Circadian production of melatonin in cartilage modifies rhythmic gene expression

Endochondral ossification, including bone growth and other metabolic events, is regulated by circadian rhythms. Herein, we provide evidence that melatonin has a direct effect on the circadian rhythm of chondrocytes. We detected mRNA expression of the genes which encode the melatonin-synthesizing enzymes AANAT (arylalkylamine N-acetyltransferase) and HIOMT (hydroxyindole O-methyltransferase), as well as the melatonin receptors MT1 and MT2 in mouse primary chondrocytes and cartilage. Production of melatonin was confirmed by mass spectrometric analysis of primary rat and chick chondrocytes. Addition of melatonin to primary mouse chondrocytes caused enhanced cell growth and increased expression of Col2a1, Aggrecan, and Sox9, but inhibited Col10a1 expression in primary BALB/c mouse chondrocytes. Addition of luzindole, an MT1 and MT2 antagonist, abolished these effects. These data indicate that chondrocytes produce melatonin, which regulates cartilage growth and maturation via the MT1 and MT2 receptors. Kinetic analysis showed that melatonin caused rapid upregulation of Aanat, Mt1, Mt2, and Pthrp expression, followed by Sox9 and Ihh. Furthermore, expression of the clock gene Bmal1 was induced, while that of Per1 was downregulated. Chronobiological analysis of synchronized C3H mouse chondrocytes revealed that melatonin induced the cyclic expression of Aanat and modified the cyclic rhythm of Bmal1, Mt1, and Mt2. In contrast, Mt1 and Mt2 showed different rhythms from Bmal1 and Aanat, indicating the existence of different regulatory genes. Our results indicate that exogenous and endogenous melatonin work in synergy in chondrocytes to adjust rhythmic expression to the central suprachiasmatic nucleus clock

Search for VHE gamma rays from SS433/W50 with the CANGAROO-II telescope

SS433, located at the center of the supernova remnant W50, is a close proximity binary system consisting of a compact star and a normal star. Jets of material are directed outwards from the vicinity of the compact star symmetrically to the east and west

Detection of diffuse TeV gamma-ray emission from the nearby starburst galaxy NGC 253

We report the TeV gamma-ray observations of the nearby normal spiral galaxy NGC 253. At a distance of $\sim$2.5 Mpc, NGC 253 is one of the nearest starburst galaxies. This relative closeness, coupled with the high star formation rate in the galaxy, make it a good candidate TeV gamma-ray source. Observations were carried out in 2000 and 2001 with the CANGAROO-II 10 m imaging atmospheric Cerenkov telescope. TeV gamma-ray emission is detected at the $\sim 11\sigma$ level with a flux of $(7.8 \pm 2.5)\times 10^{-12} {\rm cm}^{-2} {\rm sec}^{-1}$ at energies $>$0.5 TeV. The data indicate that the emission region is broader than the point spread function of our telescope.Comment: 4 pages, double colomn, 3 figures, aa.cl

Quantification of Cell Migration and Invasion, and Their Association with Periostin in Anaplastic Thyroid Cancer, Using a Real-time Cell Analyzer

Anaplastic thyroid cancer (ATC) is known to be a highly malignant cancer of the thyroid with a high mortality rate. In a previous study, we used real-time cell analysis (RTCA) to analyze cell migration and invasion of oral squamous cell carcinomas (OSCCs) of the tongue and floor of the mouth. In the present study, we investigated cell migration and invasion of ATC using RTCA, as well as their association with periostin, matrix metalloproteinases (MMPs), and integrins. Experiments were performed on TCO-1 and HTC/C3 cells, which are human ATC cell lines. OSCC cell lines were used for comparison. Using the cell analysis system, cell migration was assessed on fibronectin-coated CIM-Plates, whereas invasion was assessed on fibronectin- and matrigel-coated CIM-Plates. SCC-4 cells exhibited high cell migration and invasion activity compared with other OSCC cell lines. TCO-1 cells exhibited equivalent cell invasion but stronger migration than SCC-4 cells. Although TCO-1 cells had strong invasive activity, they did not express MMP-9, unlike SCC-4 cells. Conversely, periostin expression was high in TCO-1 cells. Therefore, periostin expression appears to be associated with the cell migration and invasion activity of ATC. The RTCA system will be useful for the analysis of the metastatic characteristics of ATC in head and neck cancer

