Inhibitor kinazy Brutona u chorych z nawrotowym lub opornym na leczenie chłoniakiem z komórek płaszcza – wyniki międzynarodowego,wieloośrodkowego,badania II fazy z ibrutynibem (PCI-32765) – EHA Encore

Bruton's tyrosine kinase (BTK) is a central mediator of B-cell receptor (BCR) signaling essential for normal B-cell development. Ibrutinib is an oral BTK inhibitor that induces apoptosis and inhibits migration and adhesion of malignant B-cells. Updated results of this international, multicenter, phase 2 study of single agent ibrutinib in relapsed or refractory MCL will be presented.Ibrutinib 560 mg PO QD was administered continuously until disease progression. Tumor response was assessed every 2 cycles (one cycle = 28 days). The study enrolled 115 patients (65 bortezomib-naïve, 50 bortezomib-exposed); 111 patients were treated; 110 were evaluable for response. Baseline characteristics included: median age 68 years, time since diagnosis 42 months, number of prior treatments 3; bulky disease (>10 cm) 13%, prior stem cell transplant 10%, high risk MIPI 49%.Median time on treatment was 9.2 months; 53% of patients remain on therapy. Median PFS was 13.9 months and DOR has not yet been reached. Responses increased with longer treatment: comparing to previous data described at ASH 2011, the CR rate increased from 16% to 39%, and the ORR increased from 69% to 75%.     

Serum concentration of immunoglobulin G‐type antibodies against the whole Epstein–Barr nuclear antigen 1 and its aa35–58 or aa398–404 fragments in the sera of patients with systemic lupus erythematosus and multiple sclerosis

Several studies suggest that infection by Epstein–Barr virus (EBV) might be one of the environmental factors which facilitates the development of autoimmune disorders in genetically susceptible individuals. Recent data indicate that high anti‐Epstein–Barr nuclear antigen 1 (EBNA)‐1 immunoglobulin (Ig)G titre is a strong risk factor for multiple sclerosis (MS) in patients both with and without the main genetic predisposing trait, human leucocyte antigen (HLA)‐DRB1*15:01. Because no similar studies have been published in systemic lupus erythematosus (SLE) patients, we determined the HLA‐DRB1*15:01 carrier state and the serum titres against the whole EBNA‐1 and its small fragments aa35–58 and aa398–404 in 301 SLE patients, 135 MS patients and in 345 healthy controls. The carrier state of the HLA‐DRB1*15:01 allele was deduced from genotyping of a tagSNP (rs3135388) by applying a Taqman‐based assay. The serum concentrations of antibodies to EBNA‐1 and its aa35–58 or aa398–404 fragments were determined using a commercial assay (ETI‐EBNA‐G) and home‐made enzyme‐linked immunosorbent assays, respectively. The serum concentration of anti‐EBNA‐1 antibodies was significantly (P < 0·001) higher both in MS and SLE patients than in controls. Similar significant differences were found both in HLA‐DRB1*15:01 carriers and non‐carriers. Furthermore, titres of antibodies against the aa35–58 EBNA‐1 fragment were elevated both in MS and SLE patients. By contrast, the levels of aa398–404 EBNA‐1 antibodies were elevated significantly only in the SLE patients. These findings indicate that high anti‐EBNA‐1 IgG titres are HLA‐DRB1*15:01‐independent risk factors not only for MS, but also for SLE, while high antibody titres against the aa398–404 fragment are characteristic for SLE.     

Results of Duchenne muscular dystrophy family screening in practice: leaks rather than cascades?

McGowan R, Challoner BR, Ross S, Holloway S, Joss S, Wilcox D, Holden ST, Tolmie J, Longman C. Results of Duchenne muscular dystrophy family screening in practice: leaks rather than cascades? Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease caused by mutations in the gene that encodes the protein dystrophin. Approximately 2 of 3 affected boys inherit their mutation from their carrier mother whereupon other female relatives are at risk of carrying the mutation. Female carriers are also at risk of developing cardiomyopathy and regular cardiac screening is recommended. Clinical genetics services offer genetic counselling and carrier tests for consenting relatives of DMD patients known as ‘cascade screening’. We retrospectively analysed data from two genetics centres, West of Scotland and South East Thames where the latter centre operated a computer‐held DMD register. Over the period, 1971–2008, a total of 843 potential carriers, in 195 West of Scotland families, were tested: 16% of 1st degree relatives and 48% of 2nd degree and more distant relatives were not tested. In South East Thames, a total of 1223 potential carriers in 349 families were tested: 49% of 1st degree and 65% of 2nd degree and more distant relatives were not tested. These data are similar to Becker muscular dystrophy/DMD carrier screening results recently reported from the Netherlands. Retrospective results from three countries indicate that despite efforts to offer extended cascade screening, significant numbers of potential carriers of DMD remain unaware of their reproductive and health risks.     

