In the past decade, the characterization of non-small-cell lung cancer (NSCLC) into subtypes based on genotype and histology has resulted in dramatic improvements in disease outcome in select patient ...subgroups. In particular, molecularly targeted agents that inhibit EGFR or ALK are approved for the treatment of NSCLC harbouring genetic alterations in the genes encoding these proteins. Although acquired resistance usually limits the duration of response to these therapies, a number of new agents have proven effective at tackling specific resistance mechanisms to first-generation inhibitors. Large initiatives are starting to address the role of biomarker-driven targeted therapy in squamous lung cancers, and in the adjuvant setting. Immunotherapy undeniably holds great promise and our understanding of subsets of NSCLC based on patterns of immune response is continuing to evolve. In addition, efforts are underway to identify rare genomic subsets through genomic screening, functional studies, and molecular characterization of exceptional responders. This Review provides an overview of the key developments in the treatment of NSCLC, and discusses potential strategies to further optimize therapy by targeting disease subtypes.
This is the first published case report of a successful radial forearm free flap harvest on the same side in a patient who had undergone a mastectomy, axillary dissection, and radiotherapy 10 years ...prior to flap harvest.
► Drag law for gas–solids flow using particle-resolved simulation of fixed spheres. ► Numerical method PUReIBM based on immersed boundary method with no forcing in fluid. ► PUReIBM is accurate, ...numerically convergent and consistent with two-fluid theory. ► New drag correlation is proposed that can be used in CFD simulation of fluidized beds.
Gas–solid momentum transfer is a fundamental problem that is characterized by the dependence of normalized average fluid–particle force
F on solid volume fraction
ϕ and the Reynolds number based on the mean slip velocity Re
m
. In this work we report particle-resolved direct numerical simulation (DNS) results of interphase momentum transfer in flow past fixed random assemblies of monodisperse spheres with finite fluid inertia using a continuum Navier–Stokes solver. This solver is based on a new formulation we refer to as the Particle-resolved Uncontaminated-fluid Reconcilable Immersed Boundary Method (PUReIBM). The principal advantage of this formulation is that the fluid stress at the particle surface is calculated directly from the flow solution (velocity and pressure fields), which when integrated over the surfaces of all particles yields the average fluid–particle force. We demonstrate that PUReIBM is a consistent numerical method to study gas–solid flow because it results in a force density on particle surfaces that is reconcilable with the averaged two-fluid theory. The numerical convergence and accuracy of PUReIBM are established through a comprehensive suite of validation tests. The normalized average fluid–particle force
F is obtained as a function of solid volume fraction
ϕ (0.1
⩽
ϕ
⩽
0.5) and mean flow Reynolds number Re
m
(0.01
⩽
Re
m
⩽
300) for random assemblies of monodisperse spheres. These results extend previously reported results of
Hill et al. (2001a,b) to a wider range of
ϕ, Re
m
, and are more accurate than those reported by
Beetstra et al. (2007). Differences between the drag values obtained from PUReIBM and the drag correlation of
Beetstra et al. (2007) are as high as 30% for Re
m
in the range 100–300. We take advantage of PUReIBM’s ability to directly calculate the relative contributions of pressure and viscous stress to the total fluid–particle force, which is useful in developing drag correlations. Using a scaling argument,
Hill et al. (2001b) proposed that the viscous contribution is independent of Re
m
but the pressure contribution is linear in Re
m
(for Re
m
>
50). However, from PUReIBM simulations we find that the viscous contribution is not independent of the mean flow Reynolds number, although the pressure contribution does indeed vary linearly with Re
m
in accord with the analysis of
Hill et al. (2001b). An improved correlation for
F in terms of
ϕ and Re
m
is proposed that corrects the existing correlations in Re
m
range 100–300. Since this drag correlation has been inferred from simulations of fixed particle assemblies, it does not include the effect of mobility of the particles. However, the fixed-bed simulation approach is a good approximation for high Stokes number particles, which are encountered in most gas–solid flows. This improved drag correlation can be used in CFD simulations of fluidized beds that solve the average two-fluid equations where the accuracy of the drag law affects the prediction of overall flow behavior.
The 2-team approach in major head and neck/reconstructive surgery can occasionally lead to delays between flap harvest and detachment, due to the complexity and length of the ablative procedure. In ...order to minimize the potential for flap cooling and the adverse impact on microcirculation, active warming can be beneficial. We present an inexpensive, readily available method of active flap warming, that can be easily introduced into practice.
