Robust Surface States and Coherence Phenomena in Magnetically Alloyed SmB_{6}.

Samarium hexaboride is a candidate for the topological Kondo insulator state, in which Kondo coherence is predicted to give rise to an insulating gap spanned by topological surface states. Here we investigate the surface and bulk electronic properties of magnetically alloyed Sm_{1-x}M_{x}B_{6} (M=Ce, Eu), using angle-resolved photoemission spectroscopy and complementary characterization techniques. Remarkably, topologically nontrivial bulk and surface band structures are found to persist in highly modified samples with up to 30% Sm substitution and with an antiferromagnetic ground state in the case of Eu doping. The results are interpreted in terms of a hierarchy of energy scales, in which surface state emergence is linked to the formation of a direct Kondo gap, while low-temperature transport trends depend on the indirect gap.

Development of a core outcome set for cutaneous squamous cell carcinoma trials: identification of core domains and outcomes.

BACKGROUND: The lack of uniformity in the outcomes reported in clinical studies of the treatment of cutaneous squamous cell carcinoma (cSCC) complicates efforts to compare treatment effectiveness across trials. OBJECTIVES: To develop a core outcome set (COS), a minimum set of agreed-upon outcomes to be measured in all clinical trials of a given disease or outcome, for the treatment of cSCC. METHODS: One hundred and nine outcomes were identified via a systematic literature review and interviews with 28 stakeholders. After consolidation of this long list, 55 candidate outcomes were rated by 19 physician and 10 patient stakeholders, in two rounds of Delphi exercises. Outcomes scored 'critically important' (score of 7, 8 or 9) by ≥ 70% of patients and ≥ 70% of physicians were provisionally included. At the consensus meeting, after discussion and voting of 44 international experts and patients, the provisional list was reduced to a final core set, for which consensus was achieved among all meeting participants. RESULTS: A core set of seven outcomes was finalized at the consensus meeting: (i) serious or persistent adverse events, (ii) patient-reported quality of life, (iii) complete response, (iv) partial response, (v) recurrence-free survival, (vi) progression-free survival and (vii) disease-specific survival. CONCLUSIONS: In order to increase the comparability of results across trials and to reduce selective reporting bias, cSCC researchers should consider reporting these core outcomes. Further work needs to be performed to identify the measures that should be reported for each of these outcomes.

Application of emitter-sample hybrid terahertz time-domain spectroscopy to investigate temperature-dependent optical constants of doped InAs.

We investigate temperature-dependent carrier dynamics of InAs crystal by using reflection-type terahertz time-domain spectroscopy, particularly with a recently developed emitter-sample hybrid structure. We successfully obtain the optical conductivity in a terahertz frequency of bulk InAs whose dc conductivity is in the range of 100-150 Ω-1 cm-1. We find that both real and imaginary parts of the optical conductivity can be fit well with the simple Drude model, and the free-carrier density and the scattering rate obtained from the fit are in good agreement with corresponding values obtained by using other techniques, such as the Hall measurement and the dc-resistivity measurement. These results clearly demonstrate that the proposed technique of adopting the emitter-sample hybrid structure can be exploited to determine temperature-dependent optical constants in a reflection geometry and hence to investigate electrodynamics of bulk metallic systems.

Effect of the gel elasticity of model skin matrices on the distance/depth-dependent transmission of vibration energy supplied from a cosmetic vibrator.

OBJECTIVE: The purpose of this study was to determine how the energies supplied from a cosmetic vibrator are deeply or far transferred into organs and tissues, and how these depths or distances are influenced by tissue elasticity. METHODS: External vibration energy was applied to model skin surfaces through a facial cleansing vibrator, and we measured a distance- and depth-dependent energy that was transferred to model skin matrices. As model skin matrices, we synthesized hard and soft poly(dimethylsiloxane) (PDMS) gels, as well as hydrogels with a modulus of 2.63 MPa, 0.33 MPa and 21 kPa, respectively, mostly representing those of skin and other organs. The transfer of vibration energy was measured either by increasing the separation distances or by increasing the depth from the vibrator. RESULTS: The energies were transmitted deeper into the hard PDMS than into the soft PDMS and hydrogel matrices. This finding implies that the vibration forces influence a larger area of the gel matrices when the gels are more elastic (or rigid). There were no appreciable differences between the soft PDMS and hydrogel matrices. However, the absorbed energies were more concentrated in the area closest to the vibrator with decreasing elasticity of the matrix. Softer materials absorbed most of the supplied energy around the point of the vibrator. In contrast, harder materials scattered the external energy over a broad area. CONCLUSIONS: The current results are the first report in estimating how the external energy is deeply or distantly transferred into a model skins depending on the elastic moduli of the models skins. In doing so, the results would be potentially useful in predicting the health of cells, tissues and organs exposed to various stimuli.

