Search

This article presents simulation results on the effects of neutral gas flow for nanoparticle transport in atmospheric-pressure, radio-frequency (RF), capacitively-coupled, and acetylene discharge. The acetylene gas is set to flow into the chamber from the upper showerhead electrode. The internal energy of the gas medium therein is transferred into kinetic energy so the gas advection can be triggered. This is represented by the pressure volume work term of the gas energy converse equation. The gas advection leads to the gas temperature sink at the gas inlet, hence a large gas temperature gradient is formed. The thermophoresis relies on the gas temperature gradient, and causes the profile of nanoparticle density to vary from a double-peak structure to a single-peak one. The gas advection influences the properties of electron density and temperature as well and causes the DA mode profile of electron density asymmetric. In the bulk region, i.e., away from the inlet, the gas advection is more like one isovolumetric compression, which slightly increases the temperature of the gas medium at consuming its kinetic energy.

Supplemental Figure 2: STING agonists stimulate cytokines in tumor, plasma and peripheral tissues following IT dosing.

Supplementary Methods and Figures

Supplementary Figures - PDF file 1385K, File contains Supplementary figures of resistant cell lines, proliferation assay of a panel of cell lines, TdF binding assay transcriptional out and kinome selectivity

Supplemental Table 1: Log2Ratio and p values for all 310 genes shown in Figure 6

Imbalance of autonomic nerve is the cause of lots of cardiovascular and psychological diseases. Many studies have shown that Heart Rate Variability Biofeedback through respiratory training is an effective way to regulate the status of human autonomic nerves. However, due to the immature quantification of Respiratory Sinus Arrhythmia, the respiratory training process cannot be optimal personalized. In this paper, we propose the Cardiopulmonary Resonance Indices based on the Cardiopulmonary Coupling Model to calculate the personalized optimal breathing training frequency. Then the respiratory feedback training system is constructed to provide real-time audio-visual guidance for each subject. The results in the clinical trial of pregnant women in their third trimester showed that, compared to control group, with the intervention of personalized respiratory feedback training at home, pregnant women could stabilize their blood pressure and blood glucose, relieve mental stress, as well as exert positive effects on fetal development. This provides a new possibility of the autonomic imbalance treatment.

A two-dimensional multi-fluid model is developed to investigate the effects of dilution gas on microplasma properties and nanoparticle behavior in atmospheric-pressure radio-frequency acetylene discharges. The percentage of dilution gases (argon and helium) percentage varied from 0% to 90%, with the pressure kept constant. Simulation results show that the dilution gas percentage has a significant influence on the spatial distributions of the electron density and temperature, as well as on the formation of nanoparticles in acetylene microplasmas. With increasing dilution gas percentage, the electron density profile changes continuously from being high at the edge to high in the center. A mode transition from a mixed discharge mode with both α regime and drift-ambipolar regime into α regime occurs, which is associated with a sudden decrease in the electron density of the presheaths and an increase in the electron temperature of the bulk plasma. The mode transition point corresponds to the lowest number density ratio of hydrocarbon ions to acetylene. The highest number density ratio is observed at a dilution percentage of 90%, and causes more effective nucleation and coagulation of nanoparticles. Furthermore, owing to the high ionization potential of helium, the transition point moves to a larger dilution gas percentage in C 2 H 2 /He microplasmas. Finally, the growth of nanoparticles via coagulation is studied.

The innate immune agonist STING (STimulator of INterferon Genes) binds its natural ligand 2′3′-cGAMP (cyclic guanosine-adenosine monophosphate) and initiates type I IFN production. This promotes systemic antigen-specific CD8+ T-cell priming that eventually provides potent antitumor activity. To exploit this mechanism, we synthesized a novel STING agonist, MSA-1, that activates both mouse and human STING with higher in vitro potency than cGAMP. Following intratumoral administration of MSA-1 to a panel of syngeneic mouse tumors on immune-competent mice, cytokine upregulation and its exposure were detected in plasma, other tissues, injected tumors, and noninjected tumors. This was accompanied by effective antitumor activity. Mechanistic studies in immune-deficient mice suggested that antitumor activity of intratumorally dosed STING agonists is in part due to necrosis and/or innate immune responses such as TNF-α activity, but development of a robust adaptive antitumor immunity is necessary for complete tumor elimination. Combination with PD-1 blockade in anti–PD-1–resistant murine models showed that MSA-1 may synergize with checkpoint inhibitors but can also provide superior tumor control as a single agent. We show for the first time that potent cyclic dinucleotides can promote a rapid and stronger induction of the same genes eventually regulated by PD-1 blockade. This may have contributed to the relatively early tumor control observed with MSA-1. Taken together, these data strongly support the development of STING agonists as therapy for patients with aggressive tumors that are partially responsive or nonresponsive to single-agent anti–PD-1 treatment by enhancing the anti–PD-1 immune profile.

