A New p53 Target Gene, RKIP, Is Essential for DNA Damage-Induced Cellular Senescence and Suppression of ERK Activation

Abstractp53, a strong tumor suppressor protein, is known to be involved in cellular senescence, particularly premature cellular senescence. Oncogenic stresses, such as Ras activation, can initiate p53-mediated senescence, whereas activation of the Ras-mitogen-activated protein kinase (MAPK) pathway can promote cell proliferation. These conflicting facts imply that there is a regulatory mechanism for balancing p53 and Ras-MAPK signaling. To address this, we evaluated the effects of p53 on the extracellular signal-regulated kinase (ERK) activation and found that p53 could suppress ERK activation through de novo synthesis. Through several molecular biologic analyses, we found that RKIP, an inhibitor of Raf kinase, is responsible for p53-mediated ERK suppression and senescence. Overexpression of RKIP can induce cellular senescence in several types of cell lines, including p53-deficient cells, whereas the elimination of RKIP by siRNA or forced expression of ERK blocks p53-mediated cellular senescence. These results suggested that RKIP is an essential protein for cellular senescence. Moreover, modification of the p53 serine 46 residue was critical for RKIP induction and ERK suppression as well as cellular senescence. These results indicated that RKIP is a novel p53 target gene that is responsible for p53-mediated cellular senescence and tumor suppressor protein expression

Hearing Abilities at Ultra-High Frequency in Patients with Tinnitus

ObjectivesTo compare tinnitus patients who have normal hearing between 250 Hz and 8 kHz with normal controls with regard to the ability of each group to hear extended high-frequency pure tone thresholds.MethodsWe enrolled 18 tinnitus patients, each of whom had a threshold of HL <25 dB and threshold differences of <10 dB between ears at frequencies of 250 and 500 Hz and 1, 2, 4, and 8 kHz. We also enrolled age- and gender-matched normal volunteers (10 ears), for each patient. Extended high frequency pure tone audiometry was performed, and the mean hearing thresholds at 10, 12, 14, and 16 kHz of each tinnitus ear were compared with those of the 10 age- and sex-matched normal ears.ResultsOf the 18 patients with tinnitus, 12 had significantly increased hearing thresholds at more than one of the four high frequencies, compared with the normal group. When we assessed results according to frequency, we found that 8 patients had decreased hearing ability at 10 kHz, 10 at 12 kHz, 8 at 14 kHz, and 4 at 16 kHz.ConclusionSome patients with tinnitus who have normal hearing below 8 kHz have decreased hearing ability at extended high-frequencies. Thus, the proportion of patients with tinnitus who have normal hearing over the entire audible range is smaller than in previous reports

KITENIN increases invasion and migration of mouse squamous cancer cells and promotes pulmonary metastasis in a mouse squamous tumor model

AbstractKAI1 C-terminal interacting tetraspanin (KITENIN) is reported to promote metastasis in mouse colon cancer models. We investigated the role of KITENIN on the progression of squamous cell carcinoma (SCC). In a preliminary clinical study using resected tissues from head and neck SCC patients, KITENIN was highly expressed in tumors and metastatic lymph nodes, while KAI1 was more increased in adjacent mucosa than in tumor. KITENIN-transfected mouse squamous cancer (SCC VII/KITENIN) cells showed significantly higher invasion, migration, and proliferation than empty vector-transfected cells. In syngeneic mouse squamous tumor models, more increased tumor volume and enhanced lung metastasis were found in SCC VII/KITENIN cells-injected mice. Thus, KITENIN increases invasion and migration of squamous cancer cells and thereby promotes distant metastasis in mouse squamous tumor models

WATCHFUL OBSERVATION VERSUS EARLY AORTIC VALVE REPLACEMENT FOR SYMPTOMATIC PATIENTS WITH LOW-GRADIENT SEVERE AORTIC STENOSIS AND PRESERVED EJECTION FRACTION

Brief Communications Arising: arising from X. Dong, B. Milholland & J. Vijg Nature 538, 257–259 (2016); doi:10.1038/nature19793. Comments by: Beer, J.A.A. de, Bardoutsos, A. & Janssen, F. (2017)

Minimally Invasive versus Conventional Lumbar Interbody Fusion at L5–S1: A Retrospective Comparative Study

