor cells in the bloodstream with neoadjuvant taxane treatment and a two-fold higher frequency of relapse compared to adjuvant taxane treatment . Furthermore, higher paclitaxel concentrations have been correlated with increased survival in some tumor cells compared to lower doses . Research from our laboratory has identified tubulin-based McTNs in detached cells that facilitate reattachment to endothelial layers, a tubulin-driven mechanism that possibly connects the data observed in vivo and in patients treated with microtubule stabilizers. These data necessitate a strategic and cautious approach for selecting the most appropriate patient treatment when circulating tumor cells are present.
Our present results show that Parth and Cost can reduce McTNs by specifically targeting detyrosinated tubulin unlike traditional tubulin-targeted compounds, Tax and Col. These observations support previous evidence showing that Tax alone is insufficient to stimulate the formation of new McTNs in invasive cell lines but can stabilize existing structures to promote MT-dependent adhesion and cell spreading . Interestingly, conditions where filamentous actin is disrupted within the cell show a robust increase in stable microtubules  and McTN frequency when treated with Tax , highlighting the consequences when the microtubule-microfilament interaction is unbalanced and stable microtubules are unrestricted. This evidence is of particular relevance given data showing that EMT destabilizes cortical actin  and that malignant cells have a 40% reduction in filamentous actin . Furthermore, microtubules can continue to grow after membrane contact, divert along the plasma membrane, push the membrane outward, and even grow inward in TTL knockout cells , conditions that increase detyrosinated tubulin and promote invasiveness. Therefore, the effects of indiscriminate disruption of major cytoskeletal networks may contribute to metastasis or toxic side effects.
Chronic tissue damage and inflammation have been associated with tumor development as well as EMT [13, 31, 32], conditions that may promote persistent microtubule stability and aberrant detyrosinated tubulin elevation. Persistent stimuli that activate inflammatory pathways and elicit a microtubule stabilization response may provide selective pressure for mutations that suppress TTL activity and/or upregulate the TCP. Interestingly, suppression of TTL has been associated with poor prognosis in several cancers [7–9]. Due to the limited characterization of the TCP or resources to measure its expression, it is unclear what alterations in the TCP might exist in cancer cells to increase microtubule stability and possibly provide the cell a selective advantage. Only recently has AGLB2 been identified as the TCP that regulates the tubulin tyrosination cycle by interacting with retinoic acid receptor responder 1 (RARRES1), a carboxypeptidase inhibitor that is suppressed in aggressive prostate and breast cancer cells with a mesenchymal phenotype . Nevertheless, research has shown that detyrosinated microtubules are oriented towards a wound site  in addition to being upregulated at the tumor invasive front . This increase in tubulin detyrosination supports cell migration, proliferation and EMT, likely influencing metastatic success and chemoresistance. Once detached and disseminated from the primary tumor, a circulating tumor cell can reattach at a distant site, a process proposed to be microtubule-driven [25, 34]. Therefore, compounds that can reduce detyrosinated tubulin as well as inflammation could be a multi-pronged approach for cancer treatment as well as prevention.
There is growing evidence that select nonsteroidal anti-inflammatory drugs (NSAID) have anti-cancer properties, although the mechanisms are still being elucidated . We show that the NSAIDs Parth, Cost and ResV can inhibit TNF-α activation of NF-κB; however, only Parth and Cost can selectively reduce detyrosinated tubulin highlighting that NF-κB inhibition is independent of effects on tubulin detyrosination. Parth and Cost could be capable of modulating the enzymatic reaction responsible for tubulin detyrosination  and reduce McTNs without total microtubule disruption. Modulating microtubule stability with alternative chemotherapeutics may also enable the benefits of Tax treatment to be realized with combination therapy . Supporting data indicate that Parth has displayed a significantly better prognosis in combination therapy with paclitaxel than paclitaxel alone in vivo using human gastric cancer cells as well as breast cancer cells [37, 38]. The combination treatment with Parth in vitro using non-small cell lung cancer lowered the effective Tax dose required to induce cytotoxicity  as well as resensitized Tax-resistant cells . Moreover, NSAID sesquiterpene lactones in cancer clinical trials, including Parth, have displayed selectivity to target tumor and cancer stem cells while sparing normal cells . Of particular relevance is Parth’s ability to suppress the formation of disseminated nodules in vivo (gastric cancer) and inhibit bone metastasis of W256 breast cancer cells in mice . Cost has also shown antiproliferative activity in leukemia cells as well as efficacy in drug resistant lines  but has been studied to a lesser extent than Parth. Given detyrosinated tubulin’s role in cell migration and reattachment, it is possible that Parth’s ability to reduce detyrosinated tubulin and McTN formation is a contributing factor to the inhibition of metastasis, a mechanism that is independent from its anti-inflammatory effects.
