Summary Objective To study the effect of intra-articular injection of meloxicam (Mobic) on the development of osteoarthritis (OA) in rats and examine concomitant changes in nociceptive behavior and ...the expression of mitogen-activated protein kinases (MAPKs) in articular cartilage chondrocytes. Methods OA was induced in Wistar rats by right anterior cruciate ligament transection (ACLT); the left knee was not treated. The OA + meloxicam (1.0 mg) group was injected intra-articularly in the ACLT knee with 1.0 mg of meloxicam once a week for 5 consecutive weeks starting 5 weeks after ACLT. The OA + meloxicam (0.25 mg) group was treated similarly with 0.25 mg meloxicam. The sham group underwent arthrotomy only and received vehicle of 0.1 mL sterile 0.9% saline injections, whereas the naive rats in meloxicam-only groups were treated similarly with 1.0- and 0.25-mg meloxicam. Nociception was measured as secondary mechanical allodynia and hind paw weight-bearing distribution at before (pre-) and 5, 10, 15, and 20 weeks post-ACLT. Histopathology of the cartilage and synovia was examined 20 weeks after ACLT. Immunohistochemical analysis was performed to examine the effect of meloxicam on MAPKs (p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK)) expression in the articular cartilage chondrocytes. Results OA rats receiving intra-articular meloxicam treatment showed significantly less cartilage degeneration and synovitis than saline-treated controls. Nociception were improved in the OA + meloxicam groups compared with the OA group. Moreover, meloxicam attenuated p38 and JNK but enhanced ERK expression in OA-affected cartilage. Conclusions Intra-articular injection of meloxicam (1) attenuates the development of OA, (2) concomitantly reduces nociception, and (3) modulates chondrocyte metabolism, possibly through inhibition of cellular p38 and JNK, but enhances ERK expression.
Activation of Akt signaling pathway has been suggested involving in chemoresistance, metastasis and tumorigenesis of gastric cancer. However, the mechanism of Akt regulation in gastric cancer is not ...fully understood. RUNX3, which was first identified as a transcription factor, suppresses gastric tumorigenesis through regulating expression of target genes. Here, we found that restoration of RUNX3 significantly downregulates the protein and mRNA expression of Akt1 in gastric cancer cell lines, AGS and SNU-1. Knockdown of RUNX3 upregulates protein and mRNA expression of Akt1 in normal gastric epithelial cell line, GES-1. The negative correlation of RUNX3 and Akt expression and downstream β-catenin/cyclin D1 effectors was further confirmed in AGS and GES-1 cell lines, as well as clinical specimens of gastric cancer. We identified two RUNX3-binding sites in Akt1 promoter and the binding of RUNX3 on Akt1 promoter significantly inhibits Akt1 expression. The RUNX3-mediated inhibition of Akt1 caused β-catenin protein degradation and then cyclin D1 downregulation. Restoration of cyclin D1 reverses cell growth inhibition and G1 phase arrest induced by RUNX3 in gastric cancer cells. Our results show that loss of RUNX3 expression can enhance the Akt1-mediated signaling pathway and promote the tumorigenesis process in human gastric cancer.
