A Case of Metastatic Atypical Neuroendocrine Tumor with ALK Translocation and Diffuse Brain Metastases.

A challenge in precision medicine requires identification of actionable driver mutations. Critical to such effort is the deployment of sensitive and well-validated assays for mutation detection. Although identification of such alterations within the tumor tissue remains the gold standard, many advanced non-small cell lung cancer cases have only limited tissue samples, derived from small biopsies or fine-needle aspirates, available for testing. More recently, noninvasive methods using either circulating tumor cells or tumor DNA (ctDNA) have become an alternative method for identifying molecular biomarkers and screening patients eligible for targeted therapies. In this article, we present a case of a 52-year-old never-smoking male who presented with widely metastatic atypical neuroendocrine tumor to the bones and the brain. Molecular genotyping using DNA harvested from a bone metastasis was unsuccessful due to limited material. Subsequent ctDNA analysis revealed an ALK translocation. The clinical significance of the mutation in this particular cancer type and therapeutic strategies are discussed.Key pointsTo our knowledge, this index case represents the first reported ALK translocation identified in an atypical carcinoid tumor.Liquid biopsy such as circulating tumor DNA is a feasible alternative platform for identifying sensitizing genomic alterations.Second-generation ALK inhibitors represent a new paradigm for treating ALK-positive patients with brain metastases

Factor analysis of attentional set-shifting performance in young and aged mice

<p>Abstract</p> <p>Background</p> <p>Executive dysfunction may play a major role in cognitive decline with aging because frontal lobe structures are particularly vulnerable to advancing age. Lesion studies in rats and mice have suggested that intradimensional shifts (IDSs), extradimensional shifts (EDSs), and reversal learning are mediated by the anterior cingulate cortex, the medial prefrontal cortex, and the orbitofrontal cortex, respectively. We hypothesized that the latent structure of cognitive performance would reflect functional localization in the brain and would be altered by aging.</p> <p>Methods</p> <p>Young (4 months, n = 16) and aged (23 months, n = 18) C57BL/6N mice performed an attentional set-shifting task (ASST) that evaluates simple discrimination (SD), compound discrimination (CD), IDS, EDS, and reversal learning. The performance data were subjected to an exploratory factor analysis to extract the latent structures of ASST performance in young and aged mice.</p> <p>Results</p> <p>The factor analysis extracted two- and three-factor models. In the two-factor model, the factor associated with SD and CD was clearly separated from the factor associated with the rest of the ASST stages in the young mice only. In the three-factor model, the SD and CD loaded on distinct factors. The three-factor model also showed a separation of factors associated with IDS, EDS, and CD reversal. However, the other reversal learning variables, ID reversal and ED reversal, had somewhat inconsistent factor loadings.</p> <p>Conclusions</p> <p>The separation of performance factors in aged mice was less clear than in young mice, which suggests that aged mice utilize neuronal networks more broadly for specific cognitive functions. The result that the factors associated with SD and CD were separated in the three-factor model may suggest that the introduction of an irrelevant or distracting dimension results in the use of a new/orthogonal strategy for better discrimination.</p

Role of carotid duplex imaging in carotid screening programmes - an overview.

BACKGROUND: Stroke is the third most common cause of death in the UK and the largest single cause of severe disability. Each year more than 110,000 people in England suffer from a stroke which costs the National Health Service (NHS) over GBP2.8 billion. Thus, it is imperative that patients at risk be screened for underlying carotid artery atherosclerosis. AIM: To assess the role of carotid ultrasound in different carotid screening programmes. METHODS: A literature overview was carried out by using PubMed search engine, to identify different carotid screening programmes that had used ultrasound scan as a screening tool. RESULTS: It appears that the carotid ultrasound is an effective method for screening carotid artery disease in community as it effectively predicts the presence of stenosis with high accuracy. There is a need for primary care to recommend high risk patients for regular screening, to reduce stroke and transient ischemic attack (TIA) related morbidity and mortality. CONCLUSION: Screening programmes using carotid ultrasonography contribute to public health awareness and promotion which in long term could potentially benefit in disease prevention and essentially promote better standards of healthcare.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Characterization of healing following atherosclerotic carotid plaque rupture in acutely symptomatic patients: an exploratory study using in vivo cardiovascular magnetic resonance.

