Computerized paired associate learning performance and imaging biomarkers in older adults without dementia

Brain Imaging and Behavior - This cross-sectional study examined whether performance on the computerized Paired Associate Learning (PAL) task from the Cambridge Neuropsychological Test Automated...     

Caspase-cleaved HPK1 induces CD95L-independent activation-induced cell death in T and B lymphocytes

Life and death of peripheral lymphocytes is strictly controlled to maintain physiologic levels of T and B cells. Activation-induced cell death (AICD) is one mechanism to delete superfluous lymphocytes by restimulation of their immunoreceptors and it depends partially on the CD95/CD95L system. Recently, we have shown that hematopoietic progenitor kinase 1 (HPK1) determines T-cell fate. While full-length HPK1 is essential for NF-kappaB activation in T cells, the C-terminal fragment of HPK1, HPK1-C, suppresses NF-kappaB and sensitizes toward AICD by a yet undefined cell death pathway. Here we show that upon IL-2-driven expansion of primary T cells, HPK1 is converted to HPK1-C by a caspase-3 activity below the threshold of apoptosis induction. HPK1-C selectively blocks induction of NF-kappaB-dependent antiapoptotic Bcl-2 family members but not of the proapoptotic Bcl-2 family member Bim. Interestingly, T and B lymphocytes from HPK1-C transgenic mice undergo AICD independently of the CD95/CD95L system but involving caspase-9. Knock down of HPK1/HPK1-C or Bim by small interfering RNA shows that CD95L-dependent and HPK1/HPK1-C-dependent cell death pathways complement each other in AICD of primary T cells. Our results define HPK1-C as a suppressor of antiapoptotic Bcl-2 proteins and provide a molecular basis for our understanding of CD95L-independent AICD of lymphocytes.     

Multiple sclerosis and the CTLA4 autoimmunity polymorphism CT60: no association in patients from Germany, Hungary and Poland

Polymorphisms in the CTLA4 gene region have been associated with susceptibility to autoimmune diseases. The recently described single nucleotide polymorphism CT60, located in the 3' untranslated region of CTLA4 is associated with Graves' disease, thyroiditis, autoimmune diabetes and other autoimmune diseases. A case-control association study was conducted in German, Hungarian and Polish multiple sclerosis (MS) patients and regional control individuals for the CTLA4 CT60 and +49A/G polymorphisms. No significant association of these polymorphisms or respective haplotypes with MS was found. No association of CT60 genotypes with T cell expression of ICOS and CTLA-4 after in vitro stimulation was detected.     

Patients with advanced and metastatic renal cell carcinoma treated with targeted therapy in the Czech Republic: twenty cancer centres, six agents, one database

The incidence and mortality of renal cell carcinoma (RCC) in the Czech Republic are among the highest in the world. Several targeted agents have been recently approved for the treatment of advanced/metastatic RCC. Objective: Presentation of a national clinical database for monitoring and assessment of patients with advanced/metastatic RCC treated with targeted therapy. The RenIS (RENal Information System, http://renis.registry.cz) registry is a non-interventional post-registration database of epidemiological and clinical data of patients with RCC treated with targeted therapies in the Czech Republic. Twenty cancer centres eligible for targeted therapy administration participate in the project. As of November 2011, six agents were approved and reimbursed from public health insurance, including bevacizumab, everolimus, pazopanib, sorafenib, sunitinib, and temsirolimus. As of 10 October 2011, 1,541 patients with valid records were entered into the database. Comparison with population-based data from the Czech National Cancer Registry revealed that RCC patients treated with targeted therapy are significantly younger (median age at diagnosis 59 vs. 66?years). Most RenIS registry patients were treated with sorafenib and sunitinib, many patients sequentially with both agents. Over 10?% of patients were also treated with everolimus in the second or third line. Progression-free survival times achieved were comparable to phase III clinical trials. The RenIS registry has become an important tool and source of information for the management of cancer care and clinical practice, providing comprehensive data on monitoring and assessment of RCC targeted therapy on a national level.     

Transthoracic echocardiography in the detection of chronic total coronary artery occlusion

Aims: The aim of our study was to detect chronic total occlusion ofthe left anterior descending coronary artery (LAD), circumflexcoronary artery (Cx), and right coronary artery (RCA) usingtransthoracic echocardiography (TTE) in 110 consecutive patientswho underwent coronary angiography for investigation of angina. Methods and results: Coronary blood flow direction was assessed in the epicardialcollaterals [distal LAD (dLAD), obtuse marginal branches andright posterior descending artery (PDA)] and intramyocardialcollaterals [LAD septal branch (SB LAD) and RCA septal branch(SB RCA)]. The sensitivity and specificity of retrograde flowfor identification of the occluded LAD by TTE in the dLAD onlywere 78 and 96%, respectively, and those in both dLAD and SBLAD were 89 and 96%, respectively. The retrograde SB LAD flowdetects proximal LAD occlusion with 88% sensitivity and 75%specificity. The sensitivity and specificity of retrograde flowfor identification of the occluded RCA by TTE in the PDA onlywere 79 and 97%, respectively, and those in both PDA and SBRCA were 89 and 97%, respectively. The retrograde SB RCA flowdoes not allow us to differentiate between proximal and non-proximalRCA occlusion. Transthoracic echocardiography is not a methodfor diagnosing Cx occlusions as the success in visualizing theCx epicardial collaterals was achieved in 31% of cases only. Conclusion: TTE is a sensitive and highly specific non-invasive method fordiagnosis of LAD and RCA occlusions, based on the detectionof the coronary blood flow direction in the epicardial and intramyocardialcollaterals.     

