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The hybrid Voronoi-Latin Hypercube Sampling (Voronoi-LHS) method is proposed for the surrogate-aided optimization of the axial compressor blades. The hybrid method is first applied to the fundamental test cases. The analytical results show that, compared with the Voronoi and LHS strategies, the hybrid method generally improves the robustness and convergency. Then the multi-objective genetic algorithm (MOGA) in conjunction with the artificial neural network (ANN) is applied to optimize the aerodynamic performance of an axial compressor rotor. Before the optimization process, the hybrid Voronoi-LHS sample infilling method is employed to refine the ANN surrogate model. Considering the typical intake distortion, the sweep and lean distributions of this rotor are optimized to pursue the maximum total pressure ratio and adiabatic efficiency. The results show that the optimization significantly improves the pressure ratio, efficiency and surge margin of the compressor with low computing cost.

Supplementary Figure S2 shows the results of intracellular staining of aNK cells for perforin and granzyme A, as requested by reviewer #3.

Supplementary Table S1 is a list of antibodies used in the study. It has been updated to include antibodies used in experiments requested by reviewer #3.

The efficacy of immune checkpoint inhibitors (ICIs) on KRAS-mutant advanced non-small cell lung cancer (NSCLC) remains controversial. This retrospective study compared the effects of ICIs treatment and chemotherapy on the prognosis of patients with KRAS-mutant advanced NSCLC and different mutant subtypes in the real world. The study included 95 patients with KRAS-mutant advanced NSCLC. Patients treated with first-line ICIs plus platinum-containing chemotherapy had better progression-free survival (PFS) (7.4 vs 4.5 months, P = 0.035) and overall survival (OS) (24.1 vs 13.2 months, P = 0.007) than those receiving platinum-containing chemotherapy alone, and second-line ICI monotherapy was associated with better PFS (4.8 vs 3.0 months, P = 0.043) and OS (18.0 vs 13.8 months, P = 0.013) than chemotherapy monotherapy. There was no significant difference in PFS (5.267 vs 6.734 months, P = 0.969) and OS (19.933 vs 20.933 months, P = 0.808) between patients with KRAS-mutant and KRAS-wild-type NSCLC treated with ICIs or between KRAS G12C and KRAS non-G12C patients (PFS: 8.1 vs 4.8 months, P = 0.307; OS: 21.3 vs 21.8 months, P = 0.434). In summary, patients with advanced NSCLC with KRAS mutations can benefit from ICIs, but no difference between KRAS mutant subtypes was observed.

Extracellular vesicles (EVs) derived from immune cells have shown great anti-cancer therapeutic potential. However, inefficiency in EV generation has considerably impeded the development of EV-based basic research and clinical translation. Here, we developed a seesaw-motion bioreactor (SMB) system by leveraging mechanical stimuli such as shear stress and turbulence for generating EVs with high quality and quantity from natural killer (NK) cells. Compared to EV production in traditional static culture (229 ± 74 particles per cell per day), SMB produced NK-92MI-derived EVs at a higher rate of 438 ± 50 particles per cell per day and yielded a total number of 2 × 1011 EVs over two weeks via continuous dynamic fluidic culture. In addition, the EVs generated from NK-92MI cells in SMB shared a similar morphology, size distribution, and protein profile to EVs generated from traditional static culture. Most importantly, the NK-92MI-derived EVs in SMB were functionally active in killing melanoma and liver cancer cells in both 2D and 3D culture conditions in vitro, as well as in suppressing melanoma growth in vivo. We believe that SMB is an attractive approach to producing EVs with high quality and quantity; it can additionally enhance EV production from NK92-MI cells and promote both the basic and translational research of EVs.

