The Splicing Efficiency of Activating HRAS Mutations Can Determine Costello Syndrome Phenotype and Frequency in Cancer

Costello syndrome (CS) may be caused by activating mutations in codon 12/13 of the HRAS proto-oncogene. HRAS p.Gly12Val mutations have the highest transforming activity, are very frequent in cancers, but very rare in CS, where they are reported to cause a severe, early lethal, phenotype. We identified an unusual, new germline p.Gly12Val mutation, c.35_36GC>TG, in a 12-year-old boy with attenuated CS. Analysis of his HRAS cDNA showed high levels of exon 2 skipping. Using wild type and mutant HRAS minigenes, we confirmed that c.35_36GC>TG results in exon 2 skipping by simultaneously disrupting the function of a critical Exonic Splicing Enhancer (ESE) and creation of an Exonic Splicing Silencer (ESS). We show that this vulnerability of HRAS exon 2 is caused by a weak 3' splice site, which makes exon 2 inclusion dependent on binding of splicing stimulatory proteins, like SRSF2, to the critical ESE. Because the majority of cancer- and CS- causing mutations are located here, they affect splicing differently. Therefore, our results also demonstrate that the phenotype in CS and somatic cancers is not only determined by the different transforming potentials of mutant HRAS proteins, but also by the efficiency of exon 2 inclusion resulting from the different HRAS mutations. Finally, we show that a splice switching oligonucleotide (SSO) that blocks access to the critical ESE causes exon 2 skipping and halts proliferation of cancer cells. This unravels a potential for development of new anti-cancer therapies based on SSO-mediated HRAS exon 2 skipping

Effects of a Three-week Core Training Program on Different Unstable Platforms

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Same-Day Physical Therapy Consults in an Outpatient Neuromuscular Disease Physician Clinic

Background: Team-based care has been shown to offer more comprehensive benefits to patients when compared to standard physician-based care alone in clinics for chronic conditions. However, apart from grant-funded multidisciplinary clinics, there are no reports on the usage of same-day physical therapy (PT) consults within a daily outpatient neuromuscular disease (NMD) physician clinic. Objective: To determine the impact of same-day PT consults at the University of Utah’s outpatient Clinical Neurosciences Center. Design: A qualitative assessment and survey of patient satisfaction. Methods: An eight question Health Insurance Portability and Accountability Act-compliant patient satisfaction survey using a 5-point Likert scale was administered. Demographic data and Press-Ganey Provider Satisfaction surveys were retrospectively collected from electronic medical records for patients receiving same-day PT encounters in the neuromuscular division over 1 year. Results: Mean (standard deviation) age was 54.22 (19.81) years for 134 patient encounters, median age was 60 years, with 76 male (57%) and 58 female (43%) patients. Mean Likert score for 61 self-reported patient satisfaction surveys for same-day PT consults was 4.87 (97.4%). Press-Ganey Provider Satisfaction scores improved from 89.9% (N=287) for the year prior to 90.8% (N=320) for the corresponding year (P=0.427). A total of 46 (75.4%) patients have either never before received PT care or never before received PT care for their NMD, 67.4% of whom were male. Conclusion: Same-day PT consults in an outpatient NMD physician clinic demonstrated excellent patient satisfaction and improved access to specialty care. This model could potentially be implemented in other academic medical centers to improve access to rehabilitation services for patients with NMD

Insulin Increases Ceramide Synthesis in Skeletal Muscle

Aims. The purpose of this study was to determine the effect of insulin on ceramide metabolism in skeletal muscle. Methods. Skeletal muscle cells were treated with insulin with or without palmitate for various time periods. Lipids (ceramides and TAG) were isolated and gene expression of multiple biosynthetic enzymes were quantified. Additionally, adult male mice received daily insulin injections for 14 days, followed by muscle ceramide analysis. Results. In muscle cells, insulin elicited an increase in ceramides comparable to palmitate alone. This is likely partly due to an insulin-induced increase in expression of multiple enzymes, particularly SPT2, which, when knocked down, prevented the increase in ceramides. In mice, 14 days of insulin injection resulted in increased soleus ceramides, but not TAG. However, insulin injections did significantly increase hepatic TAG compared with vehicle-injected animals. Conclusions. This study suggests that insulin elicits an anabolic effect on sphingolipid metabolism in skeletal muscle, resulting in increased ceramide accumulation. These findings reveal a potential mechanism of the deleterious consequences of the hyperinsulinemia that accompanies insulin resistance and suggest a possible novel therapeutic target to mitigate its effects

Prognostic impact of lymphadenectomy in clinically early stage malignant germ cell tumour of the ovary

