Possible mechanism of action potential propagation mediated by static electric field: A novel assumption of understanding nerve interaction and ephaptic coupling.

The generation and propagation of physical signals in living biosystems are continuous issues. Traditional Hodgkin-Huxley model based on ionic current conduction could not explain the fast transmission of action potential in myelinated axons and factors influencing action potential velocity. We propose that the ion flow induced by N a v channel generates near field quasi-static electric field at extracellular space, termed as an ephaptic field which is able to excite nearby passive axons. Our simulation indicates that the static electric field produced by sodium ion channels in one node of Ranvier is improbable to stimulate the ion channels in the adjacent neighboring node. However, the ion channel ring in one node of Ranvier could induce the shift of membrane potential (0.01 mV) on the node at nearby axons (100 µm) in a bundle of axon synchronously, suggesting zig-zag propagation of action potential. Together with the superposition effect of ephaptic feedback field generated by the synchronized movement of adjacent parallel axons stimulate the adjacent node of the original axon, strengthen the action potential to travel in a zig-zag pattern. Our model also provides an explanation for the rapid velocity of action potential propagation reported in experimental studies.

Impaired calcium influx underlies skewed T helper cell differentiation in children with IgE-mediated food allergies.

BACKGROUND: Reasons for Th2 skewing in IgE-mediated food allergies remains unclear. Clinical observations suggest impaired T cell activation may drive Th2 responses evidenced by increased atopic manifestations in liver transplant patients on tacrolimus (a calcineurin inhibitor). We aimed to assess differentiation potential, T cell activation and calcium influx of naïve CD4+ T cells in children with IgE-mediated food allergies. METHODS: Peripheral blood mononuclear cells from infants in the Starting Time for Egg Protein (STEP) Trial were analyzed by flow cytometry to assess Th1/Th2/Treg development. Naïve CD4+ T cells from children with and without food allergies were stimulated for 7 days to assess Th1/Th2/Treg transcriptional factors and cytokines. Store operated calcium entry (SOCE) was measured in children with and without food allergies. The effect of tacrolimus on CD4+ T cell differentiation was assessed by treating stimulated naïve CD4+ T cells from healthy volunteers with tacrolimus for 7 days. RESULTS: Egg allergic infants had impaired development of IFNγ+ Th1 cells and FoxP3+ transitional CD4+ T cells compared with non-allergic infants. This parallels reduced T-bet, IFNγ and FoxP3 expression in naïve CD4+ T cells from food allergic children after in vitro culture. SOCE of naïve CD4+ T cells was impaired in food allergic children. Naïve CD4+ T cells treated with tacrolimus had reduced IFNγ, T-bet, and FoxP3, but preserved IL-4 expression. CONCLUSIONS: In children with IgE-mediated food allergies, dysregulation of T helper cell development is associated with impaired SOCE, which underlies an intrinsic impairment in Th1 and Treg differentiation. Along with tacrolimus-induced Th2 skewing, this highlights an important role of SOCE/calcineurin pathway in T helper cell differentiation.

Depressive Symptoms in Newly Diagnosed Lung Carcinoma: Prevalence and Associated Risk Factors.

BACKGROUND: Depression is a recognized complication of lung cancer underreported in developing countries such as Malaysia. Treating and identifying depression in cancer patients increases survival and quality of life. Our objectives are to study prevalence of depressive symptoms in newly diagnosed lung carcinoma, and examine the relationship of depressive symptoms with other influencing risk factors. METHODS: A 2-year, cross sectional study February 2015-February 2017, was conducted at Hospital Tengku Ampuan Afzan, and Penang General Hospital. One hundred and three patients with newly diagnosed, biopsy confirmed primary lung carcinoma were recruited. Self-rated patient's identification sheet, validated Center for Epidemiologic Studies Depression (CES-D), and Dukes University Religion Index score from three different main languages were used. RESULTS: Prevalence of current depressive symptoms (CES-D total score ≥16) is 37.9%. The result suggests prevalence of those at high risk of moderate to major depression, may need treatment. Multivariate analysis reveals those with good Eastern Cooperation Oncology Group factor (η2=0.24, p<0.001) married (η=0.14, p<0.001) with intrinsic religiosity (IR) (η=0.07, p<0.02) are more resistant to depression. CONCLUSION: One in three of lung carcinoma patients, are at increased risk for depression. Clinicians should be aware that risk is highest in those with poor performance status, single, and with poor IR. We suggest routine screening of depression symptoms as it is feasible, to be performed during a regular clinic visit with immediate referral to psychiatrist when indicated.

