Tumor-associated macrophages (TAMs) frequently help to sustain tumor growth and mediate immune suppression in the tumor microenvironment (TME). Here, we identified a subset of iron-loaded, ...pro-inflammatory TAMs localized in hemorrhagic areas of the TME. The occurrence of iron-loaded TAMs (iTAMs) correlated with reduced tumor size in patients with non-small cell lung cancer.
experiments established that TAMs exposed to hemolytic red blood cells (RBCs) were converted into pro-inflammatory macrophages capable of directly killing tumor cells. This anti-tumor effect could also be elicited
iron oxide nanoparticles. When tested
, tumors injected with such iron oxide nanoparticles led to significantly smaller tumor sizes compared to controls. These results identify hemolytic RBCs and iron as novel players in the TME that repolarize TAMs to exert direct anti-tumor effector function. Thus, the delivery of iron to TAMs emerges as a simple adjuvant therapeutic strategy to promote anti-cancer immune responses.
Smoothed particle hydrodynamics (SPH) is a meshless Lagrangian method that has been successfully applied to computational fluid dynamics (CFD), solid mechanics and many other multi-physics problems. ...gpuSPHASE is a graphics processing unit (GPU) accelerated solver for 2D SPH simulations that is optimized for relatively small numbers of particles but long physical simulation times as required to solve transport phenomena in process engineering applications. The software aims at a low latency execution pipeline with thousands of iterations per second on contemporary GPU accelerator cards, while using symplectic time integration for long term stability of the simulations. For this, a novel caching algorithm for CUDA shared memory is proposed and implemented. gpuSPHASE is validated against SPHERIC test cases and the performance is evaluated and compared to state of the art implementations of the SPH method.
Program Title: gpuSPHASE
Program Files doi:http://dx.doi.org/10.17632/8vpwwh8th5.2
Licensing provisions: GPLv3
Programming language: CUDA C++
Journal reference of previous version: Comput. Phys. Comm., 213 (2017), 165–180
Does the new version supersede the previous version?: Yes
Reasons for the new version: The software is in active development and thus several new features have been added since the initial release. Those improvements are related to accuracy, maintainability and platform independence.
Summary of revisions:•Build process: The previous distribution was relatively complicated to build due to the external dependencies of the software. This process has been optimized such that CMake is used for all platforms to build the software. For performance reasons several decisions have to be taken at compile time, which can be configured through the CMake configuration. External dependencies are platform independently retrieved and included using CMake features.•Code: While optimized for performance, zero-cost decorators were added to improve the readability of the code. Furthermore, a weak form of type punning was used previously, which was entirely replaced by a custom defined type to eliminate the possibility of undefined behavior.•Floating point precision: As described in the literature and in the original version of the manuscript, 32 bit floating point precision is generally sufficient for SPH simulations of water 1,2. While not optimized for the opportunistic caching strategy, 64 bit floating point precision has been added. Due to the significant performance loss of consumer grade GPUs for FP64 computations the performance may be considerably worse. FP64 precision can be used to check if FP32 is sufficient and thus detect simulations where FP64 is required. This feature does not influence the already implemented cell relative position calculations that allow for large computational domains without any loss in accuracy 2. Improvements can be observed e.g. in the Poiseuille flow test case released with DualSPHysics 4.2 3 with the configuration of ν=10−6 m2.s−1, ρ=1000 kg.m−3 and a body force of Fx=10−4 m.s−2, as shown in Fig. 1.•Particle shifting: The diffusion based particle shifting method proposed by Skillen et al. (2013) 4 is implemented. As suggested by Lind et al. (2012) 5, the particle concentration is augmented with the factor fij to prevent pairing instability for free surface flows 6. The improvements are best observed with Poiseuille flow configuration of ν=10−2 m2.s−1, ρ=1 kg.m−3 and a body force of Fx=10−1 m.s−2 7. This test case does not converge with gpuSPHASE using single or double precision due to the problems described by 8. Enabling particle shifting allows to execute the simulation until t>100, as shown in Fig. 2.•Advective-diffusion and heat transfer: Heat transfer is modeled based on the temperature T and the thermal conductivity k as dT∕dt=ρ−1cp−1k∇2T. The SPH discretization is implemented according to Alshaer et al. (2017) 9 and successfully verified 10. The mass transfer of concentration C is modeled using the advective-diffusion equation dC∕dt=D∇2C−∇⋅(vC). The model is implemented according to the discretization of Aristodemo et al. 11 and successfully verified 12.Nature of problem: gpuSPHASE aims at free surface fluid dynamics simulations of long running physical phenomena that must be calculated in the order of real-time. Due to the long physical time and thus the requirement of millions to billions of iterations, the code is restricted to 2D. This restriction allows for optimizations that would not be possible for more generic approaches 13.