BACKGROUND: Carotid plaque rupture, characterized by ruptured fibrous cap (FC), is associated with subsequent cerebrovascular events. However, ruptured FC may heal following stroke and convey decreased risk of future events. This study aims to characterize the healing process of ruptured FC by assessing the lumen conditions, quantified by the lumen curvature and roughness, using in vivo carotid cardiovascular magnetic resonance (CMR). METHODS: Patients suffering from transient ischemic attack underwent high resolution carotid MR imaging within 72 hours of the acute cerebrovascular ischemic event. CMR imaging was repeated at 3 and 12 months in 26 patients, in whom FC rupture/erosion was observed on baseline images and subsequent cerebrovascular events were recorded during the follow-up period. Lumen curvature and roughness were quantified from carotid CMR images and changes in these values were monitored on follow-up imaging. RESULTS: Healing of ruptured plaque was observed in patients (23 out of 26) without any ischemic symptom recurrence as shown by the lumen surface becoming smoother during the follow-up period, characterized by decreasing maximum lumen curvature (p < 0.05), increasing minimum lumen curvature (p < 0.05) and decreasing lumen roughness (p < 0.05) during the one year follow-up period. CONCLUSIONS: Carotid plaque healing can be assessed by quantification of the lumen curvature and roughness and the incidence of recurrent cerebrovascular events may be high in plaques that do not heal with time. The assessment of plaque healing may facilitate risk stratification of recent stroke patients on the basis of CMR results.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Lithium-aluminate-catalyzed hydrophosphination applications

Synthesized, isolated, and characterized by X-ray crystallography and NMR spectroscopic studies, lithium phosphidoaluminate iBu3AlPPh2Li(THF)3 has been tested as a catalyst for hydrophosphination of alkynes, alkenes, and carbodiimides. Based on the collective evidence of stoichiometric reactions, NMR monitoring studies, kinetic analysis, and DFT calculations, a mechanism involving deprotonation, alkyne insertion and protonolysis is proposed for the [iBu3AlHLi]2 aluminate-catalyzed hydrophosphination of alkynes with diphenylphosphine. This study enhances further the development of transition metal free, atom economical homogeneous catalysis using common sustainable main group metals

Measuring disease-specific quality of life in rare populations: a practical approach to cross-cultural translation

<p>Abstract</p> <p>Background</p> <p>Disease-specific quality of life (QoL) measures have enhanced the capacity of outcome measures to evaluate subtle changes and differences between groups. However, when the specific disease is rare, the cohort of patients is small and international collaboration is often necessary to accomplish meaningful research. As many of the QoL measures have been developed in North American English, they require translation to ensure their usefulness in a multi-cultural and/or international society. Published guidelines provide formal methods to achieve cross-culturally comparable versions of a QoL tool. However, these guidelines describe a rigorous process that is not always feasible, particularly in rare disease groups. The objective of this manuscript is to describe the process that was developed to achieve accurate cross-cultural translations of a disease-specific QoL measure, to overcome the challenges of a small sample size, i.e. children with a rare disorder.</p> <p>Procedure</p> <p>A measurement study was conducted in the United Kingdom (UK), France, Germany and Uruguay, during which the validated measure was translated into the languages of the respective countries.</p> <p>Results</p> <p>This is a report of a modified, child-centric, cross-cultural translation and adaptation process in which culturally appropriate and methodologically valid translations of a disease-specific QoL measure, the Kids' ITP Tools (KIT), were performed in children with immune thrombocytopenic purpura (ITP). The KIT was translated from North American English into UK English, French, German, and Spanish.</p> <p>Conclusion</p> <p>This study was a successful international collaboration. The modified process through which culturally appropriate and methodologically valid translations of QoL measures may be achieved in a pediatric population with a relatively rare disorder is reported.</p

The ‘Healthy Dads, Healthy Kids’ community effectiveness trial: study protocol of a community-based healthy lifestyle program for fathers and their children