Information and Communication Technology (ICT) has improved education widely in China, transforming traditional teaching into an interactive one. It is important to build a new evaluation model to ...

Pregnant women at last trimester are prone to anxiety and depression, which could exert a long-term influence on both the mother and fetuses. Managing anxiety with Heart Rate Variability Biofeedback (HRVB) is possible mechanism for its fame to strengthen homeostasis via favorably altering the activity of the autonomic nervous system. In this study, we studied the effects of HRVB on pregnant women in late pregnancy by assessing the changes of blood pressure and analyzing the changes of heart rate variability (HRV) both in pregnant women and their fetuses. 20 pregnant women without pregnancy induced hypertension and diabetes were randomly assigned to the HRVB group and the control group. Participants in the HRVB group were asked to practice HRVB for 30 minutes, while participants in the control group were asked to collect 10 minutes of HRV data without training. HRV of pregnant women (PHRV) were collected during training, blood pressure and fetal HRV (FHRV) were collected at each pregnancy test. The trial ended when participants were hospitalized for childbirth. The results proved the HRVB to be an effective intervention to modulate BP and strengthen regulation ability of ANS both in pregnant women and fetuses.

Although the noninvasive continuous fetal heart rate (FHR) monitor is often recommended, the Doppler Ultrasonographic Cardiotocography (CTG) is improper for long-term monitor due to the less safety and the requirement of professional operation skill. In this paper, we design a noninvasive, continuous and real-time FHR monitoring system based on fetal phonocardiography by stationary wavelet denoising and cyclostationary process. Good agreement with CTG is obtained by Bland Altman analysis. Besides, quantitative results show that the FHR has an average accuracy of 97% compared with CTG on clinical data sets. The proposed system provides an alternative for CTG.

Chiral optical responses of bilayer metasurfaces made of twisted metallic nanorods are investigated in detail with focus on the collective effect due to lattice resonance (LR). Using an analytical approach based on the coupled dipole method (supported by full wave simulation), we find optical chirality is dramatically increased by the coupling between localized surface plasmon resonances and LR. The collective effect results in significant chiral signal even for metasurfaces made of achiral unit cells. The interlayer coupling generally destroys the Wood’s anomaly and the associated transparency. While making use of Pancharatnam–Berry (PB) phase and propagation phase, one can modulate the optical activity effectively and achieve chirality-selective transparency induced by LR in a designed structure with a g-factor of absorption as high as 1.99 (close to the upper limit of 2). Our studies not only reveal a new mechanism of modulating chiral optical response by combination effects from PB phase, propagation phase, and LR, but also give a quantitative relationship between the geometry configuration and chiral optical properties, thus providing helpful guidance for device design.

It is known that gas flow rate is a key factor in controlling industrial plasma processing. In this paper, a 2D PIC/MCC model is developed for an rf hollow cathode discharge with an axial nitrogen gas flow. The effects of the gas flow rate on the plasma parameters are calculated and the results show that: with an increasing flow rate, the total ion (N+2, N+) density decreases, the mean sheath thickness becomes wider, the radial electric field in the sheath and the axial electric field show an increase, and the energies of both kinds of nitrogen ions increase; and, as the axial ion current density that is moving toward the ground electrode increases, the ion current density near the ground electrode increases. The simulation results will provide a useful reference for plasma jet technology involving rf hollow cathode discharges in N2.