Most clinical microtubule-targeted drugs bind directly to tubulin, resulting in an increase or decrease in the microtubule mass . It has been noted that tubulin binding and subsequent dynamic suppression contribute to the benefits but also to the toxic side effects of these drugs . Intact microtubule arrays are necessary for normal cell functions, so it is expected that disrupting the microtubule network will have significant effects on both cancer and normal cells. For example, it has been reported that Col has such high toxicity to normal tissues that its development as an anticancer therapeutic has been unsuccessful . Encouragingly, it has been previously shown that it is possible to interfere with microtubule dynamics without dismantling the entire microtubule array in order to successfully reduce migration . Our data show that both Col and Tax severely affect the microtubule network while Parth and Cost selectively reduce a subset of detyrosinated, stable microtubules that are associated with tumor aggressiveness and EMT. The therapeutic goal is to reduce the broad toxicity associated with many of the microtubule chemotherapeutics and direct the treatment at malignant cell hallmarks. Therefore, the enzymes regulating the detyrosination/tyrosination cycle could be an appealing and more specific drug target to moderate microtubule stability in tumors with high levels of detyrosinated tubulin rather than broadly targeting tubulin polymerization with compounds that bind tubulin subunits directly.
Based on the developing evidence, we propose that circulating tumor cell reattachment is facilitated by detyrosinated tubulin enriched McTNs [25, 34]. Detyrosinated tubulin may favor aberrant microtubule stability associated with cell migration , proliferation , chemoresistance , EMT , McTN formation , reattachment [11, 25] and tumor aggressiveness . Our data demonstrate that targeting detyrosinated tubulin with compounds such as Parth and Cost can reduce McTN frequency and inhibit reattachment without significantly disrupting the overall microtubule network or cell viability. These actions are independent of their effects on NF-κB inhibition presenting a novel property to these sesquiterpene lactones and an opportunity to move beyond simply targeting tumor cell growth. Our results highlight Parth and Cost as potential compounds to target detyrosinated tubulin more selectively. Since this α-tubulin modification promotes McTNs and tumor cell reattachment, such treatment could reduce tumor aggressiveness and decrease the risk of recurrence with less toxicity in breast cancer patients.
green fluorescent protein
tumor necrosis factor alpha
tubulin tyrosine ligase.
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Sahab ZJ, Hall MD, Me Sung Y, Dakshanamurthy S, Ji Y, Kumar D, Byers SW: Tumor suppressor RARRES1 interacts with cytoplasmic carboxypeptidase AGBL2 to regulate the alpha-tubulin tyrosination cycle. Cancer Res. 2011, 71: 1219-1228. 10.1158/0008-5472.CAN-10-2294.
Whipple RA, Cheung AM, Martin SS: Detyrosinated microtubule protrusions in suspended mammary epithelial cells promote reattachment. Exp Cell Res. 2007, 313: 1326-1336. 10.1016/j.yexcr.2007.02.001.
Thun MJ, Henley SJ, Patrono C: Nonsteroidal anti-inflammatory drugs as anticancer agents: mechanistic, pharmacologic, and clinical issues. J Nat Cancer Inst. 2002, 94: 252-266. 10.1093/jnci/94.4.252.
Ahmed AA, Wang X, Lu Z, Goldsmith J, Le XF, Grandjean G, Bartholomeusz G, Broom B, Bast RC: Modulating microtubule stability enhances the cytotoxic response of cancer cells to Paclitaxel. Cancer Res. 2011, 71: 5806-5817. 10.1158/0008-5472.CAN-11-0025.