Case Report: Unresectable pulmonary metastases of a giant cell tumor of bone treated with denosumab: a case report and review of literature

Giant cell tumors of bone (GCTB) sometimes metastasize to distant organs. In this case report, we present pulmonary metastases of GCTB mimicking malignancies. A 49-year-old man underwent two surgical treatments for a GCTB of the right proximal radius. At the time of the second surgery, no lesions were observed on chest radiography. Three years after surgery, the patient presented with cough and dyspnea, and chest radiography and computed tomography (CT) revealed multiple lung nodules. Positron emission tomography/CT revealed a high accumulation of 18F-fluoro-2-deoxy-D-glucose (18F-FDG) in multiple lesions. Based on the rapid growth and accumulation of 18F-FDG, a metastatic malignant tumor was suspected. CT-guided needle biopsy was performed, and the histology showed proliferation of spindle cells and multinuclear giant cells without malignant changes. Denosumab was administered because multiple lung lesions were unresectable. One month after denosumab treatment, CT showed marked shrinkage of the lesions, and the symptoms significantly improved. Eighteen months after the initial treatment with denosumab, the patient had no symptoms or tumor growth. Although its long-term efficacy and safety remain unclear, denosumab may be a treatment option for patients with unresectable pulmonary GCTB

Prolonged Tachycardia with Higher Heart Rate Is Associated with Higher ICU and In-hospital Mortality

Tachycardia is common in intensive care units (ICUs). It is unknown whether tachycardia or prolonged tachycardia affects patient outcomes. We investigated the association between tachycardia and mortality in critically ill patients. This retrospective cohort study’s primary outcome was patient mortality in the ICU and the hospital. We stratified the patients (n=476) by heart rate (HR) as LowHR, MediumHR, and HighHR groups. We also stratified them by their durations of HR >100 (prolonged HR; tachycardia): MildT, ModerateT, and SevereT groups. We determined the six groups’ mortality. The ICU mortality rates of the LowHR, MediumHR, and HighHR groups were 1.0%, 1.5%, and 7.9%, respectively; significantly higher in the HighHR vs. LowHR group. The in-hospital mortality rates of these groups were 1%, 4.5%, and 14.6%, respectively; significantly higher in the HighHR vs. LowHR group. The ICU mortality rates of the MildT, ModerateT, and SevereT groups were 0.9%, 5.6%, and 57.1%, respectively. The mortality of the HRT=0 (i.e., all HR ≤ 100) patients was 0%. The in-hospital mortality rates of the MildT, ModerateT, and SevereT groups were 1.8%, 16.7%, and 85.7%, respectively; that of the HRT=0 patients was 0.5%. Both higher HR and prolonged tachycardia were associated with poor outcomes

Search for VHE gamma rays from SS433/W50 with the CANGAROO-II telescope

SS433, located at the center of the supernova remnant W50, is a close proximity binary system consisting of a compact star and a normal star. Jets of material are directed outwards from the vicinity of the compact star symmetrically to the east and west. Non-thermal hard X-ray emission is detected from lobes lying on both sides. Shock accelerated electrons are expected to generate sub-TeV gamma rays through the inverse-Compton process in the lobes. Observations of the western X-ray lobe region of SS433/W50 system have been performed to detect sub-TeV gamma-rays using the 10m CANGAROO-II telescope in August and September, 2001, and July and September, 2002. The total observation times are 85.2 hours for ON source, and 80.8 hours for OFF source data. No significant excess of sub-TeV gamma rays has been found at 3 regions of the western X-ray lobe of SS433/W50 system. We have derived 99% confidence level upper limits to the fluxes of gamma rays and have set constraints on the strengths of the magnetic fields assuming the synchrotron/inverse-Compton model for the wide energy range of photon spectrum from radio to TeV. The derived lower limits are 4.3 microgauss for the center of the brightest X-ray emission region and 6.3 microgauss for the far end from SS433 in the western X-ray lobe. In addition, we suggest that the spot-like X-ray emission may provide a major contribution to the hardest X-ray spectrum in the lobe.Comment: 7 pages, 8 figures, to be published in Astroparticle Physic