The high frequency of activating RAS or BRAF mutations in cancer provides strong rationale for targeting the mitogen-activated protein kinase (MAPK) pathway. Selective BRAF and MAP-ERK kinase (MEK) inhibitors have shown clinical efficacy in patients with melanoma. However, the majority of responses are transient, and resistance is often associated with pathway reactivation of the extracellular signal-regulated kinase (ERK) signaling pathway. Here, we describe the identification and characterization of SCH772984, a novel and selective inhibitor of ERK1/2 that displays behaviors of both type I and type II kinase inhibitors. SCH772984 has nanomolar cellular potency in tumor cells with mutations in BRAF, NRAS, or KRAS and induces tumor regressions in xenograft models at tolerated doses. Importantly, SCH772984 effectively inhibited MAPK signaling and cell proliferation in BRAF or MEK inhibitor–resistant models as well as in tumor cells resistant to concurrent treatment with BRAF and MEK inhibitors. These data support the clinical development of ERK inhibitors for tumors refractory to MAPK inhibitors. Significance: BRAF and MEK inhibitors have activity in MAPK-dependent cancers with BRAF or RAS mutations. However, resistance is associated with pathway alterations resulting in phospho-ERK reactivation. Here, we describe a novel ERK1/2 kinase inhibitor that has antitumor activity in MAPK inhibitor-naïve and MAPK inhibitor-resistant cells containing BRAF or RAS mutations. Cancer Discov; 3(7); 742–50. ©2013 AACR. See related commentary by Nissan et al., p. 719 This article is highlighted in the In This Issue feature, p. 705

Activated STING (STimulator of INterferon Genes) bound to its natural ligand 2,3-cGAMP (cyclic guanosine-adenosine monophosphate), initiates type I interferon (IFN) and pro-inflammatory cytokine production. IFN upregulation is essential to promote antigen-specific CD8+ T-cell priming and leads to potent anti-tumor activity. To exploit this mechanism we synthesized a new STING agonist, MSA-1, that potently activates both mouse and human STING. Intratumoral (IT) administration of MSA-1 to MC38 syngeneic tumor-bearing mice increased tumor and plasma cytokine levels and was effective at driving complete responses (CRs) in 100% of the animals. Most surviving animals developed tumor-specific adaptive immune memory as demonstrated by robust protection against re-challenge with the same tumor type. Mechanistic studies in immune-deficient mice suggested that the initial antitumor activity is in part due to cytokine-driven cytotoxicity and/or other innate immune mechanisms, which may have contributed to some animals not developing an adaptive immune memory. Importantly, MSA-1 caused long-term tumor regressions or CRs in CT26 and B16-F10 tumor models, both of which are intrinsically resistant to single-agent therapy with a fully murinized anti-mouse PD-1 antibody (muDX400). The antitumor immune response in these models was further enhanced when treating the animals with MSA-1 in combination with muDX400. This combination restored T-cell responses in both blood and tumors of the treated mice and provided long-lived immunologic memory in a majority of the animals. Taken together, these data strongly support the development of STING agonists in combination with Keytruda (humanized anti-PD-1 antibody) for patients with tumors that are partially responsive or nonresponsive to single agent anti-PD-1 therapy. Citation Format: Samanthi A. Perera, Johnny E. Kopinja, Yanhong Ma, Jason Laskey, Kalyan Chakravarthy, Long Cui, Yiping Chen, Jeremy Presland, Sharad Sharma, Shuxia Zhao, Jennifer Piesvaux, Ellen C. Minnihan, Heidi Ferguson, Hyun Chong Woo, Ian Knemeyer, Ilona Kariv, Archie Tse, Saso Cemerski, Jared Cumming, B. Wesley Trotter, Bo-Sheng Pan, George H. Addona, Brian J. Long. Combination with a novel STING agonist significantly improves efficacy of anti-PD1 therapy in mouse syngeneic tumor models [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A08.

The innate immune agonist STING (STimulator of INterferon Genes) binds its natural ligand 2'3'-cGAMP (cyclic guanosine-adenosine monophosphate) and initiates type I interferon production. This promotes systemic antigen-specific CD8+ T-cell priming that eventually provides potent anti-tumor activity. To exploit this mechanism we synthesized a novel STING agonist, MSA-1, that activates both mouse and human STING with higher in vitro potency than cGAMP. MSA-1 was administered to immune-competent mice bearing MC38 syngeneic tumors to monitor pharmacodynamics, pharmacokinetics and in vivo efficacy. Intratumoral (IT) dosed MSA-1 demonstrated robust tumor and plasma cytokine upregulation and effective anti-tumor activity. The highest tolerated doses provided complete responses (CRs) in 100% of MC38 tumors. Tumor models such as CT26 and B16-F10 that are intrinsically resistant to single-agent therapy with a fully murinized mouse anti-PD-1 antibody (mDX400) also demonstrated long-term tumor regressions or CRs. Mechanistic studies in immune-deficient mice suggested that anti-tumor activity of IT dosed STING agonists are in part due to cytotoxicity and/or innate immune responses rather than development of robust adaptive anti-tumor immunity. To enhance the adaptive immune response, we combined MSA-1 with mDX400 in mouse syngeneic tumor models previously characterized to be unresponsive to anti-PD-1 blockade. This combination restored T-cell responses in both blood and tumors of the treated mice and provided long-lived immunologic memory in a majority of the animals. Taken together, these data strongly support the development of STING agonists in combination with Keytruda for patients with tumors that are partially responsive or non-responsive to single agent anti-PD-1 therapy. Citation Format: Samanthi A. Perera, Johnny E. Kopinja, Yanhong Ma, Jason Laskey, Kalyan Chakravarthy, Yiping Chen, Long Cui, Jeremy Presland, Shuxia Zhao, Ellen Minnihan, Heidi Ferguson, Jennifer Piesvaux, Bo-Sheng Pan, Hyun Chong Woo, Ian Knemeyer, Saso Cemerski, Jared Cumming, Wesley Trotter, Archie Tse, George H. Addona, Brian J. Long. Combining STING agonists with an anti-PD-1 antagonist results in marked antitumor activity in immune-excluded tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4721.