Background: The \u27Healthy Dads, Healthy Kids\u27 program was designed to help overweight fathers lose weight and positively influence the health behaviors of their children. The aim of the current study was to evaluate the previously established program in a community setting, in a large effectiveness trial. Methods/Design: The Healthy Dads, Healthy Kids community trial consists of three stages: (i) Stage 1 - program refinement and resource development (ii) Stage 2 - community randomized controlled trial (iii) Stage 3 - community effectiveness trial. The program will be evaluated in five Local Government Areas in the Hunter Valley Region of NSW, Australia. For the community randomized controlled trial, 50 overweight/obese men (aged 18-65 years) from one Local Government Area with a child aged between 5-12 years of age will be recruited. Families will be randomized to either the program or a 6-month wait-list control group. Fathers and their children will be assessed at baseline, post-intervention (3-months) and 6-months. Inclusion criteria are: body mass index 25-40 kg/m2; no participation in other weight loss programs during the study; pass a health-screening questionnaire; and access to a computer with Internet facilities. In the community trial, the program will be evaluated using a non-randomized, prospective design in five Local Government Areas. The exclusion criteria is body mass index \u3c 25 kg/m2 or lack of doctor\u27s approval. Measures will be collected at baseline, 3-, 6- and 12-months. The program involves fathers attending seven face-to-face group sessions (three with children) over 3-months. Measures: The primary outcome is fathers\u27 weight. Secondary outcomes for both fathers and children include: waist circumference, blood pressure, resting heart rate, physical activity, sedentary behaviors and dietary intake. Father-only measures include portion size, alcohol consumption, parenting for physical activity and nutrition and parental engagement. Process evaluation will determine the fidelity, dose (delivered and received), reach, recruitment and context of the program. Discussion: As a unique approach to reducing obesity prevalence in men and improving lifestyle behaviours in children, our findings will provide important evidence relating to the translation of Healthy Dads, Healthy Kids, which will enable it to be delivered on a larger scale

Epstein-Barr virus-encoded EBNA1 enhances RNA polymerase III-dependent EBER expression through induction of EBER-associated cellular transcription factors

Background Epstein-Barr Virus (EBV)-encoded RNAs (EBERs) are non-polyadenylated RNA molecules transcribed from the EBV genome by RNA polymerase III (pol III). EBERs are the most abundant viral latent gene products, although the precise mechanisms by which EBV is able to achieve such high levels of EBER expression are not fully understood. Previously EBV has been demonstrated to induce transcription factors associated with EBER expression, including pol III transcription factors and ATF-2. We have recently demonstrated that EBV-encoded nuclear antigen-1 (EBNA1) induces cellular transcription factors, and given these findings, we investigated the role of EBNA1 in induction of EBER-associated transcription factors. Results Our data confirm that in epithelial cells EBNA1 can enhance cellular pol III transcription. Transient expression of EBNA1 in Ad/AH cells stably expressing the EBERs led to induction of both EBER1 and EBER2 and conversely, expression of a dominant negative EBNA1 led to reduced EBER expression in EBV-infected Ad/AH cells. EBNA1 can induce transcription factors used by EBER genes, including TFIIIC, ATF-2 and c-Myc. A variant chromatin precipitation procedure showed that EBNA1 is associated with the promoters of these genes but not with the promoters of pol III-transcribed genes, including the EBERs themselves. Using shRNA knock-down, we confirm the significance of both ATF-2 and c-Myc in EBER expression. Further, functional induction of a c-Myc fusion protein led to increased EBER expression, providing c-Myc binding sites upstream of EBER1 were intact. In vivo studies confirm elevated levels of the 102 kD subunit of TFIIIC in the tumour cells of EBV-positive nasopharyngeal carcinoma biopsies. Conclusions Our findings reveal that EBNA1 is able to enhance EBER expression through induction of cellular transcription factors and add to the repertoire of EBNA1's transcription-regulatory properties

Rapamycin inhibits cell proliferation in type I and type II endometrial carcinomas: A search for biomarkers of sensitivity to treatment

Our goal was to evaluate the effect of rapamycin, an mTOR inhibitor, in type I and II human endometrial cancer tumor explants