MicroRNA expression profiling identifies miR-31-5p/3p as associated with time to progression in wild-type RAS metastatic colorectal cancer treated with cetuximab

The aim of our study was to investigate whether microRNAs (miRNAs) could serve as predictive biomarkers to anti-EGFR therapy (cetuximab, panitumumab) in patients with RAS wild-type (wt-RAS) metastatic colorectal cancer (mCRC). Historical cohort of 93 patients with mCRC (2006–2009) was included and further divided into exploratory and validation cohorts. MiRNAs expression profiling was performed on the exploratory cohort of 41 wt-KRAS mCRC patients treated with cetuximab to identify miRNAs associated with time to progression (TTP). The validation was performed on two independent cohorts: 28 patients of wt-RAS mCRC treated with cetuximab and 24 patients of wt-RAS mCRC treated with panitumumab. We identified 9 miRNAs with significantly different expression between responders and non-responders to cetuximab therapy (P ≤ 0.01). These 9 miRNAs were further evaluated in two independent cohorts of patients and miR-31-3p (P < 0.001) and miR-31-5p (P < 0.001) were successfully confirmed as strongly associated with TTP in wt-RAS mCRC patients treated with cetuximab but not panitumumab. When evaluated on the complete cohort of cetuximab patients (N = 69), miR-31-3p (HR, 5.10; 95% CI, 2.52–10.32; P < 0.001) and miR-31-5p (HR, 4.80; 95% CI, 2.50–9.24; P < 0.001) were correlated with TTP on the comparable level of significance. There was no difference in miR-31-5p/3p expression levels in RAS mutated and wild-type tumor samples. MiR-31-5p/3p are promising predictive biomarkers of cetuximab response in wt-RAS mCRC patients.     

Cardiac Toxicity of Targeted Therapies Used in the Treatment for Solid Tumours: A Review

Cardiotoxicity associated with conventional cytostatics is a known phenomenon and is related to their general cytotoxic effects. This damage to the myocardium is usually irreversible. Despite the attempts to optimize safety profile of targeted anticancer drugs during their development, evidence shows that these new treatment modalities also have cardiotoxic potential or may adversely affect vascular system. Over the last years, a significant number of these agents have been introduced in medical practice. Arterial hypertension, arrhythmias, left ventricular dysfunction and a heart failure are the most frequent cardiovascular adverse effects of targeted anticancer agents, but this toxicity seems to be reversible. To enable early interventions and to minimize these cardiovascular adverse effects, health care professionals have to be well-informed and familiar with the safety profiles of the drugs they administered, the patient's cardiovascular condition and co-morbidities, and they must regularly monitor their patients for potential adverse effects. The aim of this paper is to provide an overview of cardiotoxic effects caused by targeted anticancer drugs used in the treatment of solid tumours. We discuss pathophysiological mechanisms, diagnostics and treatment, risk factors and options for prevention.     

Recovery of Industrial Wastes as Fillers in the Epoxy Thermosets for Building Application

Epoxy resins are currently used in many areas of construction, such as resistant coatings, anchors, fibre-reinforced polymer (FRP) composites, grouts, etc. This paper deals mainly with epoxy composites that can be applied during the rehabilitation of concrete constructions. The influence of a filler type on epoxy thermoset composites was monitored, whilst three different types of epoxy resin were used in order to achieve a better representation and confirmation of the results. During the testing of fillers, these were mainly secondary raw materials, including pre-treated hazardous waste (neutralisation sludge), representing various shapes and sizes of particle, while their amount in the epoxy matrix was chosen with regard to optimal viscosity and workability. Physical and mechanical parameters, like compressive and flexural strengths, cohesion with the concrete and thermal expansion of the epoxy composites containing various fillers were determined. The microstructure of epoxy composites with a different filler type and chemical resistance against chemical aggressive media were all monitored. The microstructure of epoxy composites was monitored using scanning electron microscopy (SEM) supported by energy-dispersive X-ray spectroscopy (EDX). Computed tomography (CT) was also used for the evaluation of the cohesion of the epoxy composites with concrete and dispersion of the filler in the epoxy matrix.