Observation of Orbital Order in the Half-Filled 4f Gd Compound.

Half-filled electron systems, even with the maximized spin angular moment, have been given little attention because of their zero-orbital angular moment according to Hund's rule. Nevertheless, there are several measurements that show evidence of a nonzero orbital moment as well as spin-orbit coupling. Here we report for the first time the orbital order in a half-filled 4f-electron system GdB_{4}, using the resonant soft x-ray scattering at Gd M_{4,5}-edges. Furthermore, we discovered that the development of this orbital order is strongly coupled with the antiferromagnetic spin order. These results clearly demonstrate that even in half-filled electron systems the orbital angular moment can be an important parameter to describe material properties, and may provide significant opportunities for tailoring new correlated electron systems.

Electronic Structure of YbB_{6}: Is it a Topological Insulator or Not?

To finally resolve the controversial issue of whether or not the electronic structure of YbB_{6} is nontrivially topological, we have made a combined study using angle-resolved photoemission spectroscopy (ARPES) of the nonpolar (110) surface and density functional theory (DFT). The flat-band conditions of the (110) ARPES avoid the strong band bending effects of the polar (001) surface and definitively show that YbB_{6} has a topologically trivial B 2p-Yb 5d semiconductor band gap of ∼0.3 eV. Accurate determination of the low energy band topology in DFT requires the use of a modified Becke-Johnson exchange potential incorporating spin-orbit coupling and an on-site Yb 4f Coulomb interaction U as large as 7 eV. The DFT result, confirmed by a more precise GW band calculation, is similar to that of a small gap non-Kondo nontopological semiconductor. Additionally, the pressure-dependent electronic structure of YbB_{6} is investigated theoretically and found to transform into a p-d overlap semimetal with small Yb mixed valency.

A SCAR marker for the analysis of chloroplast DNA from different cultivars of Cornus officinalis.

The aims of this study were to establish a random amplified polymorphic DNA (RAPD) fingerprint database of chloroplast DNA (cpDNA) from different cultivars of Cornus officinalis and to convert RAPD markers to sequence characterized amplified regions (SCAR) markers. A method of extraction was established that was suitable for obtaining cpDNA from samples rapidly dried in silicone; an RAPD fingerprint database was built; and the genetic distance between samples was used as statistical clustering variables for calculating DICE genetic similarity coefficients and for building a kinship tree chart. RAPD markers were converted to SCAR markers to design specific primers, and samples from C. officinalis cultivars, plants of the same family, and its adulterants, were used for amplification and identification. Fifteen amplified primers with stable polymorphisms were screened for amplification of 130 copies of materials. In total, 57 sites were achieved, 40 of which were polymorphic, and the polymorphic rate was up to 70.18%. A genetic tree was built based on seven cultivars. SCAR markers of C. officinalis cpDNA were successfully converted into RAPD markers. cpDNA samples from hawthorn, C. officinalis, Cornus wood, and grape were used for SCAR amplification, and their bands were distinctly different. In conclusion, SCAR markers and cpDNA may be used for research on C. officinalis and its adulterants, and the results may provide a basis for identifying germplasm and screening fine varieties at a molecular level.

Importance of charge fluctuations for the topological phase in SmB(6).

Typical Kondo insulators (KIs) can have a nontrivial Z_{2} topology because the energy gap opens at the Fermi energy (E_{F}) by a hybridization between odd- and even-parity bands. SmB_{6} deviates from such KI behavior, and it has been unclear how the insulating phase occurs. Here, we demonstrate that charge fluctuations are the origin of the topological insulating phase in SmB_{6}. Our angle-resolved photoemission spectroscopy results reveal that with decreasing temperature the bottom of the d-f hybridized band at the X[over ¯] point, which is predicted to have odd parity and is required for a topological phase, gradually shifts from below to above E_{F}. We conclude that SmB_{6} is a charge-fluctuating topological insulator.