Physical activity,mental health and well-being of adults during initial COVID-19 containment strategies: A multi-country cross-sectional analysis

ObjectivesTo assess physical activity (PA), mental health and well-being of adults in the United Kingdom (UK), Ireland, New Zealand and Australia during the initial stages of National governments’ Coronavirus disease (COVID-19) containment responses.DesignObservational, cross-sectional.MethodsAn online survey was disseminated to adults (n = 8,425; 44.5 ± 14.8y) residing in the UK, Ireland, New Zealand and Australia within the first 2-6 weeks of government-mandated COVID-19 restrictions. Main outcome measures included: Stages of Change scale for exercise behaviour change; International Physical Activity Questionnaire (short-form); World Health Organisation-5 Well-being Index; and the Depression Anxiety and Stress Scale-9.ResultsParticipants who reported a negative change in exercise behaviour from before initial COVID-19 restrictions to during the initial COVID-19 restrictions demonstrated poorer mental health and well-being compared to those demonstrating either a positive-or no change in their exercise behaviour (p < 0.001). Whilst women reported more positive changes in exercise behaviour, young people (18-29y) reported more negative changes (both p < 0.001). Individuals who had more positive exercise behaviours reported better mental health and well-being (p < 0.001). Although there were no differences in PA between countries, individuals in New Zealand reported better mental health and well-being (p < 0.001).ConclusionThe initial COVID-19 restrictions have differentially impacted upon PA habits of individuals based upon their age and sex, and therefore have important implications for international policy and guideline recommendations. Public health interventions that encourage PA should target specific groups (e.g., men, young adults) who are most vulnerable to the negative effects of physical distancing and/or self-isolation.     

Prazosin,an α1-adrenoceptor antagonist,prevents memory deterioration in the APP23 transgenic mouse model of Alzheimer's disease

Noradrenergic deficits have been described in the hippocampus and the frontal cortex of Alzheimer's disease brains, which are secondary to locus coeruleus degeneration. Locus coeruleus is the brain stem nucleus responsible for synthesis of noradrenaline and from where all noradrenergic neurons project. In addition, it has been suggested that noradrenaline might play a role in modulating inflammatory responses in Alzheimer's disease. In this study we aimed to investigate the effect of various agonists and antagonists for adrenergic receptors on amyloid precursor protein processing. Among them, we found that prazosin, an α₁-adrenoceptor antagonist, was able to reduce the generation of amyloid β in N2a cells. Treatment of transgenic APP23 mice with prazosin prevented memory deficits over time. Although prazosin did not influence amyloid plaque load, it induced astrocytic proliferation and increased the release of apolipoprotein E and anti-inflammatory cytokines. These findings suggest that chronic treatment with prazosin leads to an anti-inflammatory response with potential beneficial effects on cognitive performance.     

Australian Aboriginal population genetics at the D1S80 VNTR locus

The Aboriginal Australian population have continuously inhabited the vast Australian continent for in excess of 50?000 years, making them one of the most distinctive modern human population groups. At the time of European colonisation, it was estimated there were as many as 500 tribes with defined territorial lands and distinct linguistic and cultural traits. Unfortunately, the contribution of genetic data from Aboriginal Australia to studies of modern human global migration has been limited. Likewise, there are limited data from tribal populations from across Australia, and therefore a limited understanding of the genetic differentiation among tribal groups. This research is the first to analyse population data from Aboriginal Australians using the polymorphic minisatellite locus D1S80. Considerable differentiation was observed among the tribal groups that are represented in this Northern Australian dataset. The most genetically distinct tribal groups identified in this study (East Arnhem Land and Tiwi Island) are groups which have been previously noted in anthropological studies as having distinct cultural and/or linguistic characteristics.     

Nanoparticles for drug delivery in Parkinson’s disease

Journal of Neurology - Although effective symptomatic treatments for Parkinson’s disease (PD) have been available for some time, efficient and well-controlled drug delivery to the brain has...     

High prevalence of poleroviruses in field-grown pepper in Turkey and Tunisia

Open-field pepper crops were sampled in 2011 in Turkey and Tunisia and surveyed for the major pepper-infecting viruses. As expected, potato virus Y and cucumber mosaic virus (in both countries), and tobacco etch virus (in Turkey only) were quite frequent. However, poleroviruses were the most common viruses, with prevalences above 70 %. Partial sequence analyses revealed the occurrence of poleroviruses resembling either beet western yellows virus (BWYV) or pepper vein yellows virus in the sampled areas, with BWYV being predominant in Turkey but in the minority in Tunisia. Poleroviruses should therefore be taken into account in disease control of pepper crops in the Mediterranean area.