Objective This study aimed to evaluate the radiologic and clinical outcomes of minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) and conventional posterior lumbar interbody fusion (PLIF) at the L5–S1. Methods We retrospectively reviewed patients who underwent posterior lumbar fusion (MIS-TLIF and PLIF) at only the L5–S1 and were followed up for more than 12 months. Age, sex, body mass index (BMI), bone mineral density (BMD), diagnosis, comorbid conditions, fusion rate, perioperative results, and pre- and postoperative radiographic parameters at the L5–S1 level, pelvic parameters and degree of spondylolisthesis, and clinical results were analyzed. Results A total of 102 patients (46 male, 56 female) with a mean age of 57.1 years were evaluated. Fifty and fifty-two patients underwent MIS-TLIF and PLIF surgeries, respectively. Radiologic parameters increased from their preoperative measures at the last follow-up study; similarly, there were no intergroup differences. The fusion rates in the MIS-TLIF and PLIF groups were 86% and 82.7%, respectively. The subsidence rates in the MIS-TLIF and PLIF groups were 6% and 3.8%, respectively. There was no intergroup difference in terms of fusion rate and subsidence. Clinical outcomes also gradually improved after surgery in both groups without intergroup differences. Conclusion In L5–S1 posterior spinal surgery, there was no significant difference between MIS-TLIF and conventional PLIF. Considering the operation time and estimated blood loss, MIS-TLIF is more effective than PLIF surgery in terms of postoperative health care and economics

The dynamic transcriptional and translational landscape of the model antibiotic producer Streptomyces coelicolor A3(2)

Individual Streptomyces species have the genetic potential to produce a diverse array of natural products of commercial, medical and veterinary interest. However, these products are often not detectable under laboratory culture conditions. To harness their full biosynthetic potential, it is important to develop a detailed understanding of the regulatory networks that orchestrate their metabolism. Here we integrate nucleotide resolution genome-scale measurements of the transcriptome and translatome of Streptomyces coelicolor, the model antibiotic-producing actinomycete. Our systematic study determines 3,570 transcription start sites and identifies 230 small RNAs and a considerable proportion (∼21%) of leaderless mRNAs; this enables deduction of genome-wide promoter architecture. Ribosome profiling reveals that the translation efficiency of secondary metabolic genes is negatively correlated with transcription and that several key antibiotic regulatory genes are translationally induced at transition growth phase. These findings might facilitate the design of new approaches to antibiotic discovery and development

Impact of Body Mass Index on the relationship of epicardial adipose tissue to metabolic syndrome and coronary artery disease in an Asian population

<p>Abstract</p> <p>Background</p> <p>In a previous study, we demonstrated that the thickness of epicardial adipose tissue (EAT), measured by echocardiography, was increased in patients with metabolic syndrome (MS) and coronary artery disease (CAD). Several studies on obese patients, however, failed to demonstrate any relationship between EAT and CAD. We hypothesized that body mass index (BMI) affected the link between EAT and MS and CAD.</p> <p>Methods</p> <p>We consecutively enrolled 643 patients (302 males, 341 females; 59 ± 11 years), who underwent echocardiography and coronary angiography. The EAT thickness was measured on the free wall of the right ventricle at the end of diastole. All patients were divided into two groups: high BMI group, ≥27 kg/m²(n = 165), and non-high BMI group, < 27 kg/m²(n = 478).</p> <p>Results</p> <p>The median and mean EAT thickness of 643 patients were 3.0 mm and 3.1 ± 2.4 mm, respectively. In the non-high BMI group, the median EAT thickness was significantly increased in patients with MS compared to those without MS (3.5 vs. 1.9 mm, p < 0.001). In the high BMI group, however, there was no significant difference in the median EAT thickness between patients with and without MS (3.0 vs. 2.5 mm, p = 0.813). A receiver operating characteristic (ROC) curve analysis predicting MS revealed that the area under the curve (AUC) of the non-high BMI group was significantly larger than that of the high BMI group (0.659 vs. 0.506, p = 0.007). When compared to patients without CAD, patients with CAD in both the non-high and high BMI groups had a significantly higher median EAT thickness (3.5 vs. 1.5 mm, p < 0.001 and 4.0 vs. 2.5 mm, p = 0.001, respectively). However, an ROC curve analysis predicting CAD revealed that the AUC of the non-high BMI group tended to be larger than that of the high BMI group (0.735 vs. 0.657, p = 0.055).</p> <p>Conclusions</p> <p>While EAT thickness was significantly increased in patients with MS and CAD, the power of EAT thickness to predict MS and CAD was stronger in patients with BMI < 27 kg/m². These findings showed that the measurement of EAT thickness by echocardiography might be especially useful in an Asian population with a non-high BMI, less than 27 kg/m².</p