Sorafenib in patients with metastatic gastrointestinal stromal tumors who failed two or more prior tyrosine kinase inhibitors: a phase II study of Korean gastrointestinal stromal tumors study group.

PURPOSE: To evaluated the efficacy and safety of sorafenib in patients with advanced gastrointestinal stromal tumors (GIST) who failed to previous standard treatments. EXPERIMENTAL DESIGN: Thirty-one patients with measurable metastatic GIST who failed both imatinib and sunitinib were accrued. Sorafenib was administered orally at 400 mg twice daily until disease progression or development of intolerance. The primary endpoint was disease control rate (response + stable disease, DCR) at 24 weeks. RESULTS: Sorafenib was well tolerated, with hand-foot skin reaction, fatigue, hypertension, and abdominal pain being the most frequent adverse events. The relative dose intensity of sorafenib during the first 6 months was >80%. Four patients achieved partial response (response rate 13%, 95% CI 1-25%), and 16 (52%) had stable disease. DCR at 24 weeks was measured as 36% (95% CI 19-52%). Median progression-free and overall survivals were 4.9 and 9.7 months, respectively. Progression-free survival of patients with prior use of nilotinib (P = .0085) and with primary genotypes other than KIT exon 11 mutation (P = .0341) was significantly shorter than that of patients without. CONCLUSIONS: Sorafenib showed antitumor activity in this population of imatinib and sunitinib pretreated GIST. With sorafenib, about one third of patients can maintain disease control for more than 24 weeks.

A systematic review of autologous adipose-derived stromal vascular fraction (SVF) for the treatment of acute cutaneous wounds.

BACKGROUND: Stromal vascular fraction (SVF), derived enzymatically or mechanically from adipose tissue, contains a heterogenous population of cells and stroma, including multipotent stem cells. The regenerative capacity of SVF may potentially be adapted for a broad range of clinical applications, including the healing of acute cutaneous wounds. OBJECTIVE: To evaluate the available literature on the efficacy and safety of autologous adipose-derived stromal vascular fraction (SVF) for the treatment of acute cutaneous wounds in humans. METHODS: A systematic review of the literature utilizing MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials was performed to identify published clinical trials of autologous adipose-derived SVF or similar ADSC-containing derivatives for patients with acute cutaneous wounds. This was supplemented by searches for ongoing clinical trials through ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform. RESULTS: 872 records were initially retrieved. Application of inclusion and exclusion criteria yielded 10 relevant studies: two completed non-randomized controlled trials and eight ongoing clinical trials. Both completed studies reported a statistically significant benefit in percentage re-epithelialization and time to healing for the SVF treatment arms. Safety information for SVF was not provided. Ongoing clinical trials were assessing outcomes such as safety, patient and observer reported scar appearance, wound healing rate, and wound epithelization. CONCLUSION: In the context of substantial limitations in the quantity and quality of available evidence, the existing literature suggests that SVF may be a useful treatment for acute cutaneous wounds in humans. More clinical trials with improved outcome measures and safety assessment are needed.

Systemic human Netrin-1 gene delivery by adeno-associated virus type 8 alters leukocyte accumulation and atherogenesis in vivo.