Mutational Signatures in Mandibular Ameloblastoma Correlate with Smoking.

Ameloblastoma is a rare tumor of odontogenic epithelium, the low incidence rate of which precludes statistical determination of its molecular characterizations. Despite recent genomic and transcriptomic profiling, the etiology of ameloblastomas remains poorly understood. Risk factors of ameloblastoma development are also largely unknown. Whole exome sequencing was performed on 11 mandibular ameloblastoma samples. We identified 2 convergent mutational signatures in ameloblastoma: 1) a signature found in multiple types of lung cancers with probable etiology of tobacco carcinogens (COSMIC signature 4) and 2) a signature present in gingivobuccal oral squamous cell carcinoma and correlated with tobacco-chewing habits (COSMIC signature 29). These mutational signatures highlight tobacco usage or related mutagens as one possible risk factor of ameloblastoma, since the association of BRAF mutations and smoking was demonstrated in multiple studies. In addition to BRAF hotspot mutations (V600E), we observed clear inter- and intratumor heterogeneities. Interestingly, prior to BRAF mutation, important genes regulating odontogenesis mutated (e.g., corepressor BCOR), possibly playing important roles in tumorigenesis. Furthermore, recurrent mutations in the CDC73 gene, the germline mutations of which predispose patients to the development of jaw tumors, were found in 2 patients, which may lead to recurrence if not targeted by therapeutic drugs. Our unbiased profiling of coding regions of ameloblastoma genomes provides insights to the possible etiology of mandibular ameloblastoma and highlights potential disease risk factors for screening and prevention, especially for Asian patients. Because of the limited sample size and incomplete habitual, dietary, and occupational data, a causal link between tobacco usage and ameloblastoma still requires further investigations.

Identification of chronic obstructive pulmonary disease subgroups in 13 Asian cities.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a heterogeneous condition that can differ in its clinical manifestation, structural changes and response to treatment. OBJECTIVE: To identify subgroups of COPD with distinct phenotypes, evaluate the distribution of phenotypes in four related regions and calculate the 1-year change in lung function and quality of life according to subgroup. METHODS: Using clinical characteristics, we performed factor analysis and hierarchical cluster analysis in a cohort of 1676 COPD patients from 13 Asian cities. We compared the 1-year change in forced expiratory volume in one second (FEV1), modified Medical Research Council dyspnoea scale score, St George's Respiratory Questionnaire (SGRQ) score and exacerbations according to subgroup derived from cluster analysis. RESULTS: Factor analysis revealed that body mass index, Charlson comorbidity index, SGRQ total score and FEV1 were principal factors. Using these four factors, cluster analysis identified three distinct subgroups with differing disease severity and symptoms. Among the three subgroups, patients in subgroup 2 (severe disease and more symptoms) had the most frequent exacerbations, most rapid FEV1 decline and greatest decline in SGRQ total score. CONCLUSION: Three subgroups with differing severities and symptoms were identified in Asian COPD subjects.

Oncogenic activation of JAK3-STAT signaling confers clinical sensitivity to PRN371, a novel selective and potent JAK3 inhibitor, in natural killer/T-cell lymphoma.

Aberrant activation of the JAK3-STAT signaling pathway is a characteristic feature of many hematological malignancies. In particular, hyperactivity of this cascade has been observed in natural killer/T-cell lymphoma (NKTL) cases. Although the first-in-class JAK3 inhibitor tofacitinib blocks JAK3 activity in NKTL both in vitro and in vivo, its clinical utilization in cancer therapy has been limited by the pan-JAK inhibition activity. To improve the therapeutic efficacy of JAK3 inhibition in NKTL, we have developed a highly selective and durable JAK3 inhibitor PRN371 that potently inhibits JAK3 activity over the other JAK family members JAK1, JAK2, and TYK2. PRN371 effectively suppresses NKTL cell proliferation and induces apoptosis through abrogation of the JAK3-STAT signaling. Moreover, the activity of PRN371 has a more durable inhibition on JAK3 compared to tofacitinib in vitro, leading to significant tumor growth inhibition in a NKTL xenograft model harboring JAK3 activating mutation. These findings provide a novel therapeutic approach for the treatment of NKTL.

Miniaturized power limiter metasurface based on Fano-type resonance and Babinet principle.