Sohma I, Fujiwara Y, Sugita Y, Yoshioka A, Shirakawa M, Moon JH, Takiguchi S, Miyata H, Yamasaki M, Mori M, Doki Y: Parthenolide, an NF-kappaB inhibitor, suppresses tumor growth and enhances response to chemotherapy in gastric cancer. Cancer Genomics Proteomics. 2011, 8: 39-47.
Zhou J, Zhang H, Gu P, Bai J, Margolick JB, Zhang Y: NF-kappaB pathway inhibitors preferentially inhibit breast cancer stem-like cells. Breast Cancer Res Treat. 2008, 111: 419-427. 10.1007/s10549-007-9798-y.
Gao ZW, Zhang DL, Guo CB: Paclitaxel efficacy is increased by parthenolide via nuclear factor-kappaB pathways in in vitro and in vivo human non-small cell lung cancer models. Curr Cancer Drug Targets. 2010, 10: 705-715. 10.2174/156800910793605776.
Gill KK, Kaddoumi A, Nazzal S: Mixed micelles of PEG(2000)-DSPE and vitamin-E TPGS for concurrent delivery of paclitaxel and parthenolide: enhanced chemosenstization and antitumor efficacy against non-small cell lung cancer (NSCLC) cell lines. Eur J Pharm Sci. 2012, 46: 64-71. 10.1016/j.ejps.2012.02.010.
Idris AI, Libouban H, Nyangoga H, Landao-Bassonga E, Chappard D, Ralston SH: Pharmacologic inhibitors of IkappaB kinase suppress growth and migration of mammary carcinosarcoma cells in vitro and prevent osteolytic bone metastasis in vivo. Mol Cancer Ther. 2009, 8: 2339-2347.
Choi JH, Seo BR, Seo SH, Lee KT, Park JH, Park HJ, Choi JW, Itoh Y, Miyamoto K: Costunolide induces differentiation of human leukemia HL-60 cells. Arch Pharm Res. 2002, 25: 480-484. 10.1007/BF02976606.
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This research was supported by R01-CA154624 and R01-124704 from the National Cancer Institute, KG100240 from the Susan G. Komen Foundation and an Era of Hope Scholar award from the Department of Defense (BC100675).
The authors declare that they have no competing interests.
RW and MV designed the experiments and analyzed the data. RW carried out the experiments. AB assisted with the live cell imaging and immunofluorescence. MC also assisted in the experimental design. KT performed some of the preliminary research experiments. RW, MV, AB, MC, KT and SM participated in drafting and editing the manuscript. SM conceived the study and participated in the experimental design. All authors have read and approved the final manuscript.
Electronic supplementary material
Additional file 1: Figure S1: Bt-549 and MDA-MB-157 cells treated for one hour, three hours and six hours with parthenolide (Parth; 10 μM), and costunolide (Cost; 25 μM) show that detyrosinated tubulin is significantly reduced by six hours compared to DMSO (Veh; 0.1%) treated cells (N = 3). (TIFF 1 MB)
Additional file 2: Figure S2: (A) NF-κB -luciferase reporter adenovirus infected MDA-MB-436 shows that a four hour treatment of parthenolide (Parth; 10 μM, 25 μM) and costunolide (Cost; 10 μM, 25 μM) inhibits TNF-α-induced (100 ng/ml) NF-κB activation at concentrations that reduced detyrosinated tubulin. Resveratrol (ResV; 50 μg/ml, 100 μg/ml) inhibits NF-κB but does not affect detyrosination. Colchicine (Col; 50 μM) and Taxol (Tax; 0.5 μg/ml) do not inhibit NF-κB at concentrations that affect detyrosinated tubulin. (B) Cell viability assay shows that non-toxic drug concentrations are used. All compounds are expressed as a % of vehicle (set at 100%; horizontal dotted line). (TIFF 915 KB)
Additional file 3: Figure S3: (A) Detached MDA-MB-436 were pretreated for six hours and suspended in drug containing media for blind McTN scoring. Parthenolide (Parth; 10 μM), costunolide (Cost; 25 μM), and colchicine (Col; 50 μM) show a significant decrease compared to vehicle treated (*P <0.05; ** P <0.001, t-test). Resveratrol (ResV; 50 μg/ml) and Taxol (Tax; 0.5 μg/ml) did not have a significant effect on McTN frequency. Columns, mean %McTNs for four independent experiments in which at least 100 cells were scored blindly; bars, SD. (B) Live population images of suspended MDA-MB-436. McTNs are observed in vehicle, resveratrol, and Taxol (black arrows). (TIFF 3 MB)
Additional file 4: Figure S4: Real-time electrical impedance monitoring of MDA-MB-436 shows that parthenolide (10 μM) and costunolide (25 μM) significantly reduce attachment when compared to vehicle while Taxol (0.5 μg/ml) and resveratrol (50 μg/ml) did not. Colchicine (50 μM) also reduced attachment. Lines, mean for three triplicate wells; bars, SD; representative graph is shown. (TIFF 1 MB)