Atherosclerosis is an inflammatory disorder of arteries. Atherosclerotic plaque, in its early to intermediate stages, is composed largely of lipid-engorged foam cells. These foam cells are derived from the trafficking of monocytes (Mo) into the arterial intima, attracted to the site by chemoattractants. Given that foam cells are derived from the trafficking of Mo, the use of Netrin-1, an Mo chemorepellent, may be useful in limiting Mo accumulation and subsequent plaque formation. To investigate the potential of Netrin-1 for limiting atherosclerosis, we systemically delivered its human (h) cDNA by adeno-associated virus type 8 (AAV8, single-stranded structure) delivery into low-density lipoprotein receptor knockout (LDLR-/-) mice and placed the animals on a high cholesterol diet (HCD). Compared with control neomycin resistance (Neo) gene delivery/HCD, hNetrin-1 delivery resulted in a significant reduction in plaque formation, as determined by larger aortic lumen size, thinner intima-media thickness and lower blood velocity than the Neo/HCD control (all statistically significant). Indices of monocyte/macrophage (Mo/MΦ) accumulation, CD68, integrin, alpha M (ITGAM) and egf-like module containing, mucin-like, hormone receptor-like 1 (EMR-1), were reduced in hNetrin-1/HCD-treated animal's aortas and spleens compared with Neo/HCD-treated animals. Unexpectedly, CD25 and foxp3 (regulatory T cells (Tregs)) in the aorta were strongly upregulated. This is the first time the Mo/MΦ chemorepellent approach, and specific Netrin-1 gene delivery, has been performed for the reduction of Mo/MΦ burden and atherosclerosis. In addition, Netrin-1 has never before been linked to altered Treg levels. These data strongly suggest that hNetrin-1 gene delivery can reduce Mo/MΦ accumulation, inflammation and subsequent plaque formation.

Quadrupolar ordering and exotic magnetocaloric effect in RB4 (R = Dy, Ho).

The interplay of charge, spin, orbital and lattice degrees of freedom has recently received great interest due to its potential to improve the magnetocaloric effect (MCE) for the purpose of magnetic cooling applications. Here, a new mechanism for a large entropy change with low magnetic fields in rare-earth tetraborides, especially for Ho1-xDyxB4 (x = 0.0, 0.5, and 1.0), is proposed. For x = 0.0, 0.5, and 1.0, the maximum entropy changes of the giant inverse MCE are found to be 22.7 J/kgK, 19.6 J/kgK, and 19.0 J/kgK with critical fields of 25 kOe, 40 kOe, and 50 kOe, respectively. For all compounds, systematic study on how the entropy changes as a function of the field and temperature is performed to investigate their correlation with consecutive double transitions, i.e., the magnetic dipolar order at T = TN and the quadrupolar order at T = TQ (TQ < TN). Based on Landau theory, it is found that this behaviour is attributed to the strong coupling between magnetic dipoles and quadrupoles in the presence of strong spin-orbit coupling and geometric frustration. Our work offers new insights into both academic and industrial interests in the discovery of giant MCE with various applications for magnetic cooling systems.

Regulation of M2-type pyruvate kinase mediated by the high-affinity IgE receptors is required for mast cell degranulation.

BACKGROUND AND PURPOSE: M2-type pyruvate kinase (M2PK) was found to interact directly with the 'ITAM' region of the gamma chain of the high-affinity IgE receptor (FcvarepsilonRI). Our hypothesis was that mast cell degranulation might require the FcvarepsilonRI-mediated inhibition of M2PK activity. EXPERIMENTAL APPROACH: In rat basophilic leukaemia (RBL-2H3) cells, the effects of directly inhibiting M2PK or preventing the FcvarepsilonRI-mediated inhibition of M2PK (disinhibition) on degranulation was measured by hexosaminidase release. Effects of blocking the FcvarepsilonRI-mediated inhibition of M2PK was also assessed in vivo in a mouse model of allergen-induced airway hyper-responsiveness. KEY RESULTS: Activation of FcvarepsilonRI in RBL-2H3 cells caused the rapid phosphorylation of tyrosine residues in M2PK, associated with a decrease in M2PK enzymatic activity. There was an inverse correlation between M2PK activity and mast cell degranulation. FcvarepsilonRI-mediated inhibition of M2PK involved Src kinase, phosphatidylinositol 3-kinase, PKC and calcium. Direct inhibition of M2PK potentiated FcvarepsilonRI-mediated degranulation and prevention of the FcvarepsilonRI-mediated inhibition of M2PK attenuated mast cell degranulation. Transfection of RBL-2H3 cells with M1PK which prevents FcvarepsilonRI-induced inhibition of M2PK, markedly reduced their degranulation and exogenous M1PK (i.p.) inhibited ovalbumin-induced airway hyper-responsiveness in vivo. CONCLUSIONS AND IMPLICATIONS: We have identified a new control point and a novel biochemical pathway in the process of mast cell degranulation. Our study suggests that the FcvarepsilonRI-mediated inhibition of M2PK is a crucial step in responses to allergens. Moreover, the manipulation of glycolytic processes and intermediates could provide novel strategies for the treatment of allergic diseases.