Stimulatory immune receptor NKG2D binds diverse ligands to elicit differential anti‐tumor and anti‐virus immune responses. Two conflicting degeneracy recognition models based on static crystal structures and in‐solution binding affinities have been considered for almost two decades. Whether and how NKG2D recognizes and discriminates diverse ligands still remain unclear. Using live‐cell‐based single‐molecule biomechanical assay, we characterized the in situ binding kinetics of NKG2D interacting with different ligands in the absence or presence of mechanical force. We found that mechanical force application selectively prolonged NKG2D interaction lifetimes with the ligands MICA and MICB, but not with ULBPs, and that force‐strengthened binding is much more pronounced for MICA than for other ligands. We also integrated steered molecular dynamics simulations and mutagenesis to reveal force‐induced rotational conformational changes of MICA, involving formation of additional hydrogen bonds on its binding interface with NKG2D, impeding MICA dissociation under force. We further provided a kinetic triggering model to reveal that force‐dependent affinity determines NKG2D ligand discrimination and its downstream NK cell activation. Together, our results demonstrate that NKG2D has a discrimination power to recognize different ligands, which depends on selective mechanical force‐induced ligand conformational changes., Force‐induced alterations of ligand affinity and conformation allow immune receptor NKG2D to recognize different ligands and trigger distinct signaling responses for downstream natural killer cell activation.

PurposeThe NB5 assay was performed in bone marrow (BM) and peripheral blood (PB) to detect neuroblastomas (NBs) with micrometastases. The sensitivity and factors influencing the NB5 assay were preliminarily evaluated.MethodsThe NB5 assay uses RT-PCR to detect the co-expression of five mRNAs from the neuroblastoma-associated genes, CHGA, DCX, DDC, PHOX2B, and TH. We enrolled 180 cases of neuroblastoma and 65 cases of non-neuroblastoma. Bone marrow and peripheral blood were collected from every patient. The gold standard for the diagnosis of NB was pathological evaluation of solid tumor specimens or bone marrow biopsies (BMBs) from hematological tumors. STATA version 15 and SPSS version 17 software were used for analysis.ResultsWe found that 17 patients were BMB (+), and they were diagnosed as the International Neuroblastoma Staging System (INSS) stage IV and the high-risk group. All 17 patients were BM (+), while 15 patients were PB (+) (15/17, 88.2%). Among the 163 children who were BMB (−), 56 were BM (+), 40 were PB (+), and 36 were BM (+) and PB (+). The sensitivity of the NB5 assay in BM (40.5%) and PB (30.5%) was significantly higher than the sensitivity of BMB (9.4%, P = 0.000). In the non-NB group, four cases were BM (+) and one case was PB (+). The specificity of the NB5 assay in BM and PB was 93.8% and 98.5%, respectively. The sensitivity of the NB5 assay in both BM and PB in INSS stage IV patients was significantly higher than that in INSS stage I–II patients (P ConclusionsThe NB5 assay had significantly higher sensitivity than the pathological analysis of BMB in detecting NB with micrometastases. The NB5 assay had higher sensitivity in INSS stage IV or the high-risk group. Liver metastases and bone metastases were the primary factors that affected the sensitivity of the NB5 assay.

BackgroundThe bone marrow suppression during chemotherapy will cause severe platelet decline in the human body, resulting in critical organ hemorrhage and intracranial hemorrhage. Therefore, the efficacy and economics of recombinant human thrombopoietin (rhTPO) in treating different degrees of thrombocytopenia caused by chemotherapy were analyzed. MethodsFrom January 2018 to July 2019, 233 with diagnosed lung cancer treated with the course of chemotherapy or chemoradiotherapy were enrolled. After treatment with chemotherapy or chemoradiotherapy, they all happened thrombocytopenia and received rhTPO. We divided patients into three groups according to the level of platelet decline. Changes in blood platelet count, treatment plan and cost performance between them were analyzed. ResultsOf all the included patients, 39.5% was undergoing concurrent radiotherapy or chemotherapy; 42.9% had thrombocytopenia of grade II; 40.3% had thrombocytopenia of grade III; 16.7% had thrombocytopenia of grade IV; 52.8% postponed the next cycle of chemotherapy or radiotherapy due to platelet decline; 12.0% changed the treatment plan for malignant tumors due to severe platelet decline; 15.5% reduced the dose of chemotherapy drugs due to thrombocytopenia; 23.6% had platelet transfusions during this period. During the extended hospitalization period caused by thrombocytopenia, the medical expenses of patients would increase significantly, which was dominated by the cost of rhTPO. ConclusionsFor different degrees of thrombocytopenia, the treatment of rhTPO could increase platelet counts effectively. During the treatment, patients might have varying degrees of economic and the difference between the treatment duration of different patients.