The optical design and performance of the recently opened 13A biological small‐angle X‐ray scattering (SAXS) beamline at the 3.0 GeV Taiwan Photon Source of the National Synchrotron Radiation ...Research Center are reported. The beamline is designed for studies of biological structures and kinetics in a wide range of length and time scales, from angstrom to micrometre and from microsecond to minutes. A 4 m IU24 undulator of the beamline provides high‐flux X‐rays in the energy range 4.0–23.0 keV. MoB4C double‐multilayer and Si(111) double‐crystal monochromators (DMM/DCM) are combined on the same rotating platform for a smooth rotation transition from a high‐flux beam of ∼4 × 1014 photons s−1 to a high‐energy‐resolution beam of ΔE/E ≃ 1.5 × 10−4; both modes share a constant beam exit. With a set of Kirkpatrick–Baez (KB) mirrors, the X‐ray beam is focused to the farthest SAXS detector position, 52 m from the source. A downstream four‐bounce crystal collimator, comprising two sets of Si(311) double crystals arranged in a dispersive configuration, optionally collimate the DCM (vertically diffracted) beam in the horizontal direction for ultra‐SAXS with a minimum scattering vector q down to 0.0004 Å−1, which allows resolving ordered d‐spacing up to 1 µm. A microbeam, of 10–50 µm beam size, is tailored by a combined set of high‐heat‐load slits followed by micrometre‐precision slits situated at the front‐end 15.5 m position. The second set of KB mirrors then focus the beam to the 40 m sample position, with a demagnification ratio of ∼1.5. A detecting system comprising two in‐vacuum X‐ray pixel detectors is installed to perform synchronized small‐ and wide‐angle X‐ray scattering data collections. The observed beamline performance proves the feasibility of having compound features of high flux, microbeam and ultra‐SAXS in one beamline.
The optical design and performance of the BioSAXS beamline at the Taiwan Photon Source are reported
Summary Objective To identify disease relevant genes and pathways associated with knee Osteoarthritis (OA) progression in human subjects using medial and lateral compartment dominant OA knee tissue. ...Design Gene expression of knee cartilage was comprehensively assessed for three regions of interest from human medial dominant OA ( n = 10) and non-OA ( n = 6) specimens. Histology and gene expression were compared for the regions with minimal degeneration, moderate degeneration and significant degeneration. Agilent whole-genome microarray was performed and data were analyzed using Agilent GeneSpring GX11.5. Significant differentially regulated genes were further investigated by Ingenuity Pathway Analysis (IPA) to identify functional categories. To confirm their association with disease severity as opposed to site within the knee, 30 differentially expressed genes, identified by microarray, were analyzed by quantitative reverse-transcription polymerase chain reaction on additional medial ( n = 16) and lateral ( n = 10) compartment dominant knee OA samples. Results A total of 767 genes were differentially expressed ≥two-fold ( P ≤ 0.05) in lesion compared to relatively intact regions. Analysis of these data by IPA predicted biological functions related to an imbalance of anabolism and catabolism of cartilage matrix components. Up-regulated expression of IL11, POSTN, TNFAIP6, and down-regulated expression of CHRDL2, MATN4, SPOCK3, VIT, PDE3B were significantly associated with OA progression and validated in both medial and lateral compartment dominant OA samples. Conclusions Our study provides a strategy for identifying targets whose modification may have the potential to ameliorate pathological alternations and progression of disease in cartilage and to serve as biomarkers for identifying individuals susceptible to progression.
Background and purpose
Physical activity is associated with a reduced incidence of first‐time stroke. However, few studies have examined the effect of pre‐stroke physical activity on post‐stroke ...complications and clinical outcomes.
Methods
A total of 39 835 cases of stroke registered in the nationwide stroke registry system of Taiwan between 2006 and 2009 were analyzed according to five levels of severity as determined by National Institutes of Health Stroke Scale score upon hospital admission. Pre‐stroke physical activity was defined in the Taiwan Stroke Registry as dedicated leisure‐time physical activity for at least 30 min/day for 3 days/week for more than 6 months. A Cox model was used to compare complications and outcomes between active and inactive groups.
Results
The active and inactive groups were similar in age distribution and stroke type distribution, but the active group had better National Institutes of Health Stroke Scale scores upon admission. The active group also had significantly fewer post‐stroke complications. Active patients had lower hospital mortality and better functional outcomes upon discharge as per the modified Rankin Scale. Improved functional status in the active group was significant at 1, 3 and 6 months post‐stroke.
Conclusion
Dedicated leisure‐time physical activity for at least 30 min/day, at least three times per week for more than 6 months was associated with decreased stroke severity, fewer post‐stroke complications, lower mortality and better outcomes.