Background:The aim of this study was to determine the impact of lymphadenectomy and nodal metastasis on survival in clinical stage I malignant ovarian germ cell tumour (OGCT).Methods:Data were obtained from the National Cancer Institute registry from 1988 to 2006. Analyses were performed using Student's t-test, Kaplan–Meier and Cox proportional hazard methods.Results:In all, 1083 patients with OGCT who have undergone surgical treatment and deemed at time of the surgery to have disease clinically confined to the ovary were included 590 (54.48%) had no lymphadenectomy (LND−1) and 493 (45.52%) had lymphadenectomy. Of the 493 patients who had lymphadenectomy, 441 (89.5%) were FIGO surgical stage I (LND+1) and 52 (10.5%) were upstaged to FIGO stage IIIC due to nodal metastasis (LND+3C). The 5-year survival was 96.9% for LND−1, 97.7% for LND+1 and 93.4% for LND+3C (P=0.5). On multivariate analysis, lymphadenectomy was not an independent predictor of survival when controlling for age, histology and race (HR: 1.26, 95% CI: 0.62–2.58, P=0.5). Moreover, the presence of lymph node metastasis had no significant effect on survival (HR: 2.7, 95% CI: 0.67–10.96, P=0.16).Conclusion:Neither lymphadenectomy nor lymph node metastasis was an independent predictor of survival in patients with OGCT confined to the ovary. This probably reflects the highly chemosensitive nature of these tumours

Seasonal variations in the diagnosis of childhood cancer in the United States

Seasonal trends in month of diagnosis have been reported for childhood acute lymphoblastic leukaemia (ALL) and non-Hodgkin's lymphoma (NHL). This seasonal variation has been suggested to represent an underlying viral aetiology for these malignancies. Some studies have shown the highest frequency of diagnoses in the summer months, although this has been inconsistent. Data from the Children's Cancer Group and the Pediatric Oncology Group were analysed for seasonal incidence patterns. A total of 20 949 incident cancer cases diagnosed in the USA from 1 January 1989 through 31 December 1991 were available for analyses. Diagnosis-specific malignancies available for evaluation included ALL, acute myeloid leukaemia (AML), Hodgkin's disease, NHL, rhabdomyosarcoma, neuroblastoma, retinoblastoma, osteosarcoma, Wilms' tumour, retinoblastoma, Ewings' sarcoma, central nervous system (CNS) tumours and hepatoblastoma. Overall, there was no statistically significant seasonal variation in the month of diagnosis for all childhood cancers combined. For diagnosis-specific malignancies, there was a statistically significant seasonal variation for ALL (P = 0.01; peak in summer), rhabdomyosarcoma (P = 0.03; spring/summer) and hepatoblastoma (P = 0.01; summer); there was no seasonal variation in the diagnosis of NHL. When cases were restricted to latitudes greater than 40° (‘north’), seasonal patterns were apparent only for ALL and hepatoblastoma. Notably, 33% of hepatoblastoma cases were diagnosed in the summer months. In contrast, for latitudes less than 40° (‘south’), only CNS tumours demonstrated a seasonal pattern (P = 0.002; winter). Although these data provide modest support for a summer peak in the diagnosis of childhood ALL, any underlying biological mechanisms that account for these seasonal patterns are likely complex and in need of more definitive studies. © 1999 Cancer Research Campaig

Semiparametrically Efficient Inference Based on Signs and Ranks for Median Restricted Models

Since the pioneering work of Koenker and Bassett (1978), econometric models involving median and quantile rather than the classical mean or conditional mean concepts have attracted much interest.Contrary to the traditional models where the noise is assumed to have mean zero, median-restricted models enjoy a rich group-invariance structure.In this paper, we exploit this invariance structure in order to obtain semiparametrically efficient inference procedures for these models.These procedures are based on residual signs and ranks, and therefore insensitive to possible misspecification of the underlying innovation density, yet semiparametrically efficient at correctly specified densities.This latter combination is a definite advantage of these procedures over classical quasi-likelihood methods.The techniques we propose can be applied, without additional technical difficulties, to both cross-sectional and time-series models.They do not require any explicit tangent space calculation nor any projections on these.

Change in the direct cost of treatment for children and adolescents with hyperkinetic disorder in Germany over a period of four years

Abstract Background In many developed countries, the treatment of hyperkinetic disorder (or ADHD) consumes a considerable amount of resources. The primary aim of this study was to determine change in the direct cost of treatment for children and adolescents with hyperkinetic disorder in Germany over time, and compare the cost with the cost of treatment for two physical disorders: epilepsy and asthma. Methods The German Federal Statistical Office provided data on the direct cost of treating hyperkinetic disorder, epilepsy and asthma in Germany for 2002, 2004, and 2006. The direct costs of treatment incurred by hyperkinetic disorder in these years were compared with those incurred by epilepsy and asthma. Results The total direct cost of treatment for the hyperkinetic disorder was € 177 million in 2002, € 234 million in 2004, and € 341 million in 2006. The largest proportion of the cost was incurred by the age group Conclusion The direct cost of treatment for hyperkinetic disorder in the age group < 15 years increased considerably between 2002 and 2006. Over the same period of time and for the same age group, expenditure for epilepsy and asthma was more or less constant. The increase in expenditure for the treatment of hyperkinetic disorder may be due to increasing demand for diagnostic and therapeutic services and improved availability of such services. The study is limited by the difficulty of obtaining consistent data on the direct cost of treatment for both physical and psychiatric disorders in Germany.</p