Very few studies of non-axisymmetric endwall profiling in compressor have been conducted in published literatures. This study investigates the control mechanism of non-axisymmetric endwall on the flow field of a highly loaded compressor cascade and the guidelines for the design of non-axisymmetric endwall. First, CFD method was validated with existing experimental data. Then, the design method of non-axisymmetric endwall based on trigonometric function and Bezier curve was introduced. The design strategies of non-axisymmetric endwall considering axial position effect, height effect and different patterns of concave/convex were investigated in detail. Results show that non-axisymmetric endwall is an effective way to control the near endwall flow field of the compressor cascade. With the optimal non-axisymmetric endwall in this study, the loss coefficient of the cascade is reduced by 5.5%, and the cascade exhibited suppressed corner separation, reduced passage vortex and more uniformly distributed outflow angles. The optimal axial position of the concave was at 0.22 axial chord, which was near the onset of corner separation, so the best control effect was obtained. There is an optimal height for the concave of the non-axisymmetric endwall. A lower concave will not have sufficient effect on the cascade, whereas a higher concave will be detrimental on the contrary. It is indicated that the influence mechanism of non-axisymmetric endwall on the compressor cascade is basically derived from the superimposed effect of reduced cross-passage pressure gradient and increased spanwise inward pressure gradient. The cross-passage pressure gradient can be reduced by both concave on the suction side and convex on the pressure side of the endwall. However, concave can introduce spanwise inward pressure gradient, whilst convex can introduce spanwise outward pressure gradient. For better improving the performance of compressor cascades, non-axisymmetric endwall is suggested to be a concave on the entire endwall, which introduces both reduced cross-passage pressure gradient and increased spanwise inward pressure gradient.

Boundary layer suction can effectively eliminate flow separations and increase aerodynamic loading of axial compressors. The design methodology of highly loaded aspirated compressor blades was developed and illustrated in this study. In this work, Computational Fluid Dynamics (CFD) methods were first validated with existing data and then used to develop the design strategy of aspirated compressor blades. Design strategies for higher blade performances, including higher loading, larger stall margin and larger blade thickness near the suction slot of aspirated blades, were investigated through analyzing a series of highly loaded aspirated cascades with diffusion factors (DF) around 0.71. Results showed that the design methodology proposed in this paper was appropriate for designing highly loaded aspirated compressor blades. Under the condition of no boundary layer suction (BLS), severe flow separations of highly loaded blades were tailored at the aft part of suction surface by adopting the “ski-slope” velocity distribution, which almost remained unchanged within a large incidence range. The “ski-slope” velocity distribution was appropriate for removing flow separations and beneficial for obtaining thicker blade. High loading of aspirated blade was achieved by the postpositional suction peak and minimum velocity distribution on pressure surface. The stall margin of highly loaded aspirated cascades could be enlarged by designing the velocity distribution upstream of the suction slot and by selecting suction peak position and solidity. A three-dimensional (3D) highly loaded aspirated cascade was designed based on a two-dimensional (2D) cascade. Both the trailing edge separation and corner separation of the 3D highly loaded aspirated cascade were eliminated successfully with coupled suction surface and endwall suction.

Discretely sized semiconductor clusters have attracted considerable attention due to their intriguing optical properties and self-assembly behaviors. While lead halide perovskite nanostructures have been recently intensively explored, few studies have addressed perovskite clusters and their self-assembled superstructures. Here, we report the room-temperature synthesis of sub-2 nm CsPbBr3 clusters and present strong evidence that these ultrasmall perovskite species, obtained under a wide range of reaction conditions, possess a specific size, with optical properties and self-assembly characteristics resembling those of well-known II–VI semiconductor magic-sized clusters. Unlike conventional CsPbBr3 nanocrystals, the as-synthesized CsPbBr3 nanoclusters spontaneously self-assemble into a hexagonally packed columnar mesophase in solution, which can be further converted to single-crystalline CsPbBr3 quantum nanoribbons with bright deep-blue emission at room temperature. Such a conversion of CsPbBr3 nanoclusters to nanoribbons is found to be driven by a ligand-destabilization-induced crystallization and mesophase transition process. Our study will facilitate the investigation of perovskite nanoclusters and offer new possibilities in the low-temperature synthesis of anisotropic perovskite nanostructures.