Solution method: gpuSPHASE is a 2D SPH solver for CUDA capable devices that is optimized for the computation of real-time simulations. Compile time definitions allow to optimize the code for fast execution of the CUDA kernel functions. Symplectic time integration and correction methods enable stable simulations of long physical time problems.
References1K. Szewc, Granular Matter 19 (2016) 3.2D. Winkler, M. Meister, M. Rezavand, W. Rauch, Computer Physics Communications 213 (2017) 165–180.3A. J. C. Crespo, J. M. Domínguez, B. D. Rogers, M. Gómez-Gesteira, S. Longshaw, R. B. Canelas, R. Vacondio, A. Barreiro, O. García-Feal, Computer Physics Communications 187 (2015) 204–216.4A. Skillen, S. Lind, P. K. Stansby, B. D. Rogers, Computer Methods in Applied Mechanics and Engineering 265 (2013) 163–173.5S. Lind, R. Xu, P. Stansby, B. Rogers, Journal of Computational Physics 231 (4) (2012) 1499–1523.6J. J. Monaghan, Journal of Computational Physics 159 (2) (2000) 290–311.7S. Adami, X. Y. Hu, N. Adams, Journal of Computational Physics 231 (21) (2012) 7057–7075.8M. Basa, N. J. Quinlan, M. Lastiwka, International Journal for Numerical Methods in Fluids 60 (10) (2008) 1127–1148.9A. Alshaer, B. Rogers, L. Li, Computational Materials Science 127 (2017) 161–179.10M. Rezavand, D. Winkler, W. Rauch, in: Proceedings of the 13th International SPHERIC Workshop (2018) 371–378.11F. Aristodemo, I. Federico, P. Veltri, A. Panizzo, Environmental Fluid Mechanics 10 (4) (2010) 451–470.12M. Rezavand, D. Winkler, W. Rauch, in: Proceedings of the 12th International SPHERIC Workshop (2017) 426–433.13D. Winkler, M. Rezavand, W. Rauch, Computer Physics Communications 225 (2018) 140–148.
The precise mechanism and dynamics of charge generation and recombination in bulk heterojunction polymer:fullerene blend films typically used in organic photovoltaic devices have been intensively ...studied by many research groups, but nonetheless remain debated. In particular the role of interfacial charge-transfer (CT) states in the generation of free charge carriers, an important step for the understanding of device function, is still under active discussion. In this article we present direct optical probes of the exciton dynamics in pristine films of a prototypic polycarbazole-based photovoltaic donor polymer, namely polyN-11′′-henicosanyl-2,7-carbazole-alt-5,5-(4′,7′-di-2-thienyl-2′,1′,3′-benzothiadiazole) (PCDTBT), as well as the charge generation and recombination dynamics in as-cast and annealed photovoltaic blend films using methanofullerene (PC61BM) as electron acceptor. In contrast to earlier studies we use broadband (500–1100 nm) transient absorption spectroscopy including the previously unobserved but very important time range between 2 ns and 1 ms, which allows us not only to observe the entire charge carrier recombination dynamics but also to quantify the existing decay channels. We determine that ultrafast exciton dissociation occurs in blends and leads to two separate pools of products, namely Coulombically bound charge-transfer (CT) states and unbound (free) charge carriers. The recombination dynamics are analyzed within the framework of a previously reported model for poly(3-hexylthiophene):PCBM ( Howard I. A. J. Am. Chem. Soc. 2010, 132, 14866 ) based on concomitant geminate recombination of CT states and nongeminate recombination of free charge carriers. The results reveal that only ∼11% of the initial photoexcitations generate interfacial CT states that recombine exclusively by fast nanosecond geminate recombination and thus do not contribute to the photocurrent, whereas ∼89% of excitons create free charge carriers on an ultrafast time scale that then contribute to the extracted photocurrent. Despite the high yield of free charges the power conversion efficiency of devices remains moderate at about 3.0%. This is largely a consequence of the low fill factor of devices. We relate the low fill factor to significant energetic disorder present in the pristine polymer and in the polymer:fullerene blends. In the former we observed a significant spectral relaxation of exciton emission (fluorescence) and in the latter of the polaron-induced ground-state bleaching, implying that the density of states (DOS) for both excitons and charge carriers is significantly broadened by energetic disorder in pristine PCDTBT and in its blend with PCBM. This disorder leads to charge trapping in solar cells, which in turn causes higher carrier concentrations and more significant nongeminate recombination. The nongeminate recombination has a significant impact on the IV curves of devices, namely its competition with charge carrier extraction causes a stronger bias dependence of the photocurrent of devices, in turn leading to the poor device fill factor. In addition our results demonstrate the importance of ultrafast free carrier generation and suppression of interfacial CT-state formation and question the applicability of the often used Braun–Onsager model to describe the bias dependence of the photocurrent in polymer:fullerene organic photovoltaic devices.
