Towards dynamical network biomarkers in neuromodulation of episodic migraine

Computational methods have complemented experimental and clinical neursciences and led to improvements in our understanding of the nervous systems in health and disease. In parallel, neuromodulation in form of electric and magnetic stimulation is gaining increasing acceptance in chronic and intractable diseases. In this paper, we firstly explore the relevant state of the art in fusion of both developments towards translational computational neuroscience. Then, we propose a strategy to employ the new theoretical concept of dynamical network biomarkers (DNB) in episodic manifestations of chronic disorders. In particular, as a first example, we introduce the use of computational models in migraine and illustrate on the basis of this example the potential of DNB as early-warning signals for neuromodulation in episodic migraine.Comment: 13 pages, 5 figure

Surface micromachining via solid electrochemical reaction on oxide ion conductors

We propose a simple and novel route for the surface microstructuring of tough materials (glassy carbon, SiC, W and Mo) through a solid electrochemical reaction at a microcontact between the oxide ion conductor and target substrate. More specifically, the surface of materials was locally oxidized by an anodic electrochemical reaction with the oxide ion conductor via the microcontact under a dc bias. Since the oxidation products of the targets were gaseous or sublimable, a fine-patterned surface was obtained as a result of the continuous consumption of the oxidation products formed at the microcontact. The success of the proposed method may stimulate such conventional applications of oxide ion conductors

The origin of infra-slow oscillations of oxygenated hemoglobin observed in functional near-infrared spectroscopy

There is increasing interest in the intrinsic activity of the resting brain, especially the activity slower than 0.1Hz (i.e., low-frequency oscillations, or LFOs). To investigate the origin of LFOs observed in functional near-infrared spectroscopy (fNIRS), we recorded multichannel fNIRS and electroencephalography (EEG) from the frontal cortex of 11 healthy young volunteers in the resting state. Electrocardiography (ECG), electro-oculography and respiration were also measured. Synchronous oscillations of oxy-hemoglobin (oxy-Hb) around 1.0Hz were detected in all fNIRS channels, and their frequency was consistent with a peak frequency of ECG, suggesting the changes of cerebral blood flow due to heart beats. In addition, oxy-Hb oscillations around 0.1Hz (i.e., LFOs) appeared in the fNIRS. The channels where LFOs appeared differed among the subjects, and the LFOs appeared or disappeared even in the same fNIRS channels. The appearance of LFOs in fNIRS channels was significantly higher when the LFOs appeared on the EEG in the adjacent EEG electrodes compared to when LFOs did not appear on EEG. The amplitude and coherence (synchronicity) of the LFOs were increased by changing the subjects' position from dorsal to the sitting position in both fNIRS and EEG, and the coherence in particular was increased in the homologous fNIRS channels on the bilateral hemispheres. These results suggest that LFOs of oxy-Hb couple with resting-state EEG activity

The Earth Effect in the MSW Analysis of the Solar Neutrino Experiments

We consider the Earth effect in the MSW analysis of the Homestake, Kamiokande, GALLEX, and SAGE solar neutrino experiments. Using the time-averaged data and assuming two-flavor oscillations, the large-angle region of the combined fit extends to much smaller angles (to $\sin^22\theta \simeq 0.1$) than when the Earth effect is ignored. However, the additional constraint from the Kamiokande II day-night data excludes most of the parameter space sensitive to the Earth effect independent of astrophysical uncertainties, and leaves only a small large-angle region close to maximal mixing at 90\% C.L. The nonadiabatic solution remains unaffected by the Earth effect and is still preferred. Both theoretical and experimental uncertainties are included in the analysis.Comment: (11 pages, Revtex 3.0 (can be changed to Latex), 3 postscript figures included, UPR-0570T

TUMOR MARKERS IN BONE MARROW IN PATIENTS WITH PROSTATIC CANCER

We compared prostatic specific acid phosphatase (PAP), prostatic specific antigen (PA) and γ-seminoprotein (γ-SM) levels between bone marrow and serum for the purpose of assessing of the usefulness of these tumor markers in early detection of bone metastasis in cases with prostatic cancer. Thirty-three patients were entered into this study. Of the patients, 20 had prostatic cancer including 11 with bone metastasis, and 13 patients had benign prostatic hypertrophy (BPH) served as controls. It seemed unlikely that bone marrow PAP, PA and γ-SM are more useful than their serum levels for detection of bone metastasis of prostatic cancer. Because correlation between bone marrow and serum levels of each marker was observed not only in cases with prostate cancer accompanied by bone metastasis but also in metastasis-free prostatic cancer and BPH cases, it seems likely that PAP, PA and γ-SM in bone marrow circulate from peripheral blood rather than from bone metastasis of prostatic cancer

