Murine double minute 2 regulates Hu antigen R stability in human liver and colon cancer through NEDDylation

Hu antigen R (HuR) is a central RNA-binding protein regulating cell dedifferentiation, proliferation, and survival, which are well-established hallmarks of cancer. HuR is frequently overexpressed in tumors correlating with tumor malignancy, which is in line with a role for HuR in tumorigenesis. However, the precise mechanism leading to changes in HuR expression remains unclear. In the liver, HuR plays a crucial role in hepatocyte proliferation, differentiation, and transformation. Here, we unraveled a novel mean of regulation of HuR expression in hepatocellular carcinoma (HCC) and colon cancer. HuR levels correlate with the abundance of the oncogene, murine double minute 2 (Mdm2), in human HCC and colon cancer metastases. HuR is stabilized by Mdm2-mediated NEDDylation in at least three lysine residues, ensuring its nuclear localization and protection from degradation. Conclusion: This novel Mdm2/NEDD8/HuR regulatory framework is essential for the malignant transformation of tumor cells, which, in turn, unveils a novel signaling paradigm that is pharmacologically amenable for cancer therapy.     

Primera fase de validación del algoritmo europeo de evaluación funcional previa a la resección pulmonar: cuantificación del cumplimiento de las recomendaciones en la práctica clínica real

Objective

To quantify the degree of compliance with the recommendations of the clinical practice guidelines published in 2009 by the ERS and the ESTS regarding the preoperative assessment of risk of lung resection in daily clinical practice at a tertiary hospital.

Method

A prospective, observational study of real-time data collected from consecutive patients who had been referred for evaluation from September 2009 to December 2010. We recorded the presence or absence of the recommended studies included in the algorithm, their results and, when a test was missing, the reasons why it was not performed. Hospital mortality and cardio-respiratory morbidity rates are also presented.

Results

173 patients were evaluated. In 171 cases, lung resection was performed, with a mortality of 1.2% and a cardio-respiratory morbidity of 11.7%. The failure rate of the first level of the algorithm was 4.6% and for the second level (VO_2max test) it was 26%. The absence of exercise tests was mainly due to hospital structural problems and the patients’ inability to perform it. Out of the patients who performed the exercise testing, 31 reached a VO_2max of 20 ml/kg-min or more and underwent surgery without calculation of FEV₁ppo and DCLOppo; 35 patients required the calculation to determine their operability and in 2 cases the intervention was not recommended due to functional inoperability of the patient.

Conclusions

The validation process found lack of compliance with the proposed algorithm in 18.5% of the cases basically due to the absence of the exercise tests. The rate of adherence to the algorithm recommendations should be improved before performing any other validation studies.     

Análisis coste-efectividad de dabigatrán para la prevención de ictus y embolia sistémica en fibrilación auricular no valvular en España

Introduction and objectives

Assessment of the cost-effectiveness of dabigatran for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation in Spain, from the perspective of the National Health System.

Methods

Adaptation of a Markov chain model that simulates the natural history of the disease over the lifetime of a cohort of 10 000 patients with non-valvular atrial fibrillation. Model comparators were warfarin in a first scenario, and a real world prescribing pattern in a second scenario, in which 60% of the patients were treated with vitamin K antagonists, 30% with acetylsalicylic acid, and 10% received no treatment. Deterministic and probabilistic sensitivity analyses were performed.

Results

Dabigatran reduced the occurrence of clinical events in both scenarios, providing gains in quantity and quality of life. The incremental cost-effectiveness ratio for dabigatran compared to warfarin was 17 581 euros/quality-adjusted life year gained and 14 118 euros/quality-adjusted life year gained when compared to the real world prescribing pattern. Efficiency in subgroups was demonstrated. When the social costs were incorporated into the analysis, dabigatran was found to be a dominant strategy (ie, more effective and less costly). The model proved to be robust.

Conclusions

From the perspective of the Spanish National Health System, dabigatran is an efficient strategy for the prevention of stroke in patients with non-valvular atrial fibrillation compared to warfarin and to the real-world prescribing pattern; incremental cost-effectiveness ratios were below the 30 000 euros/quality-adjusted life year threshold in both scenarios. Dabigatran would also be a dominant strategy from the societal perspective, providing society with a more effective therapy at a lower cost compared to the other 2 alternatives.Full English text available from:www.revespcardiol.org     

A family with a complex clinical presentation characterized by arrhythmogenic right ventricular dysplasia/cardiomyopathy and features of branchio‐oculo‐facial syndrome

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a familial form of cardiomyopathy typically caused by mutations in genes that encode an element of the cardiac desmosome. Branchio‐oculo‐facial syndrome (BOFS) is a craniofacial disorder caused by TFAP2A mutations. In a family segregating ARVD/C, some members also had features of BOFS. Genetic testing for ARVD/C identified a mutation in PKP2, encoding plakophilin‐2, a component of the cardiac desmosome. Evaluation of dysmorphology by chromosome microarray (CMA) identified a 4.4 Mb deletion at chromosome 6p24 that included both TFAP2A and DSP, encoding desmoplakin, an additional component of the cardiac desmosome implicated in ARVD/C. A family member with both the 6p24 deletion and PKP2 mutation had more severe cardiac dysfunction. These findings suggest that this contiguous gene deletion contributes to both ARVD/C and BOFS, and that DSP haploinsufficiency may contribute to cardiomyopathy. This family provides a clinical example that underscores the need for careful evaluation in clinical scenarios where genetic heterogeneity is known to exist. Finally, it suggests that individuals with unexplained cardiomyopathy and dysmorphic facial features may benefit from CMA analysis. © 2013 Wiley Periodicals, Inc.     