Risk stratification for the prognosis of patients with chemoresistant urothelial cancer treated with pembrolizumab

The use of immune checkpoint inhibitors to treat urothelial carcinoma (UC) is increasing rapidly without clear guidance for validated risk stratification. This multicenter retrospective study collected clinicopathological information on 463 patients, and 11 predefined variables were analyzed to develop a multivariate model predicting overall survival (OS). The model was validated using an independent dataset of 292 patients. Patient characteristics and outcomes were well balanced between the discovery and validation cohorts, which had median OS times of 10.2 and 12.5 mo, respectively. The final validated multivariate model was defined by risk scores based on the hazard ratios (HRs) of independent prognostic factors including performance status, site of metastasis, hemoglobin levels, and the neutrophil-to-lymphocyte ratio. The median OS times (95% confidence intervals [CIs]) for the low-, intermediate-, and high-risk groups (discovery cohort) were not yet reached (NYR) (NYR–19.1), 6.8 mo (5.8-8.9), and 2.3 mo (1.2-2.6), respectively. The HRs (95% CI) for OS in the low- and intermediate-risk groups vs the high-risk group were 0.07 (0.04-0.11) and 0.23 (0.15-0.37), respectively. The objective response rates for in the low-, intermediate-, and high-risk groups were 48.3%, 28.8%, and 10.5%, respectively. These differential outcomes were well reproduced in the validation cohort and in patients who received pembrolizumab after perioperative or first-line chemotherapy (N = 584). In conclusion, the present study developed and validated a simple prognostic model predicting the oncological outcomes of pembrolizumab-treated patients with chemoresistant UC. The model provides useful information for external validation, patient counseling, and clinical trial design

A search for sub-TeV gamma rays from the Vela pulsar region with CANGAROO-III

© 2006 The American Astronomical Society. All rights reserved. Submitted to Cornell University’s online archive www.arXiv.org in 2006 by Ryoji Enomoto. Post-print sourced from www.arxiv.org.We made stereoscopic observations of the Vela pulsar region with two of the 10 m diameter CANGAROO-III imaging atmospheric Cerenkov telescopes in 2004 January and February in a search for sub-TeV gamma rays from the pulsar and surrounding regions. We describe the observations, provide a detailed account of the calibration methods, and introduce the improved and bias-free analysis techniques employed for CANGAROO-III data. No evidence of gamma-ray emission is found from either the pulsar position or the previously reported position offset by 0°.13, and the resulting upper limits are a factor of 5 less than the previously reported flux from observations with the CANGAROO-I 3.8 m telescope. Following the recent report by the H.E.S.S. group of TeV gamma-ray emission from the pulsar wind nebula, which is ~0°.5 south of the pulsar position, we examined this region and found supporting evidence for emission extended over ~0°.6

Detection of Sub-TeV Gamma-Rays from the Galactic Center Direction by CANGAROO-II

We have detected sub-TeV gamma-ray emission from the direction of the Galactic Center (GC) using the CANGAROO-II Imaging Atmospheric Cherenkov Telescope (IACT). We detected a statistically signicant excess at energies greater than 250GeV. The flux was one order of magnitude lower than that of Crab at 1 TeV with a soft spectrum E^{-4.6+-0.5}. The signal centroid is consistent with the GC direction and the observed prole is consistent with a point-like source. Our data suggests that the GeV source 3EG J1746-2851 is identical with this TeV source and we study the combined spectra to determine the possible origin of the gamma-ray emission. We also obtain an upper limit on the cold dark-matter density in the Galactic halo.Comment: 13 pages, 3 figures, aastex.cls, accepted by ApJ Letter