In this work, we present a miniaturize power limiter, a device with size smaller than that required by the working frequency, made of coupled self-complementary electric inductive-capacitive (CELC) resonator and original electric inductive-capacitive (ELC) structure. We also make use of Babinet principle to ensure both CELC and ELC are resonating at the same frequency. The CELC structure is loaded with a Schottky diode to achieve the effect of a nonlinear power limiter. The constructive interference of CELC and ELC structure produces a new Fano-type resonance peak at a lower frequency. The Fano peak is sharp and able to concentrate electric field at a region between the inner and outer metallic patch of the metastructure, hence enhancing the nonlinear properties of the loaded diode. The Fano peak enhances the maximum isolation of the power limiter due to the local field enhancement at where the diode is loaded. Numerical simulation and experiment are conducted in the S-band frequency to verify the power limiting effect of the device designed and to discuss the formation of Fano peak. The power limiter designed has a maximum isolation of 8.4 dB and a 3-dB isolation bandwidth of 6%.

JAK-STAT and G-protein-coupled receptor signaling pathways are frequently altered in epitheliotropic intestinal T-cell lymphoma.

Epitheliotropic intestinal T-cell lymphoma (EITL, also known as type II enteropathy-associated T-cell lymphoma) is an aggressive intestinal disease with poor prognosis and its molecular alterations have not been comprehensively characterized. We aimed to identify actionable easy-to-screen alterations that would allow better diagnostics and/or treatment of this deadly disease. By performing whole-exome sequencing of four EITL tumor-normal pairs, followed by amplicon deep sequencing of 42 tumor samples, frequent alterations of the JAK-STAT and G-protein-coupled receptor (GPCR) signaling pathways were discovered in a large portion of samples. Specifically, STAT5B was mutated in a remarkable 63% of cases, JAK3 in 35% and GNAI2 in 24%, with the majority occurring at known activating hotspots in key functional domains. Moreover, STAT5B locus carried copy-neutral loss of heterozygosity resulting in the duplication of the mutant copy, suggesting the importance of mutant STAT5B dosage for the development of EITL. Dysregulation of the JAK-STAT and GPCR pathways was also supported by gene expression profiling and further verified in patient tumor samples. In vitro overexpression of GNAI2 mutants led to the upregulation of pERK1/2, a member of MEK-ERK pathway. Notably, inhibitors of both JAK-STAT and MEK-ERK pathways effectively reduced viability of patient-derived primary EITL cells, indicating potential therapeutic strategies for this neoplasm with no effective treatment currently available.

Haem oxygenase 1 expression is associated with prognosis in cholangiocarcinoma patients and with drug sensitivity in xenografted mice.

OBJECTIVE: Haem oxygenase-1 (HO-1) plays important roles in cytoprotection and tumour growth. Cholangiocarcinoma (CCA) is a deadly malignancy with very poor prognosis. The role of HO-1 in tumour progression in CCA up to now has been relatively unexplored, thus, its possible therapeutic implications in CCA have been investigated here. MATERIALS AND METHODS: HO-1 expression in tumour tissues from 50 CCA patients was determined by immunohistochemical analysis and its association with survival time was evaluated using the Kaplan-Meier method. Its role in CCA cells in vitro was evaluated by transwell and wound healing assays and suppression of HO-1 expression by siRNA. Effects of HO-1 inhibition on gemicitabine (GEM)-mediated tumour suppression was evaluated in nude mice xenografted with CCA cells. RESULTS: HO-1 expression was inversely associated with median overall survival time. Hazard ratio of patients with high HO-1 expression was 2.42 (95% CI: 1.16-5.08) with reference to low expression and HO-1 knock-down expression inhibited transwell cell migration. Suppression of HO-1 by Zn-protoporphyrin (ZnPP) enhanced cytotoxicity to GEM in CCA cells, validated in CCA xenografts. Treatment with GEM and ZnPP almost completely arrested tumour growth, whereas treatment with only a single reagent, retarded it. Tumour inhibition was associated with reduction in expression of Ki-67 and microvascular density, and enhanced p53 and p21 immunohistochemical staining. CONCLUSION: High HO-1 expression was associated with poor prognosis of CCA. Synergistic role of HO-1 inhibition in chemotherapy of CCA is a promising insight for treatment of this tumour and warrants further investigation.

Note: electrical detection and quantification of Spin Rectification Effect enabled by shorted microstrip transmission line technique.