Discretely sized semiconductor clusters have attracted considerable attention due to their intriguing optical properties and self-assembly behaviors. While lead halide perovskite nanostructures have been recently intensively explored, few studies have addressed perovskite clusters and their self-assembled superstructures. Here, we report the room-temperature synthesis of sub-2 nm CsPbBr

Background: miRNA, a small non-coding RNA molecule containing about 22 nucleotides, functions in RNA silencing and post-transcriptional regulation of gene expression. With these qualities, miRNAs modulate multiple signaling pathways involved in cancer development, such as cellular proliferation, apoptosis, and migration. Methods: The goal of this review is to discuss possible miRNAs-based therapeutic strategies, through defining performance of miRNAs in carcinogenesis, in particular in lung cancer. Results: miRNA, a non-coding RNA, is divided into two main types: tumor suppressor miRNAs and oncogenic miRNAs. In addition, special processed miRNAs can be an assistant therapeutic tool. Conclusion: In order to develope antitumor therapy, miRNAs-based therapeutic strategies are worth of deeper studies. In this process, the stability, effectiveness, and side effects should be considered.

Purpose: Immunotherapy of high-risk neuroblastoma using the anti-GD2 antibody dinutuximab induces antibody-dependent cell-mediated cytotoxicity (ADCC). Galunisertib, an inhibitor of TGFβR1, was examined for its ability to enhance the efficacy of dinutuximab in combination with human ex vivo activated NK (aNK) cells against neuroblastoma. Experimental Design: TGFB1 and TGFBR1 mRNA expression was determined for 249 primary neuroblastoma tumors by microarray analysis. The ability of galunisertib to inhibit SMAD activity induced by neuroblastoma patient blood and bone marrow plasmas in neuroblastoma cells was tested. The impact of galunisertib on TGFβ1-induced inhibition of aNK cytotoxicity and ADCC in vitro and on anti-neuroblastoma activity in NOD-scid gamma (NSG) mice was determined. Results: Neuroblastomas express TGFB1 and TGFBR1 mRNA. Galunisertib suppressed SMAD activation in neuroblastoma cells induced by exogenous TGFβ1 or by patient blood and bone marrow plasma, and suppressed SMAD2 phosphorylation in human neuroblastoma cells growing in NSG mice. In NK cells treated in vitro with exogenous TGFβ1, galunisertib suppressed SMAD2 phosphorylation and restored the expression of DNAM-1, NKp30, and NKG2D cytotoxicity receptors and the TRAIL death ligand, the release of perforin and granzyme A, and the direct cytotoxicity and ADCC of aNK cells against neuroblastoma cells. Addition of galunisertib to adoptive cell therapy with aNK cells plus dinutuximab reduced tumor growth and increased survival of mice injected with two neuroblastoma cell lines or a patient-derived xenograft. Conclusions: Galunisertib suppresses activation of SMAD2 in neuroblastomas and aNK cells, restores NK cytotoxic mechanisms, and increases the efficacy of dinutuximab with aNK cells against neuroblastoma tumors. Clin Cancer Res; 23(3); 804–13. ©2016 AACR. See related commentary by Zenarruzabeitia et al., p. 615

All-inorganic cesium lead halide perovskite (CsPbX3, X = Cl, Br, and I) nanocrystals (NCs) are emerging as an important class of semiconductor materials with superior photophysical properties and wide potential applications in optoelectronic devices. So far, only a few studies have been conducted to control the shape and geometry of CsPbX3 NCs. Here we report a general approach to directly synthesize two-dimensional (2D) CsPbX3 perovskite and mixed perovskite nanosheets with uniform and ultrathin thicknesses down to a few monolayers. The key to the high-yield synthesis of perovskite nanosheets is the development of a new Cs-oleate precursor. The as-synthesized CsPbX3 nanosheets exhibit bright photoluminescence with broad wavelength tunability by composition modulation. The excellent optoelectronic properties of CsPbX3 nanosheets combined with their unique 2D geometry and large lateral dimensions make them ideal building blocks for building functional devices. To demonstrate their potential applications in optoelectronics, photodetectors based on CsPbBr3 nanosheets are fabricated, which exhibit high on/off ratios with a fast response time.