Polycythemia vera (PV) is a myeloproliferative disorder characterized by increased red cell mass and splenomegaly in the absence of secondary causes [Tefferi A., Spivak J.L., Polycythemia vera: scientific advances and current practice. Semin Hematol 2005;42(4):206-20.]. Recently, several laboratories have discovered that the vast majority of patients with PV carry a single, activating mutation (V617F) in the pseudokinase domain of Janus kinase 2 (Jak2) [Zhao R, Xing S, Li Z, Fu X, Li Q, Krantz SB, et al., Identification of an acquired JAK2 mutation in polycythemia vera. J Biol Chem 2005;280(24):22788-92; James C, Ugo V, Le Couedic JP, Staerk J, Delhommeau F, Lacout C, et al., A unique clonal JAK2 mutation leading to constitutive signalling causes polycythemia vera. Nature 2005;434(7037):1144-8; Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, et al., A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 2005;352(17):1779-90; Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, et al., Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 2005;7(4):387-97.]. This discovery has spurred interest in developing therapies for PV via inhibition of Jak2. We induced polycythemia in mice by administering high dose recombinant erythropoietin (Epo) and determined that administration recapitulates almost all of the major and minor diagnostic features of human PV. We then tested a selective, small molecule inhibitor of Jak2 (Jak2i) and showed that this treatment prevents polycythemia. This prevention of polycythemia was accompanied by lower hematocrits, reduced spleen sizes and reductions in Stat5 phosphorylation (pStat5). Surprisingly, Epo rapidly (

Meeting abstracts LAG-3 has been shown to act as an inhibitory molecule involved in the regulation of T cell activation, proliferation and homeostasis. Exhausted T cell populations that evolve in the tumor microenvironment or during chronic viral infections show coordinated expression of LAG-3 and

Mutations in the human ether-a-gogo-related gene (HERG) K(+) channel gene cause chromosome 7-linked long QT syndrome type 2 (LQT2), which is characterized by a prolonged QT interval in the electrocardiogram and an increased susceptibility to life-threatening cardiac arrhythmias. LQT2 mutations produce loss-of-function phenotypes and reduce I(Kr) currents either by the heteromeric assembly of non- or malfunctioning channel subunits with wild type subunits at the cell surface or by retention of misprocessed mutant HERG channels in the endoplasmic reticulum. Misprocessed mutations often encode for channel proteins that are functional upon incorporation into the plasma membrane. As a result the pharmacological correction of folding defects and restoration of protein function are of considerable interest. Here we report that the trafficking-deficient pore mutation HERG G601S was rescued by a series of HERG channel blockers that increased cell surface expression. Rescue by these pharmacological chaperones varied directly with their blocking potency. We used structure-activity relationships and site-directed mutagenesis to define the binding site of the pharmacological chaperones. We found that binding occurred in the inner cavity and correlated with hydrophobicity and cationic charge. Rescue was domain-restricted because the trafficking of two misprocessed mutations in the C terminus, HERG F805C and HERG R823W, was not restored by channel blockers. Our findings represent a first step toward the design of pharmacological chaperones that will rescue HERG K(+) channels without block.