We describe a shorted microstrip method for the sensitive quantification of Spin Rectification Effect (SRE). SRE for a Permalloy (Ni80Fe20) thin film strip sputtered onto SiO2 substrate is demonstrated. Our method obviates the need for simultaneous lithographic patterning of the sample and transmission line, therefore greatly simplifying the SRE measurement process. Such a shorted microstrip method can allow different contributions to SRE (anisotropic magnetoresistance, Hall effect, and anomalous Hall effect) to be simultaneously determined. Furthermore, SRE signals from unpatterned 50 nm thick Permalloy films of area dimensions 5 mm × 10 mm can even be detected.

Transmutation of planar media singularities in a conformal cloak.

Invisibility cloaking based on optical transformation involves materials singularity at the branch cut points. Many interesting optical devices, such as the Eaton lens, also require planar media index singularities in their implementation. We show a method to transmute two singularities simultaneously into harmless topological defects formed by anisotropic permittivity and permeability tensors. Numerical simulation is performed to verify the functionality of the transmuted conformal cloak consisting of two kissing Maxwell fish eyes.

First experimental demonstration of an isotropic electromagnetic cloak with strict conformal mapping.

In the past years quasi-conformal mapping has been generally used to design broadband electromagnetic cloaks. However, this technique has some inherit practical limitations such as the lateral beam shift, rendering the device visible or difficult to hide a large object. In this work we circumvent these issues by using strict conformal mapping to build the first isotropic cloak. Microwave near-field measurement shows that our device (with dielectric constant larger than unity everywhere) has a very good cloaking performance and a broad frequency response. The present dielectric approach could be technically extended to the fabrication of other conformal devices at higher frequencies.

Far field free-space measurement of three dimensional hole -in -Teflon invisibility cloak.

In this paper, we report a fabrication of a three-dimensional (3D) carpet cloak that works for any polarization in free space. Two-dimensional (2D) conformal mapping is first employed and the 3D structure is generated by a rotation of the 2D cloak. The structure of the cloak is hole-in-dielectric. The triangular invisible region has a height of 36 mm (one third of the height of the whole device) and a width of 240 mm. The cloaking effect is examined in free space by measuring the scattering parameters. The results show our device has very good cloaking performance in a wide frequency range from 4 to 10 GHz.

Overexpression of microRNA-21 regulating PDCD4 during tumorigenesis of liver fluke-associated cholangiocarcinoma contributes to tumor growth and metastasis.

MicroRNA, an endogenous noncoding RNA modulating gene expression, is a key molecule that by its dysregulation plays roles in inflammatory-driven carcinogenesis. This study aimed to investigate the role of oncomiR miR-21 and its target, the programmed cell death 4 (PDCD4) in tumor growth and metastasis of the liver fluke Opisthorchis viverrini-associated cholangiocarcinoma (CCA). The expression levels of miR-21 and PDCD4 were analyzed using the TaqMan miRNA expression assay and immunohistochemistry in liver tissues of both O. viverrini plus N-nitrosodimethylamine (NDMA)-treated hamsters and human CCA samples (n=23 cases). The functional assay for miR-21 was performed in CCA cell lines by the anti-miR-21 and pre-miR-21 transfection procedures. The peak of miR-21 levels were reached at 2 (hyperplastic lesions) and 6 (CCA) months of the O. viverrini plus NDMA-induced group and had a reverse response with its target PDCD4 proteins. In human CCA, miR-21 was overexpressed in tumor tissues when compared with nontumor tissues (P=0.0034) and had a negative correlation with PDCD4 protein (P=0.026). It was also found that high expression of miR-21 was significantly correlated with shorter survival (P<0.05) and lymph node metastasis (P=0.037) of CCA patients. Transient transfection of pre-miR-21 reduced the PDCD4 level and resulted in an increase of M213 CCA cell growth and wound-induced migration ability. These results indicated that miR-21 plays a role in the carcinogenesis and metastasis of O. viverrini-associated CCA by suppressing the function of PDCD4. Modulation of aberrantly expressed miR-21 may be a useful strategy to inhibit tumor cell phenotypes or improve response to chemotherapy.

Anomalous temperature dependence of magnetic anisotropy in gradient-composition sputterred thin films.

An abnormal behavior of increasing magnetic anisotropy with temperature in magnetic thin films fabricated by a gradient-composition sputtering technique is observed and consistently confirmed by two independent measurements of static magnetic hysteresis loops and dynamic magnetic permeability spectra. This peculiar behavior is suggested to be due to the physical origin of stress-induced magnetic anisotropy.

Exchange coupling driven omnidirectional rotatable anisotropy in ferrite doped CoFe thin film.