Solar Model Uncertainties, MSW Analysis, and Future Solar Neutrino Experiments

Various theoretical uncertainties in the standard solar model and in the Mikheyev-Smirnov-Wolfenstein (MSW) analysis are discussed. It is shown that two methods of estimating the solar neutrino flux uncertainties are equivalent: (a) a simple parametrization of the uncertainties using the core temperature and the nuclear production cross sections; (b) the Monte Carlo method of Bahcall and Ulrich. In the MSW analysis, we emphasize proper treatments of correlation of theoretical uncertainties between flux components and between different detectors, the Earth effect, and multiple solutions in a combined $\chi^2$ procedure. The MSW solutions for various standard and nonstandard solar models are also shown. The MSW predictions of the global solutions for the future solar neutrino experiments are given, emphasizing the measurement of the energy spectrum and the day-night effect in Sudbury Neutrino Observatory and Super-Kamiokande to distinguish the two solutions.Comment: (Revtex 3.0, 43 pages + 26 figures (uuencoded ps files attached), Easy way: ps files of entire text with embedded figures available by anonymous ftp://upenn5.hep.upenn.edu/pub/hata/papers/msw_analysis.u

Significant effect of polymorphisms in CYP2D6 and ABCC2 on clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients

Purpose The clinical efficacy of tamoxifen is suspected to be influenced by the activity of drug-metabolizing enzymes and transporters involved in the formation, metabolism, and elimination of its active forms. We investigated relationships of polymorphisms in transporter genes and CYP2D6 to clinical outcome of patients receiving tamoxifen. Patients and Methods We studied 282 patients with hormone receptor–positive, invasive breast cancer receiving tamoxifen monotherapy, including 67 patients who have been previously reported. We investigated the effects of allelic variants of CYP2D6 and haplotype-tagging single nucleotide polymorphisms (tag-SNPs) of ABCB1, ABCC2, and ABCG2 on recurrence-free survival using the Kaplan-Meier method and Cox regression analysis. Plasma concentrations of tamoxifen metabolites were measured in 98 patients receiving tamoxifen 20 mg/d. Results CYP2D6 variants were significantly associated with shorter recurrence-free survival (P = .000036; hazard ratio [HR] = 9.52; 95% CI, 2.79 to 32.45 in patients with two variant alleles v patients without variant alleles). Among 51 tag-SNPs in transporter genes, a significant association was found at rs3740065 in ABCC2 (P = .00017; HR = 10.64; 95% CI, 1.44 to 78.88 in patients with AA v GG genotypes). The number of risk alleles of CYP2D6 and ABCC2 showed cumulative effects on recurrence-free survival (P = .000000055). Patients carrying four risk alleles had 45.25-fold higher risk compared with patients with ≤ one risk allele. CYP2D6 variants were associated with lower plasma levels of endoxifen and 4-hydroxytamoxifen (P = .0000043 and .00052), whereas no significant difference was found among ABCC2 genotype groups. Conclusion Our results suggest that polymorphisms in CYP2D6 and ABCC2 are important predictors for the prognosis of patients with breast cancer treated with tamoxifen

RUNX1 transactivates BCR-ABL1 expression in Philadelphia chromosome positive acute lymphoblastic leukemia

The emergence of tyrosine kinase inhibitors as part of a front-line treatment has greatly improved the clinical outcome of the patients with Ph⁺ acute lymphoblastic leukemia (ALL). However, a portion of them still become refractory to the therapy mainly through acquiring mutations in the BCR-ABL1 gene, necessitating a novel strategy to treat tyrosine kinase inhibitor (TKI)-resistant Ph⁺ ALL cases. In this report, we show evidence that RUNX1 transcription factor stringently controls the expression of BCR-ABL1, which can strategically be targeted by our novel RUNX inhibitor, Chb-M'. Through a series of in vitro experiments, we identified that RUNX1 binds to the promoter of BCR and directly transactivates BCR-ABL1 expression in Ph⁺ ALL cell lines. These cells showed significantly reduced expression of BCR-ABL1 with suppressed proliferation upon RUNX1 knockdown. Moreover, treatment with Chb-M' consistently downregulated the expression of BCR-ABL1 in these cells and this drug was highly effective even in an imatinib-resistant Ph⁺ ALL cell line. In good agreement with these findings, forced expression of BCR-ABL1 in these cells conferred relative resistance to Chb-M'. In addition, in vivo experiments with the Ph⁺ ALL patient-derived xenograft cells showed similar results. In summary, targeting RUNX1 therapeutically in Ph⁺ ALL cells may lead to overcoming TKI resistance through the transcriptional regulation of BCR-ABL1. Chb-M' could be a novel drug for patients with TKI-resistant refractory Ph⁺ ALL