Shear bond strength evaluation of bonded molar tubes on fluorotic molars

Objective:To study the shear bond strength (SBS), sites of failure, and micromorphology of bonded molar tubes used on teeth affected by dental fluorosis.Materials and Methods:This in vitro study included 140 first molars classified according to Dean''s index for dental fluorosis. Samples were divided into seven groups: (1) healthy teeth etched for 15 seconds, (2) teeth with moderate fluorosis (MOF) etched for 15 seconds, (3) teeth with MOF etched for 150 seconds, (4) teeth with MOF microabrasion etched for 15 seconds, (5) teeth with severe fluorosis (SEF) etched for 15 seconds, (6) teeth with SEF etched for 150 seconds, and (7) teeth with SEF microabrasion etched for 15 seconds. All samples were incubated and were then submitted to the SBS test and evaluated with the modified adhesive remnant index (ARI) and analyzed by using a scanning electronic microscope.Results:The SBS mean value for healthy enamel was 20 ± 10.2 MPa. For the group with MOF, the etched 150-second mean value was the highest (19 ± 7.6 MPa); for the group with SEF treated with microabrasion and etched for 15 seconds, the mean value was (13 ± 4.1 MPa). Significant differences (P ≤ .05) were found in the ARI between healthy and fluorosed groups.Conclusions:Fluorotic enamel affects the adhesion of bonded molar tubes. The use of overetching in cases of MOF and the combination of microabrasion and etching in SEF provides a suitable adhesion for fixed appliance therapy.     

Risk factors for the development of vertebral fractures after percutaneous vertebroplasty

We have recently observed an increased risk for vertebral fractures (VF) in a randomized controlled trial comparing the analgesic effect of vertebroplasty (VP) versus conservative treatment in symptomatic VF. The aim of the present study was to evaluate the risk factors related to the development of VF after VP in these patients. We evaluated risk factors including age, gender, bone mineral density, the number, type, and severity of vertebral deformities at baseline, the number of vertebral bodies treated, the presence and location of disk cement leakage, bone remodeling (determining bone turnover markers) and 25 hydroxyvitamin D [25(OH)D] levels at baseline in all patients. Twenty‐nine radiologically new VF were observed in 17 of 57 patients undergoing VP, 72% adjacent to the VP. Patients developing VF after VP showed an increased prevalence of 25(OH)D deficiency (<20 ng/mL) and higher P1NP values. The principal factor related to the development of VF after VP in multivariate analysis was 25(OH)D levels < 20 ng/mL (RR, 15.47; 95% CI, 2.99–79.86, p < 0.0001), whereas age >80 years (RR, 3.20; 95% CI, 1.70–6.03, p = 0.0007) and glucocorticoid therapy (RR, 3.64; 95% CI, 1.61–8.26, p = 0.0055) constituted the principal factors in the overall study population. Increased risk of VF after VP was also associated with cement leakage into the inferior disk (RR, 6.14; 95% CI, 1.65–22.78, p = 0.044) and more than one vertebral body treated during VP (RR, 4.19; 95% CI, 1.03–34.3, p = 0.044). In conclusion, nearly 30% of patients with osteoporotic VF treated with VP had a new VF after the procedure. Age, especially >80 years, the presence of inferior disk cement leakage after the procedure, the number of cemented vertebrae, and low 25(OH)D serum levels were related to the development of new VF in these patients, with the latter indicating the need to correct vitamin D deficiency prior to performing VP.     

The effects of an exercise training program on hand and wrist strength,and function,and activities of daily living,in adults with severe Cerebral Palsy

The purpose of the current study was to establish measurement reliability in adults with Cerebral Palsy (CP), and to examine the feasibility and outcomes of an upper extremity strength training program (three times per week for 90 min each time). A control group design mixed with a prospective time series design for the intervention group was completed, including a pre-test, a post-test after a 12-week intervention period, and a follow-up in the intervention group after an additional 10-week period. Seventeen adults with CP with severe motor impairment took part in the study (10 in the intervention and seven in the control group). The test battery was comprised of wrist and hand dynamometry; dominant hand upper-extremity function measures (Jebsen Hand Function Test = JHFT, Minnesota Manual Dexterity Test = MMDT, and the Nine Hole Peg Test = NHPT); and activity of daily living with the Barthel Index.The results indicated that in both the control and the intervention groups, the strength tests exhibited good-to-excellent reliability during pre-test and post-test. The group comparison revealed that while in the pre-test no between-group differences existed, in the post-test the strength training group demonstrated significantly higher values in five out of eight strength measures, as well as in the MMDT. Discontinuing the program for eight weeks reversed the effects almost to baseline. In conclusion, the outcomes demonstrated the reliability of the assessments utilized in this study, as well as the feasibility of the strength training program, in adults with severe motor impairment due to CP.     

Muscle MRI characteristic pattern for late-onset TK2 deficiency diagnosis

Journal of Neurology - TK2 deficiency (TK2d) is a rare mitochondrial disorder that manifests predominantly as a progressive myopathy with a broad spectrum of severity and age of onset. The rate of...