The purpose of this work is to develop gas-solid heat transfer models using Particle-resolved Direct Numerical Simulations (PR-DNS). Gas-solid heat transfer in steady flow through a homogeneous fixed ...assembly of monodisperse spherical particles is simulated using the Particle-resolved Uncontaminated-fluid Reconcilable Immersed Boundary Method (PUReIBM). PR-DNS results are obtained over a range of mean slip Reynolds number (1-100) and solid volume fraction (0.1-0.5). Fluid heating is important in gas-solid heat transfer, especially in dense low-speed flows, and the PUReIBM formulation accounts for this through a heat ratio which appears in the thermal self-similarity boundary condition that ensures thermally fully-developed flow. The average volumetric interphase heat transfer rate (average gas-solid heat transfer) that appears in the average fluid temperature evolution equation is quantified and modeled using PR-DNS results. The Nusselt number corresponding to average gas-solid heat transfer is obtained from PR-DNS data, and compared with Gunn's Nusselt number correlation (Gunn, 1978). A new Nusselt number correlation is proposed that fits the PR-DNS data more closely and also captures the Reynolds number dependence more accurately. It is shown that the use of Nusselt number correlations based on the average bulk fluid temperature in the standard two-fluid model for gas-solid heat transfer is inconsistent, and results in up to 35% error in prediction of the average gas-solid heat transfer. Using PR-DNS data, a consistent two-fluid model is proposed that improves the predicted average gas-solid heat transfer.
We use particle-resolved direct numerical simulation (PR-DNS) as a model-free physics-based numerical approach to validate particle acceleration modelling in gas-solid suspensions. To isolate the ...effect of the particle acceleration model, we focus on point-particle direct numerical simulation (PP-DNS) of a collision-free dilute suspension with solid-phase volume fraction
$\unicodeSTIX{x1D719}=0.001$
in a decaying isotropic turbulent particle-laden flow. The particle diameter
$d_{p}$
in the suspension is chosen to be the same as the initial Kolmogorov length scale
$\unicodeSTIX{x1D702}_{0}$
(
$d_{p}/\unicodeSTIX{x1D702}_{0}=1$
) in order to overlap with the regime where PP-DNS is valid. We assess the point-particle acceleration model for two different particle Stokes numbers,
$St_{\unicodeSTIX{x1D702}}=1$
and 100. For the high Stokes number case, the Stokes drag model for particle acceleration under-predicts the true particle acceleration. In addition, second moment quantities which play key roles in the physical evolution of the gas–solid suspension are not correctly captured. Considering finite Reynolds number corrections to the acceleration model improves the prediction of the particle acceleration probability density function and second moment statistics of the point-particle model compared with the particle-resolved simulation. We also find that accounting for the undisturbed fluid velocity in the acceleration model can be of greater importance than using the most appropriate acceleration model for a given physical problem.
Discharge dynamics of granular particles from a flat-bottomed silo is studied using both continuum modeling and three-dimensional (3D) discrete element method (DEM) simulations. Using DEM, the ...influence of microscopic parameters (interparticle friction coefficient, particle–wall friction coefficient and particle coefficient of restitution) and system parameters (orifice width) on the discharge rate is quantified. The spatial extent of different regimes (quasi-static, intermediate and inertial) of granular rheology are quantified using a regime map previously established from DEM data of homogeneously sheared granular flow. It is shown that all three regimes of granular rheology coexist during silo discharge, and the intermediate regime plays a significant role in discharge dynamics. A quantitative comparison between results of continuum and DEM simulations is performed by computing discharge rates, solid velocities, and solid stresses for a three-dimensional (3D) flat-bottomed silo. It is found that the three constitutive models investigated in this study overpredict the discharge rate when compared to DEM data. Contour plots of the error in solid stress prediction are compared with the spatial extent of different regimes of granular rheology to deduce that it is inaccurate modeling of the intermediate regime that is responsible for overprediction of the discharge rate.
The Enskog kinetic theory is used as a starting point to model a suspension of solid particles in a viscous gas. Unlike previous efforts for similar suspensions, the gas-phase contribution to the ...instantaneous particle acceleration appearing in the Enskog equation is modelled using a Langevin equation, which can be applied to a wide parameter space (e.g. high Reynolds number). Attention here is limited to low Reynolds number flow, however, in order to assess the influence of the gas phase on the constitutive relations, which was assumed to be negligible in a previous analytical treatment. The Chapman–Enskog method is used to derive the constitutive relations needed for the conservation of mass, momentum and granular energy. The results indicate that the Langevin model for instantaneous gas–solid force matches the form of the previous analytical treatment, indicating the promise of this method for regions of the parameter space outside of those attainable by analytical methods (e.g. higher Reynolds number). The results also indicate that the effect of the gas phase on the constitutive relations for the solid-phase shear viscosity and Dufour coefficient is non-negligible, particularly in relatively dilute systems. Moreover, unlike their granular (no gas phase) counterparts, the shear viscosity in gas–solid systems is found to be zero in the dilute limit and the Dufour coefficient is found to be non-zero in the elastic limit.
