Pathological expansion of a G4C2 repeat, located in the 5' regulatory region of C9orf72, is the most common genetic cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis ...(ALS). C9orf72 patients have highly variable onset ages suggesting the presence of modifying factors and/or anticipation. We studied 72 Belgian index patients with FTLD, FTLD-ALS or ALS and 61 relatives with a C9orf72 repeat expansion. We assessed the effect of G4C2 expansion size on onset age, the role of anticipation and the effect of repeat size on methylation and C9orf72 promoter activity. G4C2 expansion sizes varied in blood between 45 and over 2100 repeat units with short expansions (45-78 units) present in 5.6% of 72 index patients with an expansion. Short expansions co-segregated with disease in two families. The subject with a short expansion in blood but an indication of mosaicism in brain showed the same pathology as those with a long expansion. Further, we provided evidence for an association of G4C2 expansion size with onset age (P<0.05) most likely explained by an association of methylation state of the 5' flanking CpG island and expansion size in blood (P<0.0001) and brain (P<0.05). In several informative C9orf72 parent-child transmissions, we identified earlier onset ages, increasing expansion sizes and/or increasing methylation states (P=0.0034) of the 5' CpG island, reminiscent of disease anticipation. Also, intermediate repeats (7-24 units) showed a slightly higher methylation degree (P<0.0001) and a decrease of C9orf72 promoter activity (P<0.0001) compared with normal short repeats (2-6 units). Decrease of transcriptional activity was even more prominent in the presence of small deletions flanking G4C2 (P<0.0001). Here we showed that increased methylation of CpGs in the C9orf72 promoter may explain how an increasing G4C2 size lead to loss-of-function without excluding repeat length-dependent toxic gain-of-function. These data provide insights into disease mechanisms and have important implications for diagnostic counseling and potential therapeutic approaches.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Two extended haplotypes exist across the tau gene—H1 and H2—with H1 consistently associated with increased risk of progressive supranuclear palsy (PSP). Using 15 haplotype tagging SNPs (htSNPs), ...capturing >95% of MAPT haplotype diversity, we performed association analysis in a US sample of 274 predominantly pathologically confirmed PSP patients and 424 matched control individuals. We found that PSP risk is associated with one of two major ancestral H1 haplotypes, H1B, increasing from 14% in control individuals to 22% in PSP patients (P<0.001). In young PSP patients, the H1B risk could be localized to a 22 kb regulatory region in intron 0 (P<0.001) and could be fully explained by one SNP, htSNP167, creating a LBP-1c/LSF/CP2 site, shown to regulate the expression of genes in other neurodegenerative disorders. Luciferase reporter data indicated that the 182 bp conserved regulatory region, in which htSNP167 is located, is transcriptionally active with both alleles differentially influencing expression. Further, we replicated the htSNP167 association in a second, independently ascertained US PSP patient–control sample. However, the htSNP association showed that H1 risk alone could not explain the overall differences in H1 and H2 frequencies in PSP patients and control individuals. Thus, risk variants on different H1 htSNP haplotypes and protective variants on H2 contribute to population risk for PSP.