An experiment to search for light sterile neutrinos is conducted at a reactor with a thermal power of 2.8 GW located at the Hanbit nuclear power complex. The search is done with a detector consisting ...of a ton of Gd-loaded liquid scintillator in a tendon gallery approximately 24 m from the reactor core. The measured antineutrino event rate is 1976 per day with a signal to background ratio of about 22. The shape of the antineutrino energy spectrum obtained from the eight-month data-taking period is compared with a hypothesis of oscillations due to active-sterile antineutrino mixing. No strong evidence of 3+1 neutrino oscillation is found. An excess around the 5 MeV prompt energy range is observed as seen in existing longer-baseline experiments. The mixing parameter sin^{2}2θ_{14} is limited up to less than 0.1 for Δm_{41}^{2} ranging from 0.2 to 2.3 eV^{2} with a 90% confidence level.
Background: Mutations of the epidermal growth factor receptor (EGFR) gene in non-small-cell lung cancer (NSCLC) patients predict the patients who will respond to EGFR tyrosine kinase inhibitor (TKI) ...treatment. A recent study has suggested that 33% of NSCLC showed primary tumor/metastasis discordance of EGFR expression by immunohistochemistry analysis. We intended to find out whether the EGFR mutations of primary lung cancers are concordant to that of corresponding metastatic tumors. Materials and methods: We analyzed EGFR exons 18–21 from paired primary and metastatic tumors in 67 lung cancer patients who had not received TKI before tissues were sampled. Results: Using the direct sequencing method, 9 of 18 (50%) patients with EGFR mutation-positive primary lung tumors had lost the mutations in metastases. For 26 patients who were EGFR mutation positive in the metastatic tumors, 17 (65%) were negative in the primary tumors. We analyzed these paired tissues with discrepant EGFR mutations by the Scorpion Amplified Refractory Mutation System assay. Finally, the discordant rate reached 27% (18 of 67 cases). Conclusion: EGFR mutations in primary lung tumors do not always reflect the same situation in metastases. Analysis of EGFR mutations in the primary lung tumor would be inadequate for planning the use of TKI for advanced NSCLC.
Summary Objective To evaluate the interaction of articular cartilage (AC) and subchondral bone (SB) through analysis of osteoarthritis (OA)-related genes of site-matched tissue. Design We developed a ...novel method for isolating site-matched overlying AC and underlying SB from three and four regions of interest respectively from the human knee tibial plateau ( n = 50). For each site, the severity of cartilage changes of OA were assessed histologically, and the severity of bone abnormalities were assessed by microcomputed tomography. An RNA isolation procedure was optimized that yielded high quality RNA from site-matched AC and SB tibial regions. Quantitative polymerase chain reaction (Q-PCR) analysis was performed to evaluate gene expression of 61 OA-associated genes for correlation with cartilage integrity and bone structure parameters. Results A total of 27 (44%) genes were coordinately up- or down-regulated in both tissues. The expression levels of 19 genes were statistically significantly correlated with the severity of AC degeneration and changes of SB structure; these included: ADAMTS1 , ASPN , BMP6 , BMPER , CCL2 , CCL8 , COL5A1 , COL6A3 , COL7A1 , COL16A1 , FRZB , GDF10 , MMP3 , OGN , OMD , POSTN , PTGES , TNFSF11 and WNT1. Conclusions These results provide a strategy for identifying targets whose modification may have the potential to ameliorate pathological alterations and progression of disease in both AC and SB simultaneously. In addition, this is the first study, to our knowledge, to overcome the major difficulties related to isolation of high quality RNA from site-matched joint tissues. We expect this method to facilitate advances in our understanding of the coordinated molecular responses of the whole joint organ.