Matching DMFT calculations with photoemission spectra of heavy fermion insulators: universal properties of the near-gap spectra of SmB6.

Paramagnetic heavy fermion insulators consist of fully occupied quasiparticle bands inherent to Fermi liquid theory. The gap emergence below a characteristic temperature is the ultimate sign of coherence for a many-body system, which in addition can induce a non-trivial band topology. Here, we demonstrate a simple and efficient method to compare a model study and an experimental result for heavy fermion insulators. The temperature dependence of the gap formation in both local moment and mixed valence regimes is captured within the dynamical mean field (DMFT) approximation to the periodic Anderson model (PAM). Using the topological coherence temperature as the scaling factor and choosing the input parameter set within the mixed valence regime, we can unambiguously link the theoretical energy scales to the experimental ones. As a particularly important result, we find improved consistency between the scaled DMFT density of states and the photoemission near-gap spectra of samarium hexaboride (SmB6).

Genetically engineered fibroblasts with antigen-presenting capability: efficient induction of an antigen-specific cytotoxic T-lymphocyte response and protection against tumor development in vivo.

BLK mouse fibroblasts (H-2b) were genetically engineered to express costimulatory B7.1 and interleukin-2 (BLK/IL2/B7.1). The BLK/IL2/B7.1 cells were then pulsed with an ovalbumin (OVA) epitope as a model antigen (Ag) (BLK/IL2/B7.1/OVA), and tested for the induction of OVA-specific cytotoxic T lymphocytes (CTLs) in C57BL/6 mice (H-2b). The genetically engineered fibroblasts lacking one or two of three factors (interleukin-2, B7.1, and OVA) were constructed and used as controls. Immunization with the BLK/IL2/B7.1/OVA cells induced strong cytotoxic activities against OVA-expressing EL4 (EG7) tumor cells, but not against other H-2b tumor cells, such as EL4, C1498 and B16F1 cells. The magnitude of the cytotoxic response in mice with the BLK/IL2/B7.1/OVA cells was significantly higher than the response in mice immunized with any other cell constructs. CD8+ T cells with OVA-specific cytotoxic activities were predominant in mice immunized with the BLK/IL2/B7.1/OVA cells. Furthermore, immunization with the BLK/IL2/B7.1/OVA cells significantly prolonged the survival of mice, compared with any other cell constructs, when the mice were challenged with EG7 tumor cells at 2 weeks postimmunization. Induction of antitumoral CTL immunity by the BLK/IL2/B7.1/OVA cells was independent of host Ag-presenting cells and of CD4+ T-cell and natural killer 1.1+ cell help. These results suggest that fibroblasts can be genetically modified to efficient Ag-presenting cells for the induction of an Ag-specific CTL response.

Inhibition of interleukin-12 production in lipopolysaccharide-activated mouse macrophages by parthenolide, a predominant sesquiterpene lactone in Tanacetum parthenium: involvement of nuclear factor-kappaB.

Pharmacological control of interleukin-12 (IL-12) production may be a key therapeutic strategy for modulating immunological diseases dominated by type-1 cytokine responses. In this study, we investigated the effects of parthenolide, an anti-inflammatory sesquiterpene, on the production of IL-12 from mouse macrophages stimulated with lipopolysaccharide (LPS). Parthenolide potently inhibited the LPS-induced IL-12 production in a dose-dependent manner. The effect of parthenolide on IL-12 p40 promoter activation was analyzed by transfecting RAW264.7 monocytic cells with p40 promoter/luciferase constructs. The repressive effect mapped to a region in the p40 promoter containing a binding site for nuclear factor-kappaB (p40-kappaB). Furthermore, activation of macrophages by LPS resulted in markedly enhanced binding activity to the kappaB site, which significantly decreased upon addition of parthenolide. These results suggest that parthenolide-induced inhibition of IL-12 production in macrophages may explain some of the biological effects of parthenolide including its anti-inflammatory activity.

Chloromethyl ketones inhibit interleukin-12 production in mouse macrophages stimulated with lipopolysaccharide.