Sargassum seaweeds produce abundant biomass in China and have long been used as herbal medicine and food. Their characteristic fatty acid (FA) profiles and related potential function in promoting cardiovascular health (CVH) have not been systematically investigated. In this study, FA profiles of four medicinal Sargassum were characterized using GC-MS. Principal component analysis was used to discriminate the four medicinal Sargassum, and orthogonal projection to latent structures discriminant analysis was carried out between the two official species HAI ZAO and between the two folk medicine species HAI QIAN. In all of the algae investigated, the major SFA and MUFA were palmitic and stearic acid, respectively, while the major PUFAs were linoleic, arachidonic, and eicosapentaenoic acid. S. fusiforme and S. horneri had higher concentrations of PUFAs. With respect to CVH, all of the studied species, particularly S. fusiforme, exhibited satisfactory levels such as PUFA/SFA ratio and n-6/n-3 ratio. Each species possesses a unique FA profile and is discriminated clearly. Potential key FA markers (between the two Chinese official species, and between the two folk species) are assessed. The study provides characteristic fatty acid profiles of four Chinese medicinal Sargassum and their related potential function in promoting CVH.

Neuroblastoma is the most common extracranial solid tumor in the pediatric population. Sorafenib (Nexavar), a multikinase inhibitor, blocks cell proliferation and induces apoptosis in certain types of cancers. Here, we tested antitumor effects of sorafenib (≤ 10 µM) on four human neuroblastoma cell lines, CHLA255, CHLA171, CHLA90 and SK-N-AS. Sorafenib inhibited cell proliferation and induced apoptosis of neuroblastoma tumor cells in a dose-dependent manner. Sorafenib inhibited phosphorylation of Signal Transducer and Activator of Transcription 3 (STAT3) proteins at Tyr705 in these cells, associated with inhibition of phosphorylated JAK2, an upstream kinase that mediates STAT3 phosphorylation. Expression of a constitutively-activated STAT3 mutant (pSTAT3-C) partially blocked the antitumor effects of sorafenib on neuroblastoma cells. Sorafenib also inhibited the phosphorylation of STAT3 induced by IL-6 and sphingosine-1-phosphate (S1P), a recently identified regulator for STAT3, in these tumor cells. Moreover, sorafenib downregulated phosphorylation of MAPK (p44/42) in neuroblastoma cells, consistent with inhibition of their upstream regulators MEK1/2. Sorafenib inhibited expression of cyclin E, cyclin D1/D2/D3, key regulators for cell cycle, and the antiapoptotic proteins Mcl-1 and survivin. Finally, sorafenib suppressed the growth of human neuroblastoma cells in a mouse xenograft model. Taken together, these findings suggest the potential use of sorafenib for the treatment of pediatric neuroblastomas.

Natural killer (NK) cells-based immunotherapy is one of the most promising treatments for incurable malignant tumors. NK cells in combination with monoclonal antibodies to surface antigens of the tumor cell have been proved to be effective in a number of clinical trials. A limiting step in the development of successful cellular immunotherapy lies in developing an efficient and economic method to expand appropriate amount of NK cells and CD8(+) T cells. In this study, we constructed a humanized IL-15Ralpha-IgG1-Fc, which mimicked IL-15 trans-presentation. The feasibility of expanding populations of the human NK and CD8(+) T cells by IL-15Ralpha-IgG1-Fc complexes was tested. We then measured the cytotoxicity of expanded NK and CD8(+) T cells against tumor cell lines and primary tumor cells. When tested ex vivo, IL-2/IL-15Ralpha-IgG1-Fc complexes significantly enhanced NK and CD8(+) T cells expansion, isolated or non-isolated from PBMCs. The effect of IL-15Ralpha-IgG1-Fc was dependent on the presence of IL-2 or IL-15. IL-15Ralpha-IgG1-Fc complexes increased NK, CD8(+) T and NKT cells ratio in PBMC and BMMC after 14 days incubation. High level of granzyme B expression was observed in the supernatant of the complexes-treated NK cells. Expanded NK and CD8(+) T cell populations had cytotoxic function against the PC3, LNCaP, K562 and chronic lymphocytic leukemia (CLL) patient primary B cell lymphoma. We concluded that IL-2/IL-15Ralpha-IgG1-Fc significantly enhanced NK, CD8(+) T and NKT cells expansion, which possess strong anti-tumor activity. These data support clinical testing IL-2/IL-15Ralpha-IgG1-Fc expanded NK cells in patients with prostate cancer and CLL.