Abstract Context The relative benefits and harms of hormonal treatment (HT) versus no or deferred HT in patients with nonmetastatic prostate cancer (PCa) relapse after primary curative therapy are ...controversial. Objective To assess the effectiveness of HT for nonmetastatic PCa relapse, prognostic factors for treatment outcome, timing of treatment, and the most effective treatment strategy to provide guidance for clinical practice. Evidence acquisition A systematic literature search was undertaken incorporating Medline, Embase, and the Cochrane Library (search ended March 2015). Studies were critically appraised for risk of bias. The outcomes included overall and cancer-specific survival, metastasis-free survival, symptom-free survival, progression to castrate resistance, adverse events, and quality of life. Evidence synthesis Of 9687 articles identified, 27 studies were eligible for inclusion (2 RCTs, 8 nonrandomised comparative studies, and 17 case series). The results suggest that only a subgroup of patients, especially those with high-risk disease, may benefit from early HT. The main predictors for unfavourable outcomes were shorter PSA doubling time (<6–12 mo) and higher Gleason score (>7). Early HT may be warranted for patients with high-risk disease. An intermittent HT strategy appears feasible. Most studies had a moderate to high risks of bias. Conclusions HT for PCa relapse after primary therapy with curative intent should be reserved for patients at highest risk of progression and with a long life expectancy. The potential benefits of starting HT should be judiciously balanced against the associated harms. Patient summary This article summarises the evidence on the benefits and harms of hormonal treatment in prostate cancer (PCa) patients in whom the disease has recurred following earlier curative treatment. We found that only a select group of patients with aggressive PCa and a fast rising prostate-specific antigen may benefit from early hormonal treatment (HT), whereas in others HT may be more harmful than beneficial.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Null mutations in progranulin (PGRN) cause ubiquitin-positive frontotemporal dementia (FTD) linked to chromosome 17q21 (FTDU-17). Here we examined PGRN genetic variability in amyotrophic lateral ...sclerosis (ALS), a neurodegenerative motor neuron disease that overlaps with FTD at a clinical, pathologic, and epidemiologic level.
We sequenced all exons, exon-intron boundaries, and 5' and 3' regulatory regions of PGRN in a Belgian sample of 230 patients with ALS. The frequency of observed genetic variants was determined in 436 healthy control individuals. The contribution of eight frequent polymorphisms to ALS risk, onset age, and survival was assessed in an association study in the Belgian sample and a replication series of 308 Dutch patients with ALS and 345 Dutch controls.
In patients with ALS we identified 11 mutations, 5 of which were predicted to affect PGRN protein sequence or levels (four missense mutations and one 5' regulatory variant). Moreover, common variants (rs9897526, rs34424835, and rs850713) and haplotypes were significantly associated with a reduction in age at onset and a shorter survival after onset of ALS in both the Belgian and the Dutch studies.
PGRN acts as a modifier of the course of disease in patients with amyotrophic lateral sclerosis, through earlier onset and shorter survival.
Based on a comprehensive systematic review, we formulated new recommendations regarding active surveillance for localised prostate cancer for intermediate-risk disease up to International Society of ...Urological Pathology (ISUP) grade 2, schedule of per-protocol confirmatory and surveillance repeat biopsies, and specified thresholds for increase in biopsy extent.
There is uncertainty regarding the most appropriate criteria for recruitment, monitoring, and reclassification in active surveillance (AS) protocols for localised prostate cancer (PCa).
To perform a qualitative systematic review (SR) to issue recommendations regarding inclusion of intermediate-risk disease, biopsy characteristics at inclusion and monitoring, and repeat biopsy strategy.
A protocol-driven, Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA)-adhering SR incorporating AS protocols published from January 1990 to October 2020 was performed. The main outcomes were criteria for inclusion of intermediate-risk disease, monitoring, reclassification, and repeat biopsy strategies (per protocol and/or triggered). Clinical effectiveness data were not assessed.
Of the 17 011 articles identified, 333 studies incorporating 375 AS protocols, recruiting 264 852 patients, were included. Only a minority of protocols included the use of magnetic resonance imaging (MRI) for recruitment (n = 17), follow-up (n = 47), and reclassification (n = 26). More than 50% of protocols included patients with intermediate or high-risk disease, whilst 44.1% of protocols excluded low-risk patients with more than three positive cores, and 39% of protocols excluded patients with core involvement (CI) >50% per core. Of the protocols, ≥80% mandated a confirmatory transrectal ultrasound biopsy; 72% (n = 189) of protocols mandated per-protocol repeat biopsies, with 20% performing this annually and 25% every 2 yr. Only 27 protocols (10.3%) mandated triggered biopsies, with 74% of these protocols defining progression or changes on MRI as triggers for repeat biopsy.