Interleukin-12 (IL-12) plays a pivotal role in the development of T-helper type 1 (Th1) immune response, which may be involved in the pathogenesis of chronic inflammatory autoimmune disorders. In this study, we investigated the effects of N-alpha-tosyl-L-phenylalanine chloromethyl ketone (TPCK) and N-alpha-tosyl-L-lysine chloromethyl ketone (TLCK), serine protease inhibitors, on the production of IL-12 from macrophages stimulated with lipopolysaccharide (LPS). TPCK and TLCK potently inhibited this LPS-induced IL-12 production in a dose-dependent manner. The effect of TPCK and TLCK on the IL-12 p40 promoter activation was analyzed by transfecting monocytic RAW264.7 cells with p40 promoter-reporter constructs. The repressive effect maps to a region in the p40 promoter containing a binding site for NFkappaB (p40-kappaB). A linker scan mutant of the p40-kappaB site abrogates the inhibitory effect on the p40 promoter, confirming the functional relevance of the NFkappaB site. Our results show that TPCK and TLCK inhibit NFkappaB-mediated IL-12 production in macrophages. reserved.

Inhibition of interleukin-12 production by auranofin, an anti-rheumatic gold compound, deviates CD4(+) T cells from the Th1 to the Th2 pathway.

1. Interleukin-12 (IL-12) may play a central role in the development and progression of rheumatoid arthritis by driving the immune response towards T helper 1 (Th1) type responses characterized by high IFN-gamma and low IL-4 production. In this study we investigated the effect of auranofin (AF), an anti-rheumatic gold compound, on IL-12 production in mouse macrophages and dendritic cells, and studied whether AF-mediated inhibition of IL-12 production could regulate a cytokine profile of antigen (Ag)-primed CD4(+) Th cells. 2. Treatment with AF significantly inhibited IL-12 production in lipopolysaccharide (LPS)-stimulated macrophages and also in CD40L-stimulated dendritic cells. AF-pretreated macrophages reduced their ability to induce IFN-gamma and increased the ability to induce IL-4 in Ag-primed CD4(+) T cells. AF did not influence the cell surface expression of the class II MHC molecule and the costimulatory molecules CD80 and CD86. 3. Addition of recombinant IL-12 to cultures of AF-pretreated macrophages and CD4(+) T cells restored IFN-gamma production in Ag-primed CD4(+) T cells. 4. The in vivo administration of AF resulted in the inhibition of IL-12 production by macrophages stimulated in vitro with LPS or heat-killed Listeria monocytogenes (HKL), leading to the inhibition of Th1 cytokine profile (decreased IFN-gamma and increased IL-4 production) in Ag-primed CD4(+) T cells. 5. These findings may explain some known effects of AF including anti-rheumatic effects and the inhibition of encephalitogenicity, and point to a possible therapeutic use of AF in the Th1-mediated immune diseases such as autoimmune diseases.

Retinoid-mediated inhibition of interleukin-12 production in mouse macrophages suppresses Th1 cytokine profile in CD4(+) T cells.

Interleukin-12 (IL-12) plays a central role in the immune system by driving the immune response towards T helper 1 (Th1) type responses characterized by high IFN-gamma and low IL-4 production. In this study we investigated whether retinoid-mediated inhibition of interleukin-12 production in mouse macrophages could regulate cytokine profile of antigen (Ag)-primed CD4(+) Th cells. Pretreatment with retinoids (9-cis-RA, all-trans-RA, TTNPB) significantly inhibited IL-12 production by mouse macrophages stimulated with lipopolysaccharide (LPS) or heated-killed Listeria monocytogenes (HKL). Retinoid-pretreated macrophages reduced their ability to induce IFN-gamma and increased the ability to induce IL-4 in Ag-primed CD4(+) T cells. Addition of recombinant IL-12 to cultures of retinoid-pretreated macrophages and CD4(+) T cells restored IFN-gamma production in CD4(+) T cells. The in vivo administration of 9-cis-RA resulted in the inhibition of IL-12 production by macrophages stimulated in vitro with either LPS or HKL, leading to the inhibition of Th1 cytokine profile (decreased IFN-gamma and increased IL-4 production) in CD4(+) T cells. These findings may explain some known effects of retinoids including the inhibition of encephalitogenicity, and point to a possible therapeutic use of retinoids in the Th1-mediated immune diseases such as autoimmune diseases.