Isotropic magnetic materials with high resonant frequencies are useful for applications in microwave devices. Undoped CoFe thin films, as common soft magnetic materials with high saturation magnetization, show isotropic characteristics but no high frequency response. Here, we use ferrite doped CoFe thin film to realize a resonant frequency higher than 4.5 GHz at all orientations. The exchange coupling between ferrimagnet and ferromagnet is assumed to play a key role on the omnidirectional rotatable anisotropy.

Cutaneous side-effects of epidermal growth factor receptor-tyrosine kinase inhibitor (TKI) in the treatment of lung cancer: description and its management.

Epidermal growth factor receptor (EGFR)--tyrosine kinase inhibitors (TKI) like erlotinib and gefitinib have been approved as monotherapy for the treatment of patients with locally advanced or metastatic non small cell lung cancer (NSCLC) after failure of at least one prior chemotherapy regimen. The use of EGFR-TKI is associated with unique and dramatic dermatologic side effects. We report 2 patients with NSCLC developing a typical acneiform (papulo-pustular) eruption shortly after initiation of EGFR-TKI.

Electromagnetic field attractor made of gradient index metamaterials.

We present a device that is designed with varying permittivity ε(r) such that an electromagnetic wave in the K-band of the microwave regime entering it will bend inward towards the core. The core is made of silicon composites. We follow the distribution formula of the permittivity for the device derived by Narimanov and Kildishev using the optical-mechanical analogy. The diameter of the device is 14 cm, and it is constructed out of 21 rings of two different types of etched printed circuit boards, as well as dielectric powders as adding filling materials. The experimental wave intensity profile, based on parallel plate measurements for the cases where the incident plane wave is slightly displaced to the top of the center of the device and the case of on center incidence, are presented and discussed. In spite of some mismatch of the core and metamaterial structures of the device found, approximately 80% of the wave still manages to reach the core of the device and gets trapped and absorbed. Broadband properties of the device are also investigated.

Experimental demonstration of subwavelength domino plasmon devices for compact high-frequency circuit.

In optical frequency, surface plasmons of metal provide us a prominent way to build compact photonic devices or circuits with non-diffraction limit. It is attributed by their extraordinary electromagnetic confining effect. But in the counterpart of lower frequencies, plasmonics behavior of metal is screened by eddy current induced in a certain skin depth. To amend this, spoof plasmons engineered by artificial structures have been introduced to mimic surface plasmons in these frequencies. But it is less useful for practical application due to their weak field confinement as manifested by large field decaying length in the upper dielectric space. Recently, a new type of engineered plasmons, domino plasmon was theoretically proposed to produce unusual field confinement and waveguiding capabilities that make them very attractive for ultra-compact device applications [Opt. Exp. 18, 754-764 (2010)]. In this work, we implemented these ideas and built three waveguiding devices based on domino plasmons. Their strong capabilities to produce versatile and ultra-compact devices with multiple electromagnetic functions have been experimentally verified in microwaves. And that can be extended to THz regime to pave the way for a new class of integrated wave circuits.

Temperature dependence dynamical permeability characterization of magnetic thin film using near-field microwave microscopy.

A temperature dependence characterization system of microwave permeability of magnetic thin film up to 5 GHz in the temperature range from room temperature up to 423 K is designed and fabricated as a prototype measurement fixture. It is based on the near field microwave microscopy technique (NFMM). The scaling coefficient of the fixture can be determined by (i) calibrating the NFMM with a standard sample whose permeability is known; (ii) by calibrating the NFMM with an established dynamic permeability measurement technique such as shorted microstrip transmission line perturbation method; (iii) adjusting the real part of the complex permeability at low frequency to fit the value of initial permeability. The algorithms for calculating the complex permeability of magnetic thin films are analyzed. A 100 nm thick FeTaN thin film deposited on Si substrate by sputtering method is characterized using the fixture. The room temperature permeability results of the FeTaN film agree well with results obtained from the established short-circuited microstrip perturbation method. Temperature dependence permeability results fit well with the Landau-Lifshitz-Gilbert equation. The temperature dependence of the static magnetic anisotropy H(K)(sta), the dynamic magnetic anisotropy H(K)(dyn), the rotational anisotropy H(rot), together with the effective damping coefficient α(eff), ferromagnetic resonance f(FMR), and frequency linewidth Δf of the thin film are investigated. These temperature dependent magnetic properties of the magnetic thin film are important to the high frequency applications of magnetic devices at high temperatures.