Cyclooxygenases are encoded by COX-1 and COX-2. They share over sixty percent sequence identity in human and are similar to each other in their crystallographic structures. One major difference in the primary structure of these two isozymes is the presence of eight amino acids in the amino-terminal region of COX-1 that are not present in COX-2. The function of this amino acid sequence is unknown. In this study, a human COX-1 mutant (Delta7aa) with this sequence removed was studied in parallel with COX-1. Signal peptide cleavage, N-linked glycosylation, protein expression, distribution and dimerization were not affected by the mutation. The mutant was enzymatically active and showed the same sensitivity toward aspirin. The KM for the enzyme remained the same as COX-1. However, the V(max) of the COX-1 mutant decreased by 3.3-fold. We conclude that the COX-1 specific amino-terminal sequence has a subtle but detectable effect on COX-1 catalysis.

Part 2: Adoption; International audience; Online household e-waste collection services are emerging as new solutions to disposing household e-waste in China. This study aims to investigate the adoption of online household e-waste collection services in China. Based on the previous technology diffusion theories (e.g., TAM, UTAUT), a research model with six research hypotheses was proposed in this research. The research model was empirically tested with a sample of 203 users of online household e-waste collection services in China. The results indicated that five of the six research hypotheses were significantly supported. And the most significant determinant for the behavioral intention to use online household e-waste service was effort expectancy. However, facilitating condition did not have significant impact on users’ behavior of using online household e-waste collection services.

The Joint Probabilistic Data Association algorithm is one of the most widely used Data Association algorithm which can effectively finish multi-target tracking in clutter environment. But it will cause track coalescence phenomenon in parallel neighboring or small-angle crossing scene. For avoiding track coalescence, four modified Joint Probabilistic Data Association algorithms are introduced in this paper. Through Monte Carlo simulations, it is confirmed that these algorithms all can avoid this problem, but the tracking performances of these algorithms are different. So tracking performances of them in tracking precision, computation and anti-jamming ability are compared through simulation test, which can provide the basis for applying these new algorithms in practical.

A modified Joint Probabilistic Data Association algorithm is proposed in this paper to avoid track coalescence. Above all, an arbitrary positive scaling factor will be employed to multiply the maximum probabilities of every target associated with measurements. Then an exclusive measurement is defined for every target in the new algorithm, which is the maximum probability measurement associated with the target. The association probabilities of exclusive measurement with other targets except corresponding target are set at 0. At last, the association probabilities of every measurement will be given weights by means of the Entropy Value Method in the new algorithm. The simulation results show that the new algorithm can effectively solve the track coalescence problem in all kinds of scenarios and its track performance is better than the Joint Probabilistic Data Association algorithm's.

Joint Probabilistic Data Association has been proven to be effective in tracking multiple targets from measurements amidst clutter and missed detections. But the traditional Joint Probabilistic Data Association algorithm will cause track coalescence when the targets are parallel neighboring or small-angle crossing. To avoid track coalescence, a modified Joint Probabilistic Data Association algorithm is proposed in this paper. An exclusive measurement is defined for every target in the new algorithm, and an arbitrary positive scaling factor will be employed to multiply the maximum probabilities of every target associated with measurements. At last, the Entropy Value Method will be used twice to give weights to the association probabilities of every measurement. The simulation results show that the new algorithm can effectively avoid track coalescence in all kinds of scenarios and its performance is better than the track performance when the Entropy Value Method is used only one time.

In this study, the preparation of the novel imaging agents, folate receptor (FR)-targeted liposomes encapsulating hydrophilic CdTe quantum dots (QDs), and their use as luminescence probes for live cell imaging are reported. Hydrophilic CdTe QDs were directly synthesized in the water phase, and FR-targeted QD liposomes were prepared by hydrating the lipid thin film with CdTe suspension. Formulations were characterized by UV-visible and fluorescent measurements, liposomal particle size, and zeta potential. The targeting and imaging ability of FR-targeted liposomes were investigated against the human uterine cervix cancer cell line (HeLa). Furthermore, the cytotoxicity of QD liposomes was evaluated by HeLa cells incubated with FR-targeted QD liposomes, nontargeted QD liposomes, and free QDs. The results showed that FR-targeted QD liposomes were spherically shaped with high fluorescence yield, excellent photochemical stability, good cancer targeting, and minimal cytotoxicity. The average size of FR-targeted fluorescence liposomes was ~105 nm, and their size distribution was rather narrow. After storage at 4 degrees C for 11 months, QD liposomes maintained similar size and did not show any leakage of QDs. FR-targeted CdTe QD liposomes, which can target tumor cells via FR-mediated endocytosis, would become an attractive probe for tumor cell or tissue imaging for a long-time monitoring.