For AS protocols in which the use of MRI is not mandatory or absent, we recommend the following: (1) AS can be considered in patients with low-volume International Society of Urological Pathology (ISUP) grade 2 (three or fewer positive cores and cancer involvement ≤50% CI per core) or another single element of intermediate-risk disease, and patients with ISUP 3 should be excluded; (2) per-protocol confirmatory prostate biopsies should be performed within 2 yr, and per-protocol surveillance repeat biopsies should be performed at least once every 3 yr for the first 10 yr; and (3) for patients with low-volume, low-risk disease at recruitment, if repeat systematic biopsies reveal more than three positive cores or maximum CI >50% per core, they should be monitored closely for evidence of adverse features (eg, upgrading); patients with ISUP 2 disease with increased core positivity and/or CI to similar thresholds should be reclassified.
We examined the literature to issue new recommendations on active surveillance (AS) for managing localised prostate cancer. The recommendations include setting criteria for including men with more aggressive disease (intermediate-risk disease), setting thresholds for close monitoring of men with low-risk but more extensive disease, and determining when to perform repeat biopsies (within 2 yr and 3 yearly thereafter).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Abstract
When gravitational waves pass near massive astrophysical objects, they can be gravitationally lensed. The lensing can split them into multiple wave fronts, magnify them, or imprint beating ...patterns on the waves. Here we focus on the multiple images produced by strong lensing. In particular, we investigate strong lensing forecasts, the rate of lensing, and the role of lensing statistics in strong lensing searches. Overall, we find a reasonable rate of lensed detections for double, triple, and quadruple images at the LIGO–Virgo–KAGRA design sensitivity. We also report the rates for A+ and LIGO Voyager and briefly comment on potential improvements due to the inclusion of subthreshold triggers. We find that most galaxy-lensed events originate from redshifts
z
∼ 1–4 and report the expected distribution of lensing parameters for the observed events. Besides forecasts, we investigate the role of lensing forecasts in strong lensing searches, which explore repeated event pairs. One problem associated with the searches is the rising number of event pairs, which leads to a rapidly increasing false alarm probability. We show how knowledge of the expected galaxy-lensing time delays in our searches allow us to tackle this problem. Once the time delays are included, the false alarm probability increases linearly (similar to nonlensed searches) instead of quadratically with time, significantly improving the search. For galaxy cluster lenses, the improvement is less significant. The main uncertainty associated with these forecasts are the merger-rate density estimates at high redshift, which may be better resolved in the future.
•Targeted detection and quantification of multiple celiac disease stimulating epitopes.•High-throughput screening for quantification of CD-epitopes in wheat.•Method enables selection of wheat ...varieties with reduced levels of CD-epitopes.•LC-MRM/MS technology as a standard method for quantifying CD-epitopes.
Celiac disease (CD) is a food-related disease caused by certain gluten peptides containing T-cell stimulating epitopes from wheat, rye, and barley. CD-patients have to maintain a gluten-free diet and are therefore dependent on reliable testing and labeling of gluten-free products. So far, the R5-ELISA is the approved method to detect if food products can be labeled gluten-free. Because the R5-ELISA detects gluten in general, there is a demand for an improved detection method that quantifies specifically CD-epitopes. Therefore, we developed a new method for detection and quantification of CD-epitopes, based on liquid chromatography (LC) coupled to mass spectrometry (MS) in multiple reaction monitoring (MRM) mode. This method enables targeted label free comparative analysis of the gluten proteins present in different wheat varieties and species, and in wheat-based food products. We have tested our method by analyzing several wheat varieties that vary in CD-epitope content, as was shown before using immunoblotting and specific monoclonal antibodies. The results showed that a modern bread wheat variety Toronto contained the highest amounts of CD immunogenic peptides compared with the older bread wheat variety Minaret and the tetraploid wheat variety Dibillik Sinde. Our developed method can detect quantitatively and simultaneously multiple specific CD-epitopes in a high throughput manner.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract
This article presents the design of the Radio Neutrino Observatory Greenland (RNO-G) and discusses its scientific prospects. Using an array of radio sensors, RNO-G seeks to measure neutrinos ...above 10 PeV by exploiting the Askaryan effect in neutrino-induced cascades in ice. We discuss the experimental considerations that drive the design of RNO-G, present first measurements of the hardware that is to be deployed and discuss the projected sensitivity of the instrument. RNO-G will be the first production-scale radio detector for in-ice neutrino signals.
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