Hitomi X-Ray Studies of Giant Radio Pulses from the Crab Pulsar

To search for giant X-ray pulses correlated with the giant radio pulses (GRPs) from the Crab pulsar, we performed a simultaneous observation of the Crab pulsar with the X-ray satellite Hitomi in the 2300 keV band and the Kashima NICT radio telescope in the 1.41.7 GHz band with a net exposure of about 2 ks on 2016 March 25, just before the loss of the Hitomi mission. The timing performance of the Hitomi instruments was confirmed to meet the timing requirement and about 1000 and 100 GRPs were simultaneously observed at the main pulse and inter-pulse phases, respectively, and we found no apparent correlation between the giant radio pulses and the X-ray emission in either the main pulse or inter-pulse phase. All variations are within the 2 fluctuations of the X-ray fluxes at the pulse peaks, and the 3 upper limits of variations of main pulse or inter-pulse GRPs are 22% or 80% of the peak flux in a 0.20 phase width, respectively, in the 2300 keV band. The values for main pulse or inter-pulse GRPs become 25% or 110%, respectively, when the phase width is restricted to the 0.03 phase. Among the upper limits from the Hitomi satellite, those in the 4.510 keV and 70300 keV bands are obtained for the first time, and those in other bands are consistent with previous reports. Numerically, the upper limits of the main pulse and inter-pulse GRPs in the 0.20 phase width are about (2.4 and 9.3) 10(exp 11) erg cm(exp 2), respectively. No significant variability in pulse profiles implies that the GRPs originated from a local place within the magnetosphere. Although the number of photon-emitting particles should temporarily increase to account for the brightening of the radio emission, the results do not statistically rule out variations correlated with the GRPs, because the possible X-ray enhancement may appear due to a >0.02% brightening of the pulse-peak flux under such conditions

Aberrant Methylation Inactivates Somatostatin and Somatostatin Receptor Type 1 in Head and Neck Squamous Cell Carcinoma

<div><p>Purpose</p><p>The aim of this study was to define somatostatin (<i>SST</i>) and somatostatin receptor type 1 (<i>SSTR1</i>) methylation profiles for head and neck squamous cell carcinoma (HNSCC) tumors at diagnosis and follow up and to evaluate their prognostic significance and value as a biomarker.</p><p>Methods</p><p>Gene expression was measured by quantitative RT-PCR. Promoter methylation status was determined by quantitative methylation-specific PCR (Q-MSP) in HNSCC.</p><p>Results</p><p>Methylation was associated with transcription inhibition. <i>SST</i> methylation in 81% of HNSCC tumor specimens significantly correlated with tumor size (<i>P</i> = 0.043), stage (<i>P</i> = 0.008), galanin receptor type 2 (<i>GALR2</i>) methylation (<i>P</i> = 0.041), and tachykinin-1 (<i>TAC1</i>) (<i>P</i> = 0.040). <i>SSTR1</i> hypermethylation in 64% of cases was correlated with tumor size (<i>P</i> = 0.037), stage (<i>P</i> = 0.037), <i>SST</i> methylation (<i>P</i> < 0.001), and expression of <i>galanin</i> (<i>P</i> = 0.03), <i>GALR2</i> (<i>P</i> = 0.014), <i>TAC1</i> (<i>P</i> = 0.023), and tachykinin receptor type 1 (<i>TACR1</i>) (<i>P</i> = 0.003). <i>SST</i> and <i>SSTR1</i> promoter hypermethylation showed highly discriminating receiver operator characteristic curve profiles, which clearly distinguished HNSCC from adjacent normal mucosal tissues. Concurrent hypermethylation of <i>galanin</i> and <i>SSTR1</i> promoters correlated with reduced disease-free survival (log-rank test, <i>P</i> = 0.0001). Among patients with oral cavity and oropharynx cancer, methylation of both <i>SST</i> and <i>SSTR1</i> promoters correlated with reduced disease-free survival (log-rank test, P = 0.028). In multivariate logistic-regression analysis, concomitant methylation of <i>galanin</i> and <i>SSTR1</i> was associated with an odds ratio for recurrence of 12.53 (95% CI, 2.62 to 59.8; <i>P</i> = 0.002).</p><p>Conclusions</p><p>CpG hypermethylation is a likely mechanism of <i>SST</i> and <i>SSTR1</i> gene inactivation, supporting the hypothesis that <i>SST</i> and <i>SSTR1</i> play a role in the tumorigenesis of HNSCC and that this hypermethylation may serve as an important biomarker.</p></div

Odds ratios for recurrence based on multivariate logistic-regression adjusted for stage (I, II, III vs. IV), age (65 and older vs. <65), sex, alcohol exposure, and smoking status.

<p>Methylation of <i>SSTR1</i> and <i>galanin</i> in the primary tumor was associated with the most significant odds ratios of recurrence.</p

Hypermethylation patterns in matched pairs of head and neck tumors and adjacent normal mucosal tissues.

<p><b>(A)</b><i>SST</i> NMVs of head and neck tumors were significantly higher than those of paired adjacent normal mucosal tissues (<i>P</i> < 0.001). <b>(B)</b> A higher frequency and quantity of <i>SSTR1</i> methylation was noted in head and neck tumors than in matched normal mucosal tissues (<i>P</i> < 0.01). <b>(C)</b> The area under the ROC curve (AUROC) value for the <i>SST</i> gene was 0.9375. At the cutoff value of 0.046, sensitivity was 80.6% and specificity was 94.4%. <b>(D)</b> The AUROC value for the <i>SSTR1</i> gene was 0.9522. At the cutoff value of 0.012, sensitivity was 61.1% and specificity was 100%.</p

Diagrammatic representation of <i>SST</i> methylation analysis by quantitative-MSP, expression analysis by quantitative-RT-PCR, and bisulfite sequencing analysis in UM-SCC cell lines.

<p><b>(A)</b> Relative mRNA expression of <i>SST</i> revealed lower expression in cancer cell lines than in normal fibroblasts (<i>P</i> < 0.01). The housekeeping gene <i>GAPDH</i> was run as a control for RNA integrity. <b>(B)</b> Relative mRNA expression of <i>TACR1</i> revealed lower expression in cancer cell lines than in normal fibroblasts (<i>P</i> < 0.01). <b>(C)</b> Mean <i>SST</i> NMV was significantly higher in cancer cell lines (<i>P</i> < 0.001). <b>(D)</b> Representative examples of quantitative-MSP of <i>TACR1</i> in cancer and normal fibroblasts and keratinocytes; there was a significant difference in NMV (<i>P</i> < 0.05).</p

SST and SSTR1 Genes Methylation Status in HNSCC Primary Samples.

<p>†Fisher’s exact probability test</p><p>SST and SSTR1 Genes Methylation Status in HNSCC Primary Samples.</p

Gene promoter methylation analysis by quantitative-MSP in 100 primary HNSCC samples.

<p><b>(A)</b> Percentage of patients with epigenetic alternation in <i>SST</i>, <i>SSTR1</i>, <i>TAC1</i>, <i>TACR1</i>, <i>galanin</i>, <i>GALR1</i>, and <i>GALR2</i> genes. <b>(B)</b> Comparison of MI among selected epidemiologic and clinical characteristics.</p