Pain management is an important issue which impacts the prognosis of neonates in neonatal intensive care units. Evidence has shown that professionals’ knowledge and attitudes regarding pain ...management can impact the quality of their practice. The purpose of this study was to evaluate the knowledge, attitudes, and practices of neonatal professionals regarding neonatal pain management. A cross-sectional study was performed involving neonatal physicians and nurses, using a research questionnaire to investigate the knowledge and attitudes of professionals as well as to assess their practice of pain management. Research found an apparent discrepancy between the knowledge levels of neonatologists and nurses regarding pain assessment and management, with nurses displaying weaker professional knowledge and more negative attitudes toward pain management than did neonatologists. Additionally, research revealed a lack of knowledge and negative attitudes among participants regarding the provision of sufficient opioid analgesics to sick infants during invasive procedures and even for dying neonates. There is an urgent need for continuing education regarding neonatal pain management with the goal of empowering neonatal professionals; further research is needed into the question of how to translate education into more reliable practice.
Conclusion
: This research provides useful information regarding the knowledge, attitudes, and clinical practice of neonatal pain management among neonatologists and nurses and points out some differences in the knowledge levels of these two groups.
What is Known:
•Neonates can perceive and respond to pain stimuli by showing their biological signals similarly to children and adults.
•Untreated or insufficient pain management for high-risk neonates has short-term.
negative effects and may also induce long-term negative effects.
What is New:
•
The level of knowledge, the attitudes, and the practices regarding neonatal pain in intensive care are different among neonatal professionals.
•There is an urgent need to provide interdisciplinary continuing education to improve the knowledge of neonatal professionals and encourage them to more highly prioritize neonatal pain management.
Summary
Background
Acral melanoma (AM) is the most common histopathological subtype of malignant melanoma in Asians. However, differences in the mutational profiles underlying AM and nonacral ...cutaneous melanoma (NAM) in Asians are not well understood.
Objectives
To augment the understanding of the prevalence, patterns and associations of various mutations between different subtypes of melanoma.
Methods
We performed comprehensive genomic profiling of 409 cancer‐associated genes, using next‐generation sequencing, in 66 primary melanomas comprised of 45 AMs and 21 NAMs.
Results
Most of the AMs (n = 27/45; 60%), but only five of 21 (24%) NAMs, were triple wild‐type (triple‐WT) tumours. Compared with AMs, NAMs exhibited a significantly higher frequency of BRAF mutations. The frequencies of NRAS/KRAS mutations, cell‐cycle aberrations, copy number gains in BIRC2, BIRC3 and BIRC5, and gains of receptor tyrosine kinase genes were significantly higher in AMs. Ulceration was found at significantly higher rates in the AMs and NAMs with cell‐cycle aberrations and gains of receptor tyrosine kinase genes. Notably, cell‐cycle aberrations and copy number gains in BIRC2, BIRC3 and BIRC5 were significantly associated with poor melanoma‐specific survival in the 66 patients with melanoma and especially in the 45 patients with AM. Multivariate analysis showed that lymph node metastasis and cell‐cycle aberrations were independent prognostic factors of melanoma‐specific survival.
Conclusions
This study strengthens our understanding of the patterns and clinical associations of oncogenic mutations in AMs and NAMs in Asians.
What's already known about this topic?
Mutation frequencies of driver genes vary between melanoma subtypes.
Acral melanoma is the most common subtype of melanoma in Asians.
KIT mutations and copy number variations occur more frequently in the acral subtype of melanoma than in the nonacral subtype
What does this study add?
NRAS/KRAS mutations, cell‐cycle aberrations, copy number gains in BIRC2, BIRC3 and BIRC5, and amplifications of receptor tyrosine kinase genes were significantly enriched in acral melanoma and could be potential targets for treatment.
Melanomas with cell‐cycle aberrations and gains in receptor tyrosine kinase genes were significantly more likely to contain ulceration.
What is the translational message?
Cell‐cycle aberrations and copy number gains in BIRC2, BIRC3 and BIRC5 were significantly associated with poor melanoma‐specific survival.
These observations should be explored further for future drug development.
Linked Comment: Johansson. Br J Dermatol 2020; 182:1085.
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