Gas-phase velocity fluctuations due to mean slip velocity between the gas and solid phases are quantified using particle-resolved direct numerical simulation. These fluctuations are termed ...pseudo-turbulent because they arise from the interaction of particles with the mean slip even in ‘laminar’ gas–solid flows. The contribution of turbulent and pseudo-turbulent fluctuations to the level of gas-phase velocity fluctuations is quantified in initially ‘laminar’ and turbulent flow past fixed random particle assemblies of monodisperse spheres. The pseudo-turbulent kinetic energy
$k^{(f)}$
in steady flow is then characterized as a function of solid volume fraction
${\it\phi}$
and the Reynolds number based on the mean slip velocity
$\mathit{Re}_{m}$
. Anisotropy in the Reynolds stress is quantified by decomposing it into isotropic and deviatoric parts, and its dependence on
${\it\phi}$
and
$Re_{m}$
is explained. An algebraic stress model is proposed that captures the dependence of the Reynolds stress on
${\it\phi}$
and
$Re_{m}$
. Gas-phase velocity fluctuations in freely evolving suspensions undergoing elastic and inelastic particle collisions are also quantified. The flow corresponds to homogeneous gas–solid systems, with high solid-to-gas density ratio and particle diameter greater than dissipative length scales. It is found that for the parameter values considered here, the level of pseudo-turbulence differs by only 15 % from the values for equivalent fixed beds. The principle of conservation of interphase turbulent kinetic energy transfer is validated by quantifying the interphase transfer terms in the evolution equations of kinetic energy for the gas-phase and solid-phase fluctuating velocity. It is found that the collisional dissipation is negligible compared with the viscous dissipation for the cases considered in this study where the freely evolving suspensions attain a steady state starting from an initial condition where the particles are at rest.
Endometrial cancer is the most commonly diagnosed gynecologic malignancy worldwide; yet the tumor microenvironment, especially the fibroblast cells surrounding the cancer cells, is poorly understood. ...We established four primary cultures of fibroblasts from human endometrial cancer tissues (cancer-associated fibroblasts, CAFs) using antibody-conjugated magnetic bead isolation. These relatively homogenous fibroblast cultures expressed fibroblast markers (CD90, vimentin and alpha-smooth muscle actin) and hormonal (estrogen and progesterone) receptors. Conditioned media collected from CAFs induced a dose-dependent proliferation of both primary cultures and cell lines of endometrial cancer in vitro (175%) when compared to non-treated cells, in contrast to those from normal endometrial fibroblast cell line (51%) (P<0.0001). These effects were not observed in fibroblast culture derived from benign endometrial hyperplasia tissues, indicating the specificity of CAFs in affecting endometrial cancer cell proliferation. To determine the mechanism underlying the differential fibroblast effects, we compared the activation of PI3K/Akt and MAPK/Erk pathways in endometrial cancer cells following treatment with normal fibroblasts- and CAFs-conditioned media. Western blot analysis showed that the expression of both phosphorylated forms of Akt and Erk were significantly down-regulated in normal fibroblasts-treated cells, but were up-regulated/maintained in CAFs-treated cells. Treatment with specific inhibitors LY294002 and U0126 reversed the CAFs-mediated cell proliferation (P<0.0001), suggesting for a role of these pathways in modulating endometrial cancer cell proliferation. Rapamycin, which targets a downstream molecule in PI3K pathway (mTOR), also suppressed CAFs-induced cell proliferation by inducing apoptosis. Cytokine profiling analysis revealed that CAFs secrete higher levels of macrophage chemoattractant protein (MCP)-1, interleukin (IL)-6, IL-8, RANTES and vascular endothelial growth factor (VEGF) than normal fibroblasts. Our data suggests that in contrast to normal fibroblasts, CAFs may exhibit a pro-tumorigenic effect in the progression of endometrial cancer, and PI3K/Akt and MAPK/Erk signaling may represent critical regulators in how endometrial cancer cells respond to their microenvironment.
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