Additional file 5: Figure S5: Additional real-time electrical impedance monitoring experiment trials of Bt-549 and MDA-MB-157 showing that parthenolide (10 μM) and costunolide (25 μM) significantly reduce attachment when compared to vehicle while Taxol (0.5 μg/ml) and resveratrol (50 μg/ml) did not. Colchicine (50 μM) reduced attachment to a greater extent in Bt-549 than in MDA-MB-157. Lines, mean for three triplicate wells; bars, SD. (TIFF 2 MB)
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Whipple, R.A., Vitolo, M.I., Boggs, A.E. et al. Parthenolide and costunolide reduce microtentacles and tumor cell attachment by selectively targeting detyrosinated tubulin independent from NF-κB inhibition. Breast Cancer Res 15, R83 (2013). https://doi.org/10.1186/bcr3477
- Circulate Tumor Cell
- Sesquiterpene Lactone
- Microtubule Dynamic

domain: medical


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Tube Union RMT confirmed today that following a ballot of members across London Underground in a dispute over jobs, services and safety that recorded a massive vote for both strike action and action short of a strike members are instructed to take action as follows:
Members, excluding driver grades, to cease work between 12.00 hours on 4th February until 11.59 hours on 6th February 2014. Driver members not to book on for any duties between those hours.
Members, excluding driver grades, to cease work between 12.00 hours on 11th February until 11.59 hours on 13th February 2014. Driver members not to book on for any duties between those hours.
In action short of a strike, station grades not to carry out revenue duties on 7th, 10th and 14th February 2014 between 09.30 and 11.30 hours and 18.30 and 20.30 hours.
RMT General Secretary Bob Crow said:
“RMT members on London Underground have voted by a massive majority for both strike action and action short of a strike in a dispute which is wholly about cash-led cuts plans that would see the axing of nearly a thousand safety critical jobs and the closure of ticket offices at a time when the tube network is under growing pressure from customer demand and needs more staff and not less to ensure safe and efficient operation.
“Not only are a thousand posts on the line but staff remaining are going to be forced through the humiliating and degrading experience of re-applying for their own jobs – the same staff who have been hailed as heroes when the tube has faced emergency situations. That is a kick in the teeth for the loyal and experienced tube workforce who have kept services running safely and efficiently under constant pressure from weight of demand and a creaking and under-resourced infra-structure.
“These cuts would hit the vulnerable, the elderly, those with disabilities and women the hardest. De-staffing stations, with supervisors running operations three stops down the line on an IPad, would turn the tube system into a criminals paradise where those with violence and robbery on their minds are given a clear run. RMT will work with our sister unions and passenger groups to ensure that tube users understand just what’s at stake as Boris Johnson turns his opportunist election pledges on their head.
“Before the Tories start shouting the odds they should take note of the fact that the turn out in this ballot was higher than the last mayoral and GLA elections and the vote in favour massively outstrips anything that those same politicians can even dream of in terms of a popular mandate.”

domain: news


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345 Alymer Street North
Library details: Peterborough Public Library is a Public library.
This library is affiliated with Peterborough Public Library (view map) . The collection of the library contains 160,000 volumes. The library circulates 500,000 items per year. The library serves a population of 74,000 residents .
(Use this link to refer back to this listing.)
Administration: The director of the library is Jennifer Zoethout .
|Product Name||Year Contracted|
|Current Automation System||Symphony||2009|
|Previous Automation System||Horizon||2002|
|Previous Automation System||Dynix||1992|
|Previous Automation System||None|
|(* Older versions of SirsiDynix Symphony were called Unicorn)|
|This library is responsible for the procurement of the library automation system.|
Record History: This listing was created on Nov 21, 1997 and was last modified on Nov 7, 2016.