En route to their target, pioneering motor growth cones repeatedly encounter choice points at which they make pathway decisions. In the zebrafish mutant unplugged, two of the three segmental motor axons make incorrect decisions at a somitic choice point. Using positional cloning, we show here that unplugged encodes a homolog of muscle-specific kinase (MuSK) and that, unlike mammalian MuSK, unplugged has only a limited role in neuromuscular synaptogenesis. We demonstrate that unplugged is transiently expressed in cells adjacent to the choice point and that unplugged signaling before the arrival of growth cones induces changes in the extracellular environment. In addition, we find that the unplugged locus generates three different transcripts. The splice variant 1 (SV1) isoform lacks the extracellular modules essential for agrin responsiveness, and signaling through this isoform mediates axonal pathfinding, independent of the MuSK downstream component rapsyn. Our results demonstrate a new role for MuSK homologs in axonal pathway selection.

A high percentage of patients with the myeloproliferative disorder polycythemia vera (PV) harbor a Val617→Phe activating mutation in the Janus kinase 2 (JAK2) gene, and both cell culture and mouse models have established a functional role for this mutation in the development of this disease. We describe the properties of MRLB-11055, a highly potent inhibitor of both the WT and V617F forms of JAK2, that has therapeutic efficacy in erythropoietin (EPO)-driven and JAK2V617F-driven mouse models of PV. In cultured cells, MRLB-11055 blocked proliferation and induced apoptosis in a manner consistent with JAK2 pathway inhibition. MRLB-11055 effectively prevented EPO-induced STAT5 activation in the peripheral blood of acutely dosed mice, and could prevent EPO-induced splenomegaly and erythrocytosis in chronically dosed mice. In a bone marrow reconstituted JAK2V617F-luciferase murine PV model, MRLB-11055 rapidly reduced the burden of JAK2V617F-expressing cells from both the spleen and the bone marrow. Using real-time in vivo imaging, we examined the kinetics of disease regression and resurgence, enabling the development of an intermittent dosing schedule that achieved significant reductions in both erythroid and myeloid populations with minimal impact on lymphoid cells. Our studies provide a rationale for the use of non-continuous treatment to provide optimal therapy for PV patients.

Splenic enlargement (splenomegaly) develops in numerous disease states, although a specific pathogenic role for the spleen has rarely been described. In polycythemia vera (PV), an activating mutation in Janus kinase 2 (JAK2(V617)) induces splenomegaly and an increase in hematocrit. Splenectomy is sparingly performed in patients with PV, however, due to surgical complications. Thus, the role of the spleen in the pathogenesis of human PV remains unknown. We specifically tested the role of the spleen in the pathogenesis of PV by performing either sham (SH) or splenectomy (SPL) surgeries in a murine model of JAK2(V617F)-driven PV. Compared to SH-operated mice, which rapidly develop high hematocrits after JAK2(V617F) transplantation, SPL mice completely fail to develop this phenotype. Disease burden (JAK2(V617)) is equivalent in the bone marrow of SH and SPL mice, however, and both groups develop fibrosis and osteosclerosis. If SPL is performed after PV is established, hematocrit rapidly declines to normal even though myelofibrosis and osteosclerosis again develop independently in the bone marrow. In contrast, SPL only blunts hematocrit elevation in secondary, erythropoietin-induced polycythemia. We conclude that the spleen is required for an elevated hematocrit in murine, JAK2(V617F)-driven PV, and propose that this phenotype of PV may require a specific interaction between mutant cells and the spleen.

Polycythemia vera (PV) is a myeloproliferative disorder involving hematopoietic stem cells. A recurrent somatic missense mutation in JAK2 (JAK2V617F) is thought to play a causal role in PV. Therefore, targeting Jak2 will likely provide a molecular mechanism-based therapy for PV. To facilitate the development of such new and specific therapeutics, a suitable and well-characterized preclinical animal model is essential. Although several mouse models of PV have been reported, the spatiotemporal kinetics of PV formation and progression has not been studied. To address this, we created a bone marrow transplant mouse model that co-expresses mutant Jak2 and luciferase 2 (Luc2) genes. Bioluminescent imaging (BLI) was used to visualize disease cells and analyze the kinetics of PV development in vivo. To better understand the molecular mechanism of PV, we generated mice carrying a kinase inactive mutant Jak2 (Jak2K882E), demonstrating that the PV disease was dependent on constitutive activation of the Jak2 kinase activity. We further showed that the Jak2V617F mutation caused increased stem cell renewal activity and impaired cell differentiation, which was at least in part due to deregulated transcriptional programming. The Jak2V617F–Luc2 PV mice will be a useful preclinical model to characterize novel JAK2 inhibitors for the treatment of PV.