The synergy of push–pull substitution and enlarged ligand bite angles has been used in functionalized heteroleptic bis(tridentate) polypyridine complexes of ruthenium(II) to shift the 1MLCT ...absorption and the 3MLCT emission to lower energy, enhance the emission quantum yield, and to prolong the 3MLCT excited‐state lifetime. In these complexes, that is, Ru(ddpd)(EtOOC‐tpy)PF62, Ru(ddpd‐NH2)(EtOOC‐tpy)PF62, Ru(ddpd){(MeOOC)3‐tpy}PF62, and Ru(ddpd‐NH2){(EtOOC)3‐tpy}PF62 the combination of the electron‐accepting 2,2′;6′,2′′‐terpyridine (tpy) ligand equipped with one or three COOR substituents with the electron‐donating N,N′‐dimethyl‐N,N′‐dipyridin‐2‐ylpyridine‐2,6‐diamine (ddpd) ligand decorated with none or one NH2 group enforces spatially separated and orthogonal frontier orbitals with a small HOMO–LUMO gap resulting in low‐energy 1MLCT and 3MLCT states. The extended bite angle of the ddpd ligand increases the ligand field splitting and pushes the deactivating 3MC state to higher energy. The properties of the new isomerically pure mixed ligand complexes have been studied by using electrochemistry, UV/Vis absorption spectroscopy, static and time‐resolved luminescence spectroscopy, and transient absorption spectroscopy. The experimental data were rationalized by using density functional calculations on differently charged species (charge n=0–4) and on triplet excited states (3MLCT and 3MC) as well as by time‐dependent density functional calculations (excited singlet states).
The synergy of push–pull substitution (R1–R3) and enlarged ligand bite angles lowers the energy of metal‐to‐ligand charge transfer (MLCT) states and increases the energy of metal‐centered (MC) states in isomerically pure, directional, and multifunctional heteroleptic bis(tridentate) polypyridine complexes of RuII (see figure). These combined effects promote long‐lived low‐energy emission in fluid solution at RT (λmax up to 788 nm; Φ up to 1.1 %; τ up to 841 ns) approaching the values of the ubiquitous Ru(bpy)32+ complex (bpy=2,2′‐bipyridine).
Iron-loaded tumor-associated macrophages (iTAMs) show a pro-inflammatory phenotype, hallmarked by anti-tumorigenic activity and an ability to attenuate tumor growth. Here we explored the relevance of ...these findings in lung cancer patients by investigating the impact of the iTAM content in the tumor microenvironment (TME) on patient survival. We analyzed 102 human non-small cell lung cancer (NSCLC) paraffin-embedded archival tissue samples for iron levels and macrophage numbers. Interestingly, patients with lung adenocarcinoma accumulating iron in the TME show higher numbers of M1-like pro-inflammatory TAMs and a survival advantage compared to iron-negative patients. By contrast, in patients with lung squamous cell carcinoma iron in the TME does not affect survival, suggesting a unique influence of iron on different histological subtypes of non-small cell lung cancer (NSCLC). We conclude that in lung adenocarcinoma iron may serve as a prognostic marker for patient survival and as a potential therapeutic target for anti-cancer therapy.
Paediatric rhabdomyosarcoma (RMS) is a soft tissue malignancy of mesenchymal origin that is thought to arise as a consequence of derailed myogenic differentiation. Despite intensive treatment ...regimens, the prognosis for high-risk patients remains dismal. The cellular differentiation states underlying RMS and how these relate to patient outcomes remain largely elusive. Here, we use single-cell mRNA sequencing to generate a transcriptomic atlas of RMS. Analysis of the RMS tumour niche reveals evidence of an immunosuppressive microenvironment. We also identify a putative interaction between NECTIN3 and TIGIT, specific to the more aggressive fusion-positive (FP) RMS subtype, as a potential cause of tumour-induced T-cell dysfunction. In malignant RMS cells, we define transcriptional programs reflective of normal myogenic differentiation and show that these cellular differentiation states are predictive of patient outcomes in both FP RMS and the less aggressive fusion-negative subtype. Our study reveals the potential of therapies targeting the immune microenvironment of RMS and suggests that assessing tumour differentiation states may enable a more refined risk stratification.