domain: library


Full details of the Honor tablet V7 including its price, specs and features: Hello folks, today's article will provide all the details for the Honor Tablet V7 including its price. This article discusses Honor Tablet V7 specifications, amazing features, and other information that makes this tablet a good choice. Let's first see the Honor Tablet V7 specifications and features in basic format and then we will do an in-depth analysis of this tablet to see all its cool features and functions.
Honor Tablet V7 comes with the latest android 11, Magic UI 5.0 and have 6/8GB RAM variants. It includes a powerful processor MediaTek Kompanio 900T 5G and 128GB storage, microSDXC. The mobile has a weight of 480g, 7.9mm thickness which makes it handy to use. It comes with a 10.4″ inch display of resolution 1200×2000 pixels. The tablet is equipped with a 13 megapixels rear camera that can capture up to 1080p video.
The announcement of the Honor Tablet V7 was done on 2021, September 26 and the current status of release is coming soon. Exp. release 2021, October 01. The Model of Honor Tablet V7 is KRJ2-W09. Many people were aspiring for this mobile device after the first announcement so here in this article we have bought all specs in an expanded form which will help you to decide that “Whether you should buy Honor Tablet V7 or not at the set launch price?”
The network technology used in Honor Tablet V7 is GSM / HSPA / LTE / 5G which is going to give an amazing internet connectivity experience. The company is launching this tablet in different colours which are gold, Blue, and Silver. Different colour variety means people have the choice to buy Honor Tablet V7 in their chosen colour. The Price of the Honor Tablet V7 is About 270 EUR. Now we will see the specification of the Honor Tablet V7 in full detail. Let's start with its platform and memory.
Honor Tablet V7 Platform and Memory
The Honor Tablet V7 comes with an Android 11, Magic UI 5.0 operating system that means it has all the latest and advanced capabilities. It consists of the latest MediaTek Kompanio 900T 5G (6 nm) chipset with Octa-core (2×2.4 GHz Cortex-A78 & 6×2.0 GHz Cortex-A55) CPU and Mali-G68 MC4 GPU. If we talk about the RAM it comes on a 6/8 GB RAM variation that is running on the MediaTek Kompanio 900T 5G processor. This chipset, RAM, CPU and GPU combination makes this tablet truly fantastic.
Honor Tablet V7 comes in a variant of 128GB 6GB RAM, 128GB 8GB RAM. Internal memory capacity is enough for most general use but if you want this tablet to store bigger files then for that, you guys have the option of a microSDXC (dedicated slot) card slot to increase the memory capacity facilitating more space.
|Honor Tablet V7 Specifications||Values|
|Operating system (OS)||Android 11, Magic UI 5.0|
|Internal Memory||128GB 6GB RAM, 128GB 8GB RAM|
|Chip set||MediaTek Kompanio 900T 5G (6 nm)|
|External card slot||microSDXC (dedicated slot)|
|CPU (Central processing unit)||Octa-core (2×2.4 GHz Cortex-A78 & 6×2.0 GHz Cortex-A55)|
|GPU (Graphical processing unit)||Mali-G68 MC4|
Honor Tablet V7 Body Specs
The body dimensions of Honor Tablet V7 are 245.2 x 155 x 7.9 mm (9.65 x 6.10 x 0.31 in). The total weight of the Honor Tablet V7 is 480 g (1.06 lb), which makes it lighter and premium. Honor Tablet V7 supports Stylus support Nano-SIM.
The Tablet is furnished with Accelerometer. The most interesting part is that the making company is providing this whole premium body look tablet at a lower price range. Now guys, tell us in the comment box that, which tablet can beat Honor Tablet V7's body looks in a similar price range.
|Honor Tablet V7 Body Specifications||Values|
|Body measurements||245.2 x 155 x 7.9 mm (9.65 x 6.10 x 0.31 in)|
|Available colours||Gold, Blue, Silver|
|In hand weight||480 g (1.06 lb)|
|Extra feature||Stylus support|
Honor Tablet V7 Camera
Users will get a dual camera set up on the rear side of Honor Tablet V7 as the main or primary camera. The Dual main camera specifications of Honor Tablet V7 are:-
- 13 MP, f/1.8, (wide), AF
It has up to [email protected] video capturing capacity through the main camera. The mobile device Honor Tablet V7 also includes LED flash features. Tablet has an 8 MP, f/2.2 front(selfie) camera. You can record videos up to [email protected] with the selfie(front) camera. The overall camera setup in the Honor Tablet V7 is good and can be used for numerous professional work as well.
|Honor Tablet V7 Back camera specifications||Values|
|Specs||13 MP, f/1.8, (wide), AF|
|Video capacity||[email protected]|
The Honor Tablet V7's front(selfie) camera specifications are given below.
|Honor Tablet V7 Front camera specifications||Values|
|Specs||8 MP, f/2.2|
|Video capacity||[email protected]|
honor tablet v7 display
IPS LCD, 90Hz, HDR10 type display comes in Honor Tablet V7 which is of size 10.4 inches, 307.9 cm2 (~81.0% screen-to-body ratio). As far as the screen resolution is concerned it is 1200 x 2000 pixels, 5:3 ratio (~224 ppi density).
|Honor Tablet V7 Display Specifications||Values|
|Display type||IPS LCD, 90Hz, HDR10|
|Size||10.4 inches, 307.9 cm2 (~81.0% screen-to-body ratio)|
|Screen resolution||1200 x 2000 pixels, 5:3 ratio (~224 ppi density)|
Honor Tablet V7 Battery
The tablet has a massive Li-Po 7250 mAh, non-removable battery. The tablet making company has furnished the following charging features in Honor Tablet V7:
- Charging 22.5W, 100% in 125 min (advertised)
This whole powering system of the Honor Tablet V7 will give a fast charging experience and long-lasting battery life to the users. It is very useful for most people who are busy in their life and want less charging time and long power backup in their tablets.
|Honor Tablet V7 Battery Specifications||Values|
|Battery Type & mAH||Li-Po 7250 mAh, non-removable|
|Charging||Charging 22.5W, 100% in 125 min (advertised)|
Honor Tablet V7 Sound and Communication
The suitable reply of Honor Tablet V7 has a loudspeaker or not? Is Yes, with stereo speakers (4 speakers). If you guys are looking for the answer to whether Honor Tablet V7 has a 3.5mm jack or not? Then the clear cut answer is No. The company has worked extensively on the sound quality to make it more clear and enjoyable.
|Honor Tablet V7 Sound Specifications||Values|
|3.5mm Jack compatible||No|
|Loudspeaker||Yes, with stereo speakers (4 speakers)|
The tablet comprises Yes which will fulfil your internet connectivity needs very well. It has a 5.1, A2DP, LE Bluetooth setup. Another normal query is whether Honor Tablet V7 supports GPS(Global Positioning System) or not? The answer is Yes, with A-GPS, GLONASS, GALILEO, BDS. It has USB-C which is going to charge the tablet and transfer documents at an ultimate speed. Some users also have the question, does Honor Tablet V7 has a Network File System (NFS) or not? The reply is undoubted No.
Radio admirers of our community also ask about the radio system of the Honor Tablet V7. The straight response is No.
From the above data, anyone can easily judge that the sound and communication system which is coming with Honor Tablet V7 is well and good. Users are most certainly going to love the fast internet connectivity and transfer rate of this newly launched tablet. We will discuss the honor tablet v7 price in this article as well.
|Honor Tablet V7 Communication Specifications||Values|
|GPS system||Yes, with A-GPS, GLONASS, GALILEO, BDS|
|Bluetooth||5.1, A2DP, LE|
Honor Tablet V7 Price
Overall Honor Tablet V7 is amazing and it may be going to shock the whole mobile market with its amazing features and cool functionalities. Overall Honor Tablet V7 is astounding and it will stun the whole marketplace with its extraordinary capabilities and funky functions. The company tried its level best to make this tablet hardware and software closer so that the tablet will run at its max performance. The Model of Honor Tablet V7 mobile is KRJ2-W09.
The Price of the Honor Tablet V7 is About 270 EUR. Some people had been bowled over after looking at the price. But it's True????.
|Honor Tablet V7 Price details||Values|
|Price||About 270 EUR|
Guys, it's now your turn to comment down if you are thinking to buy this newly announced Honor Tablet V7 after knowing all its lovely specs, price and functionalities in full detail. Remark down your viewpoint on the awesome and cool features of this newly launched mobile Honor Tablet V7. If you're a smartphone and tablet lover or want to try a brand new mobile phone then allow the notification to get the most recent mobile news in a split second soon after their declaration. Also, follow our mobile phone category to remain updated with the latest mobile tech advancement news.


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The largest Montenegrin supermarket chain, Voli, plans to enter the Serbian market, the Retail Serbia website unofficially finds out.
The largest Montenegrin supermarket chain Voli opened yet another hypermarket in Zeta, Montenegro in late 2020. Spanning 1,600 square metres, the supermarket sells close to 10,000 items. As part of the new hypermarket, the TAKE & GO service is also available to customers. The new hypermarket has 150 parking spaces and employs 50 workers.
With more than 60 retail outlets in 27 locations, Voli is today the largest retail chain in Montenegro.
Unofficial sources confirm that Voli plans to enter the Serbian retail market soon. Apart from Serbia, the company also examined other markets in the region. There is no official confirmation from Voli as yet about this move.
To remind, Voli recently told Podgorica-based daily, Vijesti, that it was planning to expand its network of supermarkets and enter the regional market.
Voli also has a distribution centre in Podgorica, spanning 16,000 square metres, plus, as of recently, an online store with close to 4,500 items.
This post is also available in: Italiano


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Manuel Pellegrini has revealed Financial Fair Play (FFP) did not allow Manchester City to sign Angel Di Maria earlier in the summer.
The Argentine international was told his services were no longer required at Real Madrid, despite his Man of the Match winning performance in the Champions League final against Atletico Madrid.
City's local rivals Manchester United signed Di Maria for a British record transfer fee of £59.7m in August. The Chilean manager says FFP restricted the Citizens from spending heavily in the summer transfer window.
"I think it is very easy. We have an important restriction about the budget this year. We cannot spend the money that United paid for Di Maria," Pellegrini explained.
"We have an important restriction on the amount of players we can have this year and also the amount the amount of money we can spend."
The former Real star will line up for United when Louis van Gaal's side take on the Premier League champions in the Manchester derby at the Etihad on Sunday. Di Maria has already scored three goals and registered four assists in seven league matches.
Pellegrini is aware of the threat the 27-year-old will pose for City. However, the Etihad club's manager believes United have several quality players who can trouble the English champions on Sunday.
"I think he is a very good player but not the only good player Manchester United has. But he is a very good player," the City manager added.
Di Maria joins Marcos Rojo as the two Argentine players at Old Trafford. Meanwhile, City have Sergio Aguero and Pablo Zabaleta and the four are teammates with the national side.
United's record summer signing says there will be no friendship when the 20-times English champions face City at the Etihad in the derby clash.
"We've got good friendships over the years and no matter what the colour of your shirt, you still see each other socially," Di Maria said.
"But once you're on the field, you forget all that. Everyone is fighting for the shirt. When we see each other in the tunnel before games, I think it's right to say 'Hi' and greet each other – whether it's an ex-team-mate or a good friend.
"That's normal, as long as you remember that you fight for the club and the shirt once the 90 minutes start," the former Benfica man concluded.


New research out of Edinburgh supports the idea that spending time in green spaces with trees reduces stress and brain fatigue. What makes this study different from earlier research is that it looks at real-time data from the brains of people while they were actually outside, moving through the city and the parks.
The idea that visiting green spaces like parks or tree-filled plazas lessens stress and improves concentration is not new. Researchers have long theorized that green spaces are calming, requiring less of our so-called directed mental attention than busy, urban streets do. But this theory, while agreeable, has been difficult to put to the test.


Magnus Backstedt, winner of the 2004 Paris-Roubaix, is one of three former WorldTour riders riding this year for a British-based UCI Continental team.
Like Endura Racing’s Russell Downing, whose four victories this season reflect his pre-season priorities, and Team IG-Sigma Sport’s Daniel Lloyd, who is targeting the national road race championships, Backstedt has lost none of his passion for a sport from which he briefly retired in 2009 before returning two years later.
When we spoke to Backstedt, as he prepared for the four of the Halfords Tour Series in Redditch, he confidently predicted that despite the quality of Endura Racing squad, only the slightest improvement would be required to turn the strong performances of his Team UK squad into victories. That evening, UK Youth took their first victory of the season with Niklas Gustavsson.
The Swede, known affectionately as ‘Big Maggy’, raced for the first time in two years last season after setting up the cycling team to raise awareness for Nigel Mansell’s UK Youth charity.
“In 2010, I did a charity ride with Nigel Mansell. We talked about having a team. I said, ‘lf we’re going to do this, I want to be back on the bike.’ Physically, all my injuries from 2008 and 2009 had healed. I was in a good place. I was riding my bike a lot. That made the decision for me, really,” Backstedt told RCUK.
Determined to return to the sport that had brought him success at the highest level (the Paris-Roubaix victory mentioned above, weeks after finishing second at Ghent-Wevelgem; a stage win in the 2005 Tour de France) Backstedt began the task of returning to race form. “It took a heck of a lot of a hard work that winter,” he said, work that included “big miles” and a strict diet.
“The biggest hurdle and the hardest bit was to get myself down to some kind of race weight. It went relatively quickly. By the back end of February, I was in an OK shape. My legs came back much, much quicker than I had anticipated. The power was there, but I was probably dragging a couple of kilos too many. With the races than I’m supposed to be good at the weight is important, but not as important,” he said.
Backing from a sport nutrition company (UK Youth has recently teamed up with Maxifuel) is presumably keeping Backstedt in his favoured pre-ride meal. “I cook my porridge with my protein powder. That kind of sets me up. I’m happy to do six hours on a big bowl of porridge,” he said.
His decision made to return, Backstedt hasn’t looked back. “I loved it from the first minute,” he said. Absence from the race scene had left a void, he admits; the ‘hot air’ of the races, the camaraderie of the team, all missed. “When I pin a number on, I become a different person. I love that bit of it,” he said.
Team UK Youth’s line up is “definitely” stronger than last year, says Backstedt. The “ante” has been upped, he adds, and with it the budget. “We went out and got riders that I thought fitted the bill for what we wanted to do with the team. We’ve got a strong team together.”
Two days before we spoke to Backstedt, UK Youth had placed three riders in the top 10 at the Oxford round of the Tour Series, with 24-year-old Chris Opie finishing fourth. “With a little bit of confidence, Chris Opie will start winning like there’s no tomorrow,” Backstedt told RCUK. “I think he’s one of the fastest, if not the fastest, riders in the country at the moment.” That night, Opie finished a narrow second to the winner in Redditch, Kristian House (Rapha Condor Sharp).
Backstedt remains justifiably proud of his best-known victory, crossing the line first in the Roubaix velodrome in 2004. In a race notoriously shaped by events beyond the control of the riders, he recorded three top-10 finishes, including fourth the year after his triumph. His success on the pavé was no accident. “I put an awful of hard work into preparing for that race. I lived, eat, a breathed that race pretty much every year,” he recalled. “I found a niche for riding cobblestones fast. I loved the crazy-iness of racing on cobbles.”
While it’s possible he may have ridden better (he identifies the 2005 Ghent-Wevelgem as one of his strongest performances before a crash ended his chances), Roubaix in 2004 remains the “pinnacle”.
“In my book, winning Paris-Roubaix is, and always will be, the ultimate bike race and the biggest win that I could have as a cyclist.”


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InsideOut of the Lunch Box - The Technical Side of Theatre
Thursday, February 21, 2013 from 12:00 PM to 1:00 PM (CST)
We’ll take a look at what goes on backstage as well as onstage in this Lunch Box featuring the national Broadway touring production of Traces, a show that requires detailed and precise technical execution of the performers and the crew. Fusing the traditions of circus with the energy of street performance, the artists of Traces employ every trick in the book - from music and dance to skateboarding, basketball, and high-risk acrobatics. What does it take to prepare the theater for this type of performance?
When & Where
Vanderbilt University - Office of Community, Neighborhood, & Government Relations
This special event is sponsored by Vanderbilt University and the Williamson County Public Library.