IMiDs immunomodulatory drugs, including lenalidomide and pomalidomide represent a novel class of small molecule anticancer and anti-inflammatory drugs with broad biologic activities. However, the molecular mechanism through which these drugs exert their effects is largely undefined. Using pomalidomide and primary human monocytes, we report that pomalidomide rapidly and selectively activated RhoA and Rac1, but not Cdc42 or Ras, in the absence of any costimulation. Consistent with the activation of Rho GTPases, we found that pomalidomide enhanced F-actin formation, stabilized microtubules, and increased cell migration, all of which were blocked by selective inhibitors of ROCK1 and Rac1. Further, we showed that in Swiss 3T3 cells, pomalidomide only activated RhoA, not Rac1 or Cdc42, and potently induced stress fiber formation. The pomalidomide effect on actin cytoskeleton was blocked by the ROCK1 inhibitor, but not Rac1 inhibitor. Finally, we demonstrated that pomalidomide was able to regulate the activity of Rho GTPases and the formation of F-actin in primary human T cells as it did in monocytes and showed that the activation of RhoA was essential for pomalidomide-induced interleukin-2 expression in T cells. These novel activities provide what we believe a critical mechanism by which IMiDs drugs function as therapeutic immunomodulatory agents.

The anti-inflammatory properties of aqueous extracts from Lonicera japonica (LJ) flower, an anti-inflammatory treatment in traditional Chinese medicine, were tested by radioimmunoassay of cyclooxygenase isoenzyme-generated prostaglandin E2 (PGE2) synthesis as well as by Western and Northern blot analysis of COX-2 protein and mRNA expression, respectively. Boiled LJ aqueous extracts directly inhibited both COX-1 and COX-2 activity, while non-boiled extracts stimulated COX-1. Boiled LJ extracts also inhibited expression of IL-1beta-induced COX-2 protein expression and suppressed its mRNA induction by IL-1beta in A549 cells. Suppression of COX-2 mRNA induction required a significantly higher dose of aqueous extract than did suppression of protein expression, indicating that compounds in the extract act translationally or post-translationally at lower doses and transcriptionally or post-transcriptionally at higher doses. Direct inhibition of COX isoenzymes as well as down-regulation of COX-2 mRNA and protein may represent the mechanism by which this ancient herbal treatment decreases inflammation.

Immunomodulatory drugs including the IMiDs®, lenalidomide, and pomalidomide represent a novel class of compounds that have both anti-cancer and anti-inflammatory properties. While many studies have demonstrated that IMiDs have broad in vitro and in vivo biological activities including antiangiogenesis, inhibition of TNFa expression, enhancement of antitumor immunity, and induction of IL-2 in T cells, the molecular mechanism through which these drugs exert their effects is largely undefined. In primary human monocytes, IMID1 selectively activated RhoA and Rac1, but not Cdc42 or Ras. Importantly, the activation of these GTPases occurred immediately following treatment with IMID1 in the absence of any costimulation. Consistent with the activation of Rho GTPases, we found that IMID1enhanced F-actin formation, stabilized microtubules, and increased monocyte cell migration, all of which were blocked by selective inhibitors of ROCK1, a downstream effector of RhoA or Rac1. Finally, we demonstrated that IMID1 was able to regulate the activity of Rho GTPases and formation of F-actin in primary human T cells similarly as it did in monocytes, and showed that the activation of RhoA was essential for IMID1-induced IL-2 expression in T cells. In conclusion, these studies demonstrate a novel and acute molecular activity from IMiDs mediated via Rho GTPases. Activation of Rho by IMiDs and the resulting effect on cytoskeletal reorganization may represent a critical mechanism by which IMiDs function as therapeutic immunomodulatory agents.