Hypoxia signaling plays a major role in non-malignant and malignant hyperproliferative diseases. Pulmonary hypertension (PH), a hypoxia-driven vascular disease, is characterized by a glycolytic ...switch similar to the Warburg effect in cancer. Ras association domain family 1A (RASSF1A) is a scaffold protein that acts as a tumour suppressor. Here we show that hypoxia promotes stabilization of RASSF1A through NOX-1- and protein kinase C- dependent phosphorylation. In parallel, hypoxia inducible factor-1 α (HIF-1α) activates RASSF1A transcription via HIF-binding sites in the RASSF1A promoter region. Vice versa, RASSF1A binds to HIF-1α, blocks its prolyl-hydroxylation and proteasomal degradation, and thus enhances the activation of the glycolytic switch. We find that this mechanism operates in experimental hypoxia-induced PH, which is blocked in RASSF1A knockout mice, in human primary PH vascular cells, and in a subset of human lung cancer cells. We conclude that RASSF1A-HIF-1α forms a feedforward loop driving hypoxia signaling in PH and cancer.
Abstract The chromatin remodeling Switch Sucrose Non-Fermentable (SWI/SNF) complex has been increasingly implicated in the pathogenesis and dedifferentiation of neoplasms from several organs with ...prognostic and potential therapeutic implications. We herein investigated the expression of the SWI/SNF complex catalytic subunits SMARCA4 (BRG1) and SMARCA2 (BRM) in 316 consecutive NSCLC specimens on tissue microarrays (171 adenocarcinomas/ADCA, 130 squamous cell carcinomas/SCC, 9 adenosquamous carcinomas, and 6 large cell carcinomas) excluding undifferentiated/giant cell or rhabdoid carcinomas. Complete loss of SMARCA4 was observed in 8/146 (5.5%) and 6/115 (5.2%) of evaluable pulmonary ADCA and SCC, respectively, while 9/140 (6.4%) ADCA and 2/117 (1.7%) SCC showed SMARCA2 loss, respectively. Two of 6 large cell carcinomas were SMARCA2-deficient. Concurrent loss of both markers was observed in 4 cases (2 ADCA and 2 SCC). Of 15 ADCA with loss of either or both markers, 12 (80%) were TTF1 negative. In conclusion, SMARCA4- and SMARCA2 deficiency is observed in 5.1% and 4.8% of NSCLC, respectively. SMARCB1 expression was intact in all cases. The presence of differentiated histology (glandular or squamous) is a novel aspect among SWI/SNF deficient carcinomas which in other organs generally are associated with undifferentiated/rhabdoid morphology. The predominance of TTF1-negativity among SWI/SNF-deficient pulmonary ADCA (80%) underlines the need to include these two markers in the evaluation of TTF1-negative ADCA of putative pulmonary origin. Given the recently documented potential of SMARCA4 loss as a predictor of chemosensitivity to platinum-based chemotherapy in NSCLC, recognition of the clinicopathological features of SMARCA4-deficient NSCLC in routine surgical pathology practice is recommended.
Introduction
Metastatic rhabdomyosarcoma (RMS) is a challenging tumor entity that evades conventional treatments and endogenous antitumor immune responses, highlighting the need for novel therapeutic ...strategies. Applying chimeric antigen receptor (CAR) technology to natural killer (NK) cells may offer safe, effective, and affordable therapies that enhance cancer immune surveillance.
Methods
Here, we assess the efficacy of clinically usable CAR-engineered NK cell line NK-92/5.28.z against ErbB2-positive RMS
in vitro
and in a metastatic xenograft mouse model.
Results
Our results show that NK-92/5.28.z cells effectively kill RMS cells
in vitro
and significantly prolong survival and inhibit tumor progression in mice. The persistence of NK-92/5.28.z cells at tumor sites demonstrates efficient antitumor response, which could help overcome current obstacles in the treatment of solid tumors.
Discussion
These findings encourage further development of NK-92/5.28.z cells as off-the-shelf immunotherapy